hypothesis on covid 19 vaccine

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals
• Explore content
• About the journal
• Publish with us
• Sign up for alerts
• Published: 12 August 2020

Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults

• Mark J. Mulligan 1 , 2   na1 ,
• Kirsten E. Lyke 3   na1 ,
• Nicholas Kitchin 4   na1 ,
• Judith Absalon   ORCID: orcid.org/0000-0002-1091-520X 5 ,
• Alejandra Gurtman 5 ,
• Stephen Lockhart 4 ,
• Kathleen Neuzil 3 ,
• Vanessa Raabe 1 , 2 ,
• Ruth Bailey 4 ,
• Kena A. Swanson   ORCID: orcid.org/0000-0002-3389-8414 5 ,
• Ping Li 6 ,
• Kenneth Koury 5 ,
• Warren Kalina 5 ,
• David Cooper 5 ,
• Camila Fontes-Garfias 7 ,
• Pei-Yong Shi   ORCID: orcid.org/0000-0001-5553-1616 7 ,
• Özlem Türeci 8 ,
• Kristin R. Tompkins 5 ,
• Edward E. Walsh 9 , 10 ,
• Robert Frenck 11 ,
• Ann R. Falsey 9 , 10 ,
• Philip R. Dormitzer 5 ,
• William C. Gruber 5 ,
• Uğur Şahin   ORCID: orcid.org/0000-0003-0363-1564 8 &
• Kathrin U. Jansen 5  

Nature volume  586 ,  pages 589–593 ( 2020 ) Cite this article

411k Accesses

1017 Citations

3608 Altmetric

Metrics details

• Drug development
• Randomized controlled trials
• Viral infection

A Publisher Correction to this article was published on 19 January 2021

This article has been updated

In March 2020, the World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 1 , a pandemic. With rapidly accumulating numbers of cases and deaths reported globally 2 , a vaccine is urgently needed. Here we report the available safety, tolerability and immunogenicity data from an ongoing placebo-controlled, observer-blinded dose-escalation study (ClinicalTrials.gov identifier NCT04368728) among 45 healthy adults (18–55 years of age), who were randomized to receive 2 doses—separated by 21 days—of 10 μg, 30 μg or 100 μg of BNT162b1. BNT162b1 is a lipid-nanoparticle-formulated, nucleoside-modified mRNA vaccine that encodes the trimerized receptor-binding domain (RBD) of the spike glycoprotein of SARS-CoV-2. Local reactions and systemic events were dose-dependent, generally mild to moderate, and transient. A second vaccination with 100 μg was not administered because of the increased reactogenicity and a lack of meaningfully increased immunogenicity after a single dose compared with the 30-μg dose. RBD-binding IgG concentrations and SARS-CoV-2 neutralizing titres in sera increased with dose level and after a second dose. Geometric mean neutralizing titres reached 1.9–4.6-fold that of a panel of COVID-19 convalescent human sera, which were obtained at least 14 days after a positive SARS-CoV-2 PCR. These results support further evaluation of this mRNA vaccine candidate.

Similar content being viewed by others

COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses

Safety and immunogenicity of the SARS-CoV-2 BNT162b1 mRNA vaccine in younger and older Chinese adults: a randomized, placebo-controlled, double-blind phase 1 study

Immune response to SARS-CoV-2 after a booster of mRNA-1273: an open-label phase 2 trial

In December 2019, a pneumonia outbreak of unknown cause occurred in Wuhan, China. By January 2020, a new coronavirus was identified as the aetiological agent. Within a month, the genetic sequence of the virus became available (MN908947.3). Infections with SARS-CoV-2 and the resulting disease, COVID-19, have spread globally. On 11 March 2020, the WHO declared the COVID-19 outbreak a pandemic 1 . So far, the United States has reported the highest number of cases globally 2 , 3 . No vaccines are currently available to prevent SARS-CoV-2 infection or COVID-19.

The RNA vaccine platform has enabled rapid vaccine development in response to this pandemic. RNA vaccines provide flexibility in the design and expression of vaccine antigens that can mimic the structure and expression of the antigen during natural infection. RNA is required for protein synthesis, does not integrate into the genome, is transiently expressed, is metabolized and eliminated by the natural mechanisms of the body and is therefore considered safe 4 , 5 , 6 , 7 . RNA-based prophylactic infectious-disease vaccines and RNA therapeutic agents have been shown to be safe and well-tolerated in clinical trials. In general, vaccination with RNA elicits a robust innate immune response. RNA directs the expression of the vaccine antigen in host cells and has intrinsic adjuvant effects 8 . A strength of the RNA-vaccine manufacturing platform—irrespective of the encoded pathogen antigen—is the ability to rapidly produce large quantities of vaccine doses against a new pathogen 9 , 10 .

Vaccine RNA can be modified by incorporating 1-methyl-pseudouridine, which dampens innate immune sensing and increases mRNA translation in vivo 11 . The BNT162b1 vaccine candidate that is currently investigated clinically incorporates such nucleoside-modified mRNA and encodes the RBD of the spike protein of SARS-CoV-2, a key target of virus-neutralizing antibodies 12 , 13 , 14 . The RBD antigen expressed by BNT162b1 is modified by the addition of a T4 fibritin-derived foldon trimerization domain to increase its immunogenicity 15 by multivalent display 16 . The proper folding of the RBDs in the resulting protein construct has been confirmed by high resolution structural analysis (A.B.V. et al., manuscript in preparation). The vaccine RNA is formulated in lipid nanoparticles for more-efficient delivery into cells after intramuscular injection 17 . BNT162b1 is one of several RNA-based SARS-CoV-2 vaccine candidates 18 that are studied in parallel for selection to advance to a safety and efficacy trial. Here, we present the available data, up to 14 days after a second dose in adults (18–55 years of age) from an ongoing phase I/II vaccine study with BNT162b1, which is also enrolling adults who are 65–85 years of age (ClinicalTrials.gov identifier, NCT04368728).

Study design and demographics

Between 4 May 2020 and 19 June 2020, 76 participants were screened, and 45 participants were randomized and vaccinated. Per dose level (10 μg and 30 μg), 12 participants were vaccinated with BNT162b1 on days 1 and 21, 12 participants received a 100-μg dose on day 1 and 9 participants received placebo (Fig. 1 ). The study population consisted of healthy male and female participants with a mean age of 35.4 years (range, 19–54 years); 51.1% were male and 48.9% were female. Most participants self-reported as white (82.2%) and non-Hispanic/non-Latinx (93.3%) (Extended Data Table 1 ).

Participants who were not assigned ( n  = 20) were screened but not randomized because enrolment had closed.

Safety and tolerability

In the 7 days after vaccination doses 1 and 2, pain at the injection site was the most-frequent solicited local reaction, reported after the first dose by 58.3% (7 out of 12) in the 10-μg BNT162b1 group, 100.0% (12 out of 12 each) in the 30-μg and 100-μg BNT162b1 groups, and 22.2% (2 out of 9) in the placebo group. After the second dose, pain was reported by 83.3% (10 out of 12) and 100.0% of individuals who received 10 μg and 30 μg BNT162b1, respectively, and by 16.7% of individuals who received the placebo. All local reactions were mild or moderate in severity except for one report of severe pain after the first dose of 100 μg BNT162b1 (Fig. 2 ).

Solicited injection-site (local) reactions were: pain at injection site (mild, does not interfere with activity; moderate, interferes with activity; severe, prevents daily activity; grade 4, emergency room visit or hospitalization) and redness and swelling (mild, 2.0–5.0 cm in diameter; moderate, >5.0–10.0 cm in diameter; severe, >10.0 cm in diameter; grade 4: necrosis or exfoliative dermatitis for redness, and necrosis for swelling). Data were collected with the use of electronic diaries for 7 days after each vaccination.

The most-common systemic events reported in the 7 days after each vaccination in both BNT162b1 and placebo groups were mild to moderate fatigue and headache. Reports of fatigue and headache were more common in the BNT162b1 groups than in the placebo group. In addition, chills, muscle pain and joint pain were reported by individuals who received BNT162b1 but not by individuals who received the placebo. Systemic events increased with dose level and were reported in a greater number of participants after the second dose (10-μg and 30-μg groups). After the first dose, fever (defined as ≥38.0 °C) was reported by 8.3% (1 out of 12) of participants who received 10 μg and 30 μg BNT162b1 and by 50.0% (6 out of 12) of individuals who received 100 μg BNT162b1. After the second dose, 8.3% (1 out of 12) of participants who received 10 μg BNT162b1 and 75.0% (9 out of 12) of participants who received 30 μg BNT162b1 reported fever of ≥38.0 °C. On the basis of the reactogenicity reported after the first dose of 100 μg and the second dose of 30 μg, participants who received an initial 100-μg dose did not receive a second 100-μg dose. Fevers generally resolved within 1 day of onset. No grade 4 systemic events or fever were reported (Fig. 3a, b ). Most local reactions and systemic events peaked by day 2 after vaccination and resolved by day 7.

a , Systemic events and medication use reported within 7 days after vaccination 1 for all dose levels. b , Systemic events and medication use reported within 7 days after vaccination 2 for the 10-μg and 30-μg dose levels. Solicited systemic events were: fatigue, headache, chills, new or worsened muscle pain, new or worsened joint pain (mild, does not interfere with activity; moderate, some interference with activity; severe, prevents daily activity), vomiting (mild, 1–2 times in 24 h; moderate, >2 times in 24 h; severe, requires intravenous hydration), diarrhoea (mild, 2–3 loose stools in 24 h; moderate, 4–5 loose stools in 24 h; severe: 6 or more loose stools in 24 h); grade 4 for all events: emergency room visit or hospitalization; and fever (mild, 38.0–38.4 °C; moderate, 38.5–38.9 °C; severe, 39.0–40.0 °C; grade 4, >40.0 °C). Medication indicates the proportion of participants who reported the use of antipyretic or pain medication. Data were collected with the use of electronic diaries for 7 days after each vaccination.

Adverse events (Extended Data Table 2 ) were reported by 50.0% (6 out of 12) of participants who received either 10 or 30 μg of BNT162b1, 58.3% (7 out of 12) of participants who received 100 μg of BNT162b1, and 11.1% (1 out of 9) of placebo recipients. Two participants reported a severe adverse event: grade 3 fever 2 days after vaccination in the 30-μg group, and sleep disturbance 1 day after vaccination in the 100-μg group. Related adverse events were reported by 25% (3 out of 12 in the 10-μg group) to 50% (6 out of 12 each in the 30-μg and 100-μg groups) of individuals who received BNT162b1 and by 11.1% (1 out of 9) of participants who received the placebo. No serious adverse events were reported.

No grade 1 or greater change in routine clinical laboratory values or laboratory abnormalities were observed for most participants after either of the BNT162b1 vaccinations. Of those with laboratory changes, the largest changes were decreases in the lymphocyte count after the first dose in 8.3% (1 out of 12), 45.5% (5 out of 11) and 50.0% (6 out of 12) of participants who received 10 μg, 30 μg and 100 μg BNT162b1, respectively. One participant each in the 10-μg (8.3% (1 out of 12)) and 30-μg (9.1% (1 out of 11)) groups and 4 participants in the 100-μg group (33.3% (4 out of 12)) had grade 3 decreases in the lymphocyte count. These decreases in lymphocyte count after the first dose were transient and returned to normal 6–8 days after vaccination (Extended Data Fig. 1 ). In addition, grade-2 neutropenia was noted 6–8 days after the second dose in 1 participant each in the 10-μg and 30-μg BNT162b1 groups. These two participants continue to be followed in the study, and no adverse events or clinical manifestations of neutropenia have been reported to date. None of the post-vaccination abnormalities observed were associated with clinical findings.

Immunogenicity

RBD-binding IgG concentrations and SARS-CoV-2-neutralizing titres were assessed at baseline, at 7 and 21 days after the first dose, at 7 days (day 28) and 14 days (day 35) after the second dose of BNT162b1. By 21 days after the first dose (for all three dose levels), geometric mean concentrations (GMCs) of RBD-binding IgG ranged from 534 to 1,778 U ml −1 (Fig. 4a ). In comparison, a panel of 38 SARS-CoV-2 infection and/or COVID-19 convalescent sera drawn at least 14 days after a PCR-confirmed diagnosis from patients with COVID-19 (18–83 years of age) had an RBD-binding IgG GMC of 602 U ml −1 . (Additional information on the convalescent serum panel is included in the Methods.) By 7 days after the second dose (for the 10-μg and 30-μg dose levels), RBD-binding IgG GMCs had increased to 4,813 and to 27,872 U ml −1 , respectively. RBD-binding antibody concentrations among participants who received one dose of 100 μg BNT162b1 did not increase further at 21 days after the first vaccination. In the participants who received the 10-μg and 30-μg doses of BNT162b1, highly elevated RBD-binding antibody concentrations persisted to the last time point evaluated (day 35, 14 days after the second dose). These RBD-binding antibody concentrations were 5,880–16,166 U ml −1 compared to 602 U ml −1 in the panel of human convalescent sera.

Participants in groups of 15 were vaccinated with the indicated dose levels of BNT162b1 ( n  = 12) or with placebo ( n  = 3) on days 1 (all dose levels and placebo) and 21 (10-μg and 30-μg dose levels and placebo). Reponses in individuals who received the placebo for each of the dosing groups are combined. The 28- and 35-day blood samples were obtained 7 and 14 days after the second vaccination. Sera were obtained before vaccination (day 1), and 7, 21, 28 and 35 days after the first vaccination. Human COVID-19 convalescent sera (HCS, n  = 38) were obtained at least 14 days after PCR-confirmed diagnosis and at a time when the donors were asymptomatic. a , GMCs of recombinant RBD-binding IgG. Because the measured antibody concentrations using the Luminex assay are obtained in arbitrary units, they cannot be directly translated into concentrations on a molar or mass basis. The lower limit of quantitation is 1.15. b , The 50% SARS-CoV-2-neutralizing GMTs. Each data point represents a serum sample, and each vertical bar represents a geometric mean with 95% confidence interval. The number above the bars are either the GMC ( a ) or GMT ( b ) for the group. Arrows indicate the timing of vaccination (blood was obtained before vaccination on the vaccination days).

For all doses, small increases in SARS-CoV-2-neutralizing geometric mean titres (GMTs) were observed 21 days after the first dose (Fig. 4b ). Substantially greater serum neutralizing GMTs were achieved 7 days after the second 10-μg and 30-μg dose, reaching 168–267. Neutralizing GMTs further increased by 14 days after the second dose to 180 (10-μg dose level) and 437 (30-μg dose level), compared to 94 for the panel of human convalescent sera. The kinetics and durability of the neutralizing titres are being monitored.

