vaccination research paper title

• Scoping Review
• Open access
• Published: 14 November 2021

Effectiveness and safety of SARS-CoV-2 vaccine in real-world studies: a systematic review and meta-analysis

• Qiao Liu 1   na1 ,
• Chenyuan Qin 1 , 2   na1 ,
• Min Liu 1 &
• Jue Liu   ORCID: orcid.org/0000-0002-1938-9365 1 , 2  

Infectious Diseases of Poverty volume  10 , Article number:  132 ( 2021 ) Cite this article

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To date, coronavirus disease 2019 (COVID-19) becomes increasingly fierce due to the emergence of variants. Rapid herd immunity through vaccination is needed to block the mutation and prevent the emergence of variants that can completely escape the immune surveillance. We aimed to systematically evaluate the effectiveness and safety of COVID-19 vaccines in the real world and to establish a reliable evidence-based basis for the actual protective effect of the COVID-19 vaccines, especially in the ensuing waves of infections dominated by variants.

We searched PubMed, Embase and Web of Science from inception to July 22, 2021. Observational studies that examined the effectiveness and safety of SARS-CoV-2 vaccines among people vaccinated were included. Random-effects or fixed-effects models were used to estimate the pooled vaccine effectiveness (VE) and incidence rate of adverse events after vaccination, and their 95% confidence intervals ( CI ).

A total of 58 studies (32 studies for vaccine effectiveness and 26 studies for vaccine safety) were included. A single dose of vaccines was 41% (95% CI : 28–54%) effective at preventing SARS-CoV-2 infections, 52% (31–73%) for symptomatic COVID-19, 66% (50–81%) for hospitalization, 45% (42–49%) for Intensive Care Unit (ICU) admissions, and 53% (15–91%) for COVID-19-related death; and two doses were 85% (81–89%) effective at preventing SARS-CoV-2 infections, 97% (97–98%) for symptomatic COVID-19, 93% (89–96%) for hospitalization, 96% (93–98%) for ICU admissions, and 95% (92–98%) effective for COVID-19-related death, respectively. The pooled VE was 85% (80–91%) for the prevention of Alpha variant of SARS-CoV-2 infections, 75% (71–79%) for the Beta variant, 54% (35–74%) for the Gamma variant, and 74% (62–85%) for the Delta variant. The overall pooled incidence rate was 1.5% (1.4–1.6%) for adverse events, 0.4 (0.2–0.5) per 10 000 for severe adverse events, and 0.1 (0.1–0.2) per 10 000 for death after vaccination.

Conclusions

SARS-CoV-2 vaccines have reassuring safety and could effectively reduce the death, severe cases, symptomatic cases, and infections resulting from SARS-CoV-2 across the world. In the context of global pandemic and the continuous emergence of SARS-CoV-2 variants, accelerating vaccination and improving vaccination coverage is still the most important and urgent matter, and it is also the final means to end the pandemic.

Graphical Abstract

Since its outbreak, coronavirus disease 2019 (COVID-19) has spread rapidly, with a sharp rise in the accumulative number of infections worldwide. As of August 8, 2021, COVID-19 has already killed more than 4.2 million people and more than 203 million people were infected [ 1 ]. Given its alarming-spreading speed and the high cost of completely relying on non-pharmaceutical measures, we urgently need safe and effective vaccines to cover susceptible populations and restore people’s lives into the original [ 2 ].

According to global statistics, as of August 2, 2021, there are 326 candidate vaccines, 103 of which are in clinical trials, and 19 vaccines have been put into normal use, including 8 inactivated vaccines and 5 protein subunit vaccines, 2 RNA vaccines, as well as 4 non-replicating viral vector vaccines [ 3 ]. Our World in Data simultaneously reported that 27.3% of the world population has received at least one dose of a COVID-19 vaccine, and 13.8% is fully vaccinated [ 4 ].

To date, COVID-19 become increasingly fierce due to the emergence of variants [ 5 , 6 , 7 ]. Rapid herd immunity through vaccination is needed to block the mutation and prevent the emergence of variants that can completely escape the immune surveillance [ 6 , 8 ]. Several reviews systematically evaluated the effectiveness and/or safety of the three mainstream vaccines on the market (inactivated virus vaccines, RNA vaccines and viral vector vaccines) based on random clinical trials (RCT) yet [ 9 , 10 , 11 , 12 , 13 ].

In general, RNA vaccines are the most effective, followed by viral vector vaccines and inactivated virus vaccines [ 10 , 11 , 12 , 13 ]. The current safety of COVID-19 vaccines is acceptable for mass vaccination, but long-term monitoring of vaccine safety is needed, especially in older people with underlying conditions [ 9 , 10 , 11 , 12 , 13 ]. Inactivated vaccines had the lowest incidence of adverse events and the safety comparisons between mRNA vaccines and viral vectors were controversial [ 9 , 10 ].

RCTs usually conduct under a very demanding research circumstance, and tend to be highly consistent and limited in terms of population characteristics and experimental conditions. Actually, real-world studies differ significantly from RCTs in terms of study conditions and mass vaccination in real world requires taking into account factors, which are far more complex, such as widely heterogeneous populations, vaccine supply, willingness, medical accessibility, etc. Therefore, the real safety and effectiveness of vaccines turn out to be a major concern of international community. The results of a mass vaccination of CoronaVac in Chile demonstrated a protective effectiveness of 65.9% against the onset of COVID-19 after complete vaccination procedures [ 14 ], while the outcomes of phase 3 trials in Brazil and Turkey were 50.7% and 91.3%, reported on Sinovac’s website [ 14 ]. As for the Delta variant, the British claimed 88% protection after two doses of BNT162b2, compared with 67% for AZD1222 [ 15 ]. What is surprising is that the protection of BNT162b2 against infection in Israel is only 39% [ 16 ]. Several studies reported the effectiveness and safety of the COVID-19 vaccine in the real world recently, but the results remain controversial [ 17 , 18 , 19 , 20 ]. A comprehensive meta-analysis based upon the real-world studies is still in an urgent demand, especially for evaluating the effect of vaccines on variation strains. In the present study, we aimed to systematically evaluate the effectiveness and safety of the COVID-19 vaccine in the real world and to establish a reliable evidence-based basis for the actual protective effect of the COVID-19 vaccines, especially in the ensuing waves of infections dominated by variants.

Search strategy and selection criteria

Our methods were described in detail in our published protocol [PROSPERO (Prospective register of systematic reviews) registration, CRD42021267110]. We searched eligible studies published by 22 July 2021, from three databases including PubMed, Embase and Web of Science by the following search terms: (effectiveness OR safety) AND (COVID-19 OR coronavirus OR SARS-CoV-2) AND (vaccine OR vaccination). We used EndNoteX9.0 (Thomson ResearchSoft, Stanford, USA) to manage records, screen and exclude duplicates. This study was strictly performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

We included observational studies that examined the effectiveness and safety of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines among people vaccinated with SARS-CoV-2 vaccines. The following studies were excluded: (1) irrelevant to the subject of the meta-analysis, such as studies that did not use SARS-CoV-2 vaccination as the exposure; (2) insufficient data to calculate the rate for the prevention of COVID-19, the prevention of hospitalization, the prevention of admission to the ICU, the prevention of COVID-19-related death, or adverse events after vaccination; (3) duplicate studies or overlapping participants; (4) RCT studies, reviews, editorials, conference papers, case reports or animal experiments; and (5) studies that did not clarify the identification of COVID-19.

Studies were identified by two investigators (LQ and QCY) independently following the criteria above, while discrepancies reconciled by a third investigator (LJ).

Data extraction and quality assessment

The primary outcome was the effectiveness of SARS-CoV-2 vaccines. The following data were extracted independently by two investigators (LQ and QCY) from the selected studies: (1) basic information of the studies, including first author, publication year and study design; (2) characteristics of the study population, including sample sizes, age groups, setting or locations; (3) kinds of the SARS-CoV-2 vaccines; (4) outcomes for the effectiveness of SARS-CoV-2 vaccines: the number of laboratory-confirmed COVID-19, hospitalization for COVID-19, admission to the ICU for COVID-19, and COVID-19-related death; and (5) outcomes for the safety of SARS-CoV-2 vaccines: the number of adverse events after vaccination.

We evaluated the risk of bias using the Newcastle–Ottawa quality assessment scale for cohort studies and case–control studies [ 21 ]. and assess the methodological quality using the checklist recommended by Agency for Healthcare Research and Quality (AHRQ) [ 22 ]. Cohort studies and case–control studies were classified as having low (≥ 7 stars), moderate (5–6 stars), and high risk of bias (≤ 4 stars) with an overall quality score of 9 stars. For cross-sectional studies, we assigned each item of the AHRQ checklist a score of 1 (answered “yes”) or 0 (answered “no” or “unclear”), and summarized scores across items to generate an overall quality score that ranged from 0 to 11. Low, moderate, and high risk of bias were identified as having a score of 8–11, 4–7 and 0–3, respectively.

Two investigators (LQ and QCY) independently assessed study quality, with disagreements resolved by a third investigator (LJ).

Data synthesis and statistical analysis

We performed a meta-analysis to pool data from included studies and assess the effectiveness and safety of SARS-CoV-2 vaccines by clinical outcomes (rates of the prevention of COVID-19, the prevention of hospitalization, the prevention of admission to the ICU, the prevention of COVID-19-related death, and adverse events after vaccination). Random-effects or fixed-effects models were used to pool the rates and adjusted estimates across studies separately, based on the heterogeneity between estimates ( I 2 ). Fixed-effects models were used if I 2  ≤ 50%, which represented low to moderate heterogeneity and random-effects models were used if I 2  > 50%, representing substantial heterogeneity.

We conducted subgroup analyses to investigate the possible sources of heterogeneity by using vaccine kinds, vaccination status, sample size, and study population as grouping variables. We used the Q test to conduct subgroup comparisons and variables were considered significant between subgroups if the subgroup difference P value was less than 0.05. Publication bias was assessed by funnel plot and Egger’s regression test. We analyzed data using Stata version 16.0 (StataCorp, Texas, USA).

A total of 4844 records were searched from the three databases. 2484 duplicates were excluded. After reading titles and abstracts, we excluded 2264 reviews, RCT studies, duplicates and other studies meeting our exclude criteria. Among the 96 studies under full-text review, 41 studies were excluded (Fig.  1 ). Ultimately, with three grey literatures included, this final meta-analysis comprised 58 eligible studies, including 32 studies [ 14 , 15 , 17 , 18 , 19 , 20 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 ] for vaccine effectiveness and 26 studies [ 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 ] for vaccine safety. Characteristics of included studies are showed in Additional file 1 : Table S1, Additional file 2 : Table S2. The risk of bias of all studies we included was moderate or low.

Flowchart of the study selection

Vaccine effectiveness for different clinical outcomes of COVID-19

We separately reported the vaccine effectiveness (VE) by the first and second dose of vaccines, and conducted subgroup analysis by the days after the first or second dose (< 7 days, ≥ 7 days, ≥ 14 days, and ≥ 21 days; studies with no specific days were classified as 1 dose, 2 dose or ≥ 1 dose).

For the first dose of SARS-CoV-2 vaccines, the pooled VE was 41% (95% CI : 28–54%) for the prevention of SARS-CoV-2 infection, 52% (95% CI : 31–73%) for the prevention of symptomatic COVID-19, 66% (95% CI : 50–81%) for the prevention of hospital admissions, 45% (95% CI : 42–49%) for the prevention of ICU admissions, and 53% (95% CI : 15–91%) for the prevention of COVID-19-related death (Table 1 ). The subgroup, ≥ 21 days after the first dose, was found to have the highest VE in each clinical outcome of COVID-19, regardless of ≥ 1 dose group (Table 1 ).

For the second dose of SARS-CoV-2 vaccines, the pooled VE was 85% (95% CI : 81–89%) for the prevention of SARS-CoV-2 infection, 97% (95% CI : 97–98%) for the prevention of symptomatic COVID-19, 93% (95% CI: 89–96%) for the prevention of hospital admissions, 96% (95% CI : 93–98%) for the prevention of ICU admissions, and 95% (95% CI : 92–98%) for the prevention of COVID-19-related death (Table 1 ). VE was 94% (95% CI : 78–98%) in ≥ 21 days after the second dose for the prevention of SARS-CoV-2 infection, higher than other subgroups, regardless of 2 dose group (Table 1 ). For the prevention of symptomatic COVID-19, VE was also relatively higher in 21 days after the second dose (99%, 95% CI : 94–100%). Subgroups showed no statistically significant differences in the prevention of hospital admissions, ICU admissions and COVID-19-related death (subgroup difference P values were 0.991, 0.414, and 0.851, respectively).

Vaccine effectiveness for different variants of SARS-CoV-2 in fully vaccinated people

In the fully vaccinated groups (over 14 days after the second dose), the pooled VE was 85% (95% CI: 80–91%) for the prevention of Alpha variant of SARS-CoV-2 infection, 54% (95% CI : 35–74%) for the Gamma variant, and 74% (95% CI : 62–85%) for the Delta variant. There was only one study [ 23 ] focused on the Beta variant, which showed the VE was 75% (95% CI : 71–79%) for the prevention of the Beta variant of SARS-CoV-2 infection. BNT162b2 vaccine had the highest VE in each variant group; 92% (95% CI : 90–94%) for the Alpha variant, 62% (95% CI : 2–88%) for the Gamma variant, and 84% (95% CI : 75–92%) for the Delta variant (Fig.  2 ).

Forest plots for the vaccine effectiveness of SARS-CoV-2 vaccines in fully vaccinated populations. A Vaccine effectiveness against SARS-CoV-2 variants; B Vaccine effectiveness against SARS-CoV-2 with variants not mentioned. SARS-CoV-2 severe acute respiratory syndrome coronavirus 2, COVID-19 coronavirus disease 2019, CI confidence interval

For studies which had not mentioned the variant of SARS-CoV-2, the pooled VE was 86% (95% CI: 76–97%) for the prevention of SARS-CoV-2 infection in fully vaccinated people. mRNA-1273 vaccine had the highest pooled VE (97%, 95% CI: 93–100%, Fig.  2 ).

Safety of SARS-CoV-2 vaccines

As Table 2 showed, the incidence rate of adverse events varied widely among different studies. We conducted subgroup analysis by study population (general population, patients and healthcare workers), vaccine type (BNT162b2, mRNA-1273, CoronaVac, and et al.), and population size (< 1000, 1000–10 000, 10 000–100 000, and > 100 000). The overall pooled incidence rate was 1.5% (95% CI : 1.4–1.6%) for adverse events, 0.4 (95% CI : 0.2–0.5) per 10 000 for severe adverse events, and 0.1 (95% CI : 0.1–0.2) per 10 000 for death after vaccination. Incidence rate of adverse events was higher in healthcare workers (53.2%, 95% CI : 28.4–77.9%), AZD1222 vaccine group (79.6%, 95% CI : 60.8–98.3%), and < 1000 population size group (57.6%, 95% CI : 47.9–67.4%). Incidence rate of sever adverse events was higher in healthcare workers (127.2, 95% CI : 62.7–191.8, per 10 000), Gam-COVID-Vac vaccine group (175.7, 95% CI : 77.2–274.2, per 10 000), and 1000–10 000 population size group (336.6, 95% CI : 41.4–631.8, per 10 000). Incidence rate of death after vaccination was higher in patients (7.6, 95% CI : 0.0–32.2, per 10 000), BNT162b2 vaccine group (29.8, 95% CI : 0.0–71.2, per 10 000), and < 1000 population size group (29.8, 95% CI : 0.0–71.2, per 10 000). Subgroups of general population, vaccine type not mentioned, and > 100 000 population size had the lowest incidence rate of adverse events, severe adverse events, and death after vaccination.

Sensitivity analysis and publication bias

In the sensitivity analyses, VE for SARS-CoV-2 infections, symptomatic COVID-19 and COVID-19-related death got relatively lower when omitting over a single dose group of Maria et al.’s work [ 33 ]; when omitting ≥ 14 days after the first dose group and ≥ 14 days after the second dose group of Alejandro et al.’s work [ 14 ], VE for SARS-CoV-2 infections, hospitalization, ICU admission and COVID-19-related death got relatively higher; and VE for all clinical status of COVID-19 became lower when omitting ≥ 14 days after the second dose group of Eric et al.’s work [ 34 ]. Incidence rate of adverse events and severe adverse events got relatively higher when omitting China CDC’s data [ 74 ]. P values of Egger’s regression test for all the meta-analysis were more than 0.05, indicating that there might not be publication bias.

To our knowledge, this is a comprehensive systematic review and meta-analysis assessing the effectiveness and safety of SARS-CoV-2 vaccines based on real-world studies, reporting pooled VE for different variants of SARS-CoV-2 and incidence rate of adverse events. This meta-analysis comprised a total of 58 studies, including 32 studies for vaccine effectiveness and 26 studies for vaccine safety. We found that a single dose of SARS-CoV-2 vaccines was about 40–60% effective at preventing any clinical status of COVID-19 and that two doses were 85% or more effective. Although vaccines were not as effective against variants of SARS-CoV-2 as original virus, the vaccine effectiveness was still over 50% for fully vaccinated people. Normal adverse events were common, while the incidence of severe adverse events or even death was very low, providing reassurance to health care providers and to vaccine recipients and promote confidence in the safety of COVID-19 vaccines. Our findings strengthen and augment evidence from previous review [ 75 ], which confirmed the effectiveness of the BNT162b2 mRNA vaccine, and additionally reported the safety of SARS-CoV-2 vaccines, giving insight on the future of SARS-CoV-2 vaccine schedules.

