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A new landscape for malaria vaccine development

Affiliations Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, United States of America, Molecular Microbiology and Immunology Program, Graduate Program in Life Sciences, University of Maryland School of Medicine, Baltimore, Maryland, United States of America

* E-mail: [email protected]

Affiliation Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, Maryland, United States of America

• Alexander J. Laurenson, 
• Matthew B. Laurens

Published: June 27, 2024

• https://doi.org/10.1371/journal.ppat.1012309
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Citation: Laurenson AJ, Laurens MB (2024) A new landscape for malaria vaccine development. PLoS Pathog 20(6): e1012309. https://doi.org/10.1371/journal.ppat.1012309

Editor: Audrey Ragan Odom John, Children’s Hospital of Philadelphia, UNITED STATES

Copyright: © 2024 Laurenson, Laurens. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: AJL is supported by institutional funds via University of Maryland, Baltimore, Graduate Program in Life Sciences, Graduate Research Assistantship. MBL is supported by grants and contracts to his institution from the U.S. National Institutes of Health (UM1AI148689 and U01AI155300), Bill & Melinda Gates Foundation (INV-030857), Bill & Melinda Gates Medical Research Institute, and BioNTech, SE. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: AL and ML are listed on a pending International Patent Application PCT/US2023/077892.

On October 6, 2021, the World Health Organization (WHO) recommended the first vaccine against malaria to prevent Plasmodium falciparum malaria in children living in areas with moderate to high transmission [ 1 ], a watershed moment in child health. This historic event was informed by results of WHO pilot implementation of the RTS,S vaccination in Ghana, Kenya, and Malawi, that documented feasibility to deliver through routine immunization systems, capacity to increase equity to malaria prevention, a strong safety profile, significant reduction in severe malaria, and high cost effectiveness [ 2 ]. More recent analysis of the RTS,S pilot implementation results demonstrated 13% all-cause mortality reduction even in the presence of only moderate vaccine coverage [ 3 ]. Enthusiasm for RTS,S implementation in endemic countries has resulted in 18 country approvals to date for Gavi support for vaccine introduction, and current limited supply through 2025 was allocated to 12 of these countries [ 4 ].

Two years later, the WHO recommended a second malaria vaccine R21/Matrix-M (R21) on October 2, 2023 [ 5 ]. Like RTS,S, R21 generates immunity to P . falciparum circumsporozoite protein (CSP). A recent Phase 3 clinical trial of R21 in children 5 to 36 months of age demonstrated 75% efficacy at 2 sites with seasonal transmission and 68% efficacy at 3 sites with perennial transmission [ 6 ]. While RTS,S and R21 have not been compared head-to-head, they are expected to perform similarly and substantially impact malaria morbidity and mortality in endemic areas. R21 has a significant cost advantage at US $2 to 4 per dose and is expected to fill the huge demand-supply gap.

Now, with 2 high-impact malaria vaccines becoming available, how has this milestone influenced malaria vaccine research and development efforts? This article aims to explain more about the current landscape of malaria vaccine development.

Question 1. Why are more candidate vaccines needed for malaria?

Although 2 vaccines are recommended, neither meet the desired efficacy and durability for an optimal malaria vaccine. WHO’s preferred product characteristics for a malaria vaccine target a 90% reduction in blood stage infection and clinical malaria over 12 months [ 7 ]. When administered seasonally alongside seasonal malaria chemoprophylaxis as a three-dose series, during 12 months of follow-up, RTS,S demonstrated 72% efficacy [ 8 ], and R21 demonstrated 75% efficacy [ 6 ]. Vaccine-induced immunity wanes over time, which is somewhat mitigated by a fourth and possibly fifth annual booster. Next-generation vaccines that provide even higher efficacy can achieve greater public health impact, possibly requiring fewer doses and no annual booster. Such vaccines could increase individual protection, decrease vaccine delivery system demands, improve cost effectiveness, and further increase equity to malaria prevention.

Similar to COVID-19 vaccine development, multiple vaccine products are needed to ensure vaccine supply. Though not always foreseeable or desirable, any manufacturing or safety concern could surface and indefinitely remove a vaccine from use and necessitate use of an alternate product. Plans to produce malaria vaccines in India and sub-Saharan Africa will increase capacity to meet the current demand. Having multiple products manufactured in different facilities would help to ensure replacement product is available and to provide endemic countries with uninterrupted vaccine access.

Question 2. What might next-generation malaria vaccines look like?

Many next-generation malaria vaccines are currently in clinical testing ( Table 1 ). Some use novel approaches including live attenuated sporozoite inoculations, RNA-based platforms, and a combination of existing P . falciparum CSP-based vaccines with antigens from other stages of the parasite life cycle. Live attenuated sporozoite approaches build on human studies that demonstrated 90% protection against malaria infection among adults immunized with radiation-attenuated sporozoites administered via at least 1,000 infected bites [ 9 ]. Subsequent advances in cryopreservation of live sporozoites has led to whole organism vaccination regimens tested in the US, Europe, and sub-Saharan Africa, which all demonstrate protection against P . falciparum malaria [ 10 ]. Researchers are now planning trials of late liver stage-arresting, replication competent (LARC), genetically attenuated P . falciparum sporozoite vaccines that build on safety, immunogenicity, and efficacy demonstrated using previous generation whole sporozoite vaccines but multiply asexually in the liver and thus provide a prolonged stimulation of infection-blocking immune responses.

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Based on the recent success of COVID-19 vaccine development, mRNA-lipid nanoparticle technology is being employed for malaria vaccines in 2 human studies ( Table 1 ). mRNA-based vaccines provide advantage as they can be manufactured quickly, are safe and effective for young infants and pregnant women, and can code for multiple antigens to strengthen the immune response. Disadvantages include side effects, though these are generally mild and temporary. The first mRNA-based malaria clinical trial tests a single RNA construct encoding part of the P . falciparum circumsporozoite protein (CSP), and the second tests a combination of 3 distinct RNAs—the full P . falciparum CSP and 2 conserved segments of liver stage-expressed proteins—with plans for controlled human malaria infection to determine preliminary vaccine efficacy. Other promising RNA-based malaria vaccine strategies are in preclinical development [ 11 – 14 ].

Another strategy for malaria vaccines focuses on improving RTS,S and R21 efficacy in preventing disease by adding a separate vaccine antigen targeting the parasite’s erythrocytic cycle so a single product would provide both pre-erythrocytic liver stage protection and erythrocytic efficacy against parasitic escape. One such strategy combining R21 with the blood stage antigen reticulocyte-binding protein homolog 5 (RH5) is already underway [ 15 ].

Question 3. How will computational biology inform next-generation malaria vaccines?

Most current malaria vaccine target antigens were discovered by identifying immune responses in following malaria infection, yet few have demonstrated efficacy in clinical studies. Reasons for vaccine failure include antigenic variation, off-target antibody responses diluting intended protective responses, and short durability of immunity [ 4 ]. Novel bioinformatics tools can overcome these obstacles by leveraging parasite and human genomic data to strategically identify candidate vaccine targets that generate precise and accurate immunity, and to overcome parasite diversity.

To optimize immunogenicity and targeted immunity, computational techniques such as 3D protein modeling can predict conformation-dependent immune responses to malaria proteins, which allows researchers to identify parasite gene loci that are susceptible to immune escape from vaccine-induced protection [ 16 ]. In addition, integrating known local HLA polymorphism and parasite population sequence data from endemic regions to identify T cell epitopes recognizable by common HLA alleles optimizes vaccine design, ensuring results are directly applicable to target populations.

Despite P . falciparum ’s enormous antigenic diversity, comprehensive analyses of parasite genomic and transcriptomic data collected in endemic areas can identify genomic regions under positive selection pressure to remain conserved [ 17 ]. These antigens serve as ideal candidate vaccines. Moreover, parasite transcriptomic profile analysis pinpoints essential proteins consistently expressed during distinct life cycle stages that can also serve as vaccine targets [ 17 ]. Advanced characterization of P . falciparum ’s complex genome using a combined set of approaches can provide a more credible and well-informed selection of target regions as candidate vaccine antigens for development.

A pipeline approach that incorporates high-throughput analyses in sequence can predict conserved and positively selected antigenic regions that elicit successful and protective immune responses, circumventing traditional preclinical experimentation that is costly and time-consuming. With experimentally validated bioinformatic predictive tools informed by genomic datasets, resources are deployed precisely and efficiently, thus accelerating antigen discovery for preclinical testing.

Question 4. How will next-generation malaria vaccines be down-selected?

RTS,S underwent a lengthy 35-year development from creation in 1987 [ 18 ] to 2021 when the WHO recommended it for use [ 1 ]. CSP was identified as a target of the immune response generated by radiation-attenuated sporozoites, and epitope mapping led to development of a subunit vaccine that demonstrated protection against Controlled Human Malaria Infection (CHMI). RTS,S was then tested with multiple adjuvants, in rhesus and then in human clinical trials with CHMI in malaria-naïve adults and subsequently in malaria-exposed adults and then children and infants living in endemic areas [ 18 ]. As no known correlate of RTS,S-induced protection against P . falciparum was identified, efficacy studies in the target population of children living in endemic areas were required to assess RTS,S impact.

Now, with data from multiple clinical trials of RTS,S, recent advances in our understanding of vaccine-induced immunity to P . falciparum malaria, and refinement of preclinical models, it is possible to use mouse models to improve existing CSP-based vaccines [ 19 ]. Adjuvants can now be carefully selected based on the desired effector function, [ 20 ] obviating the need for large CHMI and/or efficacy studies to optimize adjuvant selection. Cryo-electron microscopy has advanced understanding of CSP-based structures underlying high antibody avidity and potency needed for an effective vaccine [ 21 ]. As regulatory bodies and experienced clinical trial centers exist in malaria endemic areas, candidate next-generation vaccines ready for human testing can be trialed in first-in-human studies with CHMI in endemic countries, lessening the need for initial testing in the US and Europe and potentially shortening time needed for clinical development. Overall, these advances will facilitate efficient testing of improved CSP-based vaccines.

Question 5. What about vaccines that block transmission?

Vaccines that prevent malaria transmission are needed to achieve elimination goals. A highly effective pre-erythrocytic vaccine would completely prevent parasite erythrocytic development and thus halt onward transmission, though developing a vaccine with 100% efficacy may not be feasible. RTS,S and R21 are pre-erythrocytic vaccines that incompletely prevent blood stage infection, thus improving malaria morbidity and mortality. These vaccines address the first 2 WHO strategic priorities for malaria vaccines to prevent human blood-stage infection at the individual level and to reduce morbidity and mortality in individuals at risk in malaria-endemic areas [ 7 ]. However, they do not address the third WHO strategic priority to reduce parasite transmission and incidence of human infection in the community [ 22 ]. Malaria vaccines that reduce transmission exclusively would not provide health benefit to an individual but would significantly impact malaria elimination efforts at the community and regional levels.

Vaccines targeting P . falciparum antigens expressed during parasite sexual development in the mosquito midgut represent a promising approach to prevent malaria transmission to mosquitoes, blocking onward transmission to humans. As these antigens are not seen by the human immune system during parasite development, they are not targets of naturally acquired immunity. Transmission-blocking vaccines can induce antibodies that are subsequently ingested by the mosquito vector during a blood meal and that act directly on parasites. Such vaccines are based on parasite antigens expressed in the mosquito midgut, including Pfs230 and Pfs25 [ 23 ], and Pfs48/45 [ 24 ]. Transmission-blocking vaccines could be administered as a standalone product or combined with a pre-erythrocytic or erythrocytic vaccine to provide both individual and community benefit.

As clinical trials of transmission-blocking vaccines that measure community transmission as an outcome would require a large number of participants exposed to an investigational product to measure efficacy, immunogenicity studies can be used as proxies. In addition to measurements of antibody against the vaccine antigen, serum functional activity against parasite sexual stage development is measured using a standard membrane feeding assay, where mosquitoes feed on cultured gametocytes in the presence of serum and are then observed for parasite oocyst development within each mosquito [ 25 ]. Direct skin feeding assays can also be used where female Anopheles are placed in a mesh container and allowed to feed directly at the skin surface of a vaccinated participant, then later dissected to assess for parasite oocyst development [ 23 ]. Results of these functional assays inform clinical development, though no transmission-blocking vaccine has progressed beyond Phase 2 testing to date.

Conclusions

The first 2 malaria vaccines recommended by the WHO in 2021 and 2023 may have arrived just in time, as current malaria case counts remain essentially unchanged since 2015, reports of first-line antimalarial resistance are becoming more common, and climate change threatens recent advances in malaria control. The advent of these vaccines has been met with strong public interest in vaccination as a means to tackle malaria, and signals that future improvements in malaria vaccines will likely achieve similar high demand and uptake. Next-generation vaccines are needed to provide enhanced and sustained efficacy that will improve child health, increase educational outcomes for children, save lives, and advance elimination efforts. Preclinical work to define new and improved vaccine antigens can be informed by computational biology pipelines to increase efficiency. While multiple interventions are needed to control malaria in endemic areas, high-impact interventions that prevent the most illnesses and deaths with available resources are a priority. Malaria vaccines represent a high-impact intervention that can reduce clinical disease, prevent severe malaria illness, decrease hospitalizations, and improve child survival [ 3 ]. Vaccines epitomize a viable strategy that can be furthered and advanced through continued research and innovation to accelerate malaria elimination efforts and shrink existing health disparities in resource-limited areas, paving the way toward a malaria-free future.