The RNA-based SARS-CoV-2 vaccine candidate BNT162b1, which was administered as 10-μg, 30-μg or 100-μg doses in healthy adults (18–55 years of age), exhibited a tolerability and safety profile consistent with those previously observed for mRNA-based vaccines 5 . A clear dose-level response in elicited neutralizing titres was observed after doses 1 and 2 in participants with a particularly steep dose response between the 10 μg and 30 μg dose levels.

On the basis of the tolerability profile of the first dose at 100 μg and the second dose at 30 μg, participants randomized to the 100-μg group did not receive a second vaccination. Reactogenicity was generally greater after the second dose in the other two dosing levels; however, symptoms were transient and resolved within a few days. Transient decreases in lymphocyte counts (grades 1–3) were observed within a few days after vaccination, and returned to baseline within 6–8 days in all participants. These laboratory abnormalities were not associated with clinical findings. RNA vaccines are known to induce type-I interferon, which has been associated with transient migration of lymphocytes into tissues 19 , 20 , 21 , 22 .

Robust immunogenicity was observed after vaccination with BNT162b1. RBD-binding IgG concentrations were detected at 21 days after the first dose, and these were substantially increased 7 days after the second dose given at day 21. After the first dose, the RBD-binding IgG GMCs (10-μg dose) were similar to those observed in a panel of 38 convalescent human serum samples, obtained at least 14 days after a PCR-confirmed diagnosis of SARS-CoV-2 infection and/or COVID-19. After the first dose, GMCs were similar in the 30-μg and 100-μg groups and higher than those in the panel of human convalescent sera. After the second dose, with 10 μg or 30 μg BNT162b1, the RBD-binding IgG GMCs were around 8.0–50-fold that of the GMC of the convalescent serum panel.

The higher RBD-binding IgG GMC elicited by the vaccine relative to the GMC of the human convalescent serum panel may be attributed, in part, to antibodies that bind to epitopes that are exposed on the RNA-expressed RBD immunogen and the recombinant RBD target antigen of the binding assay but are buried and inaccessible to antibodies on the RBDs that are incorporated into the spikes of SARS-CoV-2 virions. Neutralization provides a measure of the vaccine-elicited antibody response that is more relevant to potential protection. Neutralization titres were measurable after a single vaccination at day 21 for all dose levels. At day 28 (7 days after the second dose), substantial SARS-CoV-2 neutralization titres were observed. The virus-neutralizing GMTs after the second dose of 10 μg and 30 μg were, respectively, 1.8-fold and 2.8-fold the GMT of the convalescent serum panel. By day 35 (14 days after the second dose)—despite a decrease in RBD-binding IgG titres since day 28—neutralizing GMTs continued to increase, to 1.9-fold and 4.6-fold the GMT of the convalescent panel for the 10 μg and 30 μg doses, respectively, which is consistent with affinity maturation.

Assuming that the neutralization titres that are induced by natural infection provide protection from COVID-19, comparing vaccine-induced SARS-CoV-2 neutralization titres to those from sera of convalescent humans provides a benchmark for the magnitude of the vaccine-elicited response and the potential of the vaccine to provide protection. Because the titre at which human neutralizing antibodies are protective remains unknown, these findings are not proof of vaccine efficacy. Efficacy will be determined in a pivotal phase III trial. Because the cohort that received the 100 μg dose level did not receive the booster dose, no data for immunogenicity after a second vaccination at this dose level are available; however, there were no substantial differences in immunogenicity between the 30-μg and 100-μg dose levels after the first dose. This observation suggests that a well-tolerated and immunogenic dose level may be between 10 μg and 30 μg for this vaccine candidate.

Our study had several limitations. Although we used convalescent sera as a comparator, the kind of immunity (T cells versus B cells or both) and level of immunity needed to protect from COVID-19 are unknown. Furthermore, this analysis of available data did not assess immune responses or safety beyond 2 weeks after the second dose of vaccine. Both are important to inform the public health use of this vaccine. Follow-up will continue for all participants and will include collection of serious adverse events for 6 months and COVID-19 infection and multiple additional immunogenicity measurements for up to 2 years. Although our population of healthy adults up to 55 years of age is appropriate for a phase I/II study, it does not accurately reflect the population at highest risk for COVID-19. Adults who are 65 years of age and over have already been enrolled in this study and results will be reported as they become available. Later phases of this study will prioritize enrolment of more diverse populations, including those with chronic underlying health conditions and from racial and ethnic groups that are adversely affected by COVID-19 23 .

The clinical testing of BNT162b1 described here has taken place in the context of a broader, ongoing COVID-19-vaccine-development program. That program includes the clinical testing of three additional vaccine candidates, including candidates that encode the full-length spike protein, and a parallel trial in Germany, in which additional immune responses, including neutralizing responses against variant strains and cell-mediated responses, are being assessed 24 . The resulting comparative data will allow us to address whether a full-length spike immunogen, which presents additional epitopes, is better able to elicit high virus-neutralizing titres that are robust to potential antigenic drift of SARS-CoV-2 than the relatively small RBD immunogen that is encoded by BNT162b1. The clinical findings for the BNT162b1 RNA-based vaccine candidate are encouraging and strongly support accelerated clinical development, including efficacy testing, and at-risk manufacturing to maximize the opportunity for the rapid production of a SARS-CoV-2 vaccine to prevent COVID-19.

Study design

This study was conducted in healthy men and women (who were not pregnant) who were 18–55 years of age to assess the safety, tolerability and immunogenicity of ascending dose levels of various BNT162 mRNA vaccine candidates. In the part of the study reported here, assessment of three dose levels (10 μg, 30 μg or 100 μg) of the BNT162b1 candidate was conducted at two sites in the USA. This study used a sentinel cohort design with progression and dose escalation taking place after review of data from the sentinel cohort at each dose level. The study is registered at ClinicalTrials.gov (NCT04368728). The phase I portion of this study was observer-blinded at the site level. Investigators were blinded to participant-level study intervention assignment; but investigators were not blinded to group-level assignment for the dataset included in this Article.

Eligibility

Key exclusion criteria included individuals with known infection with human immunodeficiency virus, hepatitis C virus or hepatitis B virus; immunocompromised individuals and those with a history of autoimmune disease; and those with increased risk for severe COVID-19, previous clinical or microbiological diagnosis of COVID-19, receipt of medications intended to prevent COVID-19, previous vaccination with any coronavirus vaccine, a positive serological test for SARS-CoV-2 IgM and/or IgG at the screening visit, and a SARS-CoV-2 nucleic acid amplification test-positive nasal swab within 24 h before study vaccination.

The final protocol and informed consent document were approved by institutional review boards for each of the participating investigational centres. This study was conducted in compliance with all International Council for Harmonisation good clinical practice guidelines and the ethical principles of the Declaration of Helsinki. A signed and dated informed consent form was required before any study-specific activity was performed.

In this report, results from the following study primary end points are presented: the proportion of participants who reported solicited local reactions, systemic events and use of antipyretic and/or pain medication within 7 days after vaccination, adverse events and serious adverse events (available up to around 45 days after dose 1), and the proportion of participants with clinical laboratory abnormalities 1 and 7 days after vaccination and grading shifts in laboratory assessments between baseline and 1 and 7 days after dose 1, and between dose 2 and 7 days after dose 2. Secondary end points included: SARS-CoV-2-neutralizing GMTs and SARS-CoV-2 RBD-binding IgG GMCs 7 and 21 days after dose 1, and 7 and 14 days after dose 2.

Study participants were randomly assigned to a vaccine group using an interactive web-based response technology system with each group comprising 15 participants (12 active vaccine recipients and 3 placebo recipients). Participants received two 0.5-ml doses of either BNT162b1 or placebo, administered by intramuscular injection into the deltoid muscle.

BNT162b1 incorporates a good manufacturing practice-grade mRNA drug substance that encodes the trimerized SARS-CoV-2 spike glycoprotein RBD antigen. The coding sequence for the antigen has been deposited with GenBank (accession number, MN908947.3 ). The mRNA is formulated with lipids as the mRNA–lipid nanoparticle drug product. The vaccine was supplied as a buffered-liquid solution for intramuscular injection and was stored at −80 °C. The placebo was a sterile saline solution for injection (0.9% sodium chloride injection, in a 0.5-ml dose).

Safety assessments

Safety assessments included a 4-h observation after vaccination (for the first 5 participants vaccinated in each group), or a 30-min observation (for the remainder of participants) for immediate adverse events. The safety assessments also included self-reporting of solicited local reactions (redness, swelling and pain at the injection site), systemic events (fever, fatigue, headache, chills, vomiting, diarrhoea, muscle pain and joint pain), the use of antipyretic and/or pain medication in an electronic diary for 7 days after vaccination, and the reporting of unsolicited adverse events and serious adverse events after vaccination. Haematology and chemistry assessments were conducted at screening, 1 and 7 days after the first dose, and 7 days after the second dose.

There were protocol-specified safety stopping rules for all sentinel cohort participants. Both an internal review committee and an external data monitoring committee reviewed all safety data. No stopping rules were met before the publication of this report.

Human convalescent serum panel

The 38 human SARS-CoV-2 infection and/or COVID-19 convalescent sera were drawn from participants, who were 18–83 years of age, at least 14 days after PCR-confirmed diagnosis, and at a time when participants were asymptomatic. The mean age of the donors was 45 years of age. Neutralizing GMTs in subgroups of the donors were as follows: ≤55 years of age, 82 ( n  = 29); >55 years of age, 142 ( n  = 9); symptomatic infections, 90 ( n  = 35); asymptomatic infections, 156 ( n  = 3). The antibody titre for the one individual who was hospitalized was 618. The sera were obtained from Sanguine Biosciences, the MT Group and Pfizer Occupational Health and Wellness.

Immunogenicity assessments

For immunogenicity assessments, 50 ml of blood was collected before each study vaccination, at 7 and 21 days after the first dose, and at 7 and 14 days after the second dose. In the RBD-binding IgG assay, a recombinant SARS-CoV-2 RBD containing a C-terminal Avitag (Acro Biosystems, SPD-C82E9) and no foldon domain was bound to streptavidin-coated Luminex microspheres. In brief, 1.25 × 10 7 microspheres/ml were coated with streptavidin by 1-ethyl-3-[3-dimethylaminopropyl] carbodiimide hydrochloride reaction. Recombinant RBD Avitag was coupled to streptavidin beads by incubating for 90 min at room temperature with shaking (35 rpm). Beads were blocked in 1% BSA buffer for 30 min at room temperature. Heat-inactivated serum from participants was diluted 1:500, 1:5,000 and 1:50,000 in assay buffer (PBS with 0.5% BSA, 0.05% Tween-20 and 0.02% sodium azide). Following a 16–20-h incubation at 2–8 °C with shaking (300 rpm), plates were washed three times in a solution containing 0.05% Tween-20. An R-phycoerythrin-conjugated goat anti-human polyclonal antibody (Jackson Labs) was then added to plates for 90 min at room temperature with shaking (300 RPM). Plates were then washed a final time in a solution containing 0.05% Tween-20. Data were captured as median fluorescent intensities using a Luminex reader and converted to U/ml antibody concentrations using a reference standard curve with arbitrary assigned concentrations of 100 U/ml and accounting for the serum dilution factor. The reference standard was composed of a pool of five COVID-19 convalescent serum samples (>14 days after PCR diagnosis). Three dilutions are used to increase the likelihood that at least one result for any sample will fall within the usable range of the standard curve. Assay results were reported in U/ml of IgG. The final assay results are expressed as the GMC of all sample dilutions that produced a valid assay result within the assay range.

The SARS-CoV-2 neutralization assay used a previously described strain of SARS-CoV-2 (USA_WA1/2020) that had been rescued by reverse genetics and engineered by the insertion of an mNeonGreen gene into open-reading frame 7 of the viral genome 25 . This reporter virus generates similar plaque morphologies and indistinguishable growth curves from the wild-type virus. Viral master stocks (2 × 10 7 plaque-forming units per ml) used for the neutralization assay were grown in Vero E6 cells as previously described 25 . When testing patient convalescent serum specimens, the fluorescent neutralization assay produced comparable results as the conventional plaque reduction neutralization assay 26 . In brief, serial dilutions of heat-inactivated sera from participants were incubated with the reporter virus to yield an infection rate of approximately 10–30% of the Vero monolayer) for 1 h at 37 °C before inoculating Vero CCL81 cell monolayers (targeted to have 8,000–15,000 cells per well) in 96-well plates to enable the accurate quantification of infected cells. Total cell counts per well were enumerated by nuclear stain (Hoechst 33342) and fluorescent virally infected foci were detected 16–24 h after inoculation with a Cytation 7 Cell Imaging Multi-Mode Reader (BioTek) with Gen5 Image Prime v.3.09. Titres were calculated in GraphPad Prism v.8.4.2 by generating a four-parameter logistical fit of the percentage neutralization at each serial serum dilution. The 50% neutralization titre was reported as the interpolated reciprocal of the dilution that yielded a 50% reduction in fluorescent viral foci.

Statistical analysis

The sample size for the reported part of the study was not based on statistical hypothesis testing. The primary safety objective was evaluated by descriptive summary statistics for local reactions, systemic events, abnormal haematology and chemistry laboratory parameters, adverse events and serious adverse events after each vaccine dose for each vaccine group. The secondary immunogenicity objectives were descriptively summarized at the various time points. All participants with data available were included in the safety and immunogenicity analyses.

Reporting summary

Further information on research design is available in the  Nature Research Reporting Summary linked to this paper.

Data availability

Upon request, and subject to review, Pfizer will provide the data that support the findings of this study. Subject to certain criteria, conditions and exceptions, Pfizer may also provide access to the related individual anonymized participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information. These data are interim data from an ongoing study for which the database is not locked. Data have not yet been source-verified or subjected to standard quality check procedures that would occur at the time of database lock and may therefore be subject to change.

Change history

19 january 2021.

A Correction to this paper has been published: https://doi.org/10.1038/s41586-020-03098-3.

World Health Organization. WHO Director-General’s Opening Remarks at the Media Briefing on COVID-19 . https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-media-briefing-on-covid-19---7-september-2020 (2020).

Coronavirus Resource Center. COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University (JHU) . https://coronavirus.jhu.edu/map.html (Johns Hopkins University & Medicine, 2020).

World Health Organization. Coronavirus Disease 2019 (COVID-19) Situation Report 154 . https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200622-covid-19-sitrep-154.pdf?sfvrsn=d0249d8d_2 (2020).

Alberer, M. et al. Safety and immunogenicity of a mRNA rabies vaccine in healthy adults: an open-label, non-randomised, prospective, first-in-human phase 1 clinical trial. Lancet 390 , 1511–1520 (2017).

Article   CAS   Google Scholar  

Feldman, R. A. et al. mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials. Vaccine 37 , 3326–3334 (2019).

Kranz, L. M. et al. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy. Nature 534 , 396–401 (2016).

Article   ADS   Google Scholar  

Şahin, U. et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547 , 222–226 (2017).