Although most vaccines for the prevention of COVID-19 are two-dose vaccines, we found that the pooled VE of a single dose of SARS-CoV-2 vaccines was about 50%. Recent study showed that the T cell and antibody responses induced by a single dose of the BNT162b2 vaccine were comparable to those naturally infected with SARE-CoV-2 within weeks or months after infection [ 76 ]. Our findings could help to develop vaccination strategies under certain circumstances such as countries having a shortage of vaccines. In some countries, in order to administer the first dose to a larger population, the second dose was delayed for up to 12 weeks [ 77 ]. Some countries such as Canada had even decided to delay the second dose for 16 weeks [ 78 ]. However, due to a suboptimum immune response in those receiving only a single dose of a vaccine, such an approach had a chance to give rise to the emergence of variants of SARS-CoV-2 [ 79 ]. There remains a need for large clinical trials to assess the efficacy of a single-dose administration of two-dose vaccines and the risk of increasing the emergence of variants.

Two doses of SARS-CoV-2 vaccines were highly effective at preventing hospitalization, severe cases and deaths resulting from COVID-19, while the VE of different groups of days from the second vaccine dose showed no statistically significant differences. Our findings emphasized the importance of getting fully vaccinated, for the fact that most breakthrough infections were mild or asymptomatic. A recent study showed that the occurrence of breakthrough infections with SARS-CoV-2 in fully vaccinated populations was predictable with neutralizing antibody titers during the peri-infection period [ 80 ]. We also found getting fully vaccinated was at least 50% effective at preventing SARS-CoV-2 variants infections, despite reduced effectiveness compared with original virus; and BNT162b2 vaccine was found to have the highest VE in each variant group. Studies showed that the highly mutated variants were indicative of a form of rapid, multistage evolutionary jumps, which could preferentially occur in the milieu of partial immune control [ 81 , 82 ]. Therefore, immunocompromised patients should be prioritized for anti-COVID-19 immunization to mitigate persistent SARS-CoV-2 infections, during which multimutational SARS-CoV-2 variants could arise [ 83 ].

Recently, many countries, including Israel, the United States, China and the United Kingdom, have introduced a booster of COVID-19 vaccine, namely the third dose [ 84 , 85 , 86 , 87 ]. A study of Israel showed that among people vaccinated with BNT162b2 vaccine over 60 years, the risk of COVID-19 infection and severe illness in the non-booster group was 11.3 times (95% CI: 10.4–12.3) and 19.5 times (95% CI: 12.9–29.5) than the booster group, respectively [ 84 ]. Some studies have found that the third dose of Moderna, Pfizer-BioNTech, Oxford-AstraZeneca and Sinovac produced a spike in infection-blocking neutralizing antibodies when given a few months after the second dose [ 85 , 87 , 88 ]. In addition, the common adverse events associated with the third dose did not differ significantly from the symptoms of the first two doses, ranging from mild to moderate [ 85 ]. The overall incidence rate of local and systemic adverse events was 69% (57/97) and 20% (19/97) after receiving the third dose of BNT162b2 vaccine, respectively [ 88 ]. Results of a phase 3 clinical trial involving 306 people aged 18–55 years showed that adverse events after receiving a third dose of BNT162b2 vaccine (5–8 months after completion of two doses) were similar to those reported after receiving a second dose [ 85 ]. Based on V-safe, local reactions were more frequently after dose 3 (5323/6283; 84.7%) than dose 2 (5249/6283; 83.5%) among people who received 3 doses of Moderna. Systemic reactions were reported less frequently after dose 3 (4963/6283; 79.0%) than dose 2 (5105/6283; 81.3%) [ 86 ]. On August 4, WHO called for a halt to booster shots until at least the end of September to achieve an even distribution of the vaccine [ 89 ]. At this stage, the most important thing we should be thinking about is how to reach a global cover of people at risk with the first or second dose, rather than focusing on the third dose.

Based on real world studies, our results preliminarily showed that complete inoculation of COVID-19 vaccines was still effective against infection of variants, although the VE was generally diminished compared with the original virus. Particularly, the pooled VE was 54% (95% CI : 35–74%) for the Gamma variant, and 74% (95% CI : 62–85%) for the Delta variant. Since the wide spread of COVID-19, a number of variants have drawn extensive attention of international community, including Alpha variant (B.1.1.7), first identified in the United Kingdom; Beta variant (B.1.351) in South Africa; Gamma variant (P.1), initially appeared in Brazil; and the most infectious one to date, Delta variant (B.1.617.2) [ 90 ]. Israel recently reported a breakthrough infection of SARS-CoV-2, dominated by variant B.1.1.7 in a small number of fully vaccinated health care workers, raising concerns about the effectiveness of the original vaccine against those variants [ 80 ]. According to an observational cohort study in Qatar, VE of the BNT162b2 vaccine against the Alpha (B.1.1.7) and Beta (B.1.351) variants was 87% (95% CI : 81.8–90.7%) and 75.0% (95% CI : 70.5–7.9%), respectively [ 23 ]. Based on the National Immunization Management System of England, results from a recent real-world study of all the general population showed that the AZD1222 and BNT162b2 vaccines protected against symptomatic SARS-CoV-2 infection of Alpha variant with 74.5% (95% CI : 68.4–79.4%) and 93.7% (95% CI : 91.6–95.3%) [ 15 ]. In contrast, the VE against the Delta variant was 67.0% (95% CI : 61.3–71.8%) for two doses of AZD1222 vaccine and 88% (95% CI : 85.3–90.1%) for BNT162b2 vaccine [ 15 ].

In terms of adverse events after vaccination, the pooled incidence rate was very low, only 1.5% (95% CI : 1.4–1.6%). However, the prevalence of adverse events reported in large population (population size > 100 000) was much lower than that in small to medium population size. On the one hand, the vaccination population in the small to medium scale studies we included were mostly composed by health care workers, patients with specific diseases or the elderly. And these people are more concerned about their health and more sensitive to changes of themselves. But it remains to be proved whether patients or the elderly are more likely to have adverse events than the general. Mainstream vaccines currently on the market have maintained robust safety in specific populations such as cancer patients, organ transplant recipients, patients with rheumatic and musculoskeletal diseases, pregnant women and the elderly [ 54 , 91 , 92 , 93 , 94 ]. A prospective study by Tal Goshen-lag suggests that the safety of BNT162b2 vaccine in cancer patients is consistent with those previous reports [ 91 ]. In addition, the incidence rate of adverse events reported in the heart–lung transplant population is even lower than that in general population [ 95 ]. On the other hand, large scale studies at the national level are mostly based on national electronic health records or adverse event reporting systems, and it is likely that most mild or moderate symptoms are actually not reported.

Compared with the usual local adverse events (such as pain at the injection site, redness at the injection site, etc.) and normal systemic reactions (such as fatigue, myalgia, etc.), serious and life-threatening adverse events were rare due to our results. A meta-analysis based on RCTs only showed three cases of anaphylactic shock among 58 889 COVID-19 vaccine recipients and one in the placebo group [ 11 ]. The exact mechanisms underlying most of the adverse events are still unclear, accordingly we cannot establish a causal relation between severe adverse events and vaccination directly based on observational studies. In general, varying degrees of adverse events occur after different types of COVID-19 vaccination. Nevertheless, the benefits far outweigh the risks.

Our results showed the effectiveness and safety of different types of vaccines varied greatly. Regardless of SARS-CoV-2 variants, vaccine effectiveness varied from 66% (CoronaVac [ 14 ]) to 97% (mRNA-1273 [ 18 , 20 , 45 , 46 ]). The incidence rate of adverse events varied widely among different types of vaccines, which, however, could be explained by the sample size and population group of participants. BNT162b2, AZD1222, mRNA-1273 and CoronaVac were all found to have high vaccine efficacy and acceptable adverse-event profile in recent published studies [ 96 , 97 , 98 , 99 ]. A meta-analysis, focusing on the potential vaccine candidate which have reached to the phase 3 of clinical development, also found that although many of the vaccines caused more adverse events than the controls, most were mild, transient and manageable [ 100 ]. However, severe adverse events did occur, and there remains the need to implement a unified global surveillance system to monitor the adverse events of COVID-19 vaccines around the world [ 101 ]. A recent study employed a knowledge-based or rational strategy to perform a prioritization matrix of approved COVID-19 vaccines, and led to a scale with JANSSEN (Ad26.COV2.S) in the first place, and AZD1222, BNT162b2, and Sputnik V in second place, followed by BBIBP-CorV, CoronaVac and mRNA-1273 in third place [ 101 ]. Moreover, when deciding the priority of vaccines, the socioeconomic characteristics of each country should also be considered.

Our meta-analysis still has several limitations. First, we may include limited basic data on specific populations, as vaccination is slowly being promoted in populations under the age of 18 or over 60. Second, due to the limitation of the original real-world study, we did not conduct subgroup analysis based on more population characteristics, such as age. When analyzing the efficacy and safety of COVID-19 vaccine, we may have neglected the discussion on the heterogeneity from these sources. Third, most of the original studies only collected adverse events within 7 days after vaccination, which may limit the duration of follow-up for safety analysis.

Based on the real-world studies, SARS-CoV-2 vaccines have reassuring safety and could effectively reduce the death, severe cases, symptomatic cases, and infections resulting from SARS-CoV-2 across the world. In the context of global pandemic and the continuous emergence of SARS-CoV-2 variants, accelerating vaccination and improving vaccination coverage is still the most important and urgent matter, and it is also the final means to end the pandemic.

Availability of data and materials

All data generated or analyzed during this study are included in this published article and its additional information files.

Abbreviations

Coronavirus disease 2019

Severe Acute Respiratory Syndrome Coronavirus 2

Vaccine effectiveness

Confidence intervals

Intensive care unit

Random clinical trials

Preferred reporting items for systematic reviews and meta-analyses

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Acknowledgements

This study was funded by the National Natural Science Foundation of China (72122001; 71934002) and the National Science and Technology Key Projects on Prevention and Treatment of Major infectious disease of China (2020ZX10001002). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper. No payment was received by any of the co-authors for the preparation of this article.

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Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, 100191, China

Qiao Liu, Chenyuan Qin, Min Liu & Jue Liu

Institute for Global Health and Development, Peking University, Beijing, 100871, China

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LQ and QCY contributed equally as first authors. LJ and LM contributed equally as correspondence authors. LJ and LM conceived and designed the study; LQ, QCY and LJ carried out the literature searches, extracted the data, and assessed the study quality; LQ and QCY performed the statistical analysis and wrote the manuscript; LJ, LM, LQ and QCY revised the manuscript. All authors read and approved the final manuscript.

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Supplementary Information

Additional file 1: table s1..

Characteristic of studies included for vaccine effectiveness.

Additional file 2: Table S2.

Characteristic of studies included for vaccine safety.

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Liu, Q., Qin, C., Liu, M. et al. Effectiveness and safety of SARS-CoV-2 vaccine in real-world studies: a systematic review and meta-analysis. Infect Dis Poverty 10 , 132 (2021). https://doi.org/10.1186/s40249-021-00915-3

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COVID-19 and vaccine hesitancy: A longitudinal study

Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

* E-mail: [email protected]

Affiliation Rady School of Management, University of California San Diego, La Jolla, California, United States of America

Roles Conceptualization, Data curation, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing

Roles Conceptualization, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Visualization, Writing – original draft, Writing – review & editing

• Ariel Fridman, 
• Rachel Gershon, 
• Ayelet Gneezy

• Published: April 16, 2021
• https://doi.org/10.1371/journal.pone.0250123
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How do attitudes toward vaccination change over the course of a public health crisis? We report results from a longitudinal survey of United States residents during six months (March 16 –August 16, 2020) of the COVID-19 pandemic. Contrary to past research suggesting that the increased salience of a disease threat should improve attitudes toward vaccines, we observed a decrease in intentions of getting a COVID-19 vaccine when one becomes available. We further found a decline in general vaccine attitudes and intentions of getting the influenza vaccine. Analyses of heterogeneity indicated that this decline is driven by participants who identify as Republicans, who showed a negative trend in vaccine attitudes and intentions, whereas Democrats remained largely stable. Consistent with research on risk perception and behavior, those with less favorable attitudes toward a COVID-19 vaccination also perceived the virus to be less threatening. We provide suggestive evidence that differential exposure to media channels and social networks could explain the observed asymmetric polarization between self-identified Democrats and Republicans.

Citation: Fridman A, Gershon R, Gneezy A (2021) COVID-19 and vaccine hesitancy: A longitudinal study. PLoS ONE 16(4): e0250123. https://doi.org/10.1371/journal.pone.0250123

Editor: Valerio Capraro, Middlesex University, UNITED KINGDOM

Received: November 12, 2020; Accepted: February 14, 2021; Published: April 16, 2021

Copyright: © 2021 Fridman et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All data and code are publicly available on the Open Science Framework at https://osf.io/kgvdy/ .

Funding: UC San Diego Global Health Initiative (GHI): awarded to all authors; Project number: 1001288. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. https://medschool.ucsd.edu/som/medicine/divisions/idgph/research/Global-Health/grant-recipients/2019-2020/Pages/Faculty-Postdoc-Travel-and-Research.aspx .

Competing interests: The authors have declared that no competing interests exist.

Introduction

Vaccinations are among the most important public health tools for reducing the spread and harm caused by dangerous diseases [ 1 ]. The World Health Organization estimates that vaccines prevented at least 10 million deaths between 2010–2015 worldwide [ 2 ]. Despite considerable evidence showing vaccines are safe [ 3 , 4 ], there is increasing skepticism toward vaccination [ 5 , 6 ]. Vaccine hesitancy has led to a decline in vaccine uptake and to an increase in the prevalence of vaccine-preventable diseases (VPDs) [ 7 , 8 ]. Ironically, the objection to vaccines is commonly a consequence of their effectiveness—because individuals have lower exposure to VPDs, they are less concerned about contracting them [ 9 ], which consequently leads to greater vaccine hesitancy [ 10 ]. The COVID-19 pandemic has created a new reality where individuals are faced with a previously unknown disease and its effects, providing a unique opportunity to investigate vaccine attitudes during a period of heightened disease salience. The present research reports findings from a longitudinal study conducted during the COVID-19 health crisis, in which we measured changes in attitudes toward a prospective vaccine, as well as shifts in vaccine attitudes in general.

Factors influencing vaccine attitudes and behaviors

Past research has identified a variety of situational and individual-level factors that influence vaccine attitudes and behavior, the most prominent of which are risk perceptions and demographic characteristics.

Assessments of risk are influenced by both cognitive evaluations (i.e., objective features of the situation such as probabilities of outcomes) and affective reactions [ 11 ], as well as by contextual factors (e.g., the information that is most available or salient at the time [ 12 ]). For example, research shows that media coverage plays a significant role in determining the extent to which we take threats seriously [ 13 ]. When individuals perceive heightened risk of a threat, they become more favorable toward interventions that mitigate that threat, including vaccination (for a meta-analysis on the effect of perceived risk on intentions and behaviors, see [ 14 ]). In the case of COVID-19, this would suggest more positive attitudes toward a vaccine and greater likelihood to get vaccinated. Indeed, research suggests that individuals should exhibit a greater interest in vaccinations during a pandemic because disease threat is more salient [ 15 ].

Past efforts to improve vaccine attitudes have had limited success or even backfired; for example, messages refuting claims about the link between vaccines and autism, as well as messages featuring images of children who were sick with VPDs, had negative effects on vaccine attitudes among those who were already hesitant to vaccinate [ 16 ]. In contrast, messaging that increases disease threat salience has shown promise in reducing vaccine hesitancy [ 5 ], and there is evidence suggesting that increased threat salience for a particular disease may also increase intentions to vaccinate for other diseases [ 17 ]. Building on these findings, we expected to find an increase in pro-vaccine attitudes and in individuals’ interest in a COVID-19 vaccine when the perceived threat of the COVID-19 virus increased.

Vaccine attitudes are also influenced by a variety of demographic and ideological factors (for a review, see [ 18 ]). For example, perceptions of vaccine risk differ among individuals of different ethnic backgrounds [ 19 ], and there is extant work demonstrating a positive correlation between socioeconomic status (SES) and vaccine hesitancy [ 20 , 21 ]. Socio-demographic factors are also linked to vaccine-related behaviors: among college students, those whose parents have attained a higher level of education are more likely to get immunized [ 22 ], and researchers have identified age as a predictor for receiving the influenza vaccine [ 23 ].

Political ideology is another well-documented determinant of vaccine-related attitudes and behaviors. Despite a common belief that liberals tend toward anti-vaccination attitudes in the United States, there is strong evidence that this trend is more present among conservatives [ 24 , 25 ]. According to a recent Gallup Poll, Republicans are twice as likely to believe the widely debunked myth that vaccines cause autism [ 26 ]. Recent work has shown that exposure to anti-vaccination tweets by President Trump—the first known U.S. president to publicly express anti-vaccination attitudes—has led to increased concern about vaccines among his supporters [ 27 ]. Based on these findings, and in conjunction with the sentiments expressed by the White House that diminished the significance of the pandemic [ 28 ], we expected to find diverging trends between Democrats and Republicans.

The current research

We collected vaccine-related attitudes of individuals living in the U.S. over a six-month period. Beginning in March 2020, we elicited attitudes from a cohort of the same individuals every month. We began data collection before any COVID-19 lockdown measures were in place (i.e., prior to the nation’s first shelter-in-place order [ 29 ]). Hence, our data spans the early phase of the pandemic, when there were fewer than 2,000 total confirmed cases in the U.S., through the following six months, at which point cumulative cases reached over 5.3 million [ 30 ].