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• Published: 23 November 2020

Building momentum for malaria vaccine research and development: key considerations

• Chetan E. Chitnis 1 ,
• David Schellenberg   ORCID: orcid.org/0000-0001-8222-0186 2 ,
• Johan Vekemans 2 ,
• Edwin J. Asturias 3 ,
• Philip Bejon 4 ,
• Katharine A. Collins 5 ,
• Brendan S. Crabb 6 ,
• Socrates Herrera 7 ,
• Miriam Laufer 8 ,
• N. Regina Rabinovich 9 , 10 ,
• Meta Roestenberg 11 ,
• Adelaide Shearley 12 ,
• Halidou Tinto 13 ,
• Marian Wentworth 14 ,
• Kate O’Brien 2 &
• Pedro Alonso 2  

Malaria Journal volume  19 , Article number:  421 ( 2020 ) Cite this article

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To maintain momentum towards improved malaria control and elimination, a vaccine would be a key addition to the intervention toolkit. Two approaches are recommended: (1) promote the development and short to medium term deployment of first generation vaccine candidates and (2) support innovation and discovery to identify and develop highly effective, long-lasting and affordable next generation malaria vaccines.

In what is a truly great public health success story, expanded efforts to control and eliminate malaria have effectively halved malaria incidence and mortality since 2000. Several million lives have been saved in that time and a number of previously endemic countries in Asia, South and Central America and Africa have been formally declared malaria free.

This astonishing success has been achieved with a limited toolkit, largely comprising methods to prevent transmission by the mosquito vector through the use of insecticide-treated bed nets and indoor residual spraying, the use of chemoprevention in specific, vulnerable groups, and effective chemotherapy following rapid point-of-care diagnosis. Current vector control and effective anti-malarial treatment strategies represent significant success in both product development and implementation science.

However, progress in areas with high transmission has slowed and further reduction in malaria incidence and deaths has stalled in recent years. The 2018 and 2019, World Health Organization (WHO) World Malaria Reports documented a global increase in the number of malaria cases. Despite some countries achieving elimination, malaria increased in both the 10 most highly burdened countries and 11 of the 21 countries earmarked for elimination by 2020 [ 1 ].

A number of daunting realities impact on the potential for substantial further progress. These include: (1) malaria remains a staggeringly large human health problem with 1,200 malaria deaths every day, (2) longitudinal tracking of the effective implementation of existing tools show imperfect outcomes and suggests that existing tools may be insufficient to control malaria in high-transmission settings, no matter how well they are applied, (3) shifts in climate, population growth and movement, and changes in the location and species of vector, threaten to introduce malaria into new settings (for example, greater urban transmission in Africa by Anopheles stephensi ), (4) problems achieving high coverage of current interventions are exacerbated by the emergence of vectors resistant to insecticides, parasites resistant to first-line treatment and parasite strains that evade diagnosis, (5) lessons from the 1970s and our knowledge of parasite biology and ecology tell us that resurgence can be rapid and devastating if public health measures fail or are not maintained, and (6) the COVID-19 pandemic has exposed the vulnerability of global supply chains and the health systems in many malaria endemic settings. Hard won gains can rapidly be lost.

New interventions are needed to reignite the fight against malaria. As for other infectious diseases, vaccines have the potential to impact burden in a cost-effective way and may, in the long term, contribute to the goal of malaria eradication. The feasibility of vaccine-induced protection against malaria has been demonstrated [ 2 ], but the development of malaria vaccines requires the vigorous and sustained engagement of many stakeholders. Recent advances in the understanding of malaria parasite biology, vaccinology and passive immunization approaches, suggest that the next advance in malaria vaccines is within reach─but only with sustained research and development efforts.

The WHO reconvened the Malaria Vaccine Advisory Committee (MALVAC) in 2019, and organized a stakeholder consultation about the state-of-the-art in malaria vaccine development [Vekemans et al. pers. commun.]. MALVAC’s mandate is to provide guidance on research priorities for the development of new malaria vaccines. Detailed WHO perspectives on the medical need and research priorities in malaria vaccine R&D will emerge over the next 12–24 months, but consultations and MALVAC discussions led to the recognition of the need to advance in parallel two distinct strategies:

To support continued engagement to ensure the availability of 1st and 2nd generation vaccine candidates with moderate efficacy, that show potential for widespread use in the next 3–10 years.

To support innovation and stimulate the discovery of next generation, highly protective and long-lasting malaria vaccines; for this to succeed, identifying efficient and cost-effective clinical development, financing and regulatory pathways will be key. Lessons can no doubt be learnt from the accelerated development pathways and approaches being developed for COVID-19 vaccines.

1st Generation Vaccines with partial protection—an important addition to the intervention toolkit

The most advanced malaria vaccine is RTS,S/AS01, developed by Glaxo Smith Kline with support from the Bill and Melinda Gates Foundation, the Walter Reed Army Institute of Research and PATH, and the collaboration of a large number of African and other international research institutions. RTS,S/AS01 targets Plasmodium falciparum sporozoites and demonstrated an efficacy of 39% over 4 years against malaria incidence in Phase III trials in African children aged 5–17 months at the time of dose 1 [ 3 ]. This moderate efficacy, documented in the context of high mosquito net use and similar to the level of protection afforded by well-implemented vector control, is potentially valuable to complement existing strategies for the reduction of malaria disease and death among young children in endemic areas. RTS,S/AS01 pilot implementation is ongoing in three malaria endemic countries—Ghana, Malawi and Kenya [ 4 ]. In addition to consolidating the vaccine’s safety profile, the pilot implementation will generate data on its survival impact and test the feasibility of delivering the four-dose RTS,S/AS01 regimen under routine conditions. Results of the implementation studies are keenly awaited and will be used to guide policy recommendations on the roll out of RTS,S/AS01 in malaria endemic countries.

RTS,S/AS01 has demonstrated the feasibility of developing a malaria vaccine and has laid down a clinical development path for future vaccines. Its use in programmatic contexts will inform our understanding of the potential value of malaria vaccines in combination with other tools for malaria control and elimination.

In addition to RTS,S/AS01, R21/Matrix-M, an RTS,S-like vaccine, is one of several potential second generation vaccines and is currently being tested for efficacy in the field. Notwithstanding enormous technical and practical challenges, the radiation-attenuated sporozoite vaccine, PfSPZ, has undergone extensive testing including in endemic African countries. Although high efficacy has been demonstrated in adults under experimental challenge conditions, efficacy in naturally exposed children is considerably lower, warranting further improvements. Progress is also being made through the evaluation of Rh5, a promising P. falciparum blood stage vaccine candidate, although it will be necessary to achieve higher rates of growth inhibition for such vaccines to yield clinically relevant efficacy.

The evaluation of sexual-stage candidates continues, and new tools to test vaccines designed to interrupt man-to mosquito transmission are being developed. Subunit vaccines that combine multiple antigens from the pre-erythrocytic and blood stages could synergize immune responses and yield higher efficacy. The addition of sexual-stage antigens to these vaccines could potentially enhance their impact on malaria transmission [ 2 ]. Continued investment in the development of these approaches is warranted given the progress to date and the scale of their potential impact on public health. In addition to subunit vaccines, innovations in the development of whole organism attenuated sporozoite vaccines are needed to develop formulations and delivery strategies that facilitate programmatic implementation in endemic countries.

Future malaria vaccines–towards highly efficacious, long-lasting vaccines and a more streamlined development pathway

Malaria vaccines that confer long-term, robust protection, that are inexpensive and relatively simple to deploy, are not on the short-term horizon. To accelerate progress in the development of such vaccines, a deliberate strategic pivot to fundamental discovery science is needed. Breakthrough science, with possibly unconventional approaches, will be required to meet these ambitious goals [ 5 ].

Decoding of the malaria parasite genome together with functional studies using molecular genetic tools, whole genome approaches as well as classical biochemistry and cell biology, are helping unravel the complex biology of the malaria parasite. Advances in understanding how malaria parasites interact with the human host and its immune system should enable new strategies to target the parasite at different stages with novel vaccine approaches. Advances in our understanding of basic human immunology and powerful new tools that enable dissection of immune responses at a systems level need to be brought to bear on malaria. Other advances such as structural vaccinology can provide unique insights into the molecular basis of protective antibody responses that could lead to therapeutic or prophylactic monoclonal antibodies and inform optimization of vaccine antigens to achieve higher efficacy.

The development of vaccines against parasitic diseases is complex and difficult due to the long history of co-evolution of parasites with their hosts. Malaria vaccines are currently envisioned as complementary tools to be added to the core package of interventions. However, the progress made in understanding malaria parasite biology and pathogenesis, as well as both basic and technological advances in human immunology and vaccinology, means the time is right to attempt the development of malaria vaccines with high efficacy. It is time to deepen and expand our ambitions at all levels, basic and translational, to develop future malaria vaccines that are game changers in efforts to eliminate malaria and create a pathway for other parasitic diseases. A highly efficacious malaria vaccine remains an ambitious target, but with commitment of necessary resources, it is more within reach today than ever before.

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Abbreviations

World Health Organization

Malaria Vaccine Advisory Committee

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Acknowledgements

Chetan E. Chitnis, Edwin J. Asturias, Philip Bejon, Katharine A. Collins, Brendan S. Crabb, Socrates Herrera, Miriam Laufer, N. Regina Rabinovich, Meta Roestenberg, Adelaide Shearley, Halidou Tinto and Marian Wentworth Members of the Malaria Vaccine WHO Advisory Committee (MALVAC).

The opinions expressed herein are those of the authors and do not necessarily reflect the views and decisions of the World Health Organization.

WHO is supported financially by the Bill and Melinda Gates foundation for malaria vaccine development-related work. The funder played no role in the present manuscript.

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Chetan E. Chitnis

World Health Organization, Geneva, Switzerland

David Schellenberg, Johan Vekemans, Kate O’Brien & Pedro Alonso

University of Colorado School of Medicine and Colorado School of Public Health, Denver, USA

Edwin J. Asturias

KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya

Philip Bejon

Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, The Netherlands

Katharine A. Collins

Burnet Institute, Melbourne, Australia

Brendan S. Crabb

Consorcio Para La Investigacion Cientifica, Cali, Colombia

Socrates Herrera

University of Maryland School of Medicine, Baltimore, USA

Miriam Laufer

IS Global, Barcelona, Spain

N. Regina Rabinovich

Harvard TH Chan School of Public Health, Boston, USA

Leiden University Medical Center, Leiden, The Netherlands

Meta Roestenberg

John Snow Inc, Research & Training Institute, Boston, USA

Adelaide Shearley

Institut de Recherche en Sciences de La Santé, Ouagadougou, Burkina Faso

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Management Sciences for Health, Arlington, USA

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Chitnis, C.E., Schellenberg, D., Vekemans, J. et al. Building momentum for malaria vaccine research and development: key considerations. Malar J 19 , 421 (2020). https://doi.org/10.1186/s12936-020-03491-3

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Malaria vaccine efficacy, safety, and community perception in Africa: a scoping review of recent empirical studies

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• Published: 05 March 2024

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• Muhammad Chutiyami 1 ,
• Priya Saravanakumar 1 ,
• Umar Muhammad Bello 2 ,
• Dauda Salihu 3 ,
• Khadijat Adeleye 4 ,
• Mustapha Adam Kolo 5 ,
• Kabiru Kasamu Dawa 6 ,
• Dathini Hamina 7 ,
• Pratibha Bhandari 1 ,
• Surajo Kamilu Sulaiman 8 &
• Jenny Sim 9 , 10  

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The review summarizes the recent empirical evidence on the efficacy, safety, and community perception of malaria vaccines in Africa.

Academic Search Complete, African Journals Online, CINAHL, Medline, PsychInfo, and two gray literature sources were searched in January 2023, and updated in June 2023. Relevant studies published from 2012 were included. Studies were screened, appraised, and synthesized in line with the review aim. Statistical results are presented as 95% Confidence Intervals and proportions/percentages.

Sixty-six ( N  = 66) studies met the inclusion criteria. Of the vaccines identified, overall efficacy at 12 months was highest for the R21 vaccine ( N  = 3) at 77.0%, compared to the RTS,S vaccine ( N  = 15) at 55%. The efficacy of other vaccines was BK-SE36 (11.0–50.0%, N  = 1), ChAd63/MVA ME-TRAP (− 4.7–19.4%, N  = 2), FMP2.1/AS02A (7.6–9.9%, N  = 1), GMZ2 (0.6–60.0%, N  = 5), PfPZ (20.0–100.0%, N  = 5), and PfSPZ-CVac (24.8–33.6%, N  = 1). Injection site pain and fever were the most common adverse events ( N  = 26), while febrile convulsion ( N  = 8) was the most reported, vaccine-related Serious Adverse Event. Mixed perceptions of malaria vaccines were found in African communities ( N  = 17); awareness was generally low, ranging from 11% in Tanzania to 60% in Nigeria ( N  = 9), compared to willingness to accept the vaccines, which varied from 32.3% in Ethiopia to 96% in Sierra Leone ( N  = 15). Other issues include availability, logistics, and misconceptions.