Petsch, B. et al. Protective efficacy of in vitro synthesized, specific mRNA vaccines against influenza A virus infection. Nat. Biotechnol . 30 , 1210–1216 (2012).

Rauch, S., Jasny, E., Schmidt, K. E. & Petsch, B. New vaccine technologies to combat outbreak situations. Front. Immunol . 9 , 1963 (2018).

Article   Google Scholar  

Şahin, U., Karikó, K. & Türeci, Ö. mRNA-based therapeutics—developing a new class of drugs. Nat. Rev. Drug Discov . 13 , 759–780 (2014).

Karikó, K. et al. Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol. Ther . 16 , 1833–1840 (2008).

He, Y. et al. Receptor-binding domain of SARS-CoV spike protein induces highly potent neutralizing antibodies: implication for developing subunit vaccine. Biochem. Biophys. Res. Commun . 324 , 773–781 (2004).

Zost, S. J. et al. Rapid isolation and profiling of a diverse panel of human monoclonal antibodies targeting the SARS-CoV-2 spike protein. Nat. Med . 26 , 1422–1427 (2020).

Brouwer, P. J. M. et al. Potent neutralizing antibodies from COVID-19 patients define multiple targets of vulnerability. Science 369 , 643–650 (2020).

Güthe, S. et al. Very fast folding and association of a trimerization domain from bacteriophage T4 fibritin. J. Mol. Biol . 337 , 905–915 (2004).

Bachmann, M. F. & Zinkernagel, R. M. Neutralizing antiviral B cell responses. Annu. Rev. Immunol . 15 , 235–270 (1997).

Pardi, N. et al. Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes. J. Control. Release 217 , 345–351 (2015).

Walsh, E. E. RNA-based COVID-19 vaccine BNT162b2 selected for a pivotal efficacy study. Preprint at https://doi.org/10.1101/2020.08.17.20176651 (2020).

Foster, G. R. et al. IFN-α subtypes differentially affect human T cell motility. J. Immunol . 173 , 1663–1670 (2004).

Hopkins, R. J. et al. Randomized, double-blind, placebo-controlled, safety and immunogenicity study of 4 formulations of Anthrax Vaccine Adsorbed plus CPG 7909 (AV7909) in healthy adult volunteers. Vaccine 31 , 3051–3058 (2013).

Regules, J. A. et al. A recombinant vesicular stomatitis virus Ebola vaccine. N. Engl. J. Med . 376 , 330–341 (2017).

Lai, L. et al. Emergency postexposure vaccination with vesicular stomatitis virus-vectored Ebola vaccine after needlestick. J. Am. Med. Assoc . 313 , 1249–1255 (2015).

Stokes, E. K. et al. Coronavirus disease 2019 case surveillance — United States, January 22–May 30, 2020. MMWR Morb. Mortal. Wkly. Rep . 69 , 759–765 (2020).

Şahin, U. et al. Concurrent human antibody and T H 1 type T-cell responses elicited by a COVID-19 RNA vaccine. Preprint at https://doi.org/10.1101/2020.07.17.20140533 (2020).

Xie, X. et al. An infectious cDNA clone of SARS-CoV-2. Cell Host Microbe 27 , 841–848 (2020).

Muruato, A. E. et al. A high-throughput neutralizing antibody assay for COVID-19 diagnosis and vaccine evaluation. Nat. Commun . 11 , 4059 (2020).

Article   ADS   CAS   Google Scholar  

Download references

Acknowledgements

We thank C. Monahan and D. Gantt for writing and editorial support; H. Ma, J. Trammel and K. Challagali for statistical analysis support in the generation of this manuscript; all of the participants who volunteered for this study; A. Kottkamp, R. Herati, R. Pellet Madan, M. Olson, M. Samanovic-Golden, E. Cohen, A. Cornelius, L. Frye, H. Youn, B. Fran, K. Ballani, N. Veling, J. Erb, M. Ali, L. Zhao, S. Rettig, H. Khan, H. Lambert, K. Hu, J. Hyde, M. McArthur, J. Ortiz, R. Rapaka, L. Wadsworth, G. Cummings, T. Robinson, N. Greenberg, L. Chrisley, W. Somrajit, J. Marron, C. Thomas, K. Brooks, L. Turek, P. Farley, S. Eddington, P. Komninou, M. Reymann, K. Strauss, B. Shrestha, S. Joshi, R. Barnes, R. Sukhavasi, M. Lee, A. Kwon, T. Sharp, E. Pierce, M. Criddle, A. Cline, S. Parker, M. Dickey, K. Buschle, A. Cawein, J. L. Perez, H. Seehra, D. Tresnan, R. Maroko, H. Smith, S. Tweedy, A. Jones, G. Adams, R. Malick, E. Worobetz, E. Weaver, L. Zhang, C. Devlin, D. Boyce, E. Harkins Tull, M. Boaz, M. Cruz, C. Rosenbaum, C. Miculka, A. Kuhn, F. Bates, P. Strecker, A. Kemmer-Brück, and the Vaccines Clinical Assay Team and Vaccines Assay Development Team for their assistance during this study. Staffing services were supported in part by an NYU CTSA grant (UL1 TR001445) from the National Center for Advancing Translational Sciences, National Institutes of Health. BioNTech is the sponsor of the study. Pfizer was responsible for the design, data collection, data analysis, data interpretation and writing of the report. The corresponding authors had full access to all of the data in the study and had final responsibility for the decision to submit the data for publication. All study data were available to all authors.

Author information

These authors contributed equally: Mark J. Mulligan, Kirsten E. Lyke, Nicholas Kitchin

Authors and Affiliations

New York University Langone Vaccine Center, New York, NY, USA

Mark J. Mulligan & Vanessa Raabe

New York University Grossman School of Medicine, New York, NY, USA

University of Maryland School of Medicine, Center for Vaccine Development and Global Health, Baltimore, MD, USA

Kirsten E. Lyke & Kathleen Neuzil

Vaccine Research and Development, Pfizer Inc, Hurley, UK

Nicholas Kitchin, Stephen Lockhart & Ruth Bailey

Vaccine Research and Development, Pfizer Inc, Pearl River, NY, USA

Judith Absalon, Alejandra Gurtman, Kena A. Swanson, Kenneth Koury, Warren Kalina, David Cooper, Kristin R. Tompkins, Philip R. Dormitzer, William C. Gruber & Kathrin U. Jansen

Vaccine Research and Development, Pfizer Inc, Collegeville, PA, USA

University of Texas Medical Branch, Galveston, TX, USA

Camila Fontes-Garfias & Pei-Yong Shi

BioNTech, Mainz, Germany

Özlem Türeci & Uğur Şahin

University of Rochester, Rochester, NY, USA

Edward E. Walsh & Ann R. Falsey

Rochester General Hospital, Rochester, NY, USA

Cincinnati Children’s Hospital, Cincinnati, OH, USA

Robert Frenck

You can also search for this author in PubMed   Google Scholar

Contributions

K.U.J., P.R.D., W.C.G., N.K., S.L., A.G., R.B., O.T. and U.Ş. were involved in the design of the overall study and strategy. K.N., M.J.M., E.E.W., R.F. and A.R.F. provided feedback on the study design. W.K., D.C., K.A.S., K.R.T., C.F.-G. and P.-Y.S. performed the immunological analyses. M.J.M., K.N., E.E.W., R.F., A.R.F., K.E.L. and V.R. collected data as study investigators. P.L. and K.K. developed the statistical design and oversaw the data analysis. J.A., K.U.J., P.R.D. and W.C.G. drafted the initial version of the manuscript. All authors reviewed and edited the manuscript and approved the final version.

Corresponding author

Correspondence to Judith Absalon .

Ethics declarations

Competing interests.

N.K., J.A., A.G., S.L., R.B., K.A.S., P.L., K.K., W.K., D.C., K.R.T., P.R.D., W.C.G. and K.U.J. are employees of Pfizer and may hold stock options. U.Ş. and Ö.T. are stock owners, management board members and employees at BioNTech and are inventors on patents and patent applications related to RNA technology. M.J.M., K.E.L., K.N., E.E.W., A.R.F., R.F. and V.R. received compensation from Pfizer for their role as study investigators. C.F.-G. and P.-Y.S. received compensation from Pfizer to perform the neutralization assay.

Additional information

Peer review information Nature thanks Barbra Richardson and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data figures and tables

Extended data fig. 1 post vaccination changes in lymphocyte count over time..

The following time points are shown: dose 1/day 1–3, around 1 day after dose 1; dose 1/day 6–8, around 7 days after dose 1; pre-dose 2, before dose 2; dose 2/day 6–8, around 7 days after dose 2. Symbols denote group means; circle, placebo; plus, 10 μg; cross, 30 μg; triangle, 100 μg. The box-and-whisker plots show the median (centre), first and third quartiles (lower and upper edges), and minimum and maximum values (lower and upper whiskers).

Supplementary information

Supplementary information.

Redacted clinical trial protocol.

Reporting Summary

Rights and permissions.

Reprints and permissions

About this article

Cite this article.

Mulligan, M.J., Lyke, K.E., Kitchin, N. et al. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults. Nature 586 , 589–593 (2020). https://doi.org/10.1038/s41586-020-2639-4

Download citation

Received : 29 June 2020

Accepted : 04 August 2020

Published : 12 August 2020

Issue Date : 22 October 2020

DOI : https://doi.org/10.1038/s41586-020-2639-4

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

This article is cited by

Computational design and engineering of self-assembling multivalent microproteins with therapeutic potential against sars-cov-2.

• Xinyi Jiang
• Qiang Huang

Journal of Nanobiotechnology (2024)

Adjuvants for cancer mRNA vaccines in the era of nanotechnology: strategies, applications, and future directions

• Lei-Ming Cao

Therapeutic induction of antigen-specific immune tolerance

• Jessica E. Kenison
• Nikolas A. Stevens
• Francisco J. Quintana

Nature Reviews Immunology (2024)

Frameworks for transformational breakthroughs in RNA-based medicines

• John R. Androsavich

Nature Reviews Drug Discovery (2024)

Enhancing Immunological Memory: Unveiling Booster Doses to Bolster Vaccine Efficacy Against Evolving SARS-CoV-2 Mutant Variants

• Sovan Samanta
• Jhimli Banerjee
• Sandeep Kumar Dash

Current Microbiology (2024)

By submitting a comment you agree to abide by our Terms and Community Guidelines . If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Help | Advanced Search

Statistics > Methodology

Important: e-prints posted on arXiv are not peer-reviewed by arXiv; they should not be relied upon without context to guide clinical practice or health-related behavior and should not be reported in news media as established information without consulting multiple experts in the field.

Title: Estimation and Hypothesis Testing of Strain-Specific Vaccine Efficacy with Missing Strain Types, with Applications to a COVID-19 Vaccine Trial

Abstract: Statistical methods are developed for analysis of clinical and virus genetics data from phase 3 randomized, placebo-controlled trials of vaccines against novel coronavirus COVID-19. Vaccine efficacy (VE) of a vaccine to prevent COVID-19 caused by one of finitely many genetic strains of SARS-CoV-2 may vary by strain. The problem of assessing differential VE by viral genetics can be formulated under a competing risks model where the endpoint is virologically confirmed COVID-19 and the cause-of-failure is the infecting SARS-CoV-2 genotype. Strain-specific VE is defined as one minus the cause-specific hazard ratio (vaccine/placebo). For the COVID-19 VE trials, the time to COVID-19 is right-censored, and a substantial percentage of failure cases are missing the infecting virus genotype. We develop estimation and hypothesis testing procedures for strain-specific VE when the failure time is subject to right censoring and the cause-of-failure is subject to missingness, focusing on $J \ge 2$ discrete categorical unordered or ordered virus genotypes. The stratified Cox proportional hazards model is used to relate the cause-specific outcomes to explanatory variables. The inverse probability weighted complete-case (IPW) estimator and the augmented inverse probability weighted complete-case (AIPW) estimator are investigated. Hypothesis tests are developed to assess whether the vaccine provides at least a specified level of efficacy against some viral genotypes and whether VE varies across genotypes, adjusting for covariates. The finite-sample properties of the proposed tests are studied through simulations and are shown to have good performances. In preparation for the real data analyses, the developed methods are applied to a pseudo dataset mimicking the Moderna COVE trial.

Submission history

Access paper:.

• Other Formats

References & Citations

• Google Scholar
• Semantic Scholar

BibTeX formatted citation

Bibliographic and Citation Tools

Code, data and media associated with this article, recommenders and search tools.

• Institution

arXivLabs: experimental projects with community collaborators

arXivLabs is a framework that allows collaborators to develop and share new arXiv features directly on our website.

Both individuals and organizations that work with arXivLabs have embraced and accepted our values of openness, community, excellence, and user data privacy. arXiv is committed to these values and only works with partners that adhere to them.

Have an idea for a project that will add value for arXiv's community? Learn more about arXivLabs .

• About This IR
• Scholar Commons

Advancing Education in Quantitative Literacy

Home > Open Access Journals > NUMERACY > Vol. 14 (2021) > Iss. 1

Using COVID-19 Vaccine Efficacy Data to Teach One-Sample Hypothesis Testing

Frank Wang , LaGuardia Community College, CUNY Follow

COVID-19, hypothesis testing, Bayes’s rule, quantitative reasoning

In late November 2020, there was a flurry of media coverage of two companies’ claims of 95% efficacy rates of newly developed COVID-19 vaccines, but information about the confidence interval was not reported. This paper presents a way of teaching the concept of hypothesis testing and the construction of confidence intervals using numbers announced by the drug makers Pfizer and Moderna publicized by the media. Instead of a two-sample test or more complicated statistical models, we use the elementary one-proportion z -test to analyze the data. The method is designed to be accessible for students who have only taken a one-semester elementary statistics course. We will justify the use of a z -distribution as an approximation for the confidence interval of the efficacy rate. Bayes’s rule will be applied to relate the probability of being in the vaccine group among the volunteers who were infected by COVID-19 to the more consequential probability of being infected by COVID-19 given that the person is vaccinated.

https://doi.org/10.5038/1936-4660.14.1.1383

Recommended Citation

Wang, Frank. "Using COVID-19 Vaccine Efficacy Data to Teach One-Sample Hypothesis Testing." Numeracy 14, Iss. 1 (2021): Article 7. DOI: https://doi.org/10.5038/1936-4660.14.1.1383

Creative Commons License

Since January 11, 2021

Included in

Clinical Trials Commons , Higher Education and Teaching Commons

• Journal Home
• About This Journal
• Editorial Board
• Instructions to Authors
• Ethics and Malpractice Statement
• Submit Article
• Most Popular Papers
• Receive Email Notices or RSS

Advanced Search

ISSN: 1936-4660 (Online)

Scholar Commons | About This IR | FAQ | My Account | Accessibility Statement

Privacy Copyright

Viral video of four doctors answering questions about COVID-19 vaccines contains inaccuracies

• Medium Text

Sign up here.