Despite our prediction—that a public health crisis would increase disease threat, consequently increasing pro-vaccine attitudes and interest in vaccination—our data show an overall decrease in favorable attitudes toward vaccines. A closer look at the data revealed that political orientation explains more variance than any other socio-demographic variable. Specifically, participants who identify as Republican showed a decrease in their intention to get the COVID-19 vaccine and the influenza vaccine as well as a general decrease in pro-vaccine attitudes, whereas Democrats’ responses to these measures did not show a significant change during this period.

Our work is the first, to our knowledge, to longitudinally measure individuals’ attitudes toward vaccines. In doing so, our findings advance the understanding of how vaccine attitudes might change during an unprecedented public health crisis, revealing a strong association between political party affiliation and vaccine attitudes.

Participants

We recruited a panel of U.S. residents on Amazon’s Mechanical Turk platform to respond to multiple survey waves. To incentivize completion of all waves, we informed participants their payment would increase for subsequent surveys. Participants were paid 30 cents for wave 1, 40 cents for wave 2, and 60 cents for waves 3 and 4, $1.00 for wave 5, and $1.20 for wave 6. In addition, participants were informed that those who completed the first three waves would enter a $100 raffle. The median survey completion time was 5.5 minutes. The sample size for the first wave was 1,018, and the number of participants ranged from 608–762 on subsequent waves (see S1 Table for attrition details). This project was certified as exempt from IRB review by the University of California, San Diego Human Research Protections Program (Project #191273XX).

Our panel represents the broad and diverse population of the United States. The first wave sample included participants from all 50 states (except Wyoming) and Washington D.C., with an age range of 18 to 82 years old (mean = 38.48, median = 35). Approximately half (53%) identified as male, 46% as female, and.6% as other. The racial makeup in our sample was: 80% White, 9% Asian, 6% Black or African American, 4% multiple racial or ethnic identities, and 1% other. Relative to the U.S. Census (2019) [ 31 ] estimates, our sample over-represents White and Asian individuals, and under-represents Black or African American individuals and other racial groups.

We elicited political affiliation using a 6-point Likert scale, ranging from Strongly Republican to Strongly Democratic. In wave 1, 62% identified as Democrats and 38% identified as Republican, which is consistent with results from the most recent General Social Survey (GSS) [ 32 ]. There was no significant change in mean political identity from wave 1 to waves 2–6 (see S2 Table ). We classified participants as Democrats or Republicans using wave 1 political party affiliation. See S2 Appendix for additional details about the correlation of political party affiliation with age, gender, and SES.

Questions and measures

Our primary measure of interest was participants’ stated intention to get the COVID-19 vaccine when it becomes available. We were also interested in their perceptions of COVID-19 threat, general vaccination attitudes, and intention to get the flu shot. For all measures, except flu shot intentions, we combined multiple items to create a composite measure (see S2 Table for specific questions and construct compositions). Questions designed to measure general vaccination attitudes were adapted from prior work [ 33 ].

Additional measures of interest were participants’ trust in broad institutions (media, local government, and federal government). These trust measures followed different trends from each other, and therefore were not combined. At the end of the survey, participants responded to demographic questions. We retained all questions used in wave 1 throughout all six waves (our survey included additional items not reported in this paper; see S2 and S3 Tables for a complete list of measured items).

Data and analysis plan

Only participants with non-missing and non-duplicated responses were included in the analyses (see S1 Appendix for additional details). For all outcomes of interest, we tested for linear trends over time using a fixed effects regression specification [ 34 ]. All regression results include individual-level fixed effects, and standard errors are clustered at the individual level, to adjust for within-person correlation. We used this approach to control for the impact of omitted or unobserved time-invariant variables. P-values are not adjusted for multiple testing (see [ 35 ]). All analyses were conducted using R (version 4.0.2), and regressions were run using the package “fixest” (version 0.6.0). All materials, data, and additional analyses including robustness checks can be found here: https://osf.io/kgvdy/ .

We report results for three different vaccination-related measures: attitudes toward a COVID-19 vaccine, general vaccination attitudes, and flu shot intentions. All measures showed a decreasing trend (Ps < .001, except flu shot intentions where p = .05) for the 6-month duration of the study, indicating a reduction in pro-vaccination attitudes and intention to get vaccinated (COVID-19 and influenza vaccines). See S4 Table for full results of all regressions.

Heterogeneity in trend by political party

To better understand whether the decline in vaccine attitudes over time was driven by a particular factor, we used a data-driven approach, regressing all demographic characteristics on vaccine attitudes, in separate regressions. These demographics included education, income, SES, race, gender, an item measuring whether participants considered themselves to be a minority, whether the participant has children, and political party. Education, income, and SES were median split; race and gender were dummy coded; and political party affiliation was dichotomized into Democrat or Republican. Among all demographic characteristics, separating time trends by political affiliation (by adding an interaction term) attained the greatest adjusted within-R 2 in explaining vaccination attitude measures. In other words, political party affiliation explains the greatest within-individual variation in vaccine attitudes over time.

An analysis of responses by political affiliation revealed that the observed decreasing trend in all three vaccine measures was mostly driven by participants who identified as Republican (all Ps < .05), whereas Democrats’ responses showed either no significant trend (for COVID-19 vaccination and flu shot intentions: Ps >.67) or a significantly less negative time trend (general vaccination: p < .001). For these regressions, and moving forward, all results included interactions between wave and political party as well as interactions for wave and age, and wave and SES, to control for potentially different time trends associated with these variables. In each regression we also tested whether the strength of political affiliation moderates the observed results, and we reported the result when it did. We also conducted ANOVAs to compare mean responses for the outcomes of interest between Democrats and Republicans, separately for each wave (see S5 Table ).

COVID-19 vaccination attitudes ( Fig 1 , Panel A).

• PPT PowerPoint slide
• PNG larger image
• TIFF original image

Points represent means, and error bars represent 95% confidence intervals. All scale responses range from 1 to 7.

https://doi.org/10.1371/journal.pone.0250123.g001

A two-item construct ( r = .78) was created, with greater values corresponding to more favorable responses.

In wave 1, Democrats ( M = 5.39, SD = 1.55) had more favorable attitudes toward a COVID-19 vaccine than Republicans ( M = 4.57, SD = 1.76; t = -7.38, p < .001, d = -.48, 95% CI = [-.61, -.35]). Among Democrats, there was no significant time trend ( β = .02, SE = .04, p >.67) whereas Republicans’ responses followed a decreasing time trend ( β = -.09, SE = .05, p = .046). These trends were significantly different from each other ( β = -.11, SE = .02, p < .001).

General vaccination attitudes ( Fig 1 , Panel B).

A ten-item construct ( α = .95) was created, with greater values corresponding to a more positive attitude toward vaccination in general.

In wave 1, Democrats ( M = 5.83, SD = 1.15) expressed more favorable general vaccination attitudes than Republicans ( M = 5.17, SD = 1.31; t = -7.91, p < .001, d = -.52, 95% CI = [-.66, -.39]). Although both Democrats and Republicans had a decreasing time trend (Democrats: β = -.04, SE = .02, p = .029; Republicans: β = -.09, SE = .02, p < .001), the trend for Republicans was significantly more negative ( β = -.04, SE = .01, p < .001).

Flu shot intentions ( Fig 1 , Panel C).

We asked participants whether they plan to get the flu shot next year, with greater values indicating greater intentions.

In wave 1, Democrats ( M = 4.84, SD = 2.34) indicated greater intentions to vaccinate against the flu than Republicans ( M = 4.35, SD = 2.39; t = -3.15, p = .002, d = -.21, 95% CI = [-.34, -.08]). Among Democrats, there was no significant time trend ( β = .01, SE = .04, p = .86), suggesting their vaccination intentions remained largely stable. Republicans’ responses, however, revealed a decreasing time trend ( β = -.12, SE = .04, p = .005), and the two trends were significantly different from each other ( β = -.12, SE = .02, p < .001).

Our analyses revealed an interaction with political affiliation strength among Republicans, whereby participants who identified as more strongly Republican had a more negative time trend ( β = -.05, SE = .02, p = .027). This interaction was not significant for Democrats ( β = -.02, SE = .01, p = .19).

Perceived threat of COVID-19 ( Fig 2 ).

https://doi.org/10.1371/journal.pone.0250123.g002

A three-item construct ( α = .82) was created, with greater perceived threat about COVID-19.

In wave 1, Democrats ( M = 4.26, SD = 1.25) expressed greater perceived threat of COVID-19 than Republicans ( M = 3.90, SD = 1.39; t = -4.14, p < .001, d = -.40, 95% CI = [-.27, -.14]). Democrats’ responses showed an increasing time trend ( β = .08, SE = .04, p = .033), indicating they became increasingly concerned about the threat posed by the virus over time. Among Republicans, there was no significant time trend ( β = -.01, SE = .04, p = .83). These trends were significantly different from each other ( β = -.09, SE = .02, p < .001). While our data does not render causal claims, it is possible that the divergence in COVID-19 threat perceptions over time among Republicans and Democrats contributes to the divergence in vaccine attitudes between these groups over time. We revisit this proposition in the General Discussion.

Our analyses revealed an interaction with political affiliation strength among Democrats—participants who identified as more strongly Democrat had a more positive time trend ( β = .03, SE = .01, p = .019), suggesting an increasing threat perception over time. This interaction was not significant for Republicans ( β = .01, SE = .02, p = .61).

Trust in broad institutions.

The measures of trust in media, local government, and federal government were not highly correlated ( α = .66), and were therefore analyzed separately.

Trust in media ( Fig 3 , Panel A) . In wave 1, Democrats ( M = 3.61, SD = 1.66) reported greater trust in the media than Republicans ( M = 2.73, SD = 1.65; t = -8.12, p < .001, d = -.53, 95% CI = [-.66, -.39]). There was no significant time trend for either Democrats ( β = .02, SE = .04, p = .57) or Republicans ( β = -.05, SE = .04, p = .20). However, the trend for Republicans was significantly more negative ( β = -.07, SE = .02, p < .001). The different trends we observe for Democrats and Republicans with respect to trust in the media may explain the divergence in perceived threat and vaccine attitudes between these groups over time (see General discussion ).

https://doi.org/10.1371/journal.pone.0250123.g003

Trust in local government ( Fig 3 , Panel B) . In wave 1, Democrats ( M = 4.07, SD = 1.60) indicated lower trust in local government than Republicans ( M = 4.28, SD = 1.60; t = 2.01, p = .045, d = .13, 95% CI = [.003,.26]). Among Democrats, there was no significant time trend ( β = -.06, SE = .04, p = .18), though among Republicans, there was a decreasing time trend ( β = -.11, SE = .05, p = .015). These trends were significantly different from each other ( β = -.06, SE = .02, p = .004).

Trust in federal government ( Fig 3 , Panel C) . In wave 1, Democrats ( M = 2.96, SD = 1.67) expressed lower trust in the federal government than Republicans ( M = 4.08, SD = 1.60; t = 10.52, p < .001, d = .68, 95% CI = [.55,.82]). Both Democrats and Republicans had decreasing time trends (Democrats: β = -.08, SE = .04, p = .036; Republicans: β = -.10, SE = .04, p = .025). These trends were not significantly different from each other ( β = -.02, SE = .02, p = .37).

To rule out differential attrition, we tested whether the composition of our sample (i.e., age, gender, and political party) changed over time (see S1 Table ). Specifically, we tested whether participants who responded to waves 2–6 were significantly different at baseline (wave 1) from the full sample at baseline. The only significant change detected (Ps < .05) was with respect to participants’ age, though the differences were small—the average age was 38.5 at baseline, and remained between 39.9 and 40.8 at baseline among participants who responded to subsequent waves. We found no other systematic pattern of attrition among our participants.

General discussion

Over the course of six months of the COVID-19 pandemic, beginning with a relatively early phase prior to any U.S. directives to stay home (March 2020) and continuing through a cumulation of over 5 million cases (August 2020), we found a decrease in pro-vaccine attitudes and COVID-19 vaccination intentions, as well as reduced intentions to get the influenza vaccine. These findings are contrary to our prediction that increased salience of COVID-19 would improve attitudes toward vaccines.

Our analyses identify political ideology as the best predictor of the decreasing time trend across our three vaccine-related attitudes and intentions measures. In particular, we found that while Democrats’ responses remained fairly stable over time, Republicans shifted away from their lower initial responses and from Democrats’ responses, leading to increased polarization throughout the six-month period.

Contrary to the polarization observed in our data, social and behavioral scientists have long argued that groups facing threats often come together, demonstrating stronger social cohesion [ 36 ], and more cooperative behaviors [ 37 , 38 ]. Researchers have also found that individuals’ sense of shared identity plays a role in promoting cooperative behavior in response to threat [ 39 – 41 ]. Considering our results in the context of these findings might suggest that our respondents’ sense of shared identity was dominated by their political ideology, as opposed to a broader (e.g. American) identity.

What might be going on?

Although the nature of our data does not render causal claims, it highlights potential explanations. First, we note that participants’ ratings of perceived COVID-19 threat followed a similar diverging pattern by party affiliation to our three vaccine-related measures during the study period. Democrats perceived COVID-19 threat to be greater at the start of the study than Republicans did, and this gap widened significantly as the study progressed. This trend is consistent with previous research showing that vaccine hesitancy is related to perceived risk of a threat; when a VPD threat level is low, individuals are less motivated to take preventative action (i.e., immunize; for a review, see [ 42 ]).

Our data offers one potential explanation for the polarization of threat perception: Republican and Democratic participants in our study reported consuming different sources of information. The most commonly checked news source for Republicans was Fox News (Republicans: 50%, Democrats: 8%; χ 2 = 164.55, p < .001) and for Democrats was CNN (Democrats: 47%, Republicans: 23%, χ 2 = 43.08, p < .001, see S6 Table ). Corroborating this proposition, a Pew Research Center poll conducted in March 2020 found that 56% of respondents whose main news source is Fox News believed that “the news media have greatly exaggerated the risks about the Coronavirus outbreak,” whereas this was only true for 25% of those whose main news source is CNN [ 43 ]. Of note, Facebook and Instagram, were also in the top four most consumed news sources for participants affiliated with either party. Extant work describes these platforms as echo chambers [ 44 , 45 ], which may exacerbate partisan exposure to news and information.

Another trend highlighted by our data shows that similar to vaccine attitudes, Republicans’ trust in the media decreased significantly more during our study than Democrats’, suggesting these patterns might be related. According to Dr. Heidi Larson, an expert on vaccine hesitancy and founder of the Vaccine Confidence Project, misinformation regarding vaccinations is more likely to take root when individuals do not trust the information source [ 46 ]. Future research might further examine the role of trust in the media on vaccine attitudes.

While trust in media or media exposure may be driving COVID-19 threat perceptions and vaccine attitudes, there are many other possible explanatory factors that are not captured by our data or analyses. For example, it is possible that threat perceptions were influenced by how a respondents’ county or state was affected by COVID-19; up until June 2020, COVID-19 cases were more common in Democrat-leaning states [ 47 ], which might have amplified its salience early on and influenced attitudes and behavior. Further, although we included individual-level fixed-effects which control for all time invariant participant characteristics, and controlled for different trends by age and SES, we cannot rule out the possibility that other factors (e.g., educational attainment or population density) may have influenced the observed trends. Finally, as our data collection began after the onset of COVID-19, it is possible that the trend we observe for Republicans represents a return to a pre-pandemic baseline of vaccine-related attitudes.

Contributions

This work advances our understanding of how health-related attitudes evolve over time. Our focus on vaccine-related attitudes and intentions is important because experts agree that having enough people vaccinate against COVID-19 is key to stemming the pandemic [ 48 ]. More broadly, negative attitudes toward vaccination in general, and reduced vaccine uptake, is increasingly a public health concern [ 49 ]. This research provides insight into the trends of such vaccine hesitancy, underlining the importance of risk salience and its roots in ideology and media exposure.

This work also contributes to our understanding of political parties and polarization. Numerous anecdotes and reports have demonstrated a partisan divide in Americans’ response to the COVID-19 pandemic. For example, research found greater negative affective responses to wearing a face covering among politically right (vs. left) leaning individuals [ 50 ]. Here, we show that although these observations are valid, the reality is more nuanced. For example, our analyses reveal that polarization on vaccine measures—both attitudes and intentions—is driven primarily by self-identified Republicans’ gradual movement away from their initial responses whereas Democrats’ responses remained largely stable. This insight has important practical implications: It informs us about the dynamics of individuals’ attitudes, bringing us closer to understanding the underlying factors that influence attitudes and behaviors. Equipped with this knowledge, one could design more effective communications and interventions.

Note on methodology and data availability

The present study contributes to a small but growing literature in the social sciences using longitudinal data [ 51 ]. Using a longitudinal methodology allowed us to track individual-level changes over time. Merely observing a single point in time would allow us to observe across-group differences, but would lack the bigger picture of how polarization between these groups evolved. Another key advantage of panel data is that it allows us to include individual-level fixed effects, which control for the impact of omitted or unobserved time-invariant variables. Finally, panel data allows for more accurate inference of model parameters [ 52 ].

While the focus of this paper is vaccine attitudes, our broad dataset offers a unique opportunity to understand attitudes and behavior over time. Due to the richness of our data, its unique nature, and its timeliness, we believe it is important to make it available to other researchers interested in exploring it and publishing additional findings. The complete dataset is available at https://osf.io/kgvdy/ (see S2 and S3 Tables for all items collected).

Supporting information

S1 appendix. additional information about sample exclusions..

https://doi.org/10.1371/journal.pone.0250123.s001

S2 Appendix. Additional information about political party affiliation.

https://doi.org/10.1371/journal.pone.0250123.s002

S1 Table. Attrition table.

https://doi.org/10.1371/journal.pone.0250123.s003

S2 Table. Summary table of measures and constructs included in the text.

https://doi.org/10.1371/journal.pone.0250123.s004

S3 Table. Summary table of measures excluded from the text.

https://doi.org/10.1371/journal.pone.0250123.s005

S4 Table. Regression results.

https://doi.org/10.1371/journal.pone.0250123.s006

S5 Table. Outcome measures by political party affiliation.

https://doi.org/10.1371/journal.pone.0250123.s007

S6 Table. Summary of news sources.