Malaria vaccines protect against malaria infection in varying degrees, with severe side effects rarely occurring. Further research is required to improve vaccine efficacy and community involvement is needed to ensure successful widespread use in African communities.

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Introduction

Malaria is prevalent in Africa and poses a significant public health threat with substantial morbidity and mortality [ 1 ]. Despite concerted efforts to curb the disease, its persistence can be attributed to socioeconomic inequality, inadequate infrastructure, and the emergence and spread of drug-resistant strains [ 2 ]. Control measures such as insecticide-treated nets (ITNs), indoor residual spraying (IRS), and antimalarial drugs are critical, but additional complementary interventions are needed. One of the promising emergent strategies is vaccination, which has been identified as a potentially pivotal measure in the fight against malaria [ 3 ].

Developing a malaria vaccine has been an arduous journey, complicated by the inherent complexity of the Plasmodium parasite's life cycle and its diverse antigenic characteristics [ 4 ]. Despite these challenges, there has been substantial progress. One particular advancement in this field is the RTS,S/AS01 and the R21/Matrix-M vaccines. These vaccines demonstrated protective efficacy in large-scale clinical trials, and have been recommended by the World Health Organization (WHO) for use in regions with moderate to high P. falciparum transmission, particularly Sub-Saharan Africa [ 5 ].

Malaria vaccine clinical trials have provided important knowledge and insights to support the implementation of large-scale vaccination programs. Mokuolo et al. [ 6 ] offered several key learnings from these trials, stressing the significance of robust local regulatory and ethical frameworks, effective community engagement and communication, as well as vigilant monitoring for potential disease enhancement or rebound morbidity following temporary interruptions of clinical infections. A critical factor in the success of vaccine implementation is community acceptance. A recent review of the literature suggests high acceptance of the RTS,S malaria vaccine across low- and middle-income countries (LMICs), with an average acceptance rate of 95.3% [ 7 ]. However, acceptance rates vary and appear to be impacted by socio-demographic factors and community apprehensions about safety, efficacy, and vaccine awareness [ 8 , 9 ].

In light of the success of the RTS,S and R21 vaccines, the need for greater global resources for malaria vaccine research and logistics in vaccine implementation cannot be over-emphasized. This study sought to address a current gap in understanding by using an in-depth scoping review to summarize recent empirical evidence on malaria vaccine efficacy, safety, and community perceptions in Africa.

A scoping review was conducted using the methodological framework outlined by Arksey and O’Malley [ 10 ], incorporated quality recomendations [ 11 ], and reported using the PRISMA extension for scoping reviews (PRISMA-ScR), as outlined in Appendix 1 [ 12 ]. The review protocol was registered at Open Science Framework (OSF) at https://doi.org/ https://doi.org/10.17605/OSF.IO/D54YC .

Eligibility criteria

Studies were included if they evaluated the efficacy, safety, or community perception of a malaria vaccine; were published after 2011; were primary/empirical research; conducted in malaria-endemic African countries; and included the general public as participants (e.g., caregivers, parents, children, or adults). Studies published from 2012 were included as a previous review that have explored malaria vaccine research prior to 2012 [ 13 ]. Studies were excluded if the participants were outside Africa, were not primary research (reviews, opinions, editorial, commentaries), and if they evaluated immunogenicity without safety or efficacy as a construct.

Information sources

Five primary databases were searched to identify relevant studies in any language: African Journals Online (AJOL), Academic Search Complete, Medline, CINAHL and PsychInfo. The initial search was conducted in January 2023 for articles published from 2012 to 2022. An update search was conducted in June 2023 for articles published from 2022 to June 2023. The search was supplemented with two gray literature sources; AfricArxiv (Achieve for African Research) and OPUS (Open Publication of UTS Scholars) to identify relevant preprints and thesis/dissertations respectively. Additionally, the reference list of articles that met the inclusion criteria was searched manually and forward literature search on Google Scholar was conducted to identify potentially missing articles. Peer review identified three additional studies published after June 2023 and those studies have also been included.

A combination of MeSh and index terms were formulated based on the PICO framework to aid the search process: Population (P)—African communities, Intervention (I)—malaria vaccine, Comparator (C)—none, and Outcome (O)—efficacy, safety, community perception. The EBSCOhost interface (including Academic Search Complete, CINAHL, Medline with full-text and PsychInfo) and the AJOL database were searched. The full search terms are reported in supplemental Table S1 . The EBSCOhost interface was expanded to; ‘Apply related words’ and ‘Apply equivalent subjects’.

For gray literature sources, the term 'malaria vaccine' was used to search for preprints papers on AfricArxiv, and any relevant thesis/publication on OPUS.

Selection of studies

Two reviewers (MC and KA) screened potentially eligible studies using the eligibility criteria. First, exact duplicates were removed in EBSCOhost and the search was narrowed to studies published from January 2012. Search results were then exported to Endnote. The duplicate screening was conducted in Endnote. The remaining articles were independently screened by 2 reviewers based on the title and abstract. The full text of all potentially relevant articles was then retrieved and screened independently by MC and UMB in-line with the eligibility criteria.

Data charting process

A data extraction form was developed by three authors (MC, UMB, DS) and included study characteristics such as the citation, year of publication, study design, and study setting. Data related to the study findings varied based on the focus of the study and included the study methods, the type of malaria vaccine assessed, the outcome assessments used, and the major findings. Two reviewers (KA and MAK) independently conducted the data extraction. Differences were resolved through discussion between the two reviewers and a third reviewer (MC).

Critical appraisal of included studies

The quality of the included studies was assessed using Joanna Briggs Institute (JBI) appraisal tools [ 14 ] and the Mixed Methods Appraisal Tool (MMAT) [ 15 ]. The appraisal was conducted independently by 2 reviewers (KKD and PB) and differences were resolved by a third reviewer (UMB). No study was excluded based on quality appraisal, but the quality of the study was considered when reaching key conclusions. JBI and MMAT do not provide a scoring guideline, therefore, studies were considered ‘above-average quality’ when they met at least half (average) of the quality criteria assessed in the specific study design. Therefore, the terms ‘below-average quality’ or ‘above-average quality’ were used to refer to study quality in the results.

Efficacy was operationally defined as the vaccine’s estimated effect on all malaria episodes (clinical, severe, or hospitalization). Efficacy was based on Intention-To-Treat (ITT) or According-To-Protocol/Per Protocol (ATP) analyses. Where ITT and ATP analyses were unavailable, efficacy was based on Hazard Ratio (HR), or any other percentage/proportion estimates reported in the studies. Safety was defined based on the presence or absence of Adverse Event (AE) and/or Serious Adverse Event (SAE). Community perception was defined as the different views of communities (general population) about malaria vaccines.

Synthesis of results

Results were synthesized narratively by summarizing the descriptive numerical data followed by a summary of the textual data. The synthesis considered the nature of the research (e.g., design), the type of malaria vaccine (for efficacy and safety), and the quality of the research studies.

Overall efficacy was classified as positive, none/negative or mixed. A result was considered as having positive efficacy if the Confidence Intervals (CI) were within the positive range; mixed efficacy if the CI ranged from negative to positive; and negative efficacy if the CI was within the negative range to zero. Similarly, safety issues were classified based on the number of subjects presenting with at least one SAE, AE, or none. Where the number of affected subjects were not available, a total number of events/incidents was reported. AEs can be solicited, unsolicited or unexpected, and the cumulative number/range was reported based on available information. For community perception, results were synthesized thematically by reporting the overall quantitative results followed by a summary of qualitative results as applicable. Overall percentages/proportions were reported with a range when available. Community perception was further classified based on 3 components: nature of the vaccine (e.g., risks, effect), systems (e.g., mistrust, logistics), or personal reasons (encompassing anything else). N refers to the number of studies reporting the same finding, while n refers to the number of participants reporting a finding in a study in this review.

We initially found 1299 articles (Fig.  1 ) from the five databases, and 661 underwent title/abstract screening. Two non-English articles, in Danish and French, were evaluated and excluded as they were secondary research. In total, 66 studies ( N ) were included (61 from the main search, 2 from the updated search, and 3 were identified during peer review) [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 ].

PRISMA flow diagram indicating screening process

Characteristics of included studies

The 66 included studies incorporated 47 Randomized Controlled Trials/clinical trials (71.4%), a case–control study (1.6%), and 17 surveys (27.0%). Sixteen African countries were included, with 64 of the 66 studies (97.0%) being above-average quality (Table S2). Further details are presented in Table S3.

Efficacy of malaria vaccines

Half of the included studies (50%, N  = 33) reported vaccine efficacy. At 12 months post-vaccination, the R21 vaccine showed the highest overall efficacy at 77% ( N  = 1, n  = 146), compared to the RTS,S vaccine at 55% ( N  = 1, n  = 273). Both of these studies were of above-average quality (Table S2). R21 further demonstrated an efficacy of 79% among younger children (5–17 months compared to 18–36 month-olds) at 12 months [ 86 ] and 80% ( N  = 1, n  = 137) at 12 months after a booster dose [ 78 ]. Similarly, RTS,S vaccine showed an efficacy of 56% among children aged 5–17 months at 12 months following vaccination [ 62 ]. PfSPZ, though tested on only five individuals, demonstrated an efficacy of 100% at three- or eleven-weeks post-vaccination. This efficacy rose from 20 to 100% at 3 weeks when PfSPZ's dosage regimen was adjusted [ 39 ]. The combined use of RTS,S/AS01 with chemoprevention yielded efficacy between 59.6 to 60.1% against clinical malaria and outperformed the vaccine in isolation against severe malaria and related deaths [ 25 ]. Other vaccines' efficacies varied significantly (Table  1 ).

Two studies [ 55 , 73 ] evaluated the long-term (up to 7 years) efficacy of RTS,S on severe and clinical malaria. While the study by Tinto et al. [ 73 ] demonstrated a decrease in severe malaria cases over time, there was a rebound against clinical malaria among older children (5–7 years). Oluto et al. [ 55 ] identified that vaccine efficacy (clinical malaria) waned over time, including negative efficacy among children with higher exposure to the malaria parasite. Similarly, a negative efficacy of ChAd63/MVA ME-TRAP for an adjusted severe malaria cohort was found [ 74 ]. Vaccine effectiveness was maintained when co-administered with malaria chemoprevention [ 24 , 25 , 27 ] or other childhood vaccinations [ 20 ].

Safety of malaria vaccines

Thirty-six studies (54.5%, N  = 36) investigated the safety of the malaria vaccines, all employing Randomized Controlled Trial design with above-average quality (Table S2). Each study reported one or more AEs ( N  = 28) or SAEs ( N  = 23). The reported AEs and SAEs ranged broadly across various vaccines; RTS,S (AEs: 1.6–87.5%, N  = 6; SAEs: 2.8–92.2%, N  = 12, vaccine-related SAEs: 0.1–1%, N  = 7), BK-SE36 (AEs: 5.6–94.4%, N  = 1; SAEs: 4.4–5.6%, N  = 2), ChAd63/MVA (AEs: 0–100%, N = 6; SAE: 0.4–8.9%, N  = 2), FMP2.1/AS02A (SAE: 4%, N = 1), GMZ2 (AEs: 23–100%, N = 2; SAEs: 49–54.5%, N  = 2), PfPZ (AEs: 1.6–83.9%, N  = 7; SAEs: 1.6%, N  = 1), PfAMA1 (AEs: 5–60%, N  = 1), PfSPZ-CVac (AEs: 19.4%, N  = 1), Pfs25H-EPA (AEs: 100%, N  = 1, SAEs: 1.7%, N  = 1) and R21 (AEs 0.7–24.6%, N  = 1, SAEs: 2.1%, N  = 1).

The local and systemic AEs that were typically reported included injection site pain and fever among other symptoms including redness, warmth, discoloration, bruising, erythema, blistering, pruritis, swelling and induration; headache; allergic rash,; drowsiness; irritability; loss of appetite; fatigue; dizziness; abdominal pain; chills; myalgia; diarrhea; nausea and vomiting [ 18 , 20 , 30 , 31 , 37 , 38 , 39 , 45 , 46 , 52 , 56 , 57 , 59 , 61 , 62 , 63 , 64 , 66 , 67 , 68 , 69 , 70 , 72 , 74 , 75 , 77 , 86 , 87 , 88 ]. Most AEs subsided within 1–7 days [ 18 , 46 , 52 , 74 , 86 ].

Commonly reported SAEs were acute gastritis, anemia, bronchitis, cerebral malaria, severe malaria, dehydration, convulsion, febrile convulsion, gastroenteritis, seizures, meningitis, paralytic ileus, pyrexia, pneumonia, respiratory distress, and death. However, most SAEs were.

deemed unrelated to the vaccination (Table  2 ) and were associated with malaria infection [ 29 , 87 ]. Only 0.1–1% and 4.3% of SAEs were possibly linked to vaccines, mainly febrile convulsion/seizures, associated with RTS,S vaccine [ 25 , 35 , 58 , 61 , 62 , 63 , 66 ] and R21 vaccine [ 86 ] respectively. Malaria vaccine safety when co-administered with other routine childhood immunization was identified [ 20 , 46 ].