Our Standards: The Thomson Reuters Trust Principles. New Tab , opens new tab

Fact Check Chevron

Fact check: no ‘hostages’ at cal state la pro-palestinian protest, says university.

Administrators were not held hostage in mid-June by pro-Palestinian protesters at a California State University campus building, a university spokesperson said, contrary to social media posts.

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• Clin Infect Dis

Evaluating the Efficacy of Coronavirus Disease 2019 Vaccines

1 Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina, USA

Donglin Zeng

Devan v mehrotra.

2 Biostatistics & Research Decision Sciences, Merck & Co, Inc, North Wales, Pennsylvania, USA

Lawrence Corey

3 Vaccine and Infectious Disease Division, Fred Hutch, Seattle, Washington, USA

Peter B Gilbert

Associated data.

A large number of studies are being conducted to evaluate the efficacy and safety of candidate vaccines against coronavirus disease 2019 (COVID-19). Most phase 3 trials have adopted virologically confirmed symptomatic COVID-19 as the primary efficacy end point, although laboratory-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is also of interest. In addition, it is important to evaluate the effect of vaccination on disease severity. To provide a full picture of vaccine efficacy and make efficient use of available data, we propose using SARS-CoV-2 infection, symptomatic COVID-19, and severe COVID-19 as dual or triple primary end points. We demonstrate the advantages of this strategy through realistic simulation studies. Finally, we show how this approach can provide rigorous interim monitoring of the trials and efficient assessment of the durability of vaccine efficacy.

To increase statistical power and meet vaccine success criteria, we propose to evaluate the efficacy of coronavirus disease 2019 (COVID-19) vaccines by using the dual or triple primary end points of severe acute respiratory syndrome coronavirus 2 infection, symptomatic COVID-19, and severe COVID-19.

There is an urgent need to develop effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus causing the global coronavirus disease 2019 (COVID-19) pandemic. Several candidate vaccines have shown strong immune responses and acceptable safety profiles and have moved rapidly into large-scale phase 3 trials [ 1–8 ]. As of 8 December 2020, 28 phase 3 trials on 13 candidate vaccines had been launched around the world [ 7 ]. Through Operation Warp Speed, the US government selected several of these candidates for phase 3 testing, including mRNA vaccines (mRNA-1273, BNT162b1) that encode the prefusion stabilized SARS-CoV-2 Spike protein [ 2 , 3 ], a recombinant replication-defective chimpanzee adenovirus that expresses a wild-type SARS-CoV-2 Spike protein (AZD1222) [ 4 ], a recombinant, replication-incompetent adenovirus type 26 (Ad26) vector vaccine that encodes a stabilized SARS-CoV-2 Spike protein (Ad26.COV2.S) [ 5 ], a SARS-CoV-2 recombinant stabilized Spike protein vaccine with AS03 adjuvant, and a SARS-CoV-2 recombinant stabilized Spike protein nanoparticle vaccine (SARS-CoV-2 rS) with Matrix-M1 adjuvant [ 6 ].

The vaccine regimens have generally protected against COVID-19 end points in animal models [ 5 ] and have induced binding and neutralizing antibody responses to vaccine-insert Spike proteins in most vaccine recipients, exceeding response levels seen in convalescent sera [ 2–4 , 6 ]. The antibody marker end points are of the types that have been accepted as surrogate end points for many approved vaccines [ 9 ], generating enthusiasm that the vaccines can plausibly confer protection. Interim results from Pfizer/BioNTech, Moderna, and AstraZeneca/Oxford University suggested high vaccine efficacy against COVID-19.

Rapid introduction of effective vaccines in the United States and other countries with high numbers of COVID-19 cases would be a major step toward halting the global pandemic. However, deployment of a noneffective vaccine could actually worsen the pandemic because public acceptance of a COVID-19 vaccine might diminish the implementation of other control measures. Thus, we need speedy and reliable evaluation of the efficacy of COVID-19 vaccines on the basis of clinically relevant end points.

Most phase 3 trials have adopted virologically confirmed symptomatic COVID-19 illness as the primary efficacy end point, although laboratory-confirmed SARS-CoV-2 is also acceptable [ 10 ]. It is possible that a vaccine is much more effective in preventing severe than mild COVID-19. Thus, we should also evaluate the effect of vaccination on severe COVID-19 [ 10 ]. However, a large sample size is likely required for a trial that uses a severe COVID-19 end point.

We propose using SARS-CoV-2 infection, symptomatic COVID-19, and severe COVID-19 as triple primary end points or using SARS-CoV-2 infection and symptomatic COVID-19 or symptomatic COVID-19 and severe COVID-19 as dual primary end points, the specific choice depending on the expected incidence of the 3 events and on the targeted vaccine efficacy for the 3 end points. This approach incorporates more evidence on vaccine efficacy into decision making than using only 1 of the 3 events as the primary end point. It can improve statistical power and increase the likelihood of meeting vaccine success criteria, thus accelerating the discovery and licensure of effective vaccines.

We consider the end points of SARS-CoV-2 infection, symptomatic COVID-19, and severe COVID-19, referring to them as infection, disease, and severe disease, respectively. Suppose that a large number of individuals are randomly assigned to vaccine or placebo and that the trial records whether or not each participant has developed each of the 3 end points by the end of follow-up, as well as their length of follow-up.

We formulate the effect of the vaccine on each of the 3 end points through a Poisson model. Although investigators are mainly interested in the first occurrence of each event, the Poisson modeling approach provides a reasonable approximation to the data because the event rates for all 3 end points are relatively low. We define the vaccine efficacy in terms of the proportionate reduction in the event rate between vaccinated and unvaccinated individuals.

The criteria for claiming that a vaccine is successful should be strict enough to ensure worthwhile efficacy. A vaccine with an efficacy that is higher than 50% can markedly reduce the incidence of COVID-19 among vaccinated individuals and help to build herd immunity. An advisory panel convened by the World Health Organization (WHO) recommended 50% vaccine efficacy for at least 6 months post-vaccination as a minimal criterion to define an efficacious vaccine [ 11 ]. The US Food and Drug Administration (FDA) guidance defines vaccine success criteria as a point estimate of vaccine efficacy at least 50% and the interim-monitoring adjusted lower bound of the 95% confidence interval exceeding 30% [ 10 ]. The FDA guidance criteria do not specify a minimum period of follow-up. However, given the intent of current vaccine development to identify efficacious vaccines within several months of trial initiation, the expectation seems to be reliable evidence for vaccine efficacy over approximately 6 months, consistent with the WHO recommendation.

Many phase 3 trials specify assessment of vaccine efficacy over longer-term follow-up as an important study objective. The FDA guidance document states that “a lower bound ≤ 30% but >0% may be acceptable as a statistical success criterion for a secondary efficacy endpoint, provided that secondary endpoint hypothesis testing is dependent on the success on the primary endpoint.” This statement refers to earlier FDA guidance on a fixed-sequence testing method [ 12 ], under which vaccine efficacy is tested against a sequence of secondary end points in a predefined order where tests of each end point are performed at the same significance level (1-sided type I error of 2.5%), moving to the next end point only after a success on the previous end point. The WHO Solidarity Trial protocol [ 13 ] specifies symptomatic COVID-19 through longer-term follow-up (ideally 12 months or longer) and severe COVID-19 over the same time frame as secondary end points. Following these guidelines and precedents, we consider hypothesis testing of vaccine efficacy over 12 months as a secondary analysis, using a null hypothesis that is less stringent than the 30% null hypothesis value used for the primary analysis, recognizing that it is more difficult for a vaccine to provide 12-month than 6-month protection and that even moderate vaccine efficacy through 12 months could be an important characteristic of a COVID-19 vaccine. In sum, we consider both the assessment of vaccine efficacy against primary end points over 6 months using a 30% null hypothesis and the assessment of vaccine efficacy against the same end points over 12 months using a 0% or 15% null hypothesis.

For each of the 3 end points, we obtain the maximum likelihood estimator for the vaccine efficacy under the Poisson model. In addition, we calculate the score statistic for testing the null hypothesis that the vaccine efficacy is less than a certain lower limit, say 30%, against the alternative hypothesis that the vaccine efficacy is greater than the lower limit. We divide the score statistic by its standard error to create a standard-normal test statistic.

We propose to test all 3 null hypotheses, adjusting the significance threshold for the 3 test statistics to control the overall type I error at the desired level. We consider a vaccine to be successful if any of the 3 null hypotheses is rejected. We describe this multiple testing method in greater detail in Supplementary Appendix 1 , where we also describe a sequential testing procedure to determine which of the 3 null hypotheses should be rejected.

In the sequential testing procedure, we order the 3 hypotheses according to the order of the 3 observed test statistics, from the most extreme observed value to the least extreme. We test the first null hypothesis using the significance threshold from the aforementioned multiple testing procedure. If the first null hypothesis is rejected, we test the second null hypothesis by applying the multiple testing procedure to the remaining 2 test statistics. If the second null hypothesis is rejected, we test the last null hypothesis by using the unadjusted significance threshold.

Clearly, this sequential testing procedure is more powerful than the multiple testing procedure in identifying which end points the vaccine is efficacious against. Both the proposed multiple testing and sequential testing methods properly account for the correlations of the test statistics and thus are more powerful than the conventional Bonferroni correction and related multiplicity adjustments that assume independence of tests.

If the effects of a vaccine are expected to be similar among the 3 end points, then we can enhance statistical power by combining the evidence of the vaccine effects on the 3 end points and performing a single test of overall vaccine efficacy. Specifically, we propose taking the sum of the 3 score statistics and dividing the sum by its standard error to create a standard-normal test statistic. We refer to this method as the combined test ( Supplementary Appendix 1 ); this is in the same vein as combining estimators for a common effect in meta-analysis [ 14 ].

Instead of the triple primary end points, we may consider the dual primary end points of infection and disease if severe disease is very rare or the dual primary end points of disease and severe disease if the vaccine is expected to be only weakly effective against infection. Clearly, the above methods can be modified to test only 2 of the 3 end points.

It is desirable to periodically examine the accumulating data from a phase 3 trial, so that the trial can be terminated if sufficient evidence emerges for a highly effective vaccine or a weakly effective candidate. In order to obtain rigorous stopping boundaries for a trial, we need to derive the joint distribution of the test statistics over interim looks. In Supplementary Appendix 2 , we show that the proposed test statistics over interim looks are jointly normal with the independent increment structure such that standard methods for interim analyses [ 15–18 ] can be applied.

First, we conducted a series of simulation studies to compare the performance of the proposed methods with the use of a single primary end point in evaluating short-term vaccine efficacy. We assigned 27 000 participants to vaccine or placebo at a ratio of 1:1. We assumed that participants were enrolled at a constant rate over a 2-month period and that vaccine efficacy was evaluated 6 months after the first participant was enrolled. We let 1% of the placebo participants acquire infection, 0.6% experience disease, and 0.12% develop severe disease ( Supplementary Appendix 3 ). These event proportions were based on the assumption of annualized incidence of about 1.5% for symptomatic COVID-19 in the placebo group, together with the assumptions that about 40% of infections are asymptomatic and that about 20% of symptomatic COVID-19 cases will be severe. We set the vaccine efficacy for disease, denoted by VE D , to 60%; we set the vaccine efficacy for infection, denoted by VE I , to 40%, 50%, 55%, or 60%; and we set the vaccine efficacy for severe disease, denoted by VE S , to 60%, 70%, 80%, or 90% ( Supplementary Appendix 3 ). For each combination of VE I , VE D , and VE S , we simulated 100 000 datasets. (The average number of each end point can be easily calculated. For example, there are approximately 189 cases of infection, 113 cases of disease, and 23 cases of severe disease under VE I  = VE D  = VE S  = 0.6.) In each dataset, we tested the null hypothesis that the vaccine efficacy is at most 30% against the alternative hypothesis that the vaccine efficacy is greater than 30% at the 1-sided nominal significance level of 2.5%.

Table 1 summarizes the power of various methods for testing the null hypothesis of no worthwhile efficacy (ie, at most 30%). Use of the single end point of disease has 80% power under VE D  = 60%. Indeed, we chose the sample size and disease rate in the placebo group to achieve this power, which is considered the benchmark for other methods. When VE I is equal to or slightly below VE D , the single end point of infection is more powerful than the single end point of disease (eg, 96% vs 80% power under VE I  = VE D  = 60%) because infection is more frequent than disease. Due to low incidence, the single end point of severe disease has poor power unless VE S is very high (eg, 69% and 91% power under VE S  = 80% and 90%, respectively). The combined test for the dual end points of infection and disease and the combined test for the triple end points are substantially more powerful than using disease as the single end point when VE I is similar to VE D (eg, 94% and 93% power for the 2 combined tests vs 80% power for the single end point of disease under VE I  = VE D  = VE S  = 60%). The combined test for the dual end points of disease and severe disease is more powerful than the single end point of disease when VE S is high (eg, 93% vs 80% power under VE S  = 90%). The combined test is more powerful than multiple testing for the dual end points of disease and severe disease, but the opposite is true for the dual end points of infection and disease and the triple primary end points when VE I is low. The proposed multiple-testing method is appreciably more powerful than Bonferroni correction.

Statistical Power (%) for Testing the Null Hypothesis of At Most 30% Vaccine Efficacy Against Infection, Disease, and Severe Disease Over 6 Months

VE I , VE D , and VE S denote, respectively, the vaccine efficacy for infection, disease, and severe disease. I, D, and S denote, respectively, infection, disease, and severe disease. I-D, D-S, and I-D-S denote, respectively, the dual end points of infection and disease, the dual end points of disease and severe disease, and the triple end points of infection, disease, and severe disease. The power pertains to a single test at the 1-sided nominal significance level of 2.5%.

In order to investigate the ability of the proposed methods to detect long-term vaccine efficacy, we extended the follow-up time in the above simulation studies from a maximum of 6 months to a maximum of 12 months. We assumed that the event proportions for infection, disease, and severe disease in the placebo group over the 12-month period doubled those of the 6-month period. We reduced all values of vaccine efficacy by 30% to reflect the waning of vaccine efficacy against each end point over time. We tested the null hypothesis that the vaccine efficacy is 0% vs the alternative hypothesis that the vaccine efficacy is greater than 0% at the nominal significance level of 2.5%. The results are summarized in Table 2 . Again, the proposed methods can substantially improve statistical power.

Statistical Power (%) for Testing the Null Hypothesis of No Vaccine Efficacy Against Infection, Disease, and Severe Disease Over 12 Months

Here, we present a simple and rigorous framework to consider the totality of evidence when evaluating the benefit of a COVID-19 vaccine in reducing SARS-CoV-2 infection, symptomatic COVID-19, and severe COVID-19. The proposed methods are more robust to different scenarios of vaccine efficacy than the use of a single primary end point. We recommend using the combined test to provide an overall assessment of worthwhile vaccine efficacy, then using the sequential test ( Supplementary Appendix 1 ) to determine the end points against which the vaccine is efficacious.