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Serious adverse events of special interest following mRNA COVID-19 vaccination in randomized trials in adults

Affiliations.

• 1 Thibodaux Regional Health System, Thibodaux, LA, USA. Electronic address: [email protected].
• 2 Unit of Innovation and Organization, Navarre Health Service, Spain. Electronic address: [email protected].
• 3 Institute of Evidence-Based Healthcare, Bond University, Gold Coast, QLD, Australia. Electronic address: [email protected].
• 4 Fielding School of Public Health and College of Letters and Science, University of California, Los Angeles, CA, USA. Electronic address: [email protected].
• 5 Geffen School of Medicine, University of California, Los Angeles, CA, USA. Electronic address: [email protected].
• 6 Clinical Excellence Research Center, School of Medicine, Stanford University, CA, USA. Electronic address: [email protected].
• 7 School of Pharmacy, University of Maryland, Baltimore, MD, USA. Electronic address: [email protected].
• PMID: 36055877
• PMCID: PMC9428332
• DOI: 10.1016/j.vaccine.2022.08.036

Introduction: In 2020, prior to COVID-19 vaccine rollout, the Brighton Collaboration created a priority list, endorsed by the World Health Organization, of potential adverse events relevant to COVID-19 vaccines. We adapted the Brighton Collaboration list to evaluate serious adverse events of special interest observed in mRNA COVID-19 vaccine trials.

Methods: Secondary analysis of serious adverse events reported in the placebo-controlled, phase III randomized clinical trials of Pfizer and Moderna mRNA COVID-19 vaccines in adults ( NCT04368728 and NCT04470427 ), focusing analysis on Brighton Collaboration adverse events of special interest.

Results: Pfizer and Moderna mRNA COVID-19 vaccines were associated with an excess risk of serious adverse events of special interest of 10.1 and 15.1 per 10,000 vaccinated over placebo baselines of 17.6 and 42.2 (95 % CI -0.4 to 20.6 and -3.6 to 33.8), respectively. Combined, the mRNA vaccines were associated with an excess risk of serious adverse events of special interest of 12.5 per 10,000 vaccinated (95 % CI 2.1 to 22.9); risk ratio 1.43 (95 % CI 1.07 to 1.92). The Pfizer trial exhibited a 36 % higher risk of serious adverse events in the vaccine group; risk difference 18.0 per 10,000 vaccinated (95 % CI 1.2 to 34.9); risk ratio 1.36 (95 % CI 1.02 to 1.83). The Moderna trial exhibited a 6 % higher risk of serious adverse events in the vaccine group: risk difference 7.1 per 10,000 (95 % CI -23.2 to 37.4); risk ratio 1.06 (95 % CI 0.84 to 1.33). Combined, there was a 16 % higher risk of serious adverse events in mRNA vaccine recipients: risk difference 13.2 (95 % CI -3.2 to 29.6); risk ratio 1.16 (95 % CI 0.97 to 1.39).

Discussion: The excess risk of serious adverse events found in our study points to the need for formal harm-benefit analyses, particularly those that are stratified according to risk of serious COVID-19 outcomes. These analyses will require public release of participant level datasets.

Keywords: Adverse events of special interest; Brighton Collaboration; COVID-19; COVID-19 vaccines; Coalition for Epidemic Preparedness Innovations; Moderna COVID-19 vaccine mRNA-1273; NCT04368728 ; NCT04470427 ; Pfizer-BioNTech COVID-19 vaccine BNT162b2; SARS-CoV-2; Safety Platform for Emergency vACcines; Serious adverse events; Vaccines; mRNA vaccines.

Copyright © 2022 Elsevier Ltd. All rights reserved.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

• Serious adverse events following mRNA vaccination in randomized trials in adults. Black S, Evans S. Black S, et al. Vaccine. 2023 May 26;41(23):3473-3474. doi: 10.1016/j.vaccine.2023.04.040. Epub 2023 Apr 28. Vaccine. 2023. PMID: 37121802 No abstract available.

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Prevaccine and Vaccine-Era Disease Estimates

Hepatitis a, hepatitis b, haemophilus influenzae type b, measles, mumps, and rubella, streptococcus pneumoniae, conclusions, acknowledgments, impact of routine childhood immunization in reducing vaccine-preventable diseases in the united states.

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Sandra E. Talbird , Justin Carrico , Elizabeth M. La , Cristina Carias , Gary S. Marshall , Craig S. Roberts , Ya-Ting Chen , Mawuli K. Nyaku; Impact of Routine Childhood Immunization in Reducing Vaccine-Preventable Diseases in the United States. Pediatrics August 2022; 150 (3): e2021056013. 10.1542/peds.2021-056013

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Current routine immunizations for children aged ≤10 years in the United States in 2019 cover 14 vaccine-preventable diseases. We characterize the public-health impact of vaccination by providing updated estimates of disease incidence with and without universally recommended pediatric vaccines.

Prevaccine disease incidence was obtained from published data or calculated using annual case estimates from the prevaccine period and United States population estimates during the same period. Vaccine-era incidence was calculated as the average incidence over the most recent 5 years of available surveillance data or obtained from published estimates (if surveillance data were not available). We adjusted for underreporting and calculated the percent reduction in overall and age-specific incidence for each disease. We multiplied prevaccine and vaccine-era incidence rates by 2019 United States population estimates to calculate annual number of cases averted by vaccination.

Routine immunization reduced the incidence of all targeted diseases, leading to reductions in incidence ranging from 17% (influenza) to 100% (diphtheria, Haemophilus influenzae type b, measles, mumps, polio, and rubella). For the 2019 United States population of 328 million people, these reductions equate to >24 million cases of vaccine-preventable disease averted. Vaccine-era disease incidence estimates remained highest for influenza (13 412 per 100 000) and Streptococcus pneumoniae -related acute otitis media (2756 per 100 000).

Routine childhood immunization in the United States continues to yield considerable sustained reductions in incidence across all targeted diseases. Efforts to maintain and improve vaccination coverage are necessary to continue experiencing low incidence levels of vaccine-preventable diseases.

The United States childhood vaccination program has dramatically reduced morbidity, mortality, and disability for targeted diseases. Updated estimates of disease incidence and cases averted, reflecting changes in disease epidemiology, vaccine utilization, and vaccine recommendations (based on the 2017 to 2021 schedule), are needed.

The childhood vaccination program reduced the incidence of all targeted diseases—with reductions ranging from 17% (influenza) to 100% (diphtheria, Haemophilus influenzae type b, measles, mumps, polio, and rubella)—and averted >24 million disease cases for the 2019 United States population.

Childhood vaccination has dramatically reduced morbidity, mortality, and disability caused by vaccine-preventable diseases, with ∼21 million hospitalizations, 732 000 deaths, and 322 million cases of disease averted in the United States between 1994 and 2013. 1   Among diseases targeted by vaccines recommended before 1980, 3—polio, measles, and rubella—have achieved elimination status as defined by the World Health Organization 2   and 1—smallpox—has been eradicated. 3   Diphtheria and tetanus have declined markedly in incidence with routine immunization and are well controlled, 2   whereas the incidence of pertussis and mumps has declined when compared with prevaccine levels but still fluctuates given periodic outbreaks since vaccination was introduced. 3   The public health burden of diseases targeted in the childhood immunization program between 1980 and 2005, including hepatitis A, hepatitis B, invasive Haemophilus influenzae type b (Hib), varicella, and invasive pneumococcal disease (IPD), has decreased by more than 80% 3   ; reductions in related nontargeted diseases (eg, acute otitis media caused by Streptococcus pneumoniae ) have also been observed. 4   After 2005, the routine immunization schedule 5   for United States children ≤10 years of age targeted additional pathogens, such as rotavirus and further pneumococcal serotypes. 5  

This study updates estimates of the reduction in overall and age-specific disease incidence associated with the routine childhood immunization program in the United States (based on the 2017 to 2021 vaccination schedule). This update incorporates changes in vaccine utilization rates and observed incidence of the targeted vaccine-preventable diseases since previous evaluations. 3 , 6   The present analysis will be of interest to policy makers, public health decision makers, and modelers concerned with public health interventions to minimize the burden of vaccine-preventable diseases. A companion study evaluated the value of the childhood immunization program for the 2017 United States birth cohort. 7  

We estimated the epidemiologic impact of the United States routine childhood immunization program (ages ≤10 years) by calculating the percent reduction in overall and age-specific disease incidence rates for each disease targeted by the program. We multiplied the prevaccine and vaccine-era incidence rates (using age-specific data, where available) by 2019 United States population estimates, 8   accounting for underreporting where necessary, to calculate the 2019 clinical disease burden with and without childhood immunization and to estimate the cases averted by vaccination. As in previous studies, we assumed that the difference between incidence rates during these periods was entirely attributable to the childhood immunization program. 3 , 6  

For the prevaccine period, we estimated disease incidence using published incidence estimates or calculated incidence using published annual case estimates and United States population data from the same period. For the vaccine era, we calculated incidence as the average incidence over the most recent 5 years of available surveillance data; we used published incidence estimates if surveillance data were not available. For both periods, we accounted for underreporting where necessary.

Table 1 summarizes the prevaccine and vaccine-era disease incidence sources. Age-specific incidence data were used for all diseases except diphtheria, polio, tetanus, and rotavirus. Incidence of Hib and rotavirus was limited to ages <5 years and diphtheria to ages ≤10 years, given lack of data in older age groups in the prevaccine period and the fact that clinical burden was largely limited to those age groups in both periods. Incidence of measles, mumps, and rubella was included only up to age 40 years, as prevaccine incidence data in ages ≥40 years was unavailable. For pneumococcal pneumonia, pneumococcal acute otitis media (AOM), and rotavirus, resource use estimates (ie, hospitalizations, emergency department [ED] visits, and outpatient visits) are reported instead of incidence and disease cases because of limitations in the source data.

Summary of Prevaccine and Vaccine-Era Disease Incidence Sources

ABC, Active Bacterial Core; AOM, acute otitis media; CDC, Centers for Disease Control and Prevention; ED, emergency department; IPD, invasive pneumococcal disease; NNDSS, National Notifiable Diseases Surveillance System.

Dates of immunization program initiation correspond to dates of vaccine licensure and/or routine recommended use. 3 , 96   For additional details on vaccines with multiple dates listed, please see Roush and Murphy 3   and Widdowson et al. 76  

Prevaccine pertussis incidence estimates for ages >10 y were estimated from all cases reported by Roush and Murphy, 3   adjusted to account for the estimate from Cherry 95   that approximately 93% of pertussis infections in the first half of the 20th century were among ages <10 y.

An underreporting factor of 10 was taken from economic evaluations and burden-of-illness studies 53 – 55   and was multiplied by prevaccine pertussis incidence in ages >10 y and vaccine-era pertussis incidence for all ages; prevaccine incidence from birth to age 10 y (taken from Zhou et al) already accounted for underreporting. 9   This underreporting factor is conservative compared with previous studies that have tested underreporting of pertussis up to 100 to 200 times reported cases among adolescents and adults. 53 , 55 , 56  

A prevaccine underreporting factor was calculated based on an estimated 48% of notifiable polio cases being paralytic in 1954. 74   This implied underreporting factor (1 of 0.48 = 2.1 cases per reported case) was used to calculate the estimated total number of notifiable polio cases (both paralytic and nonparalytic) based on the incidence of paralytic polio reported by Baicus. 75  

The prevaccine underreporting factor (22.2) was calculated from the 1994 NNDSS report, 20   which reported that approximately 3.7 million cases of varicella occurred annually prevaccine, with 4% to 5% of cases reported. 11 – 15  

Because cases of varicella were not reported by age in 2014 and 2015, the total cases were distributed by age using the same age distribution of cases from 2016 when calculating the age-specific 5-year incidence rate. The vaccine-era underreporting factor (10.4) was calculated based on the underreporting factor used by Roush and Murphy 3   (12.7 = 612 768 cases estimated of 48 445 cases reported by 33 states in 2006), adjusted for 40 states reporting varicella cases in 2015 versus 33 states in 2006 (12.7 × 33/40 = 10.4).

We obtained prevaccine diphtheria disease incidence for children aged ≤10 years from an economic evaluation by Zhou et al, 9   which estimated incidence from a 1916 to 1919 survey of childhood vaccine-preventable diseases in 31 353 United States children and physician-reported data. 10   We assumed the incidence reported by Zhou et al 9   for ages 5 to 9 years uniformly applied to all children ≤10 years. We calculated vaccine-era incidence among children aged ≤10 years as the average value over the most recent 5 years (2014 to 2018) of available data from the Centers for Disease Control and Prevention (CDC) National Notifiable Disease Surveillance System (NNDSS) reports. 11 – 15  

We calculated prevaccine hepatitis A incidence using the average number of reported cases between 1990 and 1994 from the NNDSS 16 – 20   divided by the 1994 United States population for each respective age group. 21   We calculated vaccine-era incidence as the average value over the most recent 5 years (2014 to 2018) of available data from the NNDSS. 11 – 15   A systematic review and meta-analysis of underreporting of hepatitis A in nonendemic countries found that reported hepatitis A cases ranged from 4% to 97% of total estimated cases across 8 included studies, with a pooled proportion of 59%. 22   As a result, an underreporting factor of 1.7 (1/59% = 1.7) was applied for prevaccine and vaccine-era estimates, 22   which is similar to underreporting factors found in other studies. 23  

We estimated prevaccine hepatitis B incidence as the average number of reported cases between 1976 and 1980 from the NNDSS 24 – 28   and calculated vaccine-era incidence as the average value over the most recent 5 years (2014 to 2018) of available data from the NNDSS. 11 – 15   The underreporting factor for hepatitis B (6.5) was obtained from a probabilistic model estimating underreporting of hepatitis A, B, and C. 23  

We obtained prevaccine disease incidence for Hib for children aged <5 years for 1976 to 1984 from an economic analysis by Zhou et al. 29   We calculated overall incidence by summing the incidence values reported separately for Hib-related meningitis, epiglottitis, bacteremia, pneumonia, cellulitis, arthritis, and other invasive diseases reported in Zhou et al. 29   We calculated vaccine-era incidence among children aged <5 years as the average value over the most recent 5 years (2013–2017) of available data from CDC Active Bacterial Core (ABC) surveillance reports. 30 – 34  

For influenza, instead of using data from the period before influenza vaccines were routinely recommended, we estimated prevaccine incidence among children aged ≤10 years by using the number of cases and averted cases estimated by the CDC, assuming all averted cases would have occurred without vaccination. 35 – 42   Specifically, we summed the number of reported cases to the cases averted by vaccination among children <5 years and children aged 5 to 10 years for 5 recent influenza seasons (2014–2015 to 2018–2019) and then divided the total number of cases by the number of children in the United States in each respective age group for the same period. 8   An average incidence across the 5 years was then calculated for both age groups. For vaccine-era incidence, we used the same source and calculated the average incidence over the same 5 recent seasons (2014–2015 to 2018–2019). Our analyses did not account for the impact of adolescent and adult influenza vaccination or herd immunity in older age groups; therefore, incidence of influenza was restricted to ages ≤10 years, and we attributed all changes in incidence to vaccination in this age cohort.

For measles, mumps, and rubella, we obtained prevaccine disease incidence from Zhou et al. 43 – 47   For the vaccine era, we calculated incidence as the average value over the most recent 5 years (2014 to 2018) of available data from the NNDSS. 11 – 15  

We estimated prevaccine pertussis incidence for birth to 10 years from 2 economic evaluations of diphtheria, tetanus, and acellular pertussis vaccine, which derived age-specific risk of pertussis from United States data in the 1920s and from Sweden in the 1980s. 9 , 48   Prevaccine incidence for ages >10 years was calculated using the number of reported pertussis cases estimated by Roush and Murphy 3   for ages >10 years during 1934 to 1943 (before the start of routine pertussis vaccination in the late 1940s) divided by the size of the United States population >10 years old over the same period. 49 , 50   We calculated vaccine-era incidence as the average value over the most recent 5 years (2014 to 2018) of available data from the NNDSS. 11 – 15   An underreporting factor of 10 was applied in the prevaccine and vaccine eras ( Table 1 ). 51 – 56  

For IPD, we calculated prevaccine disease incidence as the average value from the 1997 to 1999 ABC surveillance reports 57 – 59   and calculated vaccine-era incidence as the average value from the 2013 to 2017 ABC surveillance reports. 60 – 64  

For pneumococcal pneumonia, we obtained prevaccine, age-specific, all-cause pneumonia hospitalization rates per 100 000 for the period 1997 to 1999 65   and all-cause outpatient visit rates per 100 000 for the period 1998 to 2000 66 , 67   ( Table 1 ). For the vaccine era, we used the incidence of all-cause pneumonia from 2014 based on an analysis of a large convenience insurance claims dataset (MarketScan) multiplied by the percentage hospitalized or treated in an outpatient or ED setting taken from the same study. 68   We multiplied the all-cause rates by the prevaccine 69 , 70   and postvaccine 71 , 72   percentage of all-cause pneumonia caused by pneumococcus ( Table 1 ).