Community perception of malaria vaccine

Seventeen studies (27.0%, N  = 17) assessed community perception of malaria vaccines, with a mix of below and above-average quality studies (Table S2). The overall perception of participants has been summarized in addition to five key issues that emerged from the studies: acceptance, availability, knowledge/awareness, logistics, and misconceptions about the vaccines (Table  3 ).

Overall perception

Ten of the seventeen studies that assessed community perception (58.8%) reported their overall perception of malaria vaccines (Table  3 ), and were of below and above-average quality (Table S2). Community members agreed that it was essential to have a malaria vaccine [ 44 ] and that the vaccine is necessary for malaria control [ 33 ]. More than three-quarters of participants from each study reported overall positive perceptions [ 26 , 36 , 47 , 48 ], identified malaria as a risk for their children [ 36 ], and identified that the vaccine will keep children healthy [ 23 , 44 ] even though the efficacy of the vaccine may not be 100% [ 47 ]. A significant positive association between positive perception and intent to comply with vaccination was reported [ 26 ]. More than half of respondents recommend the vaccine to others [ 48 ] and were part of the National Program on Immunisation [ 33 , 48 ]. The majority of participants preferred vaccines to malaria drugs/vector control [ 28 , 34 ]. There was a mixed reaction between oral and injectable vaccines in Ghana [ 44 ], while in Tanzania, participants were open to all modes of administration [ 60 ]. The limited side effects experienced by participants in the RTS,S/AS01 vaccine trial reinforced participants’ beliefs about its safety in Nigeria [ 28 ].

Of the studies examined, 88.2%, ( N  = 15) reported acceptance of malaria vaccines (Table  3 ), and most studies were above-average quality (Table S2). Acceptance rates varied from 32.3% in Ethiopia [ 21 ] to 96% in Sierra Leone [ 43 ]. Acceptance increased to 98.9% in malaria-endemic areas in Kenya [ 53 ]. Key drivers for acceptance were the high risk of malaria in children [ 17 , 41 ], the desire for self-protection and prevention [ 41 , 43 ], and incentives such as free consultations and medication [ 17 ].

The impact of religion on vaccine acceptance was inconsistent [ 36 , 47 , 71 ]. Some findings showed that Christian mothers were more likely to accept the vaccine than Muslim mothers in Tanzania [ 47 ], while in Ghana [ 36 ] and Nigeria [ 71 ], Christian mothers showed lower odds of accepting the vaccine. Free provision significantly increased vaccine acceptance [ 41 , 43 ], while increased costs decreased acceptance [ 41 , 76 ].

Fear of adverse events and unsuccessful intravenous vaccination attempts were linked to vaccine refusal [ 23 , 43 , 44 , 71 ]. Factors such as marital status, region, knowledge of vaccine, tribe, education level, prior vaccination experience, satisfaction with healthcare services, and parent age influenced willingness to accept vaccination [ 21 , 33 , 41 , 47 , 53 , 76 ].

Availability

Two of the studies (11.8%) reported concerns associated with the availability of malaria vaccines (Table  3 ). The need to provide malaria vaccine to adults in addition to children was reported in Mozambique [ 23 ]. The importance of an adequate supply chain to promote availability was documented from a key informant interview in Sierra Leone [ 43 ].

Knowledge/awareness

Nine of the studies (52.9%) reported knowledge of participants about malaria vaccines (Table  3 ). The percentage of participants having awareness of malaria vaccines ranged from 11% in Tanzania [ 60 ] to 60% in Nigeria [ 33 ]. Additionally, there was a low willingness to learn more about the vaccine in Mozambique [ 23 ]. Confusion and delays related to trial designs were seen to discourage participation in a malaria vaccine trial in Kenya [ 17 ]. The use of mass media, particularly Television, radio, and phones were identified as good sources of information by participants [ 23 , 26 , 44 ]. Information vans, health talks, and information from trusted community members [ 44 ] or health professionals were important but were rated equally with internet sources [ 71 ]. Awareness of vaccines was higher in older people when compared to younger people [ 36 ] and in mothers of Christian children compared to the Islamic faith [ 36 ]. There was evidence of confusion about malaria vaccines and other childhood vaccines in Ghana [ 44 ].

Four of the studies (23.5%) reported findings related to the logistics associated with malaria vaccine enrolments (Table  3 ). The need for community outreach by community health workers, including malaria vaccine campaigns alongside existing vector control programs to encourage participation was reported [ 43 ]. Negative attitudes of health staff were reported and shown to discourage participation in malaria vaccine trials [ 17 ]. Similarly, the system’s capacity to train staff for intravenous administration was noted as important [ 17 ].

Parents’ willingness to pay for the malaria vaccine was reported as a barrier [ 26 , 28 , 43 ]. Although, affordability was noted as a concern in a number of studies [ 26 , 28 , 41 , 76 ], some participants suggested that the provision of malaria vaccines was the sole responsibility of the government [ 28 ].

Misconceptions

Four of the studies (23.5%) reported misconceptions about potential malaria vaccines. Rumors of blood ‘theft and selling’ were linked to early withdrawal from malaria vaccine trials in Kenya [ 17 ]. Similarly, a widespread belief that newborns should have minimum exposure to adults and that the presence of a vaccine scar signifies a nurse had sexual intercourse with the child hindered vaccination programs in Mozambique [ 23 ]. The ideology that vaccines are harmful and can cause sickness was reported as a fear preventing vaccinations [ 23 , 43 ]. Furthermore, rumors of vaccines causing infertility and system mistrust were cited as critical reasons for hesitancy to receive the malaria vaccine [ 43 , 71 ].

This paper summarizes recent evidence on the efficacy, safety, and perception of malaria vaccines in Africa. All vaccines studied showed some degree of protection in terms of reducing the risk of contracting malaria and/or eliciting an antibody response. Overall efficacy varied; the highest overall efficacy (77%) was observed with R21 [ 30 ], which increased to 80% with a booster dose [ 78 ]. Increasing the dosage regimen of PfSPZ may also lead to an increase in efficacy from 20 to 100% [ 39 ]. Vaccination efficacy decreases over time with the highest efficacy expected up to one year after the last dose [ 55 , 73 ]. R21 showed increased efficacy between six months (74%) to one year (77%) after vaccination [ 30 ]. RTS,S, was the most-studied vaccine. RTS,S showed good efficacy (55%) up to one year after vaccination, but this decreased over time [ 24 , 55 ], with efficacy around zero after four years and negative in areas with high malaria exposure at five years of follow-up [ 55 ]. RTS,S was found to prevent clinical malaria cases in infants and children over three to four years and was further enhanced by administering a booster dose [ 63 ]. Emerging evidence suggests that the efficacy of vaccines like RTS,S increases when combined with seasonal malaria chemoprophylaxis [ 63 ]. The concomitant use of malaria vaccines with other control measures is therefore seen to be an important mitigation strategy in areas of high transmission.

Adverse events were reported in all studies. The most common adverse events were injection site pain and fever. Most adverse events were reported to subside within one week of appearance. Serious adverse events were rare (0.1–1%). Serious adverse events can occur following vaccinations, with about 1% of participants developing events such as febrile convulsions following malaria vaccines [ 23 , 25 , 35 , 58 , 61 , 62 , 63 ]. This was particularly observed in children within 2–3 days of receiving the RTS,S vaccine [ 35 ]. It is therefore possible that adverse events may arise following vaccination; however, further research is required.

Fear of unknown side effects associated with vaccines, especially newly developed ones, are often associated with low levels of acceptance [ 79 ]. Willingness to accept the malaria vaccine ranges from 32.3% in Ethiopia to 96% in Sierra Leone [ 21 , 26 ]. However, a number of factors are likely to affect the use of malaria vaccines in many African communities, including inadequate knowledge, misconceptions, availability of vaccines, and logistics.

This review has identified that knowledge about malaria vaccines is not widespread throughout Africa. Vaccine awareness was slightly lower than vaccine acceptance; however, people may have been reluctant to accept the newly developed malaria vaccines because of generalized vaccine hesitancy in some parts of Africa. Vaccine hesitancy has been reported in the literature as a consequence of misinformation about vaccine origin, efficacy, and safety, and psychological factors such as anxiety [ 80 , 81 ]. In addition to these factors, political influences, religious beliefs, and low perception of risk combine to contribute to vaccination rates in sub-Saharan Africa [ 79 , 80 ]. The extent of vaccination hesitancy may vary according to people's commitment to health protection and risk culture and their trust in conventional medicine and public health authorities. Evidence from the literature suggests that the lack of willingness to vaccinate may be due to a lack of knowledge, indifference, and irregular vaccination behavior [ 82 ]. Public education campaigns on vaccination programs are therefore important to support behavior change.

The findings of this review could assist public health experts and policymakers in Africa to develop and implement strategies to address the low acceptance and use of malaria vaccines. Wide-spread adoption of malaria vaccines is possible if awareness campaigns provide adequate factual explanations to counter rumors and mis-information [ 6 , 83 ]. Increasing local vaccine production within the African continent may further promote the use of malaria vaccines. Local production may help reduce mistrust through technology transfer. To raise awareness about vaccination, it is important to take a context-specific approach involving community and religious leaders [ 84 , 85 ]. The provision of credible information to communities by trusted sources is an important strategy to promote vaccination uptake.

There are some limitations to this review. Due to recent advances in malaria vaccines and the recommendations of Schwartz et al. [ 9 ] only studies published since 2012 were included. The scope of this review summarizes the existing evidence and highlights areas for more in-depth analysis in the future.

Different types of malaria vaccines have different efficacy levels, and combining seasonal malaria prophylaxis with a malaria vaccine might increase effectiveness. A variable degree of protection from malaria infection is provided by malaria vaccines with severe adverse events only occurring rarely. Many African communities have a high perception of malaria vaccines, but knowledge of the vaccine is relatively low. Further research and community involvement are needed to respectively improve vaccine efficacy and ensure successful widespread use in African communities.

Data availability

All data used in this review will be made available on request through the corresponding author.

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A community engagement framework to accelerate the uptake of malaria vaccines in Africa

• Nebiyu Dereje   ORCID: orcid.org/0000-0001-5406-4171 1 ,
• Mosoka Papa Fallah 1 ,
• Nicaise Ndembi 1 ,
• Alemayehu Duga   ORCID: orcid.org/0000-0003-3944-1025 1 ,
• Tamrat Shaweno 1 ,
• Merawi Aragaw   ORCID: orcid.org/0000-0001-7571-8795 1 ,
• Mohammed Abdulaziz 1 ,
• Ngashi Ngongo 1 ,
• Tajudeen Raji 1 &
• Jean Kaseya 1  

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Following the approval by the World Health Organization (WHO) of two new vaccines, RTS,S/AS01 and R21/Matrix-M, for malaria prevention in children, they are being administered in 12 malaria-endemic African countries, prioritizing areas with moderate to high transmission. These vaccines will be a game changer in the efforts to attain global elimination of malaria in the 35 or more malaria-endemic countries and achieve the Sustainable Development Goal of a 90% reduction in malaria incidence and mortality by 2030 1 . The vaccines are expected to prevent half a million child deaths annually. Addressing the cost and production limitation of the prior malaria vaccine (RTS,S/AS01), the new R21/Matrix-M vaccine will be mass produced and delivered at an affordable, minimal cost 2 . These new vaccines come at a critical moment when malaria prevention and control programs are challenged by the impacts of climate change, the emergence of insecticide and drug-resistant strains, and new variants of mosquitos, particularly in urban areas.

An additional challenge in Africa is vaccine hesitancy, which has been seen for other new vaccines, including against COVID-19. The COVID-19 vaccines activated widespread dissemination of vaccine conspiracies and misinformation 3 . Consequently, the general public have questioned the safety and quality of vaccines. For example, in Cameroon, the COVID-19 pandemic led to a substantial drop in pediatric attendance for routine childhood immunizations between 2020 and 2022, and these numbers have not yet returned to pre-pandemic levels 4 . In some cases, vaccinators have been targeted and attacked due to misinformation and conspiracies against vaccines, including the killing of polio vaccination workers in Afghanistan, Pakistan and Nigeria, with the attackers alleging that the vaccines are administered to sterilize Muslims 5 , 6 , 7 . This disinformation can quickly spread through communities, including via social media.

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Nebiyu Dereje, Mosoka Papa Fallah, Nicaise Ndembi, Alemayehu Duga, Tamrat Shaweno, Merawi Aragaw, Mohammed Abdulaziz, Ngashi Ngongo, Tajudeen Raji & Jean Kaseya

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Dereje, N., Fallah, M.P., Ndembi, N. et al. A community engagement framework to accelerate the uptake of malaria vaccines in Africa. Nat Med (2024). https://doi.org/10.1038/s41591-024-03193-2

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Safety and efficacy of PfSPZ Vaccine against malaria in healthy adults and women anticipating pregnancy in Mali: two randomised, double-blind, placebo-controlled, phase 1 and 2 trials

Collaborators.