If a vaccine is more effective in preventing severe than mild COVID-19, then using symptomatic COVID-19 and severe COVID-19 as dual primary end points will be more powerful than using either of the 2 events as a single primary end point. If the vaccine efficacy for infection is nearly as high as that for disease, then using infection, symptomatic COVID-19, and severe COVID-19 as triple primary end points will be the most powerful.

Most phase 3 trials have targeted 90% power for detecting 60% (short-term) vaccine efficacy against COVID-19. The actual power may be lower if the vaccine is less effective, the disease incidence is lower than anticipated, or it is an interim analysis. In our simulation studies, using disease as a single primary end point had only 80% power. However, the proposed methods could boost the power to 90%.

The phase 3 trials under Operation Warp Speed have thus far used symptomatic COVID-19 as the sole primary end point, assessing severe COVID-19 as a secondary end point and assessing a composite burden-of-disease end point as either a secondary end point or an exploratory end point [ 19 ]. Under such a plan with a fixed-sequence strategy, hypothesis testing on secondary end points would be permitted only if the result on the primary end point is statistically significant [ 12 ]. In the likely scenarios that VE S is higher than VE D , using disease and severe disease as dual primary end points will be more powerful than using disease alone as the sole primary end point and thus may accelerate the discovery and deployment of effective vaccines.

We focused on vaccine trials for populations enriched with high-risk individuals (eg, front-line healthcare personnel, factory workers, older adults, people with underlying health conditions) in whom the risks for infection, disease, and severe disease are all appreciable. In generally healthy populations, such as college students, the majority of infections are asymptomatic and severe disease is rare. For such settings, power can be maximized by using the dual primary end points of infection and disease.

We used Poisson models instead of Cox proportional hazards models for several reasons. First, there are considerable inaccuracies in determining the event times, especially the infection time; the Poisson modeling approach requires only the knowledge of whether or not the event has occurred by the end of follow-up. Second, Poisson models are simpler than Cox models, both conceptually and computationally. Because the event rates are relatively low, the 2 modeling approaches should provide similar results [ 20 ]. We fitted both Poisson and Cox models in our simulation studies, and the power of the 2 approaches was nearly identical ( Supplementary Appendix 3 ).

We emphasized hypothesis testing based on score statistics. In Supplementary Appendix 4 , we extend our work to general Poisson regression, which can be used to estimate vaccine efficacy, construct confidence intervals, compare multiple vaccines, and accommodate baseline risk factors (eg, age, gender, race, occupation, comorbidity). Baseline risk factors can have a major impact on the occurrences of SARS-CoV-2 infection, symptomatic COVID-19, and severe COVID-19. In addition, some participants in COVID-19 vaccine efficacy trials may become unblinded through the use of available diagnostic tests, and at some point trials may become unblinded. Covariate adjustment in the analysis of vaccine efficacy against end points during post unblinding follow-up is important for minimizing bias due to potential differences in exposure to SARS-CoV-2 between the vaccine and placebo arms.

We developed our methods in order to accelerate the discovery, characterization, and licensure of effective COVID-19 vaccines. An important function of the phase 3 trials is to continue unblinded follow-up of the vaccine and placebo groups after definite evidence of short-term efficacy has emerged. This is done in order to assess the duration of protection and improve precision for assessment of prevention of severe disease as well as for assessment of safety. Duration of vaccine efficacy is an influential parameter in models of population impact of deployed vaccines. An understanding of how vaccine efficacy wanes over time is essential when deciding whether or not booster vaccinations may be required and when estimating the optimal timing of the boosts. The ability of our framework to use the joint distribution of estimators to provide more precise confidence intervals around the 3 vaccine efficacy parameters compared with existing methods (eg, Bonferroni correction) that do not account for the correlation of end points is advantageous regardless of whether 1, 2, or 3 end points are selected as primary.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

ciaa1863_suppl_Supplementary_Materials_1

Acknowledgments. The authors are grateful to Yu Gu and Bridget I. Lin for assistance and to 2 referees for constructive comments.

Financial support. This work was supported by the National Institutes of Health grants R01 AI029168, R01 GM124104, P01 CA142538, and UM1 {"type":"entrez-nucleotide","attrs":{"text":"AI068635","term_id":"3391610","term_text":"AI068635"}} AI068635 .

Potential conflicts of interest. D. M. reports employment and stock ownership in Merck & Co, Inc. All other authors report no potential conflicts.All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

• Type 2 Diabetes
• Heart Disease
• Digestive Health
• Multiple Sclerosis
• Diet & Nutrition
• Supplements
• Health Insurance
• Public Health
• Patient Rights
• Caregivers & Loved Ones
• End of Life Concerns
• Health News
• Thyroid Test Analyzer
• Doctor Discussion Guides
• Hemoglobin A1c Test Analyzer
• Lipid Test Analyzer
• Complete Blood Count (CBC) Analyzer
• What to Buy
• Editorial Process
• Meet Our Medical Expert Board

The FDA Now Wants Fall COVID Vaccines to Target KP.2—But Not All Manufacturers Can Pivot

Morsa Images / Getty Images

Key Takeaways

• The FDA recently updated its recommendations to COVID-19 vaccine manufacturers to make the KP.2 variant the target of fall vaccines, if feasible. Just a week before, the agency recommended the JN.1 variant.
• Pfizer and Moderna, whose mRNA vaccines are easy to update, say their shots will target the KP.2 variant. 
• Novavax, which makes a protein-based vaccine, will not be able to update its formula.

Less than a week after telling COVID-19 vaccine manufacturers to target the JN.1 variant this fall , the Food and Drug Administration (FDA) reversed course. 

The FDA is now asking vaccine manufacturers Pfizer, Moderna, and Novavax to target an offshoot of JN.1, called KP.2, instead—“if feasible.” The shift comes six days after the agency took the advice of its advisory panel and announced early fall vaccines should target JN.1.

While that advisory committee did discuss the emergence of KP.2 before the initial FDA decision to target JN.1, it concluded that the JN.1 vaccines already in development should be sufficient. That was in part to accommodate Novavax, who indicated it wouldn’t be able to pivot to KP.2 for an early fall vaccine rollout. Experts like epidemiologist Katelyn Jetelina, PhD, MPH , believe a vaccine option like Novavax, which doesn’t use mRNA technology like Pfizer and Moderna, is important to offer alongside mRNA vaccines for better uptake. That’s because some people are wary of the newness of mRNA technology. Plus, unlike the mRNA vaccines, the Novavax vaccine does not include an ingredient called PEG , which a small number of people are allergic to. 

Moderna and Pfizer told Verywell in emails that they would be able to comply with the newest FDA request. In a statement, Novavax implied their planned JN.1 vaccine should still do the trick, indicating it’s not possible to update the vaccine platform in time: “Novavax's JN.1 vaccine has demonstrated broad cross-neutralizing antibodies against multiple variant strains, including KP.2” 

Is KP.2 the Right Choice?

Even if Pfizer and Moderna produce KP.2 vaccines in the coming months, that doesn’t guarantee the vaccine will keep pace with COVID, which is constantly mutating. The FDA said that the agency will continue to monitor the safety and effectiveness of the COVID-19 vaccines.

“If a markedly more virulent variant occurs that results in more morbidity or mortality, the agency could consider recommending a change in vaccine composition at any time,” an FDA spokesperson told Verywell. “Although it is true that protein-based vaccines [such as Novavax] currently take longer to manufacture, most COVID-19 vaccines administered in the U.S. have been mRNA-based, and these products could potentially be manufactured relatively quickly.”

What Happens Next?

An advisory committee to the Centers for Disease Control and Prevention (CDC) will determine who should actually get an updated COVID vaccine late next week. While COVID doesn’t have a typical “season” like flu does, it still tends to mutate and spread easily when people are in close quarters during the winter. Therefore, the CDC has begun recommending an annually-updated vaccine, especially for people at risk of severe COVID, each fall. 

Once the CDC makes its recommendations, people who are eligible for another shot should ask their doctors or pharmacists about which vaccine brand is best for them. 

Amesh Adalja, MD, senior scholar at the Johns Hopkins Center for Health Security, suspects a Novavax vaccine that lags behind other options will have the lowest uptake, even though “targeting JN.1 still offers cross-protection, because these variants are all very similar.”

No matter what you choose, though, “when it comes to protection against severe disease, any of the vaccines, including ones against outdated variants, confer that protection,” he added. “It will be important to look at the actual efficacy numbers [for Novavax], but I suspect that it would probably be much better than not getting an updated vaccine if you’re in a high-risk group.”

What This Means For You

A CDC advisory committee will meet next week to determine who should get the vaccine. Your doctor or pharmacist can tell you whether an updated COVID vaccine—and which one—is recommended for you.

The information in this article is current as of the date listed, which means newer information may be available when you read this. For the most recent updates on COVID-19, visit our  coronavirus news page .

By Fran Kritz Kritz is a healthcare reporter with a focus on health policy. She is a former staff writer for Forbes Magazine and U.S. News and World Report.

Advertisement

We finally know why some people seem immune to catching covid-19

Unique cell responses mean some people may be immune to catching the coronavirus, even if they are unvaccinated

By Sonali Roy

19 June 2024

Volunteers have been exposed to the coronavirus that causes covid-19 as part of a scientific study

koto_feja/GETTY

Deliberately exposing people to the coronavirus behind covid-19 in a so-called challenge study has helped us understand why some people seem to be immune to catching the infection.

As part of the first such covid-19 study, carried out in 2021, a group of international researchers looked at 16 people with no known health conditions who had neither tested positive for the SARS-CoV-2 virus nor been vaccinated against it.

How to tell if your immune system is weak or strong

The…

Sign up to our weekly newsletter

Receive a weekly dose of discovery in your inbox! We'll also keep you up to date with New Scientist events and special offers.

To continue reading, subscribe today with our introductory offers

No commitment, cancel anytime*

Offer ends 2nd of July 2024.

*Cancel anytime within 14 days of payment to receive a refund on unserved issues.

Inclusive of applicable taxes (VAT)

Existing subscribers

More from New Scientist

Explore the latest news, articles and features

Long covid linked to signs of ongoing inflammatory responses in blood

What is Disease X and do we need to worry about it?

Does getting even mild covid-19 affect our cognitive skills?

Subscriber-only

Covid-19 vaccines seem to cut the risk of heart attacks and strokes

Popular articles.

Trending New Scientist articles

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings
• My Bibliography
• Collections
• Citation manager

Save citation to file

Email citation, add to collections.

• Create a new collection
• Add to an existing collection

Add to My Bibliography

Your saved search, create a file for external citation management software, your rss feed.

• Search in PubMed
• Search in NLM Catalog
• Add to Search

Catecholamines Are the Key Trigger of COVID-19 mRNA Vaccine-Induced Myocarditis: A Compelling Hypothesis Supported by Epidemiological, Anatomopathological, Molecular, and Physiological Findings

Affiliations.

• 1 Clinical Endocrinology, Corpometria Institute, Brasilia, BRA.
• 2 Clinical Endocrinology, Applied Biology, Inc., Irvine, USA.
• PMID: 35971401
• PMCID: PMC9372380
• DOI: 10.7759/cureus.27883

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine-induced myocarditis is a rare but well-documented complication in young males. The increased incidence of sudden death among athletes following vaccination has been reported and requires further investigation. Whether the risk of myocarditis, a known major cause of sudden death in young male athletes, also increases after coronavirus disease 2019 (COVID-19) infection is unknown. The severity and implications of these critical adverse effects require a thorough analysis to elucidate their key triggering mechanisms. The present review aimed to evaluate whether there is a justification to hypothesize that catecholamines in a "hypercatecholaminergic" state are the key trigger of SARS-CoV-2 mRNA vaccine-induced myocarditis and related outcomes and whether similar risks are also present following COVID-19 infection. A thorough, structured scoping review of the literature was performed to build the hypothesis through three pillars: detection of myocarditis risk, potential alterations and abnormalities identified after SARS-CoV-2 mRNA vaccination or COVID-19 infection and consequent events, and physiological characteristics of the most affected population. The following terms were searched in indexed and non-indexed peer review articles and recent preprints (<12 months): agent, "SARS-CoV-2" or "COVID-19"; event, "myocarditis" or "sudden death(s)" or "myocarditis+sudden death(s)" or "cardiac event(s)"; underlying cause, "mRNA" or "spike protein" or "infection" or "vaccine"; proposed trigger, "catecholamine(s)" or "adrenaline" or "epinephrine" or "noradrenaline" or "norepinephrine" or "testosterone"; and affected population, "young male(s)" or "athlete(s)." The rationale and data that supported the hypothesis were as follows: SARS-CoV-2 mRNA vaccine-induced myocarditis primarily affected young males, while the risk was not observed following COVID-19 infection; independent autopsies or biopsies of patients who presented post-SARS-CoV-2 mRNA vaccine myocarditis in different geographical regions enabled the conclusion that a primary hypercatecholaminergic state was the key trigger of these events; SARS-CoV-2 mRNA was densely present, and SARS-CoV-2 spike protein was progressively produced in adrenal medulla chromaffin cells, which are responsible for catecholamine production; the dihydroxyphenylalanine decarboxylase enzyme that converts dopamine into noradrenaline was overexpressed in the presence of SARS-CoV-2 mRNA, leading to enhanced noradrenaline activity; catecholamine responses were physiologically higher in young adults and males than in other populations; catecholamine responses and resting catecholamine production were higher in male athletes than in non-athletes; catecholamine responses to stress and its sensitivity were enhanced in the presence of androgens; and catecholamine expressions in young male athletes were already high at baseline, were higher following vaccination, and were higher than those in non-vaccinated athletes. The epidemiological, autopsy, molecular, and physiological findings unanimously and strongly suggest that a hypercatecholaminergic state is the critical trigger of the rare cases of myocarditis due to components from SARS-CoV-2, potentially increasing sudden deaths among elite male athletes.

Keywords: athlete; catecholamine; covid-19; hypercatecholaminergic; myocarditis; sars-cov-2; sars-cov-2 mrna vaccine; sars-cov-2 spike protein; sudden death.

Copyright © 2022, Cadegiani et al.

PubMed Disclaimer

Conflict of interest statement

No funding was received for the time taken to develop this hypothesis. The author left financially compensatory work to develop this manuscript.

Figure 1. Pillars and search methods for…

Figure 1. Pillars and search methods for the proposed hypothesis.

Figure 2. Summary of the rationale and…

Figure 2. Summary of the rationale and supporting data for the present hypothesis.