For pneumococcal AOM, we used prevaccine, age-specific incidence from 1997 to 1999 and vaccine-era incidence from 2012 to 2014 from a retrospective analysis of the National Ambulatory Medical Care Survey comparing ambulatory visit rates before the introduction of 7-valent and following 13-valent pneumococcal conjugate vaccine. 4   We summed annual rates of physician office, hospital outpatient, and hospital ED visits to calculate a total annual ambulatory visit rate per 1000 children. To calculate pneumococcal AOM burden for each period, we multiplied all-cause rates by the percentage of AOM caused by pneumococcus in the prevaccine period (1995 to 2001) (44%) and vaccine era (2010 to 2016) (21%). 73  

For polio, we obtained the average number of paralytic poliomyelitis cases for the period 1951 to 1954 (before the introduction of the first polio vaccine in 1955) from Roush and Murphy 3   . We divided the total number of cases by the average United States population size from 1951 to 1954 to estimate an overall incidence rate. 49   Age-specific data were not available in the prevaccine period; therefore, the same incidence rate was used for all ages. A prevaccine underreporting factor of 2.1 was applied ( Table 1 ). 74 , 75   We calculated vaccine-era incidence as the average value over the most recent 5 years (2014 to 2018) of available data from the NNDSS. 11 – 15  

We calculated prevaccine estimates of rotavirus-related burden among children aged <5 years using 1993 to 2002 data on the cumulative individual risk of event by age 59 months for events including hospitalizations, ED visits, and hospital or ambulatory outpatient visits. 76   The median values were used to calculate annual probabilities of each type of rotavirus-related resource use. We further assumed rotavirus events were uniformly distributed from birth to age 5 years ( Supplemental Table 3 ). In the vaccine era, we calculated rotavirus-related burden by multiplying prevaccine event rates by the estimated reduction in hospitalizations 77   and reduction in ED and outpatient visits. 78  

We calculated prevaccine tetanus incidence based on the number of cases reported during 1947 to 1949 (before routine vaccination began in the late 1940s 3   ) divided by the average size of the United States population during that same period. 49   Data were not available by age in the prevaccine period; therefore, the same incidence rate was used across all ages in the model. We calculated vaccine-era incidence as the average value over the most recent 5 years (2014 to 2018) of available data from the NNDSS. 11 – 15  

We calculated prevaccine varicella incidence using the average number of reported varicella cases between 1990 and 1994 (before vaccine introduction in 1995) from the NNDSS 16 – 20   divided by the 1994 United States population for each respective age group. 20 , 21   We calculated vaccine-era incidence as the average value over the most recent 5 years (2014 to 2018) of available data from the NNDSS. 11 – 15   Underreporting factors of 22.2 and 10.4 were applied to prevaccine and vaccine-era incidence, respectively ( Table 1 ). 3 , 20  

We report calculated incidence overall and by age for both the prevaccine and 2019 vaccine-era periods. We calculated the percent reduction in incidence overall and by age group for each disease by comparing the 2 periods. Using 2019 United States population estimates from the United States Census Bureau, we calculated the number of cases of each disease that would be expected in 2019 without and with the routine childhood immunization program and the number of cases of disease averted.

For infants (<1 year), prevaccine annual incidence per 100 000 was highest for pneumococcal AOM (49 324), influenza (18 903), measles (9200), and pertussis (4720) ( Supplemental Tables 3 – 5 ). For young children (ages 1 to 4 years), as for infants, incidence in the prevaccine period was highest for pneumococcal AOM (15 004–49 324), influenza (18 903), measles (10 641–11 503), and pertussis (4720), as well as for varicella (4519). For school-aged children (ages 5–18 years), prevaccine incidence varied by age group but was highest for influenza (14 066), varicella (389–6480), pneumococcal AOM (4840), and pertussis (131–4720). For adults, prevaccine incidence was highest for pneumococcal pneumonia (29–1553), rubella (300), mumps (99–256), and pertussis (131).

After vaccines were introduced, incidence decreased for all diseases evaluated ( Fig 1 ; Table 2 ). Incidence was reduced to less than 1 per 100 000 for 6 of the diseases: diphtheria, Hib, measles, polio, rubella, and tetanus. The incidence of mumps was reduced by >99% and varicella by 98%. The incidence of rotavirus-related hospitalizations among children aged <5 years was reduced by 91%; a lower reduction was observed for rotavirus-related ED visits (61%) and outpatient visits (45%). The incidence of pertussis was reduced by 91%, hepatitis A by 87%, hepatitis B by 86%, and IPD by 60%. Pneumococcal pneumonia hospitalization rates and outpatient visit rates decreased by 84% and 69%, respectively, and incidence of pneumococcal AOM decreased by 75%. The incidence of influenza among people aged <11 years was reduced by 17%.

Percentage reduction in disease incidence in the vaccine era by disease. Percentage reduction for rotavirus is hospitalizations. IPD does not include pneumococcal pneumonia or acute otitis media. Percentage reductions in disease incidence round up to 100% for several diseases, although there are still some cases in the vaccine era ( Table 2 ). IPD, invasive pneumococcal disease.

Prevaccine and Vaccine-Era Disease Incidence Estimates, Annual Cases, and 2019 Cases Averted in the United States by Disease

Annual cases are rounded to the nearest thousand. AOM, acute otitis media; ED, emergency department; IPD, invasive pneumococcal disease.

Incidence estimates are adjusted by underreporting factors of 1.7 for hepatitis A, 6.5 for hepatitis B, 10.0 for pertussis (in ages 11 y and older prevaccine and all ages in the vaccine era), 2.1 for polio prevaccine (to capture paralytic and nonparalytic cases), 22.2 for varicella prevaccine, and 10.4 for varicella in the vaccine era (with all other diseases assumed fully reported and/or already adjusted to account for underreporting from the source data).

Prevaccine and vaccine-era case estimates are calculated using 2019 United States population estimates and are rounded to the nearest thousand. For Haemophilus influenzae type b and rotavirus, the population size for ages <5 y ( n = 19 576 683) was used to calculate annual cases. Annual cases for diphtheria and influenza were calculated using the population size for ages ≤10 y ( n = 43 833 518). The population size for ages <40 y ( n = 170 936 198) was used to calculate annual cases for measles, mumps, and rubella. For all other diseases, the total United States population size ( n = 328 239 523) was used to calculate annual prevaccine and vaccine-era cases.

Rotavirus and pneumococcal disease results are shown separately by healthcare resource use because of a lack of incidence data.

The calculated value for cases averted may not precisely equal the difference between the number of cases in the “with immunization” and “without immunization” period because of rounding.

For the 2019 United States population of 328 million people, the number of cases of each disease without and with the childhood immunization program and the estimated number of cases averted are shown in Table 2 . In the vaccine era with routine immunization, the annual number of cases of disease was 0 for polio, <10 cases per year for diphtheria and rubella, and <100 cases per year for Hib and tetanus. Pneumococcal AOM and influenza represented the largest clinical burden annually (>1 000 000 cases per year), followed by pertussis, pneumococcal pneumonia, outpatient rotavirus gastroenteritis, and outpatient varicella (between 100 000 and 1 million cases per year).

Routine immunization was estimated to avert over 24 million cases of vaccine-preventable disease in 2019 across all age groups, ranging from approximately 1000 cases of tetanus averted to more than 4.2 million varicella cases averted ( Table 2 ). Cases averted were greatest (>1 000 000) for influenza, measles, mumps, rubella, pertussis, varicella, and outpatient visits for pneumococcal AOM.

This analysis found that routine childhood immunization in the United States has continued to reduce the incidence of all targeted diseases. Landmark achievements have been the reduction in incidence of diphtheria, Hib, measles, polio, rubella, and tetanus to negligible levels (<1 case per 100 000 population annually); and >90% reduction in incidence for 10 diseases targeted by the routine childhood immunization program for children ≤10 years of age. These reductions equate to the prevention of over 24 million cases of disease for the 2019 US population.

Roush and Murphy 3   evaluated the impact of routine childhood immunization on vaccine-preventable diseases for which recommendations were in place before 2005, using 2006 disease data. Our estimates were generally consistent with the previous results and other published studies, 79   although we estimated a greater reduction in incidence of IPD (60% versus 34%) and of varicella (98% versus 85%). A potential explanation for these differences may be that our analysis used vaccine-era incidence from 2013 to 2017 for pneumococcal disease and from 2014 to 2018 for varicella, capturing the greater impact of the 13-valent pneumococcal conjugate vaccine (recommended in 2010 for infants) compared with the 7-valent pneumococcal conjugate vaccine and capturing the greater impact of 2-dose varicella vaccine compared with 1 dose (second dose added to recommendations in 2007). 80  

With sustained vaccine coverage at levels greater than 80% for most pediatric vaccines (with the exception of hepatitis A, rotavirus, and annual influenza vaccine), many vaccine-preventable diseases are now controlled as a public health problem or eliminated in the United States. However, despite significant impact of vaccines, continued risk from these vaccine-preventable diseases remains. When whole-cell pertussis vaccine was withdrawn in Sweden in 1979 because of concerns about safety and efficacy, incidence rates of pertussis similar to those observed in the prevaccine era returned in Sweden within a few years; after introduction of the diphtheria, tetanus, and acellular pertussis vaccine in 1996, incidence rates decreased markedly compared with the 1986 to 1995 10-year period. 81 , 82   Similarly, despite elimination status being declared for measles in 2000, under-vaccination has led to continued measles outbreaks in the United States, jeopardizing elimination status for the disease. 83 – 85   Diphtheria outbreaks continue to occur where vaccination rates are low, particularly in areas of social disruption, and are often associated with high rates of mortality. 86 , 87   The most recent large outbreak occurred in Russia from 1990 to 1997, resulting in ∼115 000 cases and 3000 deaths across the population. 88   These experiences underscore the importance of continued immunization in sustaining reductions in incidence of infectious diseases.

This analysis includes some limitations. First, consistent with previous studies, 3 , 6   the analysis does not directly account for other public health measures (eg, better sanitation, healthcare access, and improved standards of care) that have been introduced over the past 70 years and likely contributed to the reduction in vaccine-preventable diseases. Furthermore, this analysis did not account for random error in the parameter estimates or account for the proportion of disease incidence reduction that may be attributed to adolescent and adult vaccines or to booster doses. As a result, the analysis may overestimate reductions in burden directly attributable to childhood immunization. Future analyses could address these methodological limitations using time-series analysis to identify and adjust for trends to explore the extent to which adolescent and adult vaccination programs, which have expanded since 2005, 80 , 89 , 90   contribute to reduction in disease incidence.

Second, owing to limited data on differences among racial and ethnic groups, this analysis did not account for racial or ethnic disparities in vaccine coverage and incidence of vaccine-preventable diseases. Evaluating the public health impact of routine immunization among racial and ethnic groups is an important direction for future research. Moreover, this analysis was limited in scope to vaccine-preventable disease for vaccines included in the United States routine childhood immunization program for children ages ≤10 years. Expansion of this analysis to include vaccine-preventable diseases, such as meningococcus and human papillomavirus targeted by routine adolescent vaccines, is another potential area of future research.

Third, because annual incidence varies substantially from year to year for many vaccine-preventable diseases, we have calculated prevaccine and vaccine-era incidence as averages across multiple years, where data allowed. Despite our efforts to estimate average incidence values in both periods, significant epidemics or outbreaks occurred for some diseases that may not be reflected in the annual averages used in this analysis. 91   For the vaccine era, data used to derive disease incidence were for years preceding the coronavirus disease 2019 (COVID-19) pandemic. There are multiple factors that may influence the impact of COVID-19 on the incidence of vaccine-preventable diseases. For example, behavior changes caused by nonpharmaceutical interventions, including lockdowns, face-covering use, and other social distancing measures may reduce the transmission of some diseases, while simultaneously causing disruptions to vaccine uptake and coverage for the pediatric population that may adversely impact the prevention of vaccine-preventable diseases. 92 – 94   Future surveillance and survey data will help to understand the impact of the COVID-19 pandemic and other potential “shocks” to the immunization program on the transmission of other vaccine-preventable diseases.

Routine childhood immunization in the United States has continued to reduce the incidence of all targeted vaccine-preventable diseases. In the vaccine era, the incidence of diphtheria, Hib, measles, polio, rubella, and tetanus has been reduced to <1 per 100 000; across all targeted diseases, ∼24 million cases have been averted because of vaccination for the 2019 United States population. Routine immunization remains an effective public health intervention to avert disease; maintenance of high rates of vaccination coverage is necessary for sustained impact.

We thank Kate Lothman of RTI Health Solutions, who provided medical writing support for the development of this manuscript and whose services were funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA.

Ms Talbird, Mr Carrico, and Dr La conceptualized and designed the study, reviewed the literature, interpreted the results, and drafted the initial manuscript; Drs Chen, Nyaku, Carias, and Roberts conceptualized the study and provided input on the study design, secured funding, and interpreted the results; Dr Marshall interpreted the results; and all authors reviewed and revised the manuscript, approved the final manuscript as submitted, and agree to be accountable for all aspects of the work.

COMPANION PAPERS: companions to this article can be found online at http://www.pediatrics.org/cgi/doi/10.1542/peds.2021-056007 and http://www.pediatrics.org/cgi/doi/10.1542/peds.2022-057831 .

Dr La’s current affiliation is GSK, Philadelphia, Pennsylvania.

FUNDING: This study was funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA.

CONFLICT OF INTEREST DISCLOSURES: Ms Talbird and Mr Carrico are employed by RTI Health Solutions, which received funding for the conduct of this study. Dr La was an employee of RTI Health Solutions when this study was conducted and is now an employee and shareholder in the GSK group of companies. Drs Chen, Carias, and Roberts are employees of Merck Sharp and Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, and are shareholders in Merck & Co, Inc. Rahway, NJ. Dr Nyaku was an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ and a shareholder in Merck & Co, Inc, Rahway, NJ when this study was conducted. Dr Marshall has been an investigator on clinical trials funded by GlaxoSmithKline, Merck, Pfizer, Sanofi Pasteur, and Seqirus, and he has received honoraria from these companies for service on advisory boards and/or nonbranded presentations.

active bacterial core

acute otitis media

Centers for Disease Control and Prevention

coronavirus disease 2019

emergency department

Haemophilus influenzae type b

invasive pneumococcal disease

National Notifiable Disease Surveillance System

Supplementary data

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Institute of Medicine (US) Forum on Emerging Infections; Knobler SL, Mahmoud AAF, Pray LA, editors. Biological Threats and Terrorism: Assessing The Science and Response Capabilities: Workshop Summary. Washington (DC): National Academies Press (US); 2002.

Biological Threats and Terrorism: Assessing The Science and Response Capabilities: Workshop Summary.

• Hardcopy Version at National Academies Press

3 Vaccines: Research, Development, Production, and Procurement Issues

Vaccines not only afford the best protection against infectious disease but can serve as strong deterrence factors as well. From a bioterrorist perspective, vaccine-resistant agents are more difficult to engineer than drug-resistant agents. But the potential market has been too small and uncertain to encourage the vaccine industry to make large investments in research, development, and manufacturing of new products. This is alarming considering the eight to ten years often needed to develop a new vaccine, compared to only two to three years to develop a new bioweapon.

Even among the four major vaccine manufacturers, there is insufficient production capacity. It was suggested during this session that in order to move animal and clinical testing forward, incentives need to be established to reduce the current challenges of vaccine development; vaccine production priorities need to be set and a central office or leader authorized to declare top priorities; and the role of the major vaccine manufacturers needs to be facilitated by clear directions and active collaboration between industry and government.

The use of vaccines as a civilian biodefense measure presents multiple challenges that are quite different from those of vaccine use by the military. Much of the challenge is due to the fact that the threats are uncertain and risk-benefit information difficult to assess. The very nature of terrorism produces a high level of uncertainty about what to expect and how to prepare. Additionally, DoD has developed vaccines to be used in normal healthy adults between the ages of 18 and 65, not pediatric, geriatric, immunocompromised or other subsets of the civilian population. Currently, there is no policy in place for immunizing the civilian population as a bioweapons defense measure, however several government agencies are working at unprecedented speed to put the correct policies into place.

The threat of a global pandemic makes smallpox one of the top vaccine priorities. An aggressive clinical development plan is currently in place; its goal is to build the stockpile with enough vaccine to protect the entire country within the year. The vaccine immune globulin (VIG) supply also needs to be expanded. Long-term goals include developing a safer vaccine that can be used in immunocompromised or other at-risk individuals.

Anthrax vaccine is another top priority. As of May 2001, over two million doses of the current anthrax vaccine have been administered to over 500,000 individuals, mostly military personnel. But there is an urgent need for more anthrax vaccine for the immunization of high risk civilian populations, as well as for use in medical management of exposed individuals in conjunction with antibiotics. Currently, there is only one manufacturer of licensed anthrax vaccine, but production is limited because of regulatory problems. Several commercial firms have offered to aid in scaled-up production, but the inherent variability of the manufacturing process and the risk of failure when scaling up so rapidly to such a high volume could create problems. Other mid to long-term anthrax vaccine needs include the development of a second-generation vaccine (e.g., a recombinant protective antigen vaccine) as well as better delivery technologies (e.g., plasmid DNA).

Of lesser importance than vaccines against smallpox and anthrax are vaccines against bacterial infections for which antibiotics can be used and other viral agents that, for the present, seem to be a lesser threat.

A recent independent review of DoD's vaccine acquisition program recommended an integrated approach between DoD and industry and the establishment of a dedicated national vaccine production facility that allows for maximal flexibility and expandable manufacturing capability for the production of various types of vaccines. Whether the proposed facility will be government-owned and contractor-operated or contractor-owned and contractor operated is open for discussion.

Ebola virus provides a useful paradigm for how a molecular-level understanding of the pathogenesis of a virus can be used to develop a new vaccine for an infectious agent that would otherwise be difficult to tackle. This type of molecular genetics approach can reveal possible targets for antiviral drugs as well. For example, recent studies have shown that one of the domains of the ebola virus forms a coil-to-coil structure that is similar to structures found in other viruses, including HIV and influenza. This similarity suggests that the approach being used to develop products for antiviral use against HIV may also be useful for targeting the coil-to-coil region of ebola virus. In fact, targeting this coil-to-coil structure may prove to be a useful general antiviral strategy against many different viruses.