• PfSPZ Vaccine Study Team : Moussa Traore ,  Mamoudou Samassekou ,  Oumar Mohamed Dicko ,  Oulematou N'Diaye ,  Youssoufa Sidibe ,  Sidi Mohamed Niambele ,  Kalifa Diarra ,  Kadidia Baba Cisse ,  Ibrahim Diarra ,  Amadou Niangaly ,  Balla Diarra ,  Karim Bengaly ,  M'Bouye Doucoure ,  Adama Dembele ,  Idrissa Samake ,  Bakary Soumana Diarra ,  Jacquelyn Lane ,  J Patrick Gorres ,  Omely Marte-Salcedo ,  Daniel Tran ,  Jillian Neal ,  Aissatou Bah ,  Mahesh Gupta ,  Yonas Abebe ,  Eric R James ,  Anita Manoj

Affiliations

• 1 Malaria Research and Training Center, University of Sciences, Techniques, and Technologies of Bamako, Bamako, Mali.
• 2 Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
• 3 Columbia University Medical Center, Columbia University, New York, NY, USA.
• 4 Clinical Monitoring Research Program Directorate, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
• 5 Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
• 6 Sanaria, Rockville, MD, USA.
• 7 Laboratory of Malaria Immunology and Vaccinology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. Electronic address: [email protected].
• PMID: 39153490
• DOI: 10.1016/S1473-3099(24)00360-8

Background: Plasmodium falciparum parasitaemia during pregnancy causes maternal, fetal, and infant mortality. Poor pregnancy outcomes are related to blood-stage parasite sequestration and the ensuing inflammatory response in the placenta, which decreases over successive pregnancies. A radiation-attenuated, non-replicating, whole-organism vaccine based on P falciparum sporozoites (PfSPZ Vaccine) has shown efficacy at preventing infection in African adults. Here, we aimed to examine vaccine safety and efficacy of the PfSPZ Vaccine in adults and women who anticipated conception.

Methods: Two randomised, double-blind, placebo-controlled trials (phase 1 MLSPZV3 and phase 2 MLSPZV4) were conducted at a clinical research centre in Mali. MLSPZV3 included adults aged 18-35 years and MLSPZV4 included non-pregnant women aged 18-38 years who anticipated conception within a year of enrolment. In MLSPZV3, participants were stratified by village and randomly assigned (2:1) using block randomisation to receive three doses of 9 × 10 5 PfSPZ Vaccine or saline placebo at weeks 0, 1, and 4 (4-week schedule) or at weeks 0, 8, and 16 (16-week schedule) and a booster dose around 1 year later. In MLSPZV4, women received presumptive artemether-lumefantrine twice per day for 3 days 2 weeks before dose one and were randomly assigned (1:1:1) using block randomisation to receive three doses of 9 × 10 5 or 1·8 × 10 6 PfSPZ Vaccine or saline placebo all administered at weeks 0, 1, and 4 (4-week schedule). Participants in both studies received artemether-lumefantrine 2 weeks before dose three and additionally 2 weeks before dose four (booster dose) in MLSPZV3. Investigators and participants were masked to group assignment. The primary outcome, assessed in the as-treated population, was PfSPZ Vaccine safety and tolerability within 7 days after each dose. The secondary outcome, assessed in the modified intention-to-treat population, was vaccine efficacy against P falciparum parasitaemia (defined as the time-to-first positive blood smear) from dose three until the end of transmission season. In exploratory analyses, MLSPZV4 evaluated incidence of maternal obstetric and neonatal outcomes as safety outcomes, and vaccine efficacy against P falciparum parasitaemia during pregnancy (defined as time-to-first positive blood smear post-conception). In MLSPZV4, women were followed at least once a month with human chorionic gonadotropin testing, and those who became pregnant received standard of care (including intermittent presumptive sulfadoxine-pyrimethamine antimalarial drugs after the first trimester) during routine antenatal visits. These studies are registered with ClinicalTrials.gov, NCT03510481 and NCT03989102 .

Findings: Participants were enrolled for vaccination during the onset of malaria seasons for two sequential studies conducted from 2018 to 2019 for MLSPZV3 and from 2019 to 2021 for MLSPZV4, with follow-up during malaria seasons across 2 years. In MLSPZV3, 478 adults were assessed for eligibility, of whom 220 were enrolled between May 30 and June 12, 2018, and then between Aug 13 and Aug 18, 2018, and 210 received dose one. 66 (96%) of 69 participants who received the 16-week schedule and 68 (97%) of 70 who received the 4-week schedule of the 9 × 10 5 PfSPZ Vaccine and 70 (99%) of 71 who received saline completed all three doses in year 1. In MLSPZV4, 407 women were assessed for eligibility, of whom 324 were enrolled from July 3 to July 27, 2019, and 320 received dose one of presumptive artemether-lumefantrine. 300 women were randomly assigned with 100 per group (PfSPZ Vaccine 9 × 10 5 , 1·8 × 10 6 , or saline) receiving dose one. First trimester miscarriages were the most commonly reported serious adverse event but occurred at a similar rate across study groups (eight [15%] of 54 with 9 × 10 5 PfSPZ Vaccine, 12 [21%] of 58 with 1·8 × 10 6 PfSPZ Vaccine, and five [12%] of 43 with saline). One unrelated maternal death occurred 425 days after the last vaccine dose in the 1·8 × 10 6 PfSPZ Vaccine group due to peritonitis shortly after childbirth. Most related adverse events reported in MLSPZV3 and MLSPZV4 were mild (grade 1) and frequency of adverse events in the PfSPZ Vaccine groups did not differ from that in the saline group. Two unrelated serious adverse events occurred in MLSPZV3 (one participant had appendicitis in the 9 × 10 5 PfSPZ Vaccine group and the other in the saline group died due to a road traffic accident). In MLSPZV3, the 9 × 10 5 PfSPZ Vaccine did not show vaccine efficacy against parasitaemia with the 4-week (27% [95% CI -18 to 55] in year 1 and 42% [-5 to 68] in year 2) and 16-week schedules (16% [-34 to 48] in year 1 and -14% [-95 to 33] in year 2); efficacies were similar or worse against clinical malaria compared with saline. In MLSPZV4, the PfSPZ Vaccine showed significant efficacy against parasitaemia at doses 9 × 10 5 (41% [15 to 59]; p=0·0069 in year 1 and 61% [36 to 77]; p=0·0011 in year 2) and 1·8 × 10 6 (54% [34 to 69]; p<0·0001 in year 1 and 45% [13 to 65]; p=0·029 in year 2); and against clinical malaria at doses 9 × 10 5 (47% [20 to 65]; p=0·0045 in year 1 and 56% [22 to 75]; p=0·0081 in year 2) and 1·8 × 10 6 (48% [22 to 65]; p=0·0013 in year 1 and 40% [2 to 64]; p=0·069 in year 2). Vaccine efficacy against post-conception P falciparum parasitaemia during first pregnancies that arose in the 2-year follow-up was 57% (14 to 78; p=0·017) in the 9 × 10 5 PfSPZ Vaccine group versus 49% (3 to 73; p=0·042) in the 1·8 × 10 6 PfSPZ Vaccine group. Among 55 women who became pregnant within 24 weeks after dose three, vaccine efficacy against parasitaemia was 65% (23 to 84; p=0·0088) with the 9 × 10 5 PfSPZ Vaccine and 86% (64 to 94; p<0·0001) with the 1·8 × 10 6 PfSPZ Vaccine. When combined in a post-hoc analysis, women in the PfSPZ Vaccine groups had a non-significantly reduced time-to-first pregnancy after dose one compared with those in the saline group (log-rank test p=0·056). Exploratory maternal obstetric and neonatal outcomes did not differ significantly between vaccine groups and saline.

Interpretation: PfSPZ Vaccine was safe and well tolerated in adults in Mali. The 9 × 10 5 and 1·8 × 10 6 doses of PfSPZ Vaccine administered as per the 4-week schedule, which incorporated presumptive antimalarial treatment before the first vaccine dose, showed significant efficacy against P falciparum parasitaemia and clinical malaria for two malaria transmission seasons in women of childbearing age and against pregnancy malaria. PfSPZ Vaccine without presumptive antimalarial treatment before the first vaccine dose did not show efficacy.

Funding: National Institute of Allergy and Infectious Diseases, National Institutes of Health, and Sanaria.

Copyright © 2024 Elsevier Ltd. All rights reserved.

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Conflict of interest statement

Declaration of interests TM, NKC, BKLS, PFB, TLR, and SLH are employees of Sanaria, the developer and sponsor of Sanaria PfSPZ Vaccine. All other authors declare no competing interests.

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Malaria vaccine candidate provides lasting protection in trials

by NIH/National Institute of Allergy and Infectious Diseases

Two trials of an experimental malaria vaccine in healthy Malian adults found that all three tested regimens were safe. The findings are published in The Lancet Infectious Diseases journal.

One of the trials enrolled 300 healthy women ages 18 to 38 years who anticipated becoming pregnant soon after immunization. That trial began with drug treatment to remove malaria parasites, followed by three injections spaced over a month of either saline placebo or the investigational vaccine at one of two dosages.

Both dosages of the vaccine candidate conferred a significant degree of protection from parasite infection and clinical malaria that was sustained over a span of two years without the need for a booster dose —a first for any malaria vaccine .

In an exploratory analysis of women who conceived during the study, the vaccine significantly protected them from malaria in pregnancy. If confirmed through additional clinical trials, the approach modeled in this study could open improved ways to prevent malaria in pregnancy.

Spread by Anopheles mosquitoes, malaria parasites, including those of the species Plasmodium falciparum (Pf), can cause illness in people of any age. However, pregnant women, infants and very young children are especially vulnerable to life-threatening disease. Malarial parasitemia in pregnancy is estimated to cause up to 50,000 maternal deaths and 200,000 stillbirths in Africa each year.

The trials were co-led by investigators from the NIH's National Institute of Allergy and Infectious Diseases (NIAID) and the University of Sciences, Techniques and Technologies, Bamako (USTTB), Mali.

The investigational vaccine used in both trials was PfSPZ Vaccine, a radiation-attenuated vaccine based on Pf sporozoites (a stage of the parasite's lifecycle), manufactured by Sanaria Inc., Rockville, Maryland. Multiple previous clinical trials of PfSPZ Vaccine have shown it to be safe, including in malaria-endemic countries such as Mali.

In results published in 2022, for example, an NIAID-sponsored, placebo-controlled trial of a three-dose regimen of PfSPZ Vaccine in Burkina Faso found that the vaccine had up to 46% efficacy that lasted at least 18 months.

In the first year of the current trial, 55 women became pregnant within 24 weeks of the third vaccine dose. Among these women, vaccine efficacy against parasitemia (whether before or during pregnancy) was 65% in those who received the lower dose vaccine and 86% in those who received the higher dose.

Among 155 women who became pregnant across both study years, vaccine efficacy was 57% for those who received lower dose vaccine and 49% in those in the higher dosage group.

Women who received the investigational vaccine at either of the dosages conceived sooner than those who received placebo, although this finding did not reach the level of statistical significance, reported the investigators. The researchers speculate that the PfSPZ Vaccine might avert malaria-related early pregnancy losses since parasitemia risk during the periconception period was reduced by 65 to 86%.

"Preconception immunization is a new strategy to reduce mortality for women with malaria in pregnancy," the researchers note. They plan to investigate the safety of the PfSPZ Vaccine administered during pregnancy, then examine the efficacy of PfSPZ given preconception or during pregnancy in larger clinical trials .

"Existing measures are not protecting women from malaria in pregnancy ," they added. "A safe and effective vaccine is urgently needed, and our results indicate PfSPZ Vaccine might be a suitable candidate," they conclude.

Additional information about the trials is available at clinicaltrials.gov using the identifiers NCT03510481 or NCT03989102 .

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Candidate malaria vaccine provides lasting protection in NIH-sponsored trials

Approach could have role in preventing malaria in pregnancy.

Two National Institutes of Health (NIH)-supported trials of an experimental malaria vaccine in healthy Malian adults found that all three tested regimens were safe. One of the trials enrolled 300 healthy women ages 18 to 38 years who anticipated becoming pregnant soon after immunization. That trial began with drug treatment to remove malaria parasites, followed by three injections spaced over a month of either saline placebo or the investigational vaccine at one of two dosages. Both dosages of the vaccine candidate conferred a significant degree of protection from parasite infection and clinical malaria that was sustained over a span of two years without the need for a booster dose—a first for any malaria vaccine. In an exploratory analysis of women who conceived during the study, the vaccine significantly protected them from malaria in pregnancy. If confirmed through additional clinical trials, the approach modeled in this study could open improved ways to prevent malaria in pregnancy.

Spread by Anopheles mosquitoes, malaria parasites, including those of the species Plasmodium falciparum ( Pf ), can cause illness in people of any age. However, pregnant women, infants and very young children are especially vulnerable to life-threatening disease. Malarial parasitemia in pregnancy is estimated to cause up to 50,000 maternal deaths and 200,000 stillbirths in Africa each year.  

The trials were co-led by investigators from the NIH’s National Institute of Allergy and Infectious Diseases (NIAID) and the University of Sciences, Techniques and Technologies, Bamako (USTTB), Mali. The investigational vaccine used in both trials was PfSPZ Vaccine, a radiation-attenuated vaccine based on Pf sporozoites (a stage of the parasite’s lifecycle), manufactured by Sanaria Inc., Rockville, Maryland. Multiple previous clinical trials of PfSPZ Vaccine have shown it to be safe, including in malaria-endemic countries such as Mali. In results published in 2022, for example, an NIAID-sponsored, placebo-controlled trial of a three-dose regimen of PfSPZ Vaccine in Burkina Faso found that the vaccine had up to 46% efficacy that lasted at least 18 months.