Similar articles

• Cardiac sequelae in athletes following COVID-19 vaccination: evidence and misinformation. Daems JJN, van Hattum JC, Verwijs SM, Bijsterveld NR, Groenink M, Wilde AAM, Pinto YM, Jorstad HT. Daems JJN, et al. Br J Sports Med. 2023 Nov;57(21):1400-1402. doi: 10.1136/bjsports-2023-106847. Epub 2023 Aug 10. Br J Sports Med. 2023. PMID: 37562938
• Circulating Spike Protein Detected in Post-COVID-19 mRNA Vaccine Myocarditis. Yonker LM, Swank Z, Bartsch YC, Burns MD, Kane A, Boribong BP, Davis JP, Loiselle M, Novak T, Senussi Y, Cheng CA, Burgess E, Edlow AG, Chou J, Dionne A, Balaguru D, Lahoud-Rahme M, Arditi M, Julg B, Randolph AG, Alter G, Fasano A, Walt DR. Yonker LM, et al. Circulation. 2023 Mar 14;147(11):867-876. doi: 10.1161/CIRCULATIONAHA.122.061025. Epub 2023 Jan 4. Circulation. 2023. PMID: 36597886 Free PMC article.
• COVID-19 vaccine-associated myocarditis. Morgan MC, Atri L, Harrell S, Al-Jaroudi W, Berman A. Morgan MC, et al. World J Cardiol. 2022 Jul 26;14(7):382-391. doi: 10.4330/wjc.v14.i7.382. World J Cardiol. 2022. PMID: 36161056 Free PMC article. Review.
• Acute cardiac side effects after COVID-19 mRNA vaccination: a case series. Freise NF, Kivel M, Grebe O, Meyer C, Wafaisade B, Peiper M, Zeus T, Schmidt J, Neuwahl J, Jazmati D, Luedde T, Bölke E, Feldt T, Jensen BEO, Bode J, Keitel V, Haussmann J, Tamaskovics B, Budach W, Fischer JC, Knoefel WT, Schneider M, Gerber PA, Pedoto A, Häussinger D, van Griensven M, Rezazadeh A, Flaig Y, Kirchner J, Antoch G, Schelzig H, Matuschek C. Freise NF, et al. Eur J Med Res. 2022 Jun 2;27(1):80. doi: 10.1186/s40001-022-00695-y. Eur J Med Res. 2022. PMID: 35655235 Free PMC article.
• Comorbidities and Symptomatology of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2)-Related Myocarditis and SARS-CoV-2 Vaccine-Related Myocarditis: A Review. Cushion S, Arboleda V, Hasanain Y, Demory Beckler M, Hardigan P, Kesselman MM. Cushion S, et al. Cureus. 2022 Apr 12;14(4):e24084. doi: 10.7759/cureus.24084. eCollection 2022 Apr. Cureus. 2022. PMID: 35573496 Free PMC article. Review.
• COVID-19 mRNA Vaccines: Lessons Learned from the Registrational Trials and Global Vaccination Campaign. Mead MN, Seneff S, Wolfinger R, Rose J, Denhaerynck K, Kirsch S, McCullough PA. Mead MN, et al. Cureus. 2024 Jan 24;16(1):e52876. doi: 10.7759/cureus.52876. eCollection 2024 Jan. Cureus. 2024. Retraction in: Cureus. 2024 Feb 26;16(2):r137. doi: 10.7759/cureus.r137. PMID: 38274635 Free PMC article. Retracted. Review.
• MicroRNAs in Myocarditis-Review of the Preclinical In Vivo Trials. Procyk G, Grodzka O, Procyk M, Gąsecka A, Głuszek K, Wrzosek M. Procyk G, et al. Biomedicines. 2023 Oct 8;11(10):2723. doi: 10.3390/biomedicines11102723. Biomedicines. 2023. PMID: 37893097 Free PMC article. Review.
• Common pathological findings in the heart in COVID-19-related sudden death cases: An autopsy case series. Kyuno D, Tateno M, Ono Y, Magara K, Takasawa K, Takasawa A, Osanai M. Kyuno D, et al. Heliyon. 2023 Oct 2;9(10):e20564. doi: 10.1016/j.heliyon.2023.e20564. eCollection 2023 Oct. Heliyon. 2023. PMID: 37842587 Free PMC article.
• Pheochromocytoma crisis with refractory Acute Respiratory Distress Syndrome (ARDS), Takotsubo syndrome, emergency adrenalectomy, and need for Extracorporeal Membrane Oxygenation (ECMO) in a previously undiagnosed and asymptomatic patient, due to the use of metoclopramide. Xie Y, Zhang A, Qi M, Xiong B, Zhang S, Zhou J, Cao Y. Xie Y, et al. BMC Endocr Disord. 2023 Jul 10;23(1):145. doi: 10.1186/s12902-023-01404-4. BMC Endocr Disord. 2023. PMID: 37430225 Free PMC article.
• The Deceptive COVID-19: Lessons from Common Molecular Diagnostics and a Novel Plan for the Prevention of the Next Pandemic. Mouliou DS. Mouliou DS. Diseases. 2023 Jan 28;11(1):20. doi: 10.3390/diseases11010020. Diseases. 2023. PMID: 36810534 Free PMC article.
• Myocarditis with COVID-19 mRNA vaccines. Bozkurt B, Kamat I, Hotez PJ. Circulation. 2021;144:471–484. - PMC - PubMed
• Myocarditis following immunization with mRNA COVID-19 vaccines in members of the US military. Montgomery J, Ryan M, Engler R, et al. JAMA Cardiol. 2021;6:1202–1206. - PMC - PubMed
• Cardiac MRI assessment of nonischemic myocardial inflammation: state of the art review and update on myocarditis associated with COVID-19 vaccination. Sanchez Tijmes F, Thavendiranathan P, Udell JA, Seidman MA, Hanneman K. Radiol Cardiothorac Imaging. 2021;3:0. - PMC - PubMed
• Cardiac MRI findings of myocarditis after COVID-19 mRNA vaccination in adolescents. Chelala L, Jeudy J, Hossain R, Rosenthal G, Pietris N, White CS. AJR Am J Roentgenol. 2022;218:651–657. - PubMed
• Features of inflammatory heart reactions following mRNA COVID-19 vaccination at a global level. Chouchana L, Blet A, Al-Khalaf M, et al. Clin Pharmacol Ther. 2022;111:605–613. - PMC - PubMed

Publication types

• Search in MeSH

Related information

Linkout - more resources, full text sources.

• Europe PubMed Central
• PubMed Central

Miscellaneous

• NCI CPTAC Assay Portal
• Citation Manager

NCBI Literature Resources

MeSH PMC Bookshelf Disclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

Supreme Court rejects appeals brought by RFK Jr.-founded anti-vaccine group over Covid shots

WASHINGTON — The Supreme Court on Monday turned away two Covid-related appeals brought by Children's Health Defense, the anti-vaccine group founded by independent presidential candidate Robert F. Kennedy Jr.

The decision by the justices not to hear the cases leaves in place lower court rulings against the group.

One case challenged the Food and Drug Administration's emergency authorization of Covid-19 vaccines in December 2020, while the other was brought against Rutgers University in New Jersey over its Covid-19 vaccine mandate.

In the FDA case, the group claimed in court papers that Covid vaccines were "ineffective and lacked proper vetting." The New Orleans-based 5th U.S. Circuit Court of Appeals found that Kennedy's group did not have legal standing to sue.

In the Rutgers dispute, the Philadelphia-based 3rd U.S. Circuit Court of Appeals concluded that the plaintiffs "have not stated any plausible claim for relief."

Kennedy himself took leave from the group in April 2023 to run for president. He failed to make inroads in the Democratic primaries and is now running as an independent.

On the campaign trail he has mostly downplayed his anti-vaccine activity, but in November he spoke at a Children's Health Defense conference.

Kennedy is listed as a lawyer on the Rutgers filing at the Supreme Court despite his leave of absence from the group.

In a separate vaccine-related case, the court also turned away a challenge to Connecticut's decision to repeal a religious exemption for school vaccinations.

Lawrence Hurley covers the Supreme Court for NBC News.

• Election 2024
• Entertainment
• Newsletters
• Photography
• Personal Finance
• AP Investigations
• AP Buyline Personal Finance
• AP Buyline Shopping
• Press Releases
• Israel-Hamas War
• Russia-Ukraine War
• Global elections
• Asia Pacific
• Latin America
• Middle East
• Election Results
• Delegate Tracker
• AP & Elections
• Auto Racing
• 2024 Paris Olympic Games
• Movie reviews
• Book reviews
• Financial Markets
• Business Highlights
• Financial wellness
• Artificial Intelligence
• Social Media

Supreme Court rejects COVID-19 vaccine appeals from nonprofit founded by Robert F. Kennedy Jr.

The U.S Supreme Court is seen, Thursday, June 20, 2024, in Washington. (AP Photo/Mariam Zuhaib)

Visitors pose for photographs outside the U.S. Supreme Court Tuesday, June 18, 2024, in Washington. ( AP Photo/Jose Luis Magana)

• Copy Link copied

WASHINGTON (AP) — The Supreme Court on Monday rejected two appeals related to COVID-19 vaccines from Children’s Health Defense , the anti-vaccine nonprofit founded by independent presidential candidate Robert F. Kennedy Jr.

The justices did not comment in letting stand rulings against the group from the federal appeals courts in New Orleans and Philadelphia.

In a case from Texas, the group joined parents in objecting to the U.S. Food and Drug Administration’s authorization to administer coronavirus vaccines to children. In a case from New Jersey, Children’s Health Defense challenged a Rutgers University requirement , imposed in 2021, for most students to be vaccinated to attend courses on campus, though the school did not force faculty or staff to be vaccinated.

Children’s Health Defense has a lawsuit pending against a number of news organizations, among them The Associated Press, accusing them of violating antitrust laws by taking action to identify misinformation, including about COVID-19 and COVID-19 vaccines. Kennedy took leave from the group when he announced his run for president but is listed as one of its attorneys in the lawsuit.

Follow the AP’s coverage of the U.S. Supreme Court at https://apnews.com/hub/us-supreme-court .

Column: How a blunder by a respected medical journal is fueling an anti-vaccine lie

• Show more sharing options
• Copy Link URL Copied!

The paper published by the respected British Medical Journal earlier this month was eye-opening, to say the least. It questioned why excess deaths in Western countries remained unusually elevated during the COVID-19 pandemic even after vaccines were introduced in 2021.

The implication seemed clear: Rather than reducing cases and deaths, the COVID vaccines had fueled the tragic tide.

That finding was picked up within 48 hours by the Telegraph , a conservative British daily. It leaped across the Atlantic Ocean to the New York Post , a part of the Murdoch media empire, one day later.

Various news outlets have claimed that this research implies a direct causal link between COVID-19 vaccination and mortality. This study does not establish any such link.

— British Medical Journal

Since then, it has been widely spread on social media by the anti-vaccination camp . The repetitions have become increasingly febrile, with some tweets blaming the vaccines for tens of millions of deaths .

Here’s what you need to know: There is no truth to this finding, or to the anti-vaccine camp’s interpretation of the BMJ paper.

Get the latest from Michael Hiltzik

Commentary on economics and more from a Pulitzer Prize winner.

You may occasionally receive promotional content from the Los Angeles Times.

The journal, which posted the paper on its Public Health webpage on June 3, has acknowledged that. In a public statement issued June 6, after the faulty interpretation began to spread worldwide, the journal observed: “Various news outlets have claimed that this research implies a direct causal link between COVID-19 vaccination and mortality. This study does not establish any such link.”

On the contrary, the journal wrote, “Vaccines have, in fact, been instrumental in reducing the severe illness and death associated with COVID-19 infection.”

Alas, the journal’s warning came too late. As I write, the Telegraph’s June 4 tweet hawking its misleading story has received 1.5 million views on X (formerly-Twitter), but the BMJ’s warning notice, only 388,000 views.

These figures are proof positive of the old saw (attributed to Winston Churchill, among many others) that “a lie can make it halfway around the world before the truth can get its boots on.”

Some researchers argue that the original paper, by a team of Dutch scientists, was so shoddy and inconsequential that it should not have been published at all.

Column: Two Rutgers professors are accused of poisoning the debate over COVID’s origins. Here’s why

Richard Ebright and Bryce Nickels of Rutgers have labeled leading virologists fraudsters, perjurers, felons and murderers. Is this how scientific debate is supposed to be conducted?

March 20, 2024

Among the critics is Ariel Karlinsky, an Israeli economist and statistician whose data constituted the core of the Dutch paper. Karlinsky has written that the BMJ should retract the paper and “open an inquiry into what happened there with editors and reviewers.” The journal hasn’t responded.

The use that anti-vaccine propagandists have made of the BMJ paper underscores the dangers of disinformation in public health today.

A recent study in Science analyzed the impact of what its authors labeled “vaccine-skeptical” published content on vaccine refusal. The authors examined anti-vaccine posts on Facebook during the first three months of the COVID vaccine rollout in early 2021.

They found that posts flagged by third-party fact-checkers as false received a relatively minimal 8.7 million views in that period. Posts that were not flagged by fact-checkers but “nonetheless implied that vaccines were harmful to health — many of which were from credible mainstream news outlets — were viewed hundreds of millions of times.”

The flagged posts were more likely to inspire vaccine resistance, the authors wrote. Although unflagged posts individually had less impact on vaccine sentiment, the volume of those posts was so immense that cumulatively they did more damage to vaccine rates.

A single vaccine-skeptical article in the Chicago Tribune — headlined “A healthy doctor died two weeks after getting a COVID vaccine; CDC is investigating why” — was viewed by more than 50 million users on Facebook, more than 20% of the platform’s U.S. user base. That was “more than six times the number of views than all flagged misinformation combined.”

It’s also true that articles that may be innocuous or inconclusive at their core can be distorted and magnified into explicitly anti-vaccine messages by being passed through the anti-vax network.

Something of the kind happened with the BMJ paper. Its language alluding to “serious concerns” about the impact of vaccines and “containment measures” such as lockdowns on excess deaths was transmogrified into the Telegram’s headline stating that “Covid vaccines may have helped fuel rise in excess deaths” and similar language in the New York Post.

Column: RFK Jr. gets around to blaming the Jews

Like other tedious conspiracy-mongers, Robert F. Kennedy Jr. is adding antisemitism to his noxious brew of anti-vaccine lies.

July 17, 2023

The anti-vaxx camp, in repeating these claims, did so after removing or minimizing most of the qualifying language. The headline on a report published by Robert F. Kennedy Jr.’s anti-vaccine organization, Children’s Health Defense, stated that the COVID vaccines “likely fueled rise in excess deaths,” attributing that conclusion to “mainstream media.”

The CHD report cited a blog post by anti-vaxx crusader Meryl Nass, republishing the Telegraph article. The Nass post was headlined “The Dam Has Broken,” suggesting that major news sources were now accepting the dangers of the COVID vaccines.

Nass, by the way, is a Maine physician who has had her license suspended and been fined $10,000 for having prescribed ivermectin and hydroxychloroquine , two medicines known to be useless in treating COVID-19, to patients.