Other vaccine issues that were raised during this session include:

• Improving the usefulness of DNA vaccines, which work well in rodents but not primates.
• Consideration of combination vaccines, for example can we use what we have learned from ebola to make a combination vaccine for use against all hemorrhagic fevers?
• Application of genomics to vaccine research could have, for example if we could use the new high throughput technology to identify genomic biomarkers for vaccine efficacy, then we could use these biomarkers in the future to move forward more quickly toward licensure.
• The need for a strong infrastructure to receive the intense flow of resources that would be expected with a rapid deployment of vaccines in response to out-breaks.
• The need for ways to accelerate vaccine FDA licensure without compromising product safety, for example use of the proposed animal efficacy rule for products that are either not feasible or ethical for human efficacy trials.

VACCINES FOR THREATENING AGENTS: ENSURING THE AVAILABILITY OF COUNTERMEASURES FOR BIOTERRORISM *

Affiliations.

Recent events have brought the subject of vaccines as a defense against bioterrorism into very sharp focus. We have been forced to take action in an area that, for the civilian sector, had previously been largely an academic debate and planning exercise with inadequate definitive action. We have changed from a nation of skeptics concerning the threat of bioterrorism to a nation of believers. Several government agencies are working at unprecedented speed to acquire the needed vaccines and put the correct policies into place for utilization.

However, the use of vaccines for defense against bioterrorism presents multiple challenges that are quite different from the traditional public health use of vaccines for protection against endemic or epidemic diseases. The issues are also quite different from those faced by the armed forces. The appropriate use of vaccines as a defense against bioterrorism presents major challenges in public policy development as well as public education. The ongoing public debates in the media highlight the complexity of the issues and reveal the widespread lack of understanding of the limitations of the current vaccines, especially vaccinia vaccine. For example, there is a call for widespread vaccination against smallpox but, in contrast, there is much misinformation and inappropriate fear about the effects of anthrax vaccine.

Some of the challenges involved with developing vaccine policies for defense against bioterrorism lie in the uncertainty of the threats. In contrast, policies for the use of vaccines against naturally-occurring disease threats are based on a wealth of historical and current epidemiologic information about disease burden and potential. Additionally, there is extensive data available on the safety of widely used vaccines that can be used to confidently assess risk benefit and cost effectiveness. In the case of agents of bioterrorism, however, risk assessment is much more difficult. The great difficulty in obtaining timely and reliable intelligence on the threat of biologic terrorism is a major part of the problem. Critical policy decisions—such as which vaccines will be needed, how large the stockpiles should be, and how the vaccine should be used—are greatly influenced by perceptions of threat. The very nature of terrorism produces a high level of uncertainty about what to expect and prepare for, and there is a wide and varying spectrum of perceived threats.

Obtaining the vaccines that are needed to protect our military and civilian populations depends entirely on effective government action. The potential market has been too small, at least up to the present time, to encourage the vaccine industry to make the large investments needed in research, development and manufacturing facilities. This has changed dramatically in the past two months. Nevertheless, the current situation is a result of past misjudgments, which resulted in insufficient government investment in vaccine research and development, and manufacturing capacity. There is an urgent need for rapid progress in R&D, manufacturing, and licensing processes, all of which are painfully slow processes when done by the usual methodologies.

Vaccines have varying usefulness in defense against bioterrorism. At the top of the list is the need for smallpox vaccine to prevent an outbreak from becoming a catastrophic global pandemic. Both smallpox and anthrax vaccines would be very useful in the medical management of exposed individuals, if the vaccines were readily available and placed in geographic proximity to multiple centers for distribution. Less important to the civilian populations are vaccines against bacterial agents that can be managed with antibiotics and viral agents which, at least for the present, seem to be lesser threats. These include plague, tularemia, hemorrhagic fever viruses, alphavirus encephalidities, Rift Valley fever, and others. However, several of these vaccines should be available for both civilian and military use. A government-owned production facility may be the best means for meeting the needs of these lower priority vaccines which will probably, at least initially, be made in much smaller quantities than smallpox and anthrax vaccines.

Smallpox Vaccine

The acquisition of a smallpox vaccine stockpile for civilian use started in 1999, with an Acambis contract for 40 million doses which now has been increased to 54 million doses. The seed virus was developed by cloning a New York City Board of Health strain derived from Wyeth Dry Vax. Animal model studies indicate that this strain appears to be somewhat less neurovirulent than the parent virus. The clinical development plan is aggressive; the phase I clinical trial should occur, as planned, in the latter part of January 2002. A very rapid procurement action has been in progress over the past weeks. The goal is to stockpile enough smallpox vaccine to protect the entire nation within the year. The response from the vaccine industry has been very heartening and has provided excellent options for utilizing existing manufacturing capacity to meet current requirements. Every effort will be made by CDC, FDA and NIH to assure that these contractors succeed to meet goals, time lines, and regulatory requirements. This will require truly unprecedented coordination and responsiveness by both the manufacturers and the various agencies.

Although the first step in building the smallpox vaccine stockpile is to ensure that vaccine manufacturing is underway, there are several other immediate issues that need to be addressed:

• Vaccination policy issues continue to be controversial. The CDC recently sent out a draft smallpox response plan to the states for comment. The plan calls for primary reliance on ring vaccination—the traditional method—to control an outbreak. The CDC has vaccinated 140 staff members who are most likely to be involved in investigating an outbreak, but no further vaccination with potential responders or health care providers is planned at this time. Laboratory personnel working with pox viruses will, of course, continue to be vaccinated.
• There is a need for more vaccine immune globulin (VIG) or VIG substitute to deal with the consequences of vaccination in immunosuppressed or other high risk subsets of the population. An interagency working group is currently exploring options for expanding the VIG supply.
• There is a need to develop a safer vaccine for use in immunosuppressed individuals, pregnant women, and other individuals for which the current vaccine is contraindicated. This will not only be a challenging research and development problem but also a challenging regulatory problem due to the difficulties in proving efficacy.

Anthrax Vaccine

The current licensed U.S. anthrax vaccine is a filtrate of culture media that contains a high level of PA (protective antigen) absorbed to alum; it probably contains small amounts of the other factors as well. An ongoing study at CDC is testing immunization schedules that involve fewer than the currently recommended six doses for this vaccine. Conventional wisdom has it that the live attenuated vaccines used in Russia and China are too reactogenic to be licensed in the United States. Israeli scientists have published reports on animal studies of experimental vaccines engineered to over-express recombinant protective antigen, but no clinical data are available.

The problems that the manufacturer has had with meeting regulatory criteria have limited the U.S. supply. A small amount of anthrax vaccine has been made available to DHHS by DoD, but that amount is far below what will be needed. There is an urgent need for a sufficient supply of anthrax vaccine for vaccinating high risk populations and for use as post-exposure vaccination in conjunction with antibiotics.

There are several immediate issues that need to be addressed. The production method for current licensed vaccine must be scaled up. Several commercial firms have made informal proposals to do this. However, this is a high risk option because of the inherent variability of the manufacturing process and the high risk of failure when scaling up so rapidly to such a high volume. There needs to be more serious consideration of the applications of the various platform technologies—such as plasmid DNA, viral vectors, and a variety of other delivery technologies—that are being developed within the biotech industry.

Finally, we need to accelerate development of a second generation vaccine. The time to availability could be shortened by overlapping large scale production with clinical trials. It has been suggested that we might have a stockpile of IND recombinant protective antigen (PA) vaccine within 18 months. This may be an achievable goal if all involved interests work in an effective, coordinated manner. A recombinant PA vaccine produced in E. coli will likely be the first to enter a phase I trial.

In order to address this issue of a second generation vaccine, the National Institute of Allergy and Infectious Diseases has put together a team with contractor help. Efforts are underway to gather all available information on ongoing or planned development efforts for a second generation anthrax vaccine, and compile the information in a systematic fashion and convene several advisors to review the resulting data, findings, and policy options. This may involve a major research and development contract program similar to what exists for smallpox vaccine and which will hopefully build on the work that has been done by DoD and DoD-DHHS collaboration. It will hopefully involve some new players as well, including the large vaccine manufacturers. Although it is difficult to predict which particular options will receive aggressive support, there is nonetheless a system now in place that will hopefully pave the way for pursuing an effective strategy in a reasonable period of time. The speed at which a second generation anthrax vaccine is developed will depend on both the underlying science and the responsiveness of the vaccine industry to national needs.

THE DEPARTMENT OF DEFENSE AND THE DEVELOPMENT AND PROCUREMENT OF VACCINES AGAINST DANGEROUS PATHOGENS: A ROLE IN THE MILITARY AND CIVILIAN SECTOR? *

Introduction.

In October 2001, the threat of bioterrorism became a reality. In support of this Forum's efforts to identify the obstacles to preparing an optimal response to bioterrorism—particularly as it relates to the complexities of interaction between private industry, research and public health agencies, regulatory agencies, policymakers, academic researchers, and the public—this paper will highlight emerging opportunities for more effective collaboration as well as scientific and programmatic needs for responding to bioterrorism. The focus of this paper is on the potential opportunities and issues related to Department of Defense (DoD) support for the research, development, and production of biological defense vaccines for the military and civilian populations to protect against bioterrorist threats. This paper will address the following topics:

• Current medical biological defense research and development efforts;
• Current biological defense vaccine capabilities;
• Proposed national biological defense vaccine production facility; and,
• Issues related to the use of biological defense vaccines.

In accordance with Congressional direction, DoD established a Joint Service Chemical and Biological Defense Program in 1994. The vision of the program is to ensure U.S. military personnel are the best equipped and best prepared force in the world for operating in future battlespaces that may feature chemical or biological contamination. The capabilities being developed for the military may have applicability to protection of civilians, especially as the military mission may increasingly support homeland security. Vaccines to protect against biological agents provide one critical capability to protect against the threat.

Medical Biological Defense Research and Development Efforts

The primary research program for the development of biological defense vaccines to protect U.S. forces is the Medical Biological Defense Research Program (MBDRP). In developing countermeasures to biological agents, the MBDRP uses a technical approach that focuses on four areas:

• Identify mechanisms involved in disease process;
• Develop and evaluate products (vaccines or drugs) to prevent or counter effects of toxins, bacteria, viruses, and genetically engineered threats;
• Develop methods to measure effectiveness of countermeasures in animal models that predict human response; and,
• Develop diagnostic systems and reagents

Biological defense vaccines are being developed to counter viruses, toxins, bacteria, and genetically engineered biological threat agents. Research activities start with basic research activities and proceed through the following steps, as research demonstrates successful candidates: (1) construction of the infectious clone, (2) identification of attenuating mutations, (3) construction of vaccine candidates, (4) testing in rodent models, (5) testing in non-human primates, (6) final selection, and (7) formulation. The formulated production may then become a candidate for an Investigational New Drug (IND) application for transition to advanced development and clinical trials, then ultimately licensed production.

An example of a product being developed within the MBDRP is the Next Generation Anthrax Vaccine. In cooperation with the National Institutes of Health, the next generation vaccine will provide greater or equal protection, require fewer doses to produce immunity, and have fewer adverse effects than the current anthrax vaccine. The reduced number of doses would provide greater flexibility to military forces by reducing the time constraint for developing immunity, hence accelerating the time for fielding a protected force. The next generation vaccine is based on recombinant protective antigen (rPA), which binds to the lethal factor (LF) and edema factor (EF) of B. anthracis . The recombinant production technology would eliminate need for spore-forming anthrax, and hence the need for a dedicated production facility. Overall, the next generation anthrax vaccine would decrease production cost, allow a greater range of potential vaccine production facilities, and potentially allow for streamlining of the regulatory approval process.

Another example of a product being developed within the MBDRP is Multiagent Vaccines (MAV) for Biological Warfare (BW) Threat Agents. The MAV project is a proof-of-principle effort to construct a vaccine or vaccine delivery approach that could concurrently immunize an individual against a range of BW threats. Bioengineered and recombinant vaccine technologies will be exploited to achieve vaccines that are directed against multiple agents, yet use the same basic construct for all of the agents. The MAV would be analogous to commercial vaccines (e.g., measles-mumps-rubella) but would exploit new approaches—naked DNA vaccines and replicon vaccines. The MAV would result in a reduced number of doses and thus provide greater flexibility to military forces by reducing the time constraint for developing immunity, hence accelerating the time for fielding a protected force. The MAV also could decrease production cost, allow for greater range of potential vaccine production facilities, and potentially allow for streamlining of the regulatory approval process.

Current Biological Defense Vaccine Capabilities

Joint vaccine acquisition program (jvap).

In order to enable the transition of candidate biological defense vaccines developed under the MBDRP or from other sources, a Prime Systems Contract was awarded in November 1997 to DynPort Vaccine Production Corporation, LLC. The JVAP was established for the purpose of developing, testing, and Food and Drug Administration (FDA) licensure of vaccine candidates, and production and storage of vaccine stockpiles. A major objective of the program is to establish a viable industrial base for vaccine production. The next generation anthrax vaccine (rPA) is one of several vaccines being investigated for development by the JVAP. Other vaccines in advanced development include smallpox, pentavalent Botulinum Toxoid, and tularemia. The Prime Systems Contract also provides options for other biological defense vaccines. Currently, all vaccines in the JVAP are in the development phase.

Anthrax Vaccine Adsorbed (AVA) and the Anthrax Vaccine Immunization Program (AVIP)

The only vaccine currently licensed for use in the United States to protect against anthrax is AVA. AVA is cell-free filtrate, produced by an avirulent strain of Bacillus anthracis . It is manufactured by BioPort Corporation in Lansing, Michigan and procured under a separate contract. It was licensed by the FDA in 1970. Six doses of the vaccine are required for full immunity, including doses at 0, 2, and 4 weeks, 6, 12, and 18 months, followed by an annual booster.

On December 15, 1997, the Secretary of Defense approved the decision to vaccinate all of the U.S. armed forces against anthrax, contingent on the successful completion of four conditions, which were met: supplemental testing of the vaccine; tracking of immunizations; approved operational and communications plans; and review of health and medical aspects of the program by an independent expert. Implementation is determined in accordance with DoD Directive 6205.3, “DoD Immunization Program for Biological Warfare Defense,” November 26, 1993, with complete implementation of the plan contingent upon adequate supply of the licensed vaccine

On May 28, 1998, the Secretary of Defense directed vaccination of the total force. Implementation of this directive was administered by the AVIP. As of May 29, 2001, more than two million doses were administered to more than 500,000 military personnel, with at least 70,000 completing the full six-shot regimen. Since then, there has been only a few who have received vaccinations. As outlined in a June 8, 2001 memorandum, the Secretary of the Army ordered a slowdown in immunization to accommodate delays in release of vaccine pending FDA approval. Implementation of the vaccination continues to designated special mission units, to vaccine manufacturing and DoD personnel conducting anthrax research, and others conducting Congressionally mandated anthrax vaccine research. Detailed information on the status of the AVIP is available at www.anthrax.osd.mil .

What Does Producing a Vaccine Mean?

With no vaccines currently in production under the JVAP and AVA as the only currently available FDA licensed vaccine for protection against BW threats, DoD is evaluating other mechanisms to increase and sustain vaccine production. In order to identify the status of vaccines, it is important to understand the major phases of research, development, and production through which they must proceed. Within different phases of vaccine development and production, there will be varying levels of production risk and overall risk. There are three major phases in the development and production of new vaccines—science and technology base, development and licensure, and licensed production. Following is a summary comparing different activities within each phase.

Production Approach

Within the science and technology phase, production is focused on small quantities and relies on bench top methods, which may include many different approaches, including new state-of-the-art experimental approaches. When a candidate product transitions to the next phase, a best approach is selected (or in some cases two or three promising approaches) and tested for scale up for full scale production. Following licensure, production proceeds at full scale and relies on a single, fixed method. Changes in the method typically require further testing and require approval by the FDA.

Vaccine Recipients

Perhaps the most obvious difference among the phases are the numbers and types of vaccine recipients and the purposes for which they receive the vaccine. Within the science and technology phase, recipients are primarily laboratory animals and include hundreds of animals. The primary purpose for using these recipients is to demonstrate the potential effectiveness of a vaccine candidate, that is proof-of-principle testing. During the development and licensure phase, vaccine recipients are humans, who participate in clinical trials. All recipients are volunteers, who participate in clinical trials that comply with FDA regulations. The focus of these investigations is to determine the safety and efficacy of a vaccine as well as to optimize dosing and scheduling. The final phase is production and includes providing a licensed vaccine to all individuals who may be at risk, in accordance with the FDA license and based on quantities available, for the purpose of providing protection against potential threats. The effected populations could be on the order of millions of individuals.

Production Risk

Production risk during the science and technology phase is moderate since only small quantities can be produced yet only small quantities are needed. Risk is minimized since FDA approval of the product is not required. During the development and licensure phase, production risk is usually high because of the risks involved in scaling up pilot lot product to full scale production. Overall risk is also high because of reliance on and surrogate models or biomarkers to determine efficacy, since law prohibits exposure of humans to chemical or biological agents.

Overall Risk

Overall risk for production of biological defense vaccines will vary depending on the type of vaccine being produced and the policy implemented for immunization. For example, use of a live vaccine (e.g., vaccinia live vaccine) poses risk that inoculated individual may be giving off live vaccinia viruses until scarification has occurred (2–5 days), hence potentially exposing unprotected individuals. Another risk is that low rates of adverse effects may become more apparent in a large scale immunization program than had occurred during testing. For example, if 1,000 people are tested in clinical trials and only one had a serious adverse reaction, there may be hundreds of reactions if the total military force is vaccinated.