In the first year of the current trial, 55 women became pregnant within 24 weeks of the third vaccine dose. Among these women, vaccine efficacy against parasitemia (whether before or during pregnancy) was 65% in those who received the lower dose vaccine and 86% in those who received the higher dose. Among 155 women who became pregnant across both study years, vaccine efficacy was 57% for those who received lower dose vaccine and 49% in those in the higher dosage group.

Women who received the investigational vaccine at either of the dosages conceived sooner than those who received placebo, although this finding did not reach the level of statistical significance, reported the investigators. The researchers speculate that the PfSPZ Vaccine might avert malaria-related early pregnancy losses since parasitemia risk during the periconception period was reduced by 65 to 86%.

“Preconception immunization is a new strategy to reduce mortality for women with malaria in pregnancy,” the researchers note. They plan to investigate the safety of PfSPZ Vaccine administered during pregnancy, then examine the efficacy of PfSPZ given preconception or during pregnancy in larger clinical trials. “Existing measures are not protecting women from malaria in pregnancy,” they added. “A safe and effective vaccine is urgently needed, and our results indicate PfSPZ Vaccine might be a suitable candidate,” they conclude.

The PfSPZ Vaccine Study Team was led by Alassane Dicko, M.D., of the Malaria Research and Training Center (MRTC), USTTB, Mali, Stephen L. Hoffman, M.D., of Sanaria Inc., and Patrick E. Duffy, M.D., of the NIAID Laboratory of Malaria Immunology and Vaccinology. Joint co-first authors were Halimatou Diawara, M.D., of MRTC, and Sara A. Healy, M.D., NIAID.

Additional information about the trials is available at clinicaltrials.gov using the identifiers NCT03510481 or NCT03989102 .

H Diawara et al. Safety and efficacy of PfSPZ Vaccine against malaria in healthy adults and women anticipating pregnancy in Mali: two randomised, double-blind, placebo-controlled, phase 1 and 2 trials . Lancet Infectious Diseases DOI: 10.1016/ S1473-3099(24)00360-8 (2024).

Patrick E. Duffy, M.D., Chief, Laboratory of Malaria Immunology and Vaccinology, NIAID, is available to comment.

To schedule interviews, please contact Anne A. Oplinger, (301) 402-1663, [email protected] .

NIAID conducts and supports research—at NIH, throughout the United States, and worldwide—to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website .

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov .

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Malaria Vaccine Development and How External Forces Shape It: An Overview

Veronique lorenz.

1 Center of Anatomy, Medical School, University of Cologne, Cologne 50937, Germany; E-Mail: [email protected]

Gabriele Karanis

2 National Research Center for Protozoan Diseases, Obihiro University for Agriculture and Veterinary Medicine, Hokkaido 080-8555, Japan; E-Mail: ed.oohay@ldyokeleirbag

3 Centre for Biomedicine and Infectious Diseases (CBIF), Qinghai Academy for Veterinary Medicine and Animal Sciences, Qinghai University, Xining, Qinghai 810016, China

Panagiotis Karanis

The aim of this paper is to analyse the current status and scientific value of malaria vaccine approaches and to provide a realistic prognosis for future developments. We systematically review previous approaches to malaria vaccination, address how vaccine efforts have developed, how this issue may be fixed, and how external forces shape vaccine development. Our analysis provides significant information on the various aspects and on the external factors that shape malaria vaccine development and reveal the importance of vaccine development in our society.

1. Introduction

According to the WHO, a child dies of malaria every 30 seconds. In 2008, the malaria burden comprised nearly 250 million cases of the disease, causing nearly one million deaths [ 1 ]. The economically disadvantaged are the most afflicted by the disease, resulting in a deterioration of economic status in highly endemic countries [ 2 ]. The decrease in per capita economic output is estimated at 50% compared to non-malarious countries [ 3 ]. Currently, half of the world’s population is at risk for malaria infection; infants and pregnant women are particularly vulnerable to severe morbidity and mortality due to malaria infection [ 2 , 4 ]. The greatest number of malaria cases occurs in sub-Saharan Africa; however, Asia, Latin America, the Middle East and parts of Europe are also afflicted [ 2 ].

2. Malaria Vaccine Development: Overview

2.1. malaria—an underestimated danger in the west.

The massive incidence of malaria in the Third World makes the pressing need for further vaccine development undeniable. In the backdrop of malaria treatment, drug resistance and insecticides, appropriate means of disease control are currently lacking; the development of a vaccine remains the only tool for disease eradication.

Public interest in climate change is closely intertwined with concerns about the increased spread of tropical infectious diseases in Western countries. This development will heighten awareness and increase public demand for malaria vaccine research.

Currently, the degree of knowledge regarding infectious disease risk factors, reflected by the prevention measures taken by travellers to malaria-endemic countries, appears dissatisfactory and calls for improvement via public information campaigns [ 5 ]. Among the pivotal factors that will amplify future confrontation with malaria are globalisation and migration [ 5 ].

In light of highly-developed socioeconomic structures, the malaria disease risk appears to be minimal in Western societies. Consequently, diagnostics and therapies quite likely would contribute to impeding the formation of a human reservoir [ 6 ]. Still, the lack of familiarity and expertise with the vast range of clinical malaria features may result in potentially lethal misdiagnoses in western medical systems. Important differential diagnoses, which occur with higher frequency, include gastroenteritis and influenza [ 7 ].

Equally problematic is the widespread lack of effort in collecting information for thorough case histories. A stay in a malaria-endemic area or a previous malaria infection with current relapse, in cases of P. vivax and P. ovale , may be overlooked.

An illustrative example of the misdiagnosis of malaria is the case of a 38 year-old Munich man who, upon his return from Kenya, displayed textbook symptoms of malaria, which doctors failed to recognise. After a diagnosis of influenza, no further diagnostic measures were performed and the patient expired [ 8 ].

This case helps broaden our understanding of the reasons for the considerable, approximately 3.9% malaria case fatality in Germany [ 9 ]. In the context of our highly developed health infrastructure, the impressive number of lethal cases confronts us with our inadequate knowledge of tropical diseases in general, and malaria specifically, that requires improvement [ 10 ].

2.2. Lessons Learnt

The history of malaria allows us to identify how humankind substantially increased the spread of malarial disease: the invasion of the mosquito’s habitat initiated the exposure of humans to vector-borne disease.

Equally important in the analysis of malaria history is our understanding of the major impact of social and political structures on disease endemicity [ 11 ]. For instance, the U.S. support of malarious countries during the Cold War depended on a country’s obedience to political U.S. leadership. This flawed arrangement strongly contributed to unsuccessful eradication attempts, as ineffective intervention methods strongly contributed to insecticide resistance [ 12 ].

The latest intervention programmes have proven efficacy. Nevertheless, we must cautiously reflect on the lesson learned with DDT that proved how attempts at unilateral disease eradication are prone to failure. Various scientific approaches to malaria eradication do not take into consideration the economic aspects of disease endemicity: malaria is a disease of the poor. For example, economic status, the use of insecticide-treated bed nets and children’s anti-malaria treatment are positively correlated [ 11 ].

The Global Malaria Strategy already recognised how a multidimensional approach to disease eradication also must include the general improvement of standards of living: “Malaria control is not the isolated concern of the health worker. It requires partnership of community members and the involvement of those involved in education, the environment in general, and water supply, sanitation and community development in particular. Malaria control must be an integral part of national health development and health concerns must be an integral part of national development programmes”. However, these rightly formulated ideas still await fulfilment [ 11 ].

The underlying rationale for the widespread focus on a scientific micro-cosmos requires thorough analysis. Firstly, Western interests in malaria medication and vaccine development may be attributed to egoistic intentions. Western travellers, who represent the most desirable target group on an economic basis, would directly benefit from a vaccine against pre-erythrocytic malaria stages.

Secondly, researchers have frequently and correctly been characterised as competitors getting lost in episodes of rivalry that hamper research through a lack of collaboration. One of the earliest documented examples of this misbehaviour in malaria research was between Grassi and Ross.

Most importantly, we must focus on our goal: the development of an efficacious vaccine that is required to eradicate malaria. The example of smallpox vaccination and eradication provides this evidence. Nevertheless, the eradication of malaria, a vector-borne disease, calls for interventional processes, broadened from a medical basis to a socioeconomic context [ 13 ].

2.3. Why Have All Vaccine Approaches Remained Unsuccessful So Far?

Almost all scientific reviews about the currently most advanced vaccine candidate RTS,S come to a clear consensus: the formidable task of malaria disease eradication will not be accomplished with this vaccine.

Its main component is the sporozoites’ surface protein, the so-called circumsporozoite protein (CSP). The abbreviation RTS,S, includes an “R” for the B-cell repeat epitope of the CSP, a “T” for the T-cell epitope region of the CSP and an “S” for the hepatitis B surface antigen [ 14 ].

The hepatitis B surface antigen protein is grown in yeast and can spontaneously form virus-like particles with high immunogenicity. A fusion of CSP to the hepatitis surface antigen protein is performed to enhance the production of antibodies against CSP. To maintain the hepatitis B surface antigen’s ability to self-assemble, one part RTS is mixed with four parts hepatitis B surface antigen. A crucial step of vaccine engineering lies in the combination of these components with an adjuvant named AS02, which consists inter alia of lipids and an extract from the Chilean soapbark tree [ 13 ]. The typical standard aluminium adjuvant was discredited for application in a malaria vaccine, as it mainly evokes antibody responses. Due to the Plasmodium’s highly advanced immune evasion capabilities, a sole antibody response was regarded as insufficient, and the use of an adjuvant also supporting the T-cell response was favoured instead [ 15 ].

Despite these considerations, the lack of enduring protection remains a major disadvantage of this vaccine approach. Results of Phase III trials from 2013 displayed moderate results with 46% fewer cases of clinical malaria and a reduction in severe malaria by approximately 36% in infants aged 5 to 17 months, who were vaccinated once with RTS,S [ 16 ]. However, trials performed over a longer period showed a massive time-related decline in RTS,S’ efficacy. An efficacy of 16,8% was calculated for infants vaccinated three times after a follow-up of 4 years [ 17 ]. Pivotal for these disappointing trial outcomes, appears to be the brevity of antibody response [ 13 ]. The discouraging results with the precursor subunit vaccine, SPf66 (Serum Plasmodium falciparum version 66) had already indicated how the basis of the vaccine approach might be flawed [ 18 ].

In the late 1980s, Manuel E. Patarroyo, a Colombian, developed the vaccine SPf66 consisting of a polymer, which contained peptides from the surface of the merozoite (MSP-1 among others) and CSP. The first testing of SPf66 was performed in monkeys and then in humans. Trials from 1993 conducted in Brazil, Colombia, Ecuador and Venezuela with 41,000 people appeared to bode rather well, documenting an efficacy between 40% and 60%, although criticism was voiced concerning trial procedures. The trials had been performed without a control group and did not follow the gold standard of double blindness. The trials that followed, conducted with children in Tanzania and Thailand, also delivered disappointing data: very minimal data were collected and two years after vaccination, no protection against malaria infection was reported [ 19 ].

As research on the genome of P. falciparum demonstrated, it comprises approximately 5400 protein-coding genes with some only expressed at specific stages [ 20 ]. Disappointing results with a vaccine candidate that triggers antibodies only against a single surface protein therefore do not appear surprising.

Apart from its failure to trigger enduring strong immunity to malaria, the candidate RTS,S again revealed how extensively vaccine candidates are tested before their market release. Approximately 30 years will have elapsed from its first development to market release. In general, this constant and persistent concentration on one vaccination candidate bears the danger of neglecting other possibly sensible approaches to vaccination. However, a research programme that already includes 20 years of research, partly financed by a private company and improving the image of the latter, appears unlikely to be terminated without the prospect of a profitable outcome.

To guarantee the highest quality and safety of future vaccine candidates, we can anticipate that they will be subject to similar extensive and expensive trials, making the probability of the release of an efficacious malaria vaccine within the next 10 years unrealistic.

Other vaccine candidates display additional highly problematic flaws, making them prone to fail in solving the formidable task of malaria disease limitation. Proponents of an approach targeting the erythrocytic stages neglect the fact that P. vivax and P. ovale can develop so-called hypnozoites inside the liver and potentially cause a relapse of disease even after many years.

More importantly, the antigenic diversity of the parasite’s erythrocytic stages appears to primarily drive immune evasion. Finding a vaccine that successfully disrupts the life cycle at this point therefore appears to be elusive.

However, research on the erythrocytic stages of malaria has delivered significant scientific material. The evolution of erythrocytic cell defences that develop in response to malaria directs our attention to two significant phenomena: firstly, the human immune system has proven unable to combat the Plasmodium and has adapted to coexistence with the parasite. This elucidates how an imitation of natural responses may be a flawed approach to malaria vaccine development. The frequently described “clinical immunity” does not meet the criteria of the actual term “immunity”. Individuals do not avoid infection; instead, they suffer from repeated infections with malaria but experience fewer clinical symptoms. Nevertheless, they represent a human reservoir for the Plasmodium. Our goal must be to limit this human reservoir by vaccination to yield long-term reductions in the number of malaria transmissions. Secondly, the red cell defences are a reminder of the remarkably long history of malaria.