Put it all together, and the evolution of the BMJ paper into a brief claiming that the COVID vaccines are harmful to health plays into the most extreme anti-vaccine disinformation in circulation — such as the incredibly ignorant and dangerous recommendation by Joseph Ladapo, the anti-vaccine quack appointed as Florida surgeon general by Gov. Ron DeSantis, that no one under 65 take a COVID vaccine.

The medical and immunological communities have overwhelmingly concluded that the COVID-19 vaccines have massively reduced hospitalizations and death from the disease. A December 2022 report card by the Commonwealth Fund concluded that after two years of administration, the vaccines had prevented more than 18 million additional hospitalizations and more than 3 million additional deaths.

This is the progress placed at risk by the torrent of anti-vaccine propaganda purveyed by RFK Jr.’s organization and other vaccination opponents.

That brings us back to the BMJ paper and its manifest flaws.

“Excess deaths,” the metric purportedly examined by the Dutch authors, is simply the number of deaths in a country during a given period over and above those that would have been expected “under normal conditions,” based on historical patterns.

In more than 40 Western countries during the three peak years of the pandemic, the authors reported, there were 1.033 million excess deaths in 2020, about 1.26 million in 2021 and 808,000 in 2022.

The authors expressed perplexity about why excess deaths actually rose in 2021, despite the arrival of the vaccines and the implementation of social anti-pandemic measures, and remained elevated the following year. “Government leaders and policymakers,” the authors wrote, “ need to thoroughly investigate underlying causes of persistent excess mortality.”

The authors further commented that “consensus is also lacking in the medical community regarding concerns that mRNA vaccines might cause more harm than initially forecasted.” That’s a gross misrepresentation.

The consensus in the medical community is indisputably that the vaccines are safe and effective. Although they do cause occasional side effects (as do all vaccines), the health threats caused by COVID-19 itself are immeasurably more hazardous.

The truth is that the factors causing elevated excess mortality throughout the pandemic are not mysterious, but well-understood. Statistical data scientist Jeffrey S. Morris of the University of Pennsylvania put his finger on some of the most important .

Column: Meet the most dangerous quack in America

Florida Surgeon Gen. Dr. Joseph A. Ladapo is advising people to avoid the most effective COVID vaccines, just as a surge in disease cases gets worse.

Jan. 9, 2024

One is that far more people were exposed to COVID-19 in 2021 than in 2020. By the end of 2020, according to the World Health Organization, there were about 10,000 cases and about 238 deaths per million population; one year later, there 35,186 cases and 683 deaths per million. Furthermore, the COVID variants that appeared in 2021 — the Delta and Omicron waves — were far more transmissible and virulent (causing more hospitalization and death) than the initial variants.

Also in 2021, many of the most stringent anti-pandemic measures implemented in 2020 — school closings, lockdowns, business closures, mask mandates — were getting lifted by local authorities. This raised the level of exposure to the virus in the general public.

As for the vaccines, the Dutch authors seemed to conjecture that vaccination happened as if with the turning of a switch in January 2021. Of course that’s untrue.

Figures compiled by the independent statistical clearinghouse Our World in Data — which were used by the Dutch researchers — show that the vaccines were rolled out only gradually through 2021. By mid-year, only about 20% of the population of countries that submitted figures had received even a single dose; by the end of 2021, nearly 50% were still unvaccinated.

“Even with a 100% effective vaccine, we would have seen high levels of morbidity and mortality from COVID-19 in 2021, leading to high number of excess deaths,” Morris observes.

Statisticians have shown that the peaks and valleys of excess mortality during the pandemic coincide almost exactly with the emergence and peaks of Delta, Omicron and other variants of concern, indicating that excess deaths are almost certainly the result of COVID, not the COVID vaccines.

One other data point: As the British actuary Stuart McDonald points out , of the 47 countries surveyed by the Dutch researchers, the 10 with the lowest rates of excess deaths are those with the highest vaccine uptakes, such as Canada (83% vaccination rate in 2022 and only 5% excess deaths in 2020-22) and Germany (76% vaccinated and 6% excess deaths). By contrast, those with the lowest vaccination rates tended to have the most excess deaths, including North Macedonia (40% vaccinated at 28% excess deaths) and Albania (45% vaccinated, 24% excess deaths).

Is there a remedy for claptrap like the BMJ article? Sadly, very little. Qualified scientists and epidemiologists have risen up almost as one to expose the flaws of the BMJ paper. But the first line of defense against disinformation must be scientific journals themselves. In this case, if not for the first time, the BMJ has failed its responsibility for being a gatekeeper of sound science.

Latest from Michael Hiltzik

Column: this huge insurer got caught breaking a law protecting contraceptive access, but its fine is a joke, column: how anti-union southern governors may be violating federal law, column: this gop-leaning political polling firm has turned into a purveyor of anti-vaccine propaganda, more to read.

Column: Disinformation is a public health crisis. Here’s how scientists and doctors are fighting it

Feb. 22, 2024

Column: A bogus new attack on COVID vaccines from Texas’ least credible politician

Dec. 6, 2023

Column: Why anti-vaxxers are pretending a flawed study on vaccine deaths has been vindicated

Oct. 24, 2023

Pulitzer Prize-winning journalist Michael Hiltzik has written for the Los Angeles Times for more than 40 years. His business column appears in print every Sunday and Wednesday, and occasionally on other days. Hiltzik and colleague Chuck Philips shared the 1999 Pulitzer Prize for articles exposing corruption in the entertainment industry. His seventh book, “Iron Empires: Robber Barons, Railroads, and the Making of Modern America,” was published in 2020. His forthcoming book, “The Golden State,” is a history of California. Follow him on Twitter at twitter.com/hiltzikm and on Facebook at facebook.com/hiltzik.

More From the Los Angeles Times

Will Google strike a deal with California news outlets to fund journalism?

Nvidia rebounds, and it’s back to masking losses for the rest of Wall Street

June 25, 2024

Meat processing plant fined nearly $400,000 over child labor violations

Hollywood Inc.

Paramount leaders address ‘simply unacceptable’ profit declines after sale talks collapse

• COVID 19 variant

COVID-19 'FLiRT' subvariants on the rise across the US. Here's what to know

U.S. health officials are keeping an eye on the so-called "FLiRT" COVID-19 subvariants as the U.K. sees a rise in COVID hospitalizations.

"Our vigilance should increase as we see cases rise, primarily driven by increased travel and social gatherings typical of the summer months," said Dr. John Brownstein, an epidemiologist at Boston Children's Hospital.

Here's what to know.

What is the so-called FLiRT variant?

The FLiRT family, including KP.2 and JN.1, are strains of the Omicron subvariant. JN.1 has been the dominate COVID-19 strain as of late December of 2023.

The FLiRT subvariants generally cause milder illness compared to earlier strains such as Delta.

MORE | COVID JN.1 variant now leading cause of infections in US - Here's what you need to know

What are symptoms of FLiRT variants?

Common symptoms of the emerging variant include sore throat, congestion, fatigue, and other mild symptoms similar to the common cold.

In more moderate and severe cases, fever and associated symptoms are possible.

Is it typical for COVID cases to rise over the summer?

Medical experts expected a rise in COVID-19 cases after weekly COVID hospitalizations in May hit their lowest level ever reported since the pandemic began, according to data from the Centers for Disease Control.

"While this uptick aligns with expected seasonal trends, we continue to monitor new variants closely to ensure our public health response remains effective and adaptive," Dr. Brownstein said.

How can you tell if you have COVID or a cold?

PCR or rapid antigen tests are the most reliable way to distinguish between COVID-19 and other illnesses, according to the CDC. It is not possible to tell from your symptoms if you have cold, allergies or COVID without testing.

"Make sure to monitor for any symptoms and get tested promptly to prevent spreading the virus," Dr. Brownstein said.

Are current vaccines effective in combating the dominant COVID variant?

The latest available vaccines, including the updated booster targeting the XBB.1.5 subvariant, remain effective in preventing severe illness and hospitalization,

The formula of newer vaccines will be designed to protect against these FLiRT variants and are expected to be available this Fall.

"It's important to stay up to date with your vaccinations to maintain protection against current variants," Dr. Brownstein said.

The ABC News medical unit contributed to this report.

Related Topics

• HEALTH & FITNESS
• COVID 19 VARIANT
• COVID 19 PANDEMIC
• COVID 19 VACCINE
• U.S. & WORLD

Covid-19 Variant

Moderna COVID-flu shot sees strong immunity in older adults: Trial

COVID JN.1 variant now leading cause of infections in US

Here's where new COVID JN.1 variant is spreading in US

JN.1 now the 'fastest-growing' COVID variant in the US

Top stories.

Judge arrested for DWI after previous traffic stop ended in warning

2nd suspect in 12-year-old girl's murder receives $10 million bond

Friendswood teen indicted in December 2023 shooting of friend: PD

• 19 minutes ago

Wesley Hunt under investigation for $74,000 in Post Oak Hotel payments

Capital murder suspect has been in jail for 18 years waiting trial

Residents in Lakewood Pines subdivision claim their water is cloudy

• 28 minutes ago

Investigation underway into inmate's death at Pam Lychner State Jail

• 2 hours ago

Bond lowered to $300K for woman accused of stabbing stranger to death

Study reveals cannabis and tobacco users face higher COVID-19 hospitalization and adverse outcomes

• Download PDF Copy

In a recent cohort study published in JAMA Network Open , researchers from the United States of America investigated the association between the use of cannabis and tobacco and health outcomes in coronavirus disease 2019 (COVID-19). They found that smokers and cannabis users showed a greater risk of hospitalization and adverse outcomes in COVID-19 as compared to non-smokers or those not using cannabis, despite controlling for other risk factors.

COVID-19 continues to impact public health, causing morbidity and mortality. Despite 76% of US adults being partially vaccinated against the disease, factors like vaccine hesitancy and new virus strains highlight the need to identify contributors to poor outcomes. While non-modifiable factors such as age, sex, race, and comorbidity are reported to be linked to severe infection, research on modifiable factors like substance use remains limited.

Previous studies show that cigarette smoking is associated with the worsening of COVID-19 outcomes, and preliminary evidence links substance use disorders and alcohol use to higher risks of severe disease and breakthrough infections. Research on cannabis use and COVID-19 is scarce and conflicting, with some studies indicating higher infection and mortality rates among users, while others suggest protective effects.

Data from electronic health records (EHR) may help address these understanding gaps. Therefore, researchers in the present study aimed to evaluate whether substance use, specifically cannabis use and tobacco smoking, is associated with COVID–19–related outcomes such as hospitalization, admission to the intensive care unit (ICU), and all-cause mortality. The hypothesis was that both tobacco smoking and cannabis use are linked to worse outcomes following COVID-19 infection.

About the study

In the present multi-institutional, retrospective cohort study, EHR data from 72,501 patients diagnosed with COVID-19 during the period from February 2020 to January 2022 were included. COVID-19 cases were defined by diagnosis based on the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM), positive polymerase chain reaction (PCR), antibody, or antigen tests. The mean age of the participants was 48.9 years; 59.7% of them were female, and 27.6% of the patients were Black. Approximately 26.8% of patients received a COVID-19 vaccine before diagnosis.

The primary outcomes were hospitalization, admission to the ICU, and all-cause mortality, including post-hospital mortality and overall survival. Demographic and treatment-related covariates, such as age, sex, race, ethnicity, and insurance status, were additionally extracted. Tobacco smoking and cannabis use were self-reported in the EHR, with current use documented and included in analyses. Statistical analysis included the use of chi-square tests, logistic regression, Cox proportional hazards regression, scaled Schoenfeld residuals check, and Bonferroni correction.

Results and discussion

About 70.4% of the total participants were hospitalized, 6.5% required ICU visits, and 3.7% suffered mortality. Further, 13.4% of the participants were found to be current smokers, 24.4% were former smokers, and 9.7% were current cannabis users. Both current and former smoking were found to be associated with a significantly increased risk of hospitalization, ICU admission, and all-cause mortality following COVID-19 (p<0.001), even after adjusting for various demographic and health factors. The risk of progression to all-cause mortality was found to be higher in patients above 65 years of age with current or former smoking. Current smokers also showed a higher probability of hospitalization than former smokers.

Related Stories

• Cannabis use tied to increased risk of severe COVID-19
• Personal choices drive young adults' alcohol abstinence with cannabis as a common substitute
• Antenatal COVID-19 vaccination shown to be safe for pregnant women and their babies

Similarly, cannabis use was found to be significantly associated with increased risks of hospitalization (OR 1.80) and ICU admission (OR 1.27) following COVID-19 but not with increased all-cause mortality. The associations between tobacco and cannabis use with COVID-19 outcomes remained consistent when adjusted for comorbidities. While current and former smoking were found to be associated with a lower probability of receiving a COVID-19 vaccine, cannabis use did not appear to influence vaccine receipt when adjusting for variables significantly.

Further, alcohol abuse was documented in 0.3%, and vape use was recorded in 1.9% of patients, both showing a greater risk for hospitalization (OR = 3.34 and 1.20, respectively). Data limitations precluded the evaluation of their associations with COVID-19 ICU admission and mortality.

Overall, the study adds to current evidence by using extensive EHR data to identify associations between tobacco and cannabis use with increased risks of adverse COVID-19 outcomes while also exploring preliminary associations with alcohol abuse and vaping. However, the study is limited by potential confounding from time-varying factors, reliance on self-reported and variably documented substance use in EHRs, lack of details on cannabis and tobacco product use, potential detection bias, non-representativeness of the sample, and incomplete capture of patient outcomes.

In conclusion, the study suggests that current and former smoking, as well as cannabis use, increases the risk of hospitalization, ICU admission, and mortality in COVID-19 patients. The associations remain significant after adjusting for demographic and comorbidity factors, emphasizing cannabis use as an independent risk factor for adverse outcomes post-COVID-19 diagnosis. The findings highlight the need for further research on the effect of substance use on COVID-19 outcomes, especially with the increasing legalization of marijuana use.

• Cannabis, Tobacco Use, and COVID-19 Outcomes. Griffith NB et al., JAMA Network Open, 7(6):e2417977 (2024), DOI:10.1001/jamanetworkopen.2024.17977,  https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2820235

Posted in: Men's Health News | Medical Research News | Medical Condition News | Women's Health News | Disease/Infection News

Tags: Alcohol , Antibody , Antigen , Cannabis , Cigarette , Coronavirus , Coronavirus Disease COVID-19 , Hospital , Intensive Care , International Classification of Diseases , Mortality , Polymerase , Polymerase Chain Reaction , Public Health , Research , Smoking , Tobacco , Vaccine , Vaping , Virus

Dr. Sushama R. Chaphalkar

Dr. Sushama R. Chaphalkar is a senior researcher and academician based in Pune, India. She holds a PhD in Microbiology and comes with vast experience in research and education in Biotechnology. In her illustrious career spanning three decades and a half, she held prominent leadership positions in academia and industry. As the Founder-Director of a renowned Biotechnology institute, she worked extensively on high-end research projects of industrial significance, fostering a stronger bond between industry and academia.  