Biological Defense Vaccine Development and Production Issues

One of the major factors limiting the availability of biological defense vaccines is the limited interest from the pharmaceutical industry in supporting the production of these vaccines. In contrast to vaccines to support public health needs (e.g., childhood diseases, influenza), most vaccine needs are fulfilled by the private sector. However, the private sector has some challenges in fulfilling public health vaccine needs. The vaccine production industrial base is nearly at full capacity to meet public health priorities. This will pose a challenge for the production of biological defense vaccines if production of biological defense vaccines results in the deferral of production of public health vaccines. Biological defense vaccines are considered specialty biologics and interest is primarily centered on a few small to mid-sized companies. Industry interest is limited in part because of requirements to conduct large, complicated clinical studies to demonstrate safety, immunogenicity, and efficacy (where possible).

Another major factor effecting the timely availability of biological defense vaccines are issues related to compliance with Chapter 21 of the Code of Federal Regulations (21 CFR), Food and Drug Administration (FDA). The specific issue relates to the ability to determine the clinical efficacy of biological defense vaccines. 21 CFR requires that for efficacy to be established, vaccines must be tested in informed, volunteer human subject who are exposed to the condition against which the vaccine is intended to protect. However, legal and ethical constraints prohibit exposing human subjects to biological agents. This constraint plus limited availability of human data for most vaccines mean that under current regulations, biological defense vaccine efficacy cannot be established. In order to address this constraint, FDA published a proposed rule on October 5, 1999 entitled, “New Drug and Biological Products; Evidence Needed to Demonstrate Efficacy of New Drugs for Use Against Lethal or Permanently Disabling Toxic Substances When Efficacy Studies in Humans Ethically Cannot Be Conducted; Proposed Rule.” (FDA rules are available at http://www.fda.gov/cber/rules.htm .) The proposed rule is expected to be finalized during 2002. Under this rule, efficacy may be determined based on data from clinical testing on animals (using at least two different species with preference that non-human primates be one of the species.) Animal data would serve as a surrogate for human data, but there would need to be significant data demonstrating that the effects in animals is related to effects in humans. Without the ability to license vaccines based on surrogate test data, biological defense vaccines would remain as investigational new drugs, which would continue to limit availability.

Proposed National Biological Defense Vaccine Production Facility

Following years of research, development, and efforts to produce biological defense vaccines in sufficient quantities to meet DoD needs, a different approach is currently being planned. In July 2001, DoD submitted a report to Congress detailing biological defense vaccine efforts within DoD. Known as the “Top Report”—because it provides the results of an independent expert panel chaired by Franklin Top, M.D.—this report summarized key shortcomings of current biological defense vaccine acquisition efforts. The report made the following findings and recommendations:

• The scope and complexity of the DoD biological warfare defense requirements are too great for either the DoD or the pharmaceutical industry to accomplish alone,
• The panel recommended a combined integrated approach whereupon DoD would work closely with the vaccine industry and national scientific base, and
• The panel recommended the construction of a government-owned, contractor operated (GOCO) vaccine production facility, which would include production capacity for up to eight vaccines over the next 7–12 years and would cost an estimated $2.4–$3.2 billion over that time.

The report recognized that in order for the GOCO to be successful, it would require long-term government commitment, increased resources, innovative DoD business and program management practices, and effective participation by established pharmaceutical industry leaders in vaccine discovery, licensure, and manufacturing.

The design concept for a GOCO biological defense vaccine production facility would accommodate three bulk vaccine production suites, each with different processes: spore-forming bacteria (for which FDA requires separate facilities), microbial fermentation, and tissue culture (viral vaccines). A modular design would allow flexible and expandable manufacturing capacity for production of DoD-cntical vaccines that are intended for force health protection.

The scale of the facility will be determined in part by the quantity of vaccines to be produced. The assumptions for the production capacity requirement are categorized into three tiers. Tier 1 is the baseline requirement and reflects current production requirements, which is the same as current requirements for the JVAP and AVIP. This tier includes sufficient anthrax vaccine for the entire force (approximately 2.4 million doses). It additionally would require 300,000 Troop Equivalent Doses (TEDs) for other biological defense vaccines. (Troop equivalent dose is defined as the number of vaccine administrations to reach full immunity. Boosters are not included.) Tier 2 would require three million TEDs (2.4 million for U.S. forces + 0.6 million for Commanders Reserve) of each vaccine to be produced to allow for total force protection plus sufficient quantities to support annual requirements due to personnel turnover. This requirement was the basis for the initial GOCO cost estimate. Tier 3 would require approximately 300 million TEDs of each vaccine to support civilian protection for the entire U.S. population.

In order to define the requirements for vaccine production and to ensure that it addresses national, and not just DoD needs, an interagency advisory group has been established. Interagency participation has been led by DoD and the Department of Health and Human Services, with participation from several organizations (including the Office of Homeland Security) to ensure a broad perspective. Federal participation is essential since biological defense vaccine needs are not being met by private industry. No individual department has the sufficient, full-spectrum capability and capacity to support vaccine needs. A national vaccine authority may be essential to ensure interagency needs are addressed not only in the planning phase but also in implementation. The details of the national vaccine authority are being developed, though it is not likely to be established as a new agency.

Issues Related to the Use Of Biological Defense Vaccines

Why vaccinate vaccine use risk management decisions.

BW agents pose high risk to military forces and operations, and at least ten countries are pursuing offensive BW programs. Vaccines are the lowest risk, most effective form of protection against BW threats. Vaccines are more effective and have fewer adverse effects than antibiotics or other treatments following exposure. While masks may provide highly effective protection, they may impede performance and must be worn to provide protection. Vaccines enable force protection by providing continuous, long-lasting protection. In addition, there are currently no real-time BW detection systems available. While there are systems that provide the ability to detection respirable aerosols in near real-time, the best available systems today take 15–45 minutes to identify a specific BW agent.

Vaccines are unusual among medical products in that they are given to healthy people to keep them healthy. Table 3-1 shows several of the vaccines commonly given to protect against infectious diseases and contrasts them with the limited number of biological defense vaccines currently available. Biological agents that may be used as weapons may be naturally occurring but have a very low incidence of natural occurrence (at least in the United States.)

Selected infectious diseases vaccines and biological defense vaccines.

The risk assessment for using biological defense vaccines is different from naturally occurring infectious diseases ( Grabenstein and Wilson 1999 ). Because to vaccinate is based on potential risk of disease outbreak rather than actual incidences. Consequently, a proper risk assessment for biological defense vaccines should not be a trade-off assessment between the actual adverse effects of a vaccine vs. the actual adverse effects of the disease, but the actual adverse effects of a vaccine vs. the potential adverse effects of the disease.

The policies on the use of biological defense vaccines will affect biological defense vaccine manufacturing. The two basic options for immunization are stockpiling vaccines in anticipation of a specific contingency or routine use immunization to ensure continued general readiness. If vaccines are stockpiled, manufacturing must address issues related to maintaining the stockpile as a result of the limited shelf life of some vaccines. Additionally, if vaccines are produced in bulk, once the required quantities are produced, manufacturers must ensure that the facilities remain capable of retaining an FDA facility license when production is not ongoing.

The assessment of potential and actual effects may effect product development. For example, as polio has been significantly reduced as a result of extensive vaccination, the Centers for Disease Control have recommended use of the inactivated polio vaccine (IPV) rather than the oral polio vaccine (OPV). While OPV has greater efficacy, it is also linked with rare occurrences of vaccine-associated paralysis. As cases of polio have been virtually eliminated in the United States, the risk of rare occurrences of adverse effects of the vaccine has exceeded the risk of the occurrences and effects of the disease.

If biological defense vaccines are produced and planned for use—especially among civilians populations—vaccine development criteria may place greater emphasis on vaccine safety than on vaccine effectiveness. Risk assessments may be complicated by the fact that the limited industrial base capacity for biological defense vaccine production will likely result in only one vaccine being available for military and civilian use.

There are other key differences between the military and civilian populations that make risk assessment difficult. One factor is that biological defense vaccines made for the military population are intended for use only in healthy adults. By contrast, the general population will also include significant subgroups for which vaccine safety, efficacy, or dosing information may not be fully understood, including pediatrics, geriatrics, pregnant women, and immune-compromised individuals. Currently there is no policy in place to immunize the civilian population absent a naturally occurring threat. If a licensed biological defense vaccine were available for use by the general population, an immunization policy for civilian use would be needed to address several issues before immunization could begin. Some of the issues that would need to be addressed are, for example, who would be vaccinated—the entire population, or a subgroup? Which subgroup(s)? Those living in specific regions? First responders? If symptoms of biological agent do not appear, would that be interpreted as the absence of a threat or the effectiveness of the defense? Paradoxically, would the demand for the vaccine diminish as the apparent threat also diminished? Civilians may also have greater concerns about the long term safety effects as a result of vaccine use. Additionally, there may be concerns regarding the unknown safety of the use of biological defense vaccines when interacting with other medical products. While there is no adequate basis to assess safety, there is no basis for extraordinary concern ( Institute of Medicine, 1996 ).

Conclusions

The Department of Defense may bring valuable assets to bear to counter the use of biological agents by terrorists. Currently, the DoD mission is focused on responding to threats to the military. Because of DoD's experience in defending against biological threats, DoD will continue to play a role in addressing the threat to the civilian population as well. DoD will continue to work with other agencies, including the new Director of Homeland Security, to determine what role it will play in homeland security, which will be defined in The Federal Response Plan, presidential directives, and other sources.

The availability of vaccine to protect against anthrax and other biological agents is based on several factors. One key factor is sustained resources to transition products from the science and technology base to advanced development. Resources include not only adequate funding, but also trained personnel, which is a critical factor since the biotechnology and pharmaceutical industry as a whole is facing shortages of skilled personnel. A second factor limiting the availability of biological defense vaccines is that they are similar to orphan drugs. There is no commercial incentive for manufacturers to produce vaccines. Federal investment may be required to retain the services and capabilities of the biotechnology and pharmaceutical industry.

While the availability of vaccines is critical, the decisions of whether to vaccinate will remain equally important. Vaccination decisions will continue to have greater physiological consequences than non-medical measures to protection against the threat (e.g., whether to wear masks). The decision will need to weigh the risk of actual low rates of adverse effects against the potential for protecting against catastrophic effects. In making these decisions based on risk, communicating the risk decision will be at least as important as risk assessment. Failure to have a coordinated public policy decision on vaccination support for civilians may result in individuals self-prescribing treatments or failing to comply with recommended guidelines.

APPLICATIONS OF MODERN TECHNOLOGY TO EMERGING INFECTIONS AND DISEASE DEVELOPMENT: A CASE STUDY OF EBOLA VIRUS *

In recent years, increasing attention has been focused on the Ebola virus as a potential public health problem, either from natural or deliberate outbreaks. Like the genetically related Marburg virus, Ebola is a filovirus that causes highly lethal hemorrhagic fever in humans and primates. Infection rapidly progresses from flu-like symptoms to hemorrhage, fever, hypotensive shock, and eventually, in about 50–90% of cases, death ( Peters et al., 1996 ; Peters and Khan, 1999 ). The molecular mechanisms underlying the pathogenicity of the Ebola virus are not well understood, in part because it has emerged only relatively recently (for reviews see Balter, 2000 ; Colebunders and Borchert, 2000 ). There was a series of outbreaks in central Africa in the mid-1970s and again in the 1990s (i.e., the Ivory Coast in 1994, Gabon in 1994–1996, Zaire in 1995, Gulu, Uganda in 2000 and presently in Gabon and the Republic of Congo). Ebola virus infection has appeared once in the United States, in Reston, Virginia. The Reston strain is not pathogenic in humans, and the outbreak was fortunately restricted to non-human primates.

One of the reasons that Ebola is highly lethal is that this virus replicates at an overwhelming rate ( Sanchez et al., 1996a ). Thousands of Ebola virus particles per host cell can completely envelop the cell and take over its entire protein synthetic machinery. We have only recently begun to understand the molecular mechanisms underlying this phenomenon. Although we have a descriptive understanding of the cytopathic effects of viral replication, we lack a clear understanding of how these various changes in cell structure and viability occur. Elucidating these details will be critical for developing vaccines and other antiviral therapies.

Aside from the obvious immediate health threat that would be posed if it were introduced into the population, Ebola virus represents a useful paradigm for dissecting the molecular genetics of a virus. Most of what is known about Ebola pathogenesis is derived from genetic studies of the virus. Although Ebola is very similar to the genetically related Marburg virus, it differs in at least one important respect. The gene that encodes the viral glycoprotein in Ebola generates two gene products, whereas in Marburg, this gene encodes a single protein (Sanchez et al., 1996). One of the gene products is secreted as a soluble 50 to 70 kDa glycoprotein, whereas the other is a full-length 120 to 150 kDa glycoprotein that inserts into the viral membrane ( Volchkov et al., 1995 ; Sanchez et al., 1996). The secreted form was originally believed to serve as an immunological decoy for the full-length glycoprotein, allowing the full-length glycoprotein to attach to the target cell. However, more recent evidence now suggests that this hypothesis is unlikely. Instead, the secreted form appears to inhibit early steps in neutrophil activation and thereby inhibit the host inflammatory response to the virus ( Yang et al., 1998 ). The secreted glycoproteins have been shown to bind quite well to neutrophils, but bind poorly to endothelial cells ( Yang et al., 1998 ). In contrast, the full-length glycoprotein interacts with endothelial cells but binds poorly to neutrophils ( Yang et al., 1998 ). This glycoprotein enables the Ebola virus to recognize and introduce its viral contents into the endothelial cell lining of the blood vessels, as well as monocytes/macrophages, thereby resulting in the cellular damage that is associated with the devastating symptoms of Ebola infection.

Antiviral Targets

Detailed analyses of the mechanisms of viral entry, replication, and cell damage have identified the Ebola glycoprotein 2 (GP2) as a potential antiviral target. In particular, there is a region in the GP2 ectodomain of Ebola virus that forms a coiled coil, or hairpin-like structure similar to what exists in the human immunodeficiency virus (HIV), influenza, respiratory syncytial virus, and a variety of other viruses ( Weissenhorn et al., 1998a , 1998b ; Malashkevich et al., 1999 ). This coiled-coil region contributes to membrane fusion by undergoing conformational changes after the glycoprotein binds to the membrane receptor ( Weissenhorn et al., 1998b ; Watanabe et al., 2000 ). The fact that this structure is conserved in a number of different viruses suggests that it may represent a potential target for antiviral therapy. In fact, a peptide product directed at the analogous structure in HIV has potent antiviral effects and is currently being developed for the clinical treatment of AIDS. This or similar peptides could be useful against many other viruses as well, including Ebola.

Not only does the transmembrane glycoprotein direct the Ebola virus into specific cells, but the glycoprotein itself is also highly toxic to cells. For example, when full-length Ebola glycoprotein is overexpressed in cultured renal epithelial cells, it inserts into the membrane and causes morphological changes and detachment from culture dishes ( Yang et al., 2000 ). This finding suggests that there is a genetic determinant in the glycoprotein that mediates its toxicity and, therefore, might represent another potential target for antiviral therapies. Mapping studies identified a serine-threonine-rich, mucin-like core domain region of the glycoprotein that is required for cytotoxicity in human endothelial cells ( Yang et al., 2000 ). When the mucin-like region of the glycoprotein was deleted, its cytotoxicity was abolished, but protein expression and function remained unchanged ( Yang et al., 2000 ). Every possible open reading frame in the Ebola virus genome has been tested for toxicity, except for the polymerase region. To date, only the glycoprotein has been shown to induce toxic cytopathic changes. However, a better understanding of the detailed molecular mechanism of virus assembly may eventually provide insight into other potential antiviral targets as well.

Vaccine Development

Not only does the glycoprotein play an important role in toxicity, increasing evidence suggests that it also plays an important role in the pathogenesis of Ebola infection. Infection of cultured cells with adenoviral vectors encoding the glycoprotein causes considerable cellular damage that correlates with toxicity. However, overexpression of a glycoprotein that is unable to insert into the cell membrane is not cytotoxic. In fact, injecting adenoviral vectors, or DNA forms of these vectors, into mice, rabbits, and primates actually protects the animals from disease by inducing an effective vaccine response. No human vaccine against Ebola is currently available. However, studies in animals suggest that DNA vaccines, together with replication-defective adenoviral vectors, may be particularly promising. In the DNA vaccination platform, a plasmid expression vector is injected into muscle, thereby enabling muscle to synthesize large quantities of proteins that stimulate the immune system to generate an effective immune response. DNA vaccination technology could greatly simplify the vaccination production process that would otherwise rely on very large-scale plants for making these complex and highly purified proteins. However, although current DNA vaccines work well in rodents, they are not as effective in non-human primates and are even less robust in humans. Thus, one of the important challenges for developing an effective DNA vaccination platform technology is to improve immune responses in non-human primates and humans.