According to the author Paul W. Ewal, microbiologist René Dubos claimed in 1965, “ Given enough time a state of peaceful coexistence eventually becomes established between any host and parasite ” [ 21 ]. The extent to which the coexistence of, for instance, sickle-cell disease and malaria really is peaceful, remains to be discussed, as individuals with sickle-cell disease have a decreased life expectancy compared to healthy individuals [ 22 ]. Therefore, the proposal of host-directed drugs that imitate natural host defences appears to be problematic [ 23 ]. Bearing in mind the successful forms of malaria medication, the risks do not outweigh the costs of this form of malaria treatment.

Unfortunately, the one natural host change that sufficiently prevents infection and is not accompanied by any health-impairing consequences for the host is the Duffy antigen null. Individuals with the Duffy antigen null are protected from P. vivax but not from P. falciparum . However, we might expect René Dubos’ prognosis also to come true for the youngest form of the Plasmodium in the future: with evolutionary changes that peacefully impede the P. falciparum erythrocyte interaction.

The erythrocytic stage as a point of intervention into the Plasmodium’s life cycle is clearly too late and therefore insufficient; the parasite’s capacity to hide inside human cells hinders a successful disruption of the life cycle. If the vaccine approach is targeted to the erythrocytic surface, the parasite can evade destruction through antigenic variation. Intracellular structures, therefore, seem to represent a more reasonable approach. Still problematic is the possibility of autoimmune responses due to structural similarities between human and parasite metabolism that impede the proposed approaches [ 24 ].

Secondly, and more importantly, this vaccine approach is not particularly attractive for Western travellers, who, although they represent only a fraction of the vaccine target group, majorly drive research efforts [ 25 ]. Research, after all, is predominantly performed in Western countries.

Vaccine approaches targeting the life cycle at an even later point face other hurdles. Approximately 60 years have elapsed since the first theories on transmission-blocking vaccination were presented on the basis of investigations with chickens vaccinated with avian sexual and asexual stage malaria parasites and were shown to develop a form of transmission-blocking immunity [ 26 ].

Among the first candidates suggested were the proteins Pfs 25 and Pfs 28 that are exclusively displayed on the surface of ookinetes and zygotes in the mosquito stage of infection [ 27 ]. Considered to be possibly problematic is their lack of natural occurrence in humans that impedes a boosting by natural infection and represents the cause of the protein’s low immunogenicity [ 28 ].

The analysis of malaria history reveals how malaria is a dynamic disease accompanied by mutations in the host and, as ongoing research on antigenic variation reveals, also in the Plasmodium itself [ 4 ]. It therefore appears highly doubtful that manipulation of the Anopheles mosquito or the sexual stages of the Plasmodium and the involved proteins required for the completion of the life cycle will lead to an enduring limitation of disease. Not only can an alteration of Plasmodium surface proteins be expected to hamper intervention attempts in mid-gut and salivary gland invasion, but it also seems that an altered virulence or even the adaption to a new vector is likely to bypass the interventional approaches targeting the vector (e.g., sterile insect technology). After all, the parasite has proven its magnificent adaption capacities in the past.

Finally, a vaccine approach that is often praised as a milestone, apparently demonstrating how sterile immunity can be reached, is that of whole-parasite vaccines. The first successful trials based on the theory of whole-parasite malaria vaccines were conducted in birds, which were partially immune against infection after immunisation with killed sporozoites or sporozoites inactivated with ultraviolet light [ 29 ].

Nussenzweig et al. (1967) chose a different mechanism for the attenuation of sporozoites and vaccinated mice with X-irradiated sporozoites of P. berghei [ 30 ]. The results revealed a more than 90% protection in mice to challenge with unattenuated sporozoites that persisted approximately 2 months [ 29 ].

Evaluations of this approach seem overly optimistic as the trials were in fact conducted with a very limited number of volunteers and ultimately failed to exhibit enduring immunity. Consequently, it seems unwise to rely on these results for future vaccine approaches.

There are additional major organisational hurdles that impede the idea of performing mass immunisation with X-irradiated mosquitoes infected with P. falciparum. Among other issues, the attenuated parasites would have to be stored frozen, which is an additional financial burden and is especially problematic in those tropical countries, which represent the main target group of malaria vaccination [ 31 ].

2.4. What Do We Expect of Future Malaria Vaccine Candidates?

Before analysing the various possibilities and approaches to malaria vaccination, a definition of our expectations for a malaria vaccine is required.

Currently, applied vaccines obtain a relatively high rate of efficacy, approximately 90% [ 32 ].

With regard to a potential malaria vaccine, many scientists agree that these high standards will not be met. It was frequently stated how sterile immunity elicited through a vaccine could not be expected due to the lack of real natural immunity to malaria. Indeed, scientific data only offers cases of the before-quoted clinical immunity that decreases disease burden [ 4 ]. The ambitious aim then could be to develop a vaccine candidate eliciting an immune response that is superior to the natural response to infection [ 33 ].

Other scientists, though, are less optimistic and, with regard to many years of limited success, come to the conclusion that even a rather poorly performing vaccine such as RTS,S could accomplish a massive reduction of malaria lethality [ 13 ].

Even so, from an economic point of view, this approach finds less approval. A vaccine with low efficacy is much less cost effective in contrast to scaling up malaria treatment and investing in vector control programmes such as insecticide-treated bed nets [ 34 ]. Related to these economic factors, it has even been proposed to extend disease control with interventional methods and to terminate the thus far unsuccessful malaria vaccine research. Surely this must be regarded as a rather naive proposal: the major hurdle of resistance against malaria medication and insecticides remains unscathed and can be expected to occur with every new medication or insecticide. A vaccine against malaria is still required; however, it will have to be cost effective and elicit enduring and strong immune responses [ 20 , 34 ]. Otherwise, the useful resources that could be applied for more sensible vaccine approaches and effective interventional methods will be lost.

At this point, we must define vaccine efficacy and clearly state that efficacy would be characterised by a parasitaemia of individuals living in malaria-endemic areas of approximately zero. This has a deeper rationale due to the fact that the human reservoir that distinguishes malaria endemicity from so many other infectious diseases must be combated to achieve malaria eradication.

A further significant aspect of vaccine development that should be considered is the target group. For economic reasons, it would be middle-aged Western travellers, but from a sensible point of view, it would be young infants <1 year of age and pregnant women in whom the vaccine candidate should prove efficacy.

The illustrative numbers are as follows: in Sub-Saharan Africa, malaria infection causes approximately 400,000 cases of severe maternal anaemia and up to 200,000 infant deaths a year [ 35 ]. Therefore, it is lamentable that research in areas such as the proposed vaccine for mothers sees so little progress in comparison to candidates such as RTS,S. Nonetheless, RTS,S hopefully will contribute to a reduction in child mortality from malaria, as it may give small infants additional time to develop a form of clinical immunity. However, it is essential to insist on the long-term goal of the global malaria vaccine community and continue along this arduous path that hopefully will lead us to a malaria vaccine with 80% efficacy by 2025 [ 36 ].

2.5. What Kind of Research Do We Need for the Successful Development of a Malaria Vaccine?

The review of malaria research findings and even the latest approaches to malaria vaccination intriguingly reveal how incomplete the scientific knowledge of the molecular processes of the Plasmodium’s life cycle is. Especially, the initiation of infection; the skin stage represents a stage of the life cycle that awaits further detailed investigation [ 37 ]. Looking back on many years of malaria research, it stands out that establishing a deepened comprehension of the actual life cycle may be the crucial requisite before an efficacious vaccine candidate can be developed.

It appears striking why so few scientists have thus far insisted on basic research before initiating research on a specific vaccine candidate. The answer may again be rooted in a hunt for personal prestige, which is surely not guaranteed for those standing at the beginning of a long research path. Scientific acknowledgement or even a Nobel Prize presumably awaits the scientist eventually developing the long-desired vaccine; therefore, it appears much more interesting for scientists to directly participate in a project for a specific vaccine candidate. Clearly, the ongoing participation in clinical trials of certain vaccine candidates also offers greater possibilities for publication than long-winded basic research that may lead to inconclusive results.

The importance of basic malaria research has a profound reason that separates the hunt for a malaria vaccine from all the other past vaccine developments: malaria is a parasitic disease, and currently, no human vaccine against any parasitic disease exists [ 38 ]. Therefore, the argument of the very successful smallpox vaccine having been developed with little knowledge of host immunology can be easily refuted, as the sheer complexity of the Plasmodium parasite’s genome in comparison to the smallpox virus justifies our call for basic research [ 19 ].

Parasitism is defined by the parasite being able to live at the expense of the host; this is an unpalatable fact that clearly divides malaria from other infectious diseases [ 39 , 40 ]. A parasitic characteristic of outstanding significance is its ability to evade the immune system successfully. There are numerous immune evasion mechanisms within the life cycle.

Trials in mice suggested that the induction of immunotolerance starts early within the life cycle. The presence of sporozoites within the skin was demonstrated to increase the mobility of skin Tregs; furthermore, a lower proliferation of skin-migrated CD4-cells could be noted [ 41 , 42 ].

Additionally, it stands out that each stage of the parasite’s life cycle is characterised by certain antigens making the number of antigens expressed altogether so broad that it seems unlikely that a vaccine intervening at one certain point will successfully disrupt the entire life cycle. The vaccine would have to exhibit an unrealistic 100% efficacy to prevent the deployment of subsequent stages of the life cycle, which can again rapidly reproduce [ 11 ].

Thus far, scientists have failed to tackle the challenge of parasitic immune evasion; even so, specific stages of the life cycle appear more promising than those we have focused on so far. We therefore propose an intervention that is efficacious before the parasite’s immune evasion: an intervention targeting the skin.

2.6. The Skin as a Malaria Vaccination Target

Considering the density of the Langerhans cells and DCs inside the skin, which is higher than inside the muscle, this first barrier of our immune system may halt the parasite’s invasion altogether [ 41 , 42 ]. The first immune response is based on the Langerhans cells internalising antigens and inducing a T-cell response in the draining lymph node [ 43 ]. By contrast, the majority of currently available vaccines give rise to humoral responses [ 41 ]. Nevertheless, the analysis of the Plasmodium ’s life cycle clearly indicates how only a cellular immune response can combat the Plasmodium during the skin stage. A humoral response is unlikely to be competent for terminating the sporozoites’ migration process through the dermis, which is based on cell traversal [ 44 ].

The likely solution of transdermal vaccinations is also appealing for the following reasons: enhanced compliance and a decreased problem of safe syringe disposal, which are undoubtedly strong advantages [ 43 ].

In combination with the novel application route of transdermal vaccination, we can expect new vaccine compositions, especially DNA vaccination, to burst further into the limelight.

Veterinary medicine creates a role model pathway that will expectedly be followed by human medicine. Two DNA vaccines and therapies that were both released in 2007 must be especially emphasized: the canine melanoma vaccine and GHRH (growth hormone releasing hormone), which is applied in swine. The two vaccines target very different problems; the melanoma vaccine is a form of tumour therapy. In contrast, GHRH is a preventive vaccine with decreased perinatal mortality and morbidity [ 45 ].

The DNA vaccination is based on the following construction: a plasmid, which is a circular piece of bacterial DNA, genetically modified to produce proteins of a certain microbe or virus, is inserted into a human cell. The host cell expresses proteins on the basis of this new DNA and the immune system recognises these as foreign [ 45 ]. Most DNA vaccines that are subjects of current research programmes do not integrate into the host’s cellular DNA; they only enter the nucleus [ 46 ].

The canine melanoma vaccine serves as an illustrative example to deepen insight into the process of DNA vaccination. The vaccination results in an expression of the human tyrosinase gene, which differs from canine’s tyrosinases and thus evokes an immune response in dogs. Importantly, the human tyrosinase resembles the canine’s tyrosinase to an extent high enough to induce down-regulation of the canine’s tyrosinase as well. This serendipitous fact efficiently inhibits tumor growth [ 47 ].

There is wide agreement that one of the major immunological advantages of DNA vaccination is the activation of CTL-cells. CTL-cells require antigen presentation through MHC I, which is achieved either through direct transfection of the APCs by the plasmid vaccine or through cross-presentation. The term of cross-presentation describes the APC’s ability to ingest infected necrotic or apoptotic cells and present the exogenous antigen via MHC I [ 46 ].

A further pivotal argument in favor of DNA vaccination is economic. An attractive property of DNA vaccination is its inexpensive and pure manufacturability, which does not encounter the various production hurdles of other vaccine approaches [ 47 ].

Currently, efforts are ongoing to face a problematic weakness of DNA vaccines: their rather low immunogenicity in humans [ 46 ]. The DNA vaccination advancements made in veterinary medicine appear to be significant developments pioneering a future vaccine for humans. DNA vaccination is one of the novel approaches for developing a new generation of vaccines against malaria [ 48 ].

2.7. How Money and Research Funding Drive the Malaria Vaccine Efforts

Clearly, the investment in certain research areas is strongly influential to the acceleration or deceleration of research. The EU support provides an illustrative example. In 2009, basic malaria research was supported with €15.9 million. Research was coordinated by the French Pasteur Institute and concentrated on parasite genetics, cell biology and metabolism, pathogenesis, immunology and the mosquito vector. Malaria vaccine development was supported with only a little less: €13.5 million [ 49 ]. In 2006, resources were invested in 16 candidates that were in clinical development [ 36 ]. The value of these investments is controversial, especially with regard to the poor performance of the most advanced vaccine candidate; it offers a protection rate of only 30% [ 13 ]. Critics disapprove of the cost-intensive testing of ineffective vaccine candidates and demand that the generation of superior vaccine candidates be based on basic research [ 50 ].

Scientists appear to be pressured by the investing pharmaceutical companies and therefore tend to offer an overly optimistic hope of reaching the aim of a successful vaccination soon. An illustrative example is scientist William Trager, who in the 1970s stated in an unofficial context, “ We must promise a vaccine is on the horizon or else research funding will quickly dry up ” [ 39 ]. Evidence accumulates to suggest that this form of pressuring may in fact have slowed the research pathway and triggered a generation of various vaccine candidates that lacked a basic research background.

Generally, we are faced with the hurdle that vaccine development represents a scientific branch that includes long-winded and expensive regulatory processes and may even result in a rejection of the tested vaccine candidate. Given the cost and risks of the manufacturing process, very few companies show interest in malaria vaccine research and prefer to focus on research areas that are surely profitable [ 1 ].

These limiting economic factors massively hinder vaccine development and have contributed to the status quo with RTS,S, which has undergone cost-intensive development and will soon be released to the market, even if its efficacy remains highly doubtful.

Overall, the vaccine market was predicted to flourish in the future; however, this prognosis may be correct only for vaccine candidates for illnesses that are of concern in western societies, such as vaccines against cancer.

2.8. The Role of the State in Malaria Vaccine Development

The financial and scientific contributions to vaccine development should be accelerated through broader governmental support of vaccine industries. Furthermore, the extent of regulatory mechanisms of vaccine development may have to be reviewed to accelerate the development and market release of vaccine candidates. Especially regarding the demand for vaccine candidates that cause little to no adverse events, there appear to be exaggerated safety concerns, as the benefit of hundreds of successful vaccinations preventing serious diseases outweighs the cost of a very rare adverse event [ 51 ].

Additional support for vaccine development for diseases with predominant incidence in third-world countries is obviously favourable. The cost effectiveness of a sufficient vaccine will outweigh the massive costs of other interventional measures (e.g., bed nets, insecticide spraying) and malaria medications that currently are being utilised for disease limitation. Equally important is the economic stabilization of third-world countries, which also is of interest to western democracies. Endemic malaria infections and poverty are correlated and further linked to overall instability and a weak economy in affected countries [ 3 ]. Clearly, the community of economically successful countries should therefore feel an obligation to stabilise these countries that currently represent potentially threatening reservoirs of disease but also represent potential trade partners in the future.

Various measures show the potential to further enhance the development of life-saving vaccines, such as limited taxation for companies researching life-saving rather than profitable products and heightened support for vaccine manufacturers that face scientifically ill-founded trials raised by anti-vaccine movements [ 51 ].

Lastly, western states should have a vital interest in raising the awareness of parasitic diseases in the medical community. As previously discussed, malaria remains an underestimated danger in western countries. This is not only unfavourable and potentially dangerous in the event of an actual infection, but the lack of knowledge concerning malaria is, with regard to the current and future global impact of the disease, simply inadequate. Especially among medical students and the younger generation of doctors, most of whom have not been confronted with malaria patients, disease awareness must be increased through improved integration of the topic into their curriculum.

2.9. The Influence of the Public on Malaria Research and Control

The history of malaria and vaccination in general has shed light on the fact that public opinion massively influences the state’s application of certain forms of disease control and compliance within the population.

Clearly, the degree of knowledge about infectious diseases requires improvement and can be assumed to be directly correlated with population compliance with vaccination. The example of the polio vaccine supported by the campaign the March of Dimes in the 1940s and 1950s in the U.S. clearly illustrates how well-informed individuals who were personally affected by polio proved to be a great resource for encouraging public compliance with vaccine uptake [ 51 ].

Information politics must be forwarded before infectious diseases that are neglected by younger generations, such as measles, find an upsurge.

Equally important is that the western public can indirectly drive developments for third-world countries if the ongoing discussion on climate change brings the issue of infectious disease control further into the limelight.

2.10. What Can We Expect in the Near Future with Regard to Malaria Vaccine Development?

Generally, we can expect an extension of disease control based on vaccination in the future, with an increasing number of non-infectious diseases being targeted by vaccination. Concerning the unique effect of vaccination on general life expectancy so far, this must be considered a positive development [ 50 ].

Additionally, in contradiction to pessimistic evaluations on the unfavourable market of vaccine development, we might still hope for public-private partnerships to further enhance the development of the vaccine market, especially for vaccines that mainly target Third-World populations [ 50 ].

Notably, the vaccine market will not only broaden to include non-infectious diseases due to the increasing impact of chronic diseases, but we also can expect new techniques, including DNA vaccination, to open up doors for the thus far unsuccessful vaccination attempts.

However optimistic one might be, we must make a realistic prognosis and state that a highly effective malaria vaccine within the next ten years appears to be unrealistic based on the scientific status quo.

3. Conclusions

Due to the lack of an efficacious vaccine approach to date, vector control programmes, including insecticide-treated bed nets, artemisinin combination therapies and insecticides, have been applied. These measures are considered with the support of approximately $1 billion dollars and have been estimated to decrease the malaria disease burden by 90% (measured were cases of death and admissions to hospitals). Critical reports predict RTS,S, the currently most advanced vaccine candidate, would only improve these numbers by a meagre rate of 3%. Therefore, conclusions were drawn as to which only partially effective vaccination will yield poorer results than other malaria control measures.

Currently applied vaccines display a relatively high rate of efficacy, approximately 90%. With regard to a potential malaria vaccine, however, parts of the scientific community are in agreement that these high standards will not be met. Other scientists, though, conclude that even a rather ill performing vaccine such as RTS,S could accomplish a massive reduction of malaria lethality. Hopefully, RTS,S will particularly contribute to a reduction in child mortality, as it may provide infants with more time to develop a form of clinical immunity. Nonetheless, almost all the scientific reviews about the currently most advanced vaccine candidate RTS,S come to a clear consensus; the formidable task of malaria disease eradication will not be accomplished with this vaccine. As previously stated, the prospect of a lack of enduring protection remains a major disadvantage of this vaccine approach. The disappointing results with the precursor subunit vaccine SPf66 have already indicated how the basis of the vaccine approach might be flawed.

A generally reported problem concerning subunit vaccines and recombinant proteins is rooted in the fact that artificially produced proteins only partially resemble the conformation of the parasite protein. This aspect may constitute the crucial weakness of this vaccine development and contribute to the inadequate immune response.

Vaccine approaches targeting the skin stage of infection, as well as other approaches targeting pre-liver stages, are united by an essential advantage: they take into consideration that two species of the Plasmodium ( P. vivax and P. ovale ) induce the production of so-called hypnozoites in the liver. Other vaccine approaches intending to intervene at later stages of the Plasmodium’s life cycle neglect the fact that the hypnozoites, even after years of physical health, represent a serious threat, capable of causing a relapse of disease. The only recently discovered skin stage of infection requires further elaborated research before a promising vaccine candidate may be expected.

As malaria has been a disease affecting humankind for a very long time, it has been investigated to have had substantial influence on human genetics. Haldane pioneered hypothesising the possibility of natural selection, pressured by infectious diseases. Critically evaluated on the basis of scientific record and research, Haldane’s early “malaria hypothesis” could indeed be proven to be correct. The analysis of distinctive natural changes in erythrocytes might be highly advantageous for the development of a vaccine. For instance, the temporary induction of G6PD- (glucose-6-phosphate dehydrogenase) deficiency was proposed to mimic the natural immunity of individuals with this gene mutation against malaria. Furthermore, the evolution of erythrocytic mutations demonstrates the ineffectiveness of our natural immune response against malaria and reveals how vaccination may have to target the induction of a form of non-natural immunity.

Apart from genetic changes in humans, the parasite’s genetics also alter the course of an infection as a means of immune evasion, this is called antigenic variation. Ongoing research in the field of antigenic variation may greatly contribute to successful vaccine development: increased genetic knowledge concerning antigenic variation as well as our inter-individual different immune reactions and susceptibility to the Plasmodium may enable us to develop more effective vaccine approaches. Scientific research in endemic areas revealed how antibody responses dominantly contribute to the mammalian host’s defence mechanism against the blood stages of infection. The antibody analysis proved how they are not distinctly directed against any single antigen but operate broadly. Current observations imply the synergistic significance of cellular immunity and humoral immunity but demand our cautious review.

Additionally, malaria infections may even be influenced by co-infections. The immune reaction to malaria as well as the loss of immunity to malaria after leaving endemic areas requires further elucidation. A broadened knowledge of this natural human response to the Plasmodium represents a significant basis for future attempts of inducing non-natural immunity by vaccination.

Vaccine development specific to malarial disease in pregnant women, who are especially susceptible to malaria infection, appears to be a very reasonable approach that calls for advanced support in the future. The restricted target group, however, lowers the likelihood of noteworthy financial support through western countries.

Another field of vaccine approaches is represented by transmission-blocking vaccines. Sixty years have elapsed since the first theories on transmission-blocking vaccination were presented on the basis of investigations with chickens that were vaccinated with avian sexual and asexual stage malaria parasites and were shown to develop a form of transmission-blocking immunity. Transmission-blocking vaccines have been predicted to only extend disease control if applied in combination with other interventional methods, such as exposure prophylaxis and vector control. Alternatively, their usage in combination with poorly efficacious pre-erythrocytic vaccines or blood-stage vaccines might be proposed.

With regard to new approaches in vaccine application, we can expect plastid transformation to be of huge significance in the future, as it offers the possibility of foreign gene expression in high plants. The efficiency of plastid transformation requires the improvement of a routine application of plastid transformation that so far can only be documented for tobacco.

As long as no effective vaccine candidate is discovered, vector control remains a significant and highly political topic that always represents, whether conducted biologically or chemically, a massive intervention into the environment with possible harm to animals and humans. Because resistance to any form of chemical vector eradication can occur and sterile insect technique cannot offer broad protection, vector control as a form of malaria disease control must be considered a temporary measure that is required until the development of a vaccine is finally achieved.

Apart from the scientific micro-cosmos, we must look at the political and economic dimensions of malaria disease control; a successful malaria vaccination programme is strongly dependent on the financial interests of the pharmaceutical companies and efficient vaccine distribution mechanisms. After all, an effective vaccine that does not reach its target group for logistic reasons can prove no use.

Moreover, it remains a major future task to improve public understanding about vaccination and the massive impact of infectious diseases. Particularly in schools and kindergartens, enhanced information politics have proven to be highly effective and require further extension. Population compliance is of great importance: herd immunity with a vaccine uptake of 80%–90% is required for disease eradication.

While the research platform is driven forward, it must however, be acknowledged that malaria is a dynamic disease: simian malaria requires our consideration. Theories have been constructed as to the possible causes of this transmission from monkey to human. Reports on human infections with P. knowlesi have led scientists to the suggestion that P. knowlesi may be the 5th human malaria parasite. These parasite dynamics must be regarded in the development of new vaccine approaches. Vaccination with a certain protein could, for example, only offer protection against certain Plasmodium species.

Looking back on many years of malaria research, we can conclude that establishing a deepened comprehension of the actual life-cycle might be the crucial requisite before an efficacious vaccine candidate can be developed. The currently most advanced vaccine candidates lack this background and will therefore not serve the long-term goal of malaria eradication.

The public interest in climate change is closely interlinked with concerns about the increased spreading of tropical infectious diseases in Western countries. This development will presumably increase awareness and support the scientific community of malaria vaccine research.

Author Contributions

Veronique Lorenz and Panagiotis Karanis researched the literature and prepared the manuscript. Gabriele Karanis approved, corrected and edited the manuscript; designed the paper; and prepared the diagrams, figures, tables and references.

Conflicts of Interest

The authors declare no conflict of interest.

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Malaria vaccine implementation programme

As of October 2023, WHO recommends the programmatic use of malaria vaccines for the prevention of P. falciparum malaria in children living in malaria endemic areas, prioritizing areas of moderate and high transmission. This applies to both RTS,S/AS01 and R21/Matrix-M vaccines.

The first malaria vaccine, RTS,S, was recommended by WHO to prevent malaria in children in October 2021. The vaccine has reached nearly 2 million children in Ghana, Kenya and Malawi through the Malaria Vaccine Implementation Programme, MVIP, since 2019.

18 million doses of first-ever malaria vaccine allocated to 12 African countries for 2023–2025: Gavi, WHO and UNICEF

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The Strategic Advisory Group of Experts on Immunization (SAGE) / Malaria Policy Advisory Group (MPAG) Working Group on Malaria Vaccines is a body with up to 15 experts who support WHO in preparation of SAGE and MPAG deliberations on malaria vaccines and provide technical advice on the Malaria Vaccine Implementation Programme, MVIP.

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Sanaria® PfSPZ Vaccine protects women against malaria before and during pregnancy for at least two years

Sanaria Inc.

August 14, 2024 – In a report published in The Lancet Infectious Diseases ( Safety and efficacy of PfSPZ Vaccine against malaria in healthy adults and women anticipating pregnancy in Mali: two randomised, double-blind, placebo-controlled, phase