Please use one of the following formats to cite this article in your essay, paper or report:

Chaphalkar, Sushama R.. (2024, June 24). Study reveals cannabis and tobacco users face higher COVID-19 hospitalization and adverse outcomes. News-Medical. Retrieved on June 25, 2024 from https://www.news-medical.net/news/20240624/Study-reveals-cannabis-and-tobacco-users-face-higher-COVID-19-hospitalization-and-adverse-outcomes.aspx.

Chaphalkar, Sushama R.. "Study reveals cannabis and tobacco users face higher COVID-19 hospitalization and adverse outcomes". News-Medical . 25 June 2024. <https://www.news-medical.net/news/20240624/Study-reveals-cannabis-and-tobacco-users-face-higher-COVID-19-hospitalization-and-adverse-outcomes.aspx>.

Chaphalkar, Sushama R.. "Study reveals cannabis and tobacco users face higher COVID-19 hospitalization and adverse outcomes". News-Medical. https://www.news-medical.net/news/20240624/Study-reveals-cannabis-and-tobacco-users-face-higher-COVID-19-hospitalization-and-adverse-outcomes.aspx. (accessed June 25, 2024).

Chaphalkar, Sushama R.. 2024. Study reveals cannabis and tobacco users face higher COVID-19 hospitalization and adverse outcomes . News-Medical, viewed 25 June 2024, https://www.news-medical.net/news/20240624/Study-reveals-cannabis-and-tobacco-users-face-higher-COVID-19-hospitalization-and-adverse-outcomes.aspx.

Suggested Reading

Cancel reply to comment

• Trending Stories
• Latest Interviews
• Top Health Articles

Revolutionizing Life Science: An Interview with SCIEX on ASMS, the SCIEX 7500+ System, and AI-Driven Quantitation

Jose Castro-Perez and Chris Lock, SCIEX

In our latest interview, News Medical speaks with SCIEX, a global leader in life science analytical technologies, about their exciting announcements at ASMS, the SCIEX 7500+ System, and how they utilize AI quantitation software to streamline solutions.

From Discovery Biology to ELRIG Chair

Melanie Leveridge

In this interview, we speak with Melanie Leveridge, Vice President of Discovery Biology at AstraZeneca and Chair of the Board for ELRIG UK, to discuss her extensive career in the pharmaceutical industry, her role in fostering scientific innovation, and her vision for ELRIG's future.

Breathing New Life into Diagnostics: Plasmion's SICRIT Technology

Revolutionizing Non-Invasive Diagnostics with Plasmion’s SICRIT Breath Analysis.

Latest News

Newsletters you may be interested in

Your AI Powered Scientific Assistant

Hi, I'm Azthena, you can trust me to find commercial scientific answers from News-Medical.net.

A few things you need to know before we start. Please read and accept to continue.

• Use of “Azthena” is subject to the terms and conditions of use as set out by OpenAI .
• Content provided on any AZoNetwork sites are subject to the site Terms & Conditions and Privacy Policy .
• Large Language Models can make mistakes. Consider checking important information.

Great. Ask your question.

Azthena may occasionally provide inaccurate responses. Read the full terms .

While we only use edited and approved content for Azthena answers, it may on occasions provide incorrect responses. Please confirm any data provided with the related suppliers or authors. We do not provide medical advice, if you search for medical information you must always consult a medical professional before acting on any information provided.

Your questions, but not your email details will be shared with OpenAI and retained for 30 days in accordance with their privacy principles.

Please do not ask questions that use sensitive or confidential information.

Read the full Terms & Conditions .

Provide Feedback

COVID's side effects are still spreading. Why do Trump, Biden run from how they handled it?

3-minute read.

In the run-up to the presidential election, Misters Biden and Trump are disturbingly reticent about America’s once-in-100-year plague — and averse, even, to criticize each other’s performance.     

This is not a case of left-right harmony. Rather, the candidates fear an issue that might expose flaws in—or voter disagreement with — their COVID-19 response.    

In a matchup unique in history, the receding pandemic straddled two presidencies, giving each leader a singular moment to show presidential mettle. But it also killed 1.1 million Americans (the  highest rate among wealthy countries ); introduced a vaccine that worked poorly and  harmed some , and left a legacy of sickness,  suicide ,  overdose and government distrust .   

If the presumptive candidates believe they have earned another chance to govern, they should answer for what they did, for better or worse, to tame the SARS-CoV-2 virus. There must be an accounting, including hard questions in the first debate on June 27. 

Five months before America’s first post-COVID-19 presidential election, pollsters, pundits,  articles  on “ key   issues ” and the candidates themselves seem largely to have forgotten the last four years.    

A national poll asked voters which candidate they trusted most on democracy, crime, U.S. standing, and immigration, but did not bring up the event that grade schoolers will recall into their 80s. If they get there.   

The economy, abortion, Israel and healthcare are surely important. But so is a pandemic. Ask the families of the million-plus.   

190,000 ‘excess’ deaths

The tentacles of COVID-19 are insidious and spreading. The number of Americans with a  disability is up by 3.4 million , or 11%, from before the pandemic. Cancer is  surging  in  young adults . And more people are still  dying  than  normal  and predictable. 

In 2023,  190,742 more Americans died than in 2019, the year before the virus changed everything. Those 5.3% extra deaths are more than America’s combined military losses since Korea .  

While the elderly perished first in 2020, deaths among 25-to-44-year-olds are surging now, rising 21% from 2019 to 2023, our analysis  of CDC data shows.  

Think of these numbers when young adults succumb to unexplained causes, or when the FDA commissioner tweets  that declining longevity in America , a pre-pandemic trend, is “catastrophic.” U.S. lifespans— lower than 30 other countries — are not only going down in 70-somethings.  

Given their history with this contagion, both candidates must answer for what the British Medical Journalcalled America’s “devastating pandemic outcomes.”    

“Americans killed by covid-19 represent 16% of global deaths in a nation with 4% of the world’s population,”  BMJ said . Behind that dismal outcome is a broken public health system and an unhealthy, unequal population.  

Mike Kelly: Why is MTG screaming at Dr. Fauci? Can we ever debate with civility again?

COVID vaccines promoted, not treatment 

America’s leaders — former President Donald Trump first, then President Joe Biden — chose to vaccinate the nation’s way out of COVID-19, to the point of  mandating shots for 100 million workers and adopting them for infants, for whom they are still not  formally   licensed .   

Facilitating emergency use of an unapproved vaccine required, under law, that there be no “adequate” alternative . There was another option, but doctors were all-but banned from treating COVID-19 with cheap, approved drugs. 

The Biden FDA led a crusade against one drug in particular,  branding ivermectin — its 2015 Nobel Prize in Medicine notwithstanding—as a “dangerous and even lethal” drug meant for horses and cows . It was not true.   

In March, the FDA removed its misleading posts after a  federal judge  said it had no authority to give medical advice on a legal drug that, incidentally, “also comes in a human version.”  

Unfortunately, FDA’s advice was hyped by media  and heeded by medicine. A 52-year-old woman died after a hospital cut off her court-ordered ivermectin three times, even as she improved. (Dr. Kory is an expert witness in her family’s wrongful death lawsuit.) Many could have been saved with many  proven early treatments . 

In recent weeks, the pandemic discussion has shifted. A New York Times article told of “thousands” of vaccine-harmed people . A former FDA official, Janet Woodcock, admitted these were “life-changing” injuries that “should be taken seriously.” A former CDC director, Robert Redfield, told an interviewer , “Those of us that tried to suggest there may be significant side effects…we kind of got cancelled.”    

Such assertions have unilaterally been labeled pandemic “conspiracy theories”. The vaccine skepticism of Independent presidential candidate Robert F. Kennedy Jr. is pointedly reported.  

But less well-known is a study of 99 million COVID-19-vaccinated patients,  published in April in Vaccine , that found significant neurological, cardiovascular and hematologic side effects. In early June, another study in BMJ Public Health  found ongoing excess deaths in 43 countries, the U.S. included, despite “containment measures and COVID-19 vaccines.” 

“This raises serious concerns,” the article concluded. 

Ask the candidates: Do they share that concern? 

Dr. Pierre Kory, M.D., a pulmonologist and critical care specialist, is a founder and president emeritus of the Front Line COVID-19 Critical Care Alliance , based in Washington. Mary Beth Pfeiffer is an investigative reporter and author.   Thanks to expert actuary Mary Pat Campbell, FSA, who accessed and analyzed CDC mortality data.  

• Alzheimer's disease & dementia
• Arthritis & Rheumatism
• Attention deficit disorders
• Autism spectrum disorders
• Biomedical technology
• Diseases, Conditions, Syndromes
• Endocrinology & Metabolism
• Gastroenterology
• Gerontology & Geriatrics
• Health informatics
• Inflammatory disorders
• Medical economics
• Medical research
• Medications
• Neuroscience
• Obstetrics & gynaecology
• Oncology & Cancer
• Ophthalmology
• Overweight & Obesity
• Parkinson's & Movement disorders
• Psychology & Psychiatry
• Radiology & Imaging
• Sleep disorders
• Sports medicine & Kinesiology
• Vaccination
• Breast cancer
• Cardiovascular disease
• Chronic obstructive pulmonary disease
• Colon cancer
• Coronary artery disease
• Heart attack
• Heart disease
• High blood pressure
• Kidney disease
• Lung cancer
• Multiple sclerosis
• Myocardial infarction
• Ovarian cancer
• Post traumatic stress disorder
• Rheumatoid arthritis
• Schizophrenia
• Skin cancer
• Type 2 diabetes
• Full List »

share this!

June 21, 2024

This article has been reviewed according to Science X's editorial process and policies . Editors have highlighted the following attributes while ensuring the content's credibility:

fact-checked

peer-reviewed publication

trusted source

Community-centered approach to providing vaccine education and resources to homeless persons during COVID-19

by Boston University School of Medicine

A community-support model for providing health resources and education is a way to continuously engage unhoused people and other underserved groups who are particularly vulnerable during health emergencies like the COVID-19 pandemic.

"Having a stable system for bringing health information to unhoused people and connecting them to providers at Boston Health Care for the Homeless Program (BHCHP), is a pathway for addressing a number of health issues they experience," said Kareem King, Jr., research program manager at Boston University's Clinical & Translational Science Institute.

"Many of the people we interacted with lacked insurance or a primary care team, meaning their only option was to visit shelter clinics or the Boston Medical Center emergency room."

King is the corresponding author of the report, "Building Power on Mass&Cass: A Community-Centered Approach to Addressing Health Resource Gaps for Persons Experiencing Homelessness in Boston, MA, 2021" published online in the American Journal of Public Health .

The report outlines the joint work of two organizations, Housing Equals Health, a health justice initiative, and We Got Us, a student-led nonprofit focused on health equity.

This initiative started in November 2021. It was created from work that Housing=Health and other advocacy organizations had done earlier on in the pandemic to bring attention to the unique health issues unhoused people experienced. From April 1, 2022—March 31, 2023, RADx-UP supported them to conduct outreach events on a bi-weekly basis at four rotating Boston locations chosen with guidance from community members and insight from BHCHP.

At the outreach events, persons experiencing homelessness (PEH) received COVID information, testing, and a resource kit which included a number of items provided by nonprofit and industry partners (masks, sanitizer, wipes, water, snacks, etc). In addition to this, they were asked to participate in surveys to share their experience utilizing the programs, and what they would like to see at future events.

Longer interviews to discuss health care experiences and needs were conducted on a select group. The information was shared with BHCHP, the Boston Public Health Commission and other partners in this initiative.

"We conducted 28 outreach events, passed out 2,558 resource kits, and had over 3,000 interactions," said King.

"The events showed that community support and multi-sectoral partnerships are needed to build sustainable health programs. In times of crisis, survival and basic needs come first. Our goal was to meet those needs, through the support of our institutional partners, while engaging people with stable access to vaccinations and health education to promote ongoing public health efforts."

King felt the initiative served as a model for the infrastructure and communication needed for future health emergencies .

"We were able to provide consistent public health resources to unhoused people, break accessibility barriers to COVID-19-related information, and establish a bidirectional pipeline of trusted public health messaging," the report concluded. King felt it also showed that Boston-area students could be an important resource in building and maintaining health programs.

"This program demonstrates the value and impact that community-centered approaches have in driving sustainable public health efforts," said King. Their work with unhoused populations continues.

Explore further

Feedback to editors

New study suggests higher amounts of intervention may not be more helpful for children on the autism spectrum

4 hours ago

Health officials tell US doctors to be alert for dengue as cases ramp up worldwide

5 hours ago

How uncertainty builds anxiety

Researchers link tooth loss to increased obesity risk

Pilot study provides 'blueprint' for evaluating diet's effect on brain health

The economic impact of changing how health care is delivered to older people in emergency departments

6 hours ago

Large integrative medicine center implements processes to measure and understand clinical effectiveness

7 hours ago

Researchers develop hybrid antibody with improved immune activation

8 hours ago

Study finds better outcomes for recipients of lungs from hospital-based donor care units compared to independent units

10 hours ago

Neurobiologists reveal secret of congenital central hypoventilation syndrome

Related stories.

Recommendations to better meet the health care and social needs of unhoused populations

Feb 26, 2024

New analysis addresses homelessness in older people

May 21, 2024

A blueprint for more equitable care in public health crises

Dec 9, 2022

Structural inequities amplify homelessness challenges for pregnant people in Washington, D.C.

May 30, 2024

Primary care housing intervention linked to improved patient health outcomes

Feb 5, 2024

People experiencing homelessness more likely to develop dementia at younger ages, study finds

Mar 27, 2024

Recommended for you

Fighting the late-night bright light could reduce risk of diabetes

11 hours ago

Dietary fiber found to regulate gut bacteria's use of tryptophan, impacting health

16 hours ago

Positive emotion skills combat burnout among health care workers

14 hours ago

Moderate exercise may reduce job burnout, help curb 'quiet quitting' among employees

Let us know if there is a problem with our content.

Use this form if you have come across a typo, inaccuracy or would like to send an edit request for the content on this page. For general inquiries, please use our contact form . For general feedback, use the public comments section below (please adhere to guidelines ).

Please select the most appropriate category to facilitate processing of your request

Thank you for taking time to provide your feedback to the editors.

Your feedback is important to us. However, we do not guarantee individual replies due to the high volume of messages.

E-mail the story

Your email address is used only to let the recipient know who sent the email. Neither your address nor the recipient's address will be used for any other purpose. The information you enter will appear in your e-mail message and is not retained by Medical Xpress in any form.

Newsletter sign up

Get weekly and/or daily updates delivered to your inbox. You can unsubscribe at any time and we'll never share your details to third parties.

More information Privacy policy

Donate and enjoy an ad-free experience

We keep our content available to everyone. Consider supporting Science X's mission by getting a premium account.

E-mail newsletter