The first successful studies of a DNA vaccine for Ebola virus were carried out in guinea pigs (Xu et al., 1999). Animals that were immunized with sufficient levels of Ebola virus glycoprotein to induce a high-titer antibody response survived infection. Guinea pigs with intermediate levels of titers exhibited an intermediate chance of survival. In contrast, none of the control animals, immunized with vector alone, survived Ebola infection (Xu et al., 1999). “Prime-boost” strategies combine DNA immunization and boosting with adenoviral vectors that encode viral proteins to specifically target dendritic cells. Such DNA vector-viral vector combinations can be very potent. Animals are first immunized with a DNA vector, and typically develop titers ranging from 1:1,500 to about 1:3,500. Following the adenovirus boost, antibody titers increase dramatically, ranging from 1:50,000 to 1:100,000. This far exceeds the minimum threshold that is considered to be necessary for an effective immune response in primates. A modified prime-boost strategy was recently used to immunize cynomolgus macaques against several strains of the Ebola glycoprotein ( Sullivan et al., 2000 ). Several months later, animals were boosted with recombinant adenovirus expressing the Ebola (Zaire) glycoprotein. Control animals received empty vectors consisting of plasmid DNA and ADV-DE1 recombinant adenovirus in a parallel injection regimen. When animals were subsequently challenged with a lethal dose of the Zaire subtype of Ebola virus, all control animals (6 out of 6) exhibited rapid increases in their viral antigen levels and succumbed to infection within seven days. In striking contrast, all animals immunized with the combination DNA-adenovirus vaccine survived Ebola virus challenge (4 out of 4). The level of antibody production and the cellular proliferative response were closely correlated with immunoprotection.

It is of interest to note that vaccines are not only clinically useful, but they can also serve an important function as deterrents against bioweapons. It is much more difficult to engineer vaccine resistance than drug resistance in an organism. Having well-defined, publicly known, and effective vaccines is a critical preventive, or deterrent, strategy. Another benefit of a successful vaccine is that it opens the way for developing novel immunotherapies. In the case of Ebola virus, for example, hyperimmune serum from animals that are protected from the disease is currently being examined, to determine if it can be used during the course of infection as a possible post-exposure therapy.

Role of Genomics in Vaccine Development and Biodefense

Genomic approaches hold enormous potential for vaccine development, and these possibilities are only just beginning to be explored. For example:

• Analysis of global gene expression patterns can facilitate the early identification of both environmental and disease-associated pathogens.
• Gene expression patterns can be used to identify specific genetic susceptibility and resistance markers.
• Biomarkers for vaccine efficacy could be incorporated into the experimental design of efficacy trials, which could then accelerate approval and licensure processes.
• High throughput technology can be used to improve vaccine design, by allowing researchers to readily monitor how specific structural changes in the vaccine affect the cellular response to immunization.

It is possible that enough information will eventually be available and implemented within the technology that simply knowing the sequence of a particular open reading frame will be sufficient to understand how to generate an effective vaccine. Such technology would be useful not only as a defense measure against bioterroism, but also for the prevention or treatment of naturally occurring outbreaks, such as influenza. The influenza virus constantly mutates, but if genetic information could be acquired quickly enough, it may become possible to develop more effective countermeasures.

In conclusion, the process of vaccine development must evolve to become more responsive to the changing needs and emerging outbreaks of society today. In other words, more agile vaccines are needed. Agility includes the ability to rapidly deploy vaccines in the event of an outbreak; to accelerate immunization regimens so that such an outbreak could be effectively managed; and, finally, new technology must be applied to develop better vaccines and to accelerate the development process.

MEETING THE REGULATORY AND PRODUCT DEVELOPMENT CHALLENGES FOR VACCINES AND OTHER BIOLOGICS TO ADDRESS TERRORISM *

The FDA plays an important role in multiple stages of the product development process, from initial clinical studies through licensure, manufacturing and post-marketing studies which may be used to further evaluate safety and effectiveness. For these reasons, FDA is committed to working together with the scientific and clinical communities and with industry and the public to fulfill its regulatory and public health role in facilitating the development of biodefense biologics and therapeutics. Recent and ongoing FDA biodefense-related activities include, for example, meeting with sponsors and sister agencies and departments to encourage interest in developing safe and effective new products needed for public health biodefense, performing research that ultimately facilitates the development of these products; and providing intensive and early interactions with product sponsors to speed their availability.

As with any medical product, bioterrorism products need to be regulated to ensure consistent and objective protection of the public safety. While there is currently a sense of emergency and a set of urgent needs to address, the desire for rapid and innovative responses must not be allowed to compromise the objective assessment of safety and effectiveness. Thus we need a regulatory agency that can step back and provide a more objective perspective. If and when things go wrong in the wake of decision(s) made in a time of crisis, few people will remember the crisis and that the decision was in fact made with the best intentions. The public expects safe and effective products, and safety expectations are especially high for vaccines administered to healthy individuals. Maintaining public confidence in vaccines and medical products, in general, is critical to maintaining overall confidence in our nation's public health programs and leadership in matters extending far beyond bioterrorism. For these reasons, even in difficult times, we must continue to make and communicate clearly the best possible scientific and public health decisions about product development, licensure, availability and use.

Furthermore, bioterrorism is a moving target, not a single disease of predictable epidemiology, and all potential product uses may not be anticipated. This complicates many decisions about product use. For example, a vaccine, such as the licensed anthrax vaccine, which may have been originally studied and used in a limited population effectively and without major safety concerns may raise more significant public concerns about uncommon adverse events, whether coincidental or due to the vaccine, if and when it is administered for similar reasons to hundreds of thousands of people or when unanticipatedly used for post-exposure prophylaxis.

There are several factors that account for why we do not have an adequate supply of vaccines for bioterrorism defense:

Financial Disincentives

• Uncertain markets, especially for potentially more limited use products such as a tularemia or plague vaccine.
• Uncertain longevity of the needs, markets and of resources; short attention spans in government budgeting.
• The fact that vaccines are complex biological products that carry a high risk of uncertainty, unpredictability of success, and financial loss.
• The rigorous safety requirements and low public tolerance of risk—in part because they are often administered to healthy people as a preventative measure—and associated costs of developing biologics.
• The fact that preventive measures are generally undervalued, both perceptually and financially. Vaccines are often expected to be sold for very low prices, and the expected profit for the producer is therefore lower than for other products (e.g., drugs for treatment) competing for the same resources. However, while difficult to model when risks are unclear, it would be interesting to conduct more comprehensive and long-term cost-benefit analyses concerning the personal health impacts and the social and economic costs versus potential benefits of vaccine compared to treatment strategies for specific agents of interest.
• The added cost of the large clinical trials needed to address potential wide use including in diverse populations.
• The presence of advocacy groups with various points of view.
• A fair amount of concern about possible adverse effects of vaccines, ranging from specific disease issues to more general anti-vaccine sentiment on the part of a proportion of the public.
• A mistrust of government and industry
• Product liability issues.

Scientific Challenges

• Lack of historical or recent precedents for vaccines against many pathogens, which makes it difficult to establish good surrogates.
• The potential for genetic or other manipulation of antigenic determinants. (Although this is presently more difficult in many cases to engineer than antibacterial resistance.)
• The potential complications of live vaccine administration to increasing immunocompromised populations.
• The intense flow of resources demanded by urgent perceived needs (sometimes referred to as the “disease du jour” phenomenon), in contrast to the more normal lengthy product development cycle.

The FDA Response

There are several regulatory approaches and mechanisms that the FDA has employed in an attempt to safely speed up product availability and licensure:

• Early and frequent consultation between the sponsor producing the product, the potential end users (e.g., health officials and providers in the military and civilian sectors), and the FDA is very resource-intensive but important. This kind of up-front investment can greatly improve the product development process by identifying creative study designs, recognizing factors that are normally not anticipated in developing a product, and reducing misunderstandings and the likelihood of unwelcome surprises. Early dialogue also increases accountability.
• Emergency use under IND (investigational new drug status) allows rapid access to products that have not yet completed requirements for licensure. INDs require acceptable evidence of safety; a reasonable though not necessarily formally proven scientific basis for efficacy; a favorable nsk:benefit ratio; and an intent to license. While allowing availability of potentially lifesavmg products, a disadvantage to emergency use under this rule is that the product is not licensed, which not only reflects the true scientific limitations of the data but also raises important issues about public perception.
• Fast track processes can speed up the review process for products that will provide meaningful therapeutic benefits compared to existing therapies for serious or life-threatening illnesses. Fast track allows the FDA to review information as it becomes available and as the sponsor submits it.
• Accelerated approval through the use of surrogate end points to demonstrate benefit. The use of CD4 cells for assessment of antiviral treatment of HIV was one of the first surrogates to be approved under this rule. For bioterrorist agents, protective antibody levels for a vaccine or immunoglobulin could serve as potential surrogate end points. Clinical end points can also be utilized. There still must be good post-licensure studies to demonstrate the effects on disease outcomes and to collect additional safety information, and the FDA can place restrictions on use and promotion and even withdraw the product if agreements are violated or the product proves unsafe or ineffective. Thus far, this process has worked fairly well although, once a product is licensed, or if a disease is rare, it may be difficult to obtain patients for studies, and sponsors sometimes are unable or unmotivated to fulfill their commitments. But because most accelerated approval products also receive priority review, this process can allow for rapid approval of a product based on more limited and simpler-to-obtain clinical data than may be the case with large, randomized control trials and/or longer-term endpoints.
• Priority review is applied when a product is considered a significant advance or will be used for serious or life-threatening illness.
• Approval under the forthcoming “Animal Rule” has very important biodefense implications. In fact, the rule is specifically oriented to drugs or biologics that reduce or prevent serious or life threatening conditions caused by exposure to lethal or disabling toxic, chemical, biologic, or nuclear threats. The products should be expected to provide a meaningful therapeutic benefit over existing treatments. Human efficacy trials should either be not feasible or unethical, and the use of the animal efficacy data should be scientifically appropriate. In this proposed rule, the end point should be related to the desired benefit in humans, usually a significant outcome such as mortality or major morbidity. Clinical studies in representative populations are still needed, however, both for establishing pharmacokinetics (including, in the case of many vaccines, immunogenicity) and for assessing safety. Such studies are critical because civilian populations often include vulnerable or pharmacokinetically variable subsets. Finally, similar to the fast track and accelerated approvals, the animal rule has post-marketing and labeling commitments and restrictions. It does not apply if the product could be approved based on any other standard in FDA's regulation. It is a rule of last resort, but it certainly would be applicable to many of the situations that have been described in this workshop.

In addition to its regulatory responsibilities, the FDA's Center for Biologics conducts a significant amount of biodefense-related research, supporting approximately sixty ongoing projects that are directly relevant to identified high threat agents. The general goal is to meet otherwise unmet research needs, often with regulatory implications. Examples include how to better determine potency; defining immune and other correlates of protection; how to make safer and purer products (including characterization of the safety of cell substrates and detection of adventitious agents); better assessment of adverse events and efficacy under conditions of use, and studies which allow the agency to make regulations more scientific and less “defensive.” These types of research can benefit not only the public, but also multiple companies across industry, but are often not performed by a given sponsor as they may not provide a direct and/or immediate benefit. Furthermore, through its research and related scientific interactions, the center maintains the type of cutting edge expertise that is increasingly needed for dealing intelligently and proactively with evolving products and their underlying biotechnology. This expertise and confidence fosters the science-based objectivity necessary for anticipating and/or reacting appropriately to the issues raised during the development of a product which, ultimately, accelerates the regulatory and licensure process.

By maintaining its scientific, objective regulatory stance, the FDA can increase confidence in the likely efficacy of products primarily approved based on surrogate/animal data and reduce the likelihood of serious adverse events. The FDA brings several other unique attributes to the product development process as well, including:

• Knowledge of scientific and industrial capabilities, which is very helpful when it is necessary to identify people with specific expertise. This includes knowledge of emerging technologies which are cross-cutting among diverse products that nobody else may have the opportunity to see; knowledge of manufacturing capabilities; and knowledge of potential new uses of both licensed and investigational products, for example anti-sepsis and immune modulators.
• Day-to-day participation in what it takes to develop a product, including clinical trials, quality assurance, adverse event monitoring, timelines, etc.
• A unique ability to match product needs to industrial and academic capabilities. Much of this is informal, but it can be very helpful in getting the job done well.

However, there are several things that the FDA cannot do. FDA cannot

• provide monetary or tax incentives;
• assure that anyone will make a product;
• sponsor or directly assume the burden of product development, since this would be a conflict of interest;
• provide indemnification or compensation for injuries;

Furthermore, while the prelicensure process can provide reasonable assurances about the degree of safety and effectiveness, FDA cannot

• guarantee absolute safety;
• guarantee human efficacy under field conditions based on non-human data such as animal studies or surrogate endpoints (or, for that matter, based on efficacy observed in the controlled setting of a clinical trial).

In addition to expedited regulatory pathways, as well as orphan drug status, there are several potential incentives—both push and pull—which are outside the mission of FDA but that could be evaluated with respect to their potential to stimulate product development. Push incentives, which could be considered where markets are small or uncertain, could include:

• direct financial awards or contracts;
• tax credits;
• enhanced exclusivity;
• partnerships in product development; and
• research and development assistance to reduce the financial sting and risk of product development.

Possible pull incentives, which are probably more valuable, include:

• known markets;
• longer term financial contracts;
• defining prices that more accurately reflect known and potential public health benefit, which will require more economic discussion and modeling; and
• where possible, developing dual or multiple use products/concepts which can used not just for meeting bioterrorism needs but also for enhancing general public health and medical care.

In summary, FDA and CBER are highly committed to working with multiple partners in and outside of government to help in meeting the challenges posed by bioterrorism. Especially in times of threat and crisis, there is a need for a responsive, yet independent and science-based regulatory process. Relevant research and expertise remains critical in meeting the challenge. Existing laws and regulations can help facilitate product development in a timely manner. There are significant financial disincentives which have and may continue to impede the industrial development of some needed products where markets may be small or uncertain. Careful and open communication with the public about what is and is not known about proposed bioterrorism responses using new and existing products is critical not only in responding to specific threats and protecting the public but also in maintaining confidence in and support for the public health system as a whole.

• MOVING THE VACCINE AGENDA FORWARD: OBSTACLES AND OPPORTUNITIES

The vaccine industry is highly concentrated with only four major manufacturers providing more than three quarters of the market. Even within these four mam manufacturers production capacity may be insufficient for unseen circumstances or urgent need, as has been demonstrated by shortages of DT Acellular pertussis vaccine and pneumococcal conjugate vaccine. Following September 11th, all four major manufacturers expressed interest in biodefense/military vaccines. But how long will patriotism sustain this interest? The industry is both high risk (e.g., the rotavirus vaccine which had to be withdrawn from use) and risk adverse (e.g., certain vaccines for pregnant women have yet to be developed). There are several factors that impede vaccine product development:

• The vaccine industry is market-driven, and the major manufacturers are simply not interested if the market is insufficient.
• The industry is highly regulated, and perceived regulatory hurdles can impede product development.
• Intellectual property conflicts can prevent companies from developing products.
• Negative marketing assessment impedes vaccine production. Marketing departments often make unchecked predictions.
• An uncertain or dubious proof of concept creates reluctance to develop a particular new product.
• Biohazard to personnel, especially with regards to biodefense vaccines, can create reluctance.

The production of an adequate biodefense vaccine supply will depend on many factors:

• Development of biodefense vaccines must be in collaboration with DoD, NIH, CDC, and other agencies with national interests. With regard to the development of a new smallpox vaccine, for example, efficacy is an important issue that requires the use of monkey models for which the vaccine industry must turn to DoD or NIH.
• Development of biodefense vaccines requires better adverse reaction surveillance. With the military anthrax vaccine, for example, initially there were no data to support the claim that the vaccine was indeed safe. New vaccines must have built-in surveillance in order to discredit unsubstantiated claims about adverse reactions based on anecdotal data.
• New vaccine production requires that liability indemnification be guaranteed. One possible solution would be to place these vaccines on a list of compensable vaccines. We need to create a no-fault system which indemnifies companies against non-negligent harm but also provides some relief for injured individuals.
• Access to new technology would likely stimulate more interest in vaccine development. For example, a number of companies have pursued DNA vaccines because they are an interesting new technology which could likely be applied to a number of different targets. After all, the mam role of the vaccine industry is not to conduct basic research but apply basic research to the development of new products.
• Finally, vaccine production priorities need to be set and somebody authorized to say “this is the top priority.” For example, Gary Nabel has presented some very elegant work on an Ebola vaccine. But what does intelligence say is the real risk of Ebola? Should a virus that cannot be spread as an aerosol be considered a priority?

In summary, the major vaccine manufacturers will not be able to provide all of the needed biodefense vaccines. However, they should be asked to play a significant role. That role will be facilitated by clear directions, clear priority setting, and a tight collaboration between industry and government in order to move animal and clinical testing forward.

A. Johnson-Winegar

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This statement reflects the professional view of the author and should not be construed as an official position of the Department of Health and Human Services.

The information provided in this paper reflects the professional view of the author and not an official position of the U.S. Department of Defense.

This statement reflects the professional view of the author and should not be construed as an official position of the National Institute for Allergy and Infectious Diseases, National Institutes of Health.

This statement reflects the professional view of the author and should not be construed as an official position of the Food and Drug Administration.

• Cite this Page Institute of Medicine (US) Forum on Emerging Infections; Knobler SL, Mahmoud AAF, Pray LA, editors. Biological Threats and Terrorism: Assessing The Science and Response Capabilities: Workshop Summary. Washington (DC): National Academies Press (US); 2002. 3, Vaccines: Research, Development, Production, and Procurement Issues.
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In this Page

• VACCINES FOR THREATENING AGENTS: ENSURING THE AVAILABILITY OF COUNTERMEASURES FOR BIOTERRORISM
• THE DEPARTMENT OF DEFENSE AND THE DEVELOPMENT AND PROCUREMENT OF VACCINES AGAINST DANGEROUS PATHOGENS: A ROLE IN THE MILITARY AND CIVILIAN SECTOR?
• APPLICATIONS OF MODERN TECHNOLOGY TO EMERGING INFECTIONS AND DISEASE DEVELOPMENT: A CASE STUDY OF EBOLA VIRUS
• MEETING THE REGULATORY AND PRODUCT DEVELOPMENT CHALLENGES FOR VACCINES AND OTHER BIOLOGICS TO ADDRESS TERRORISM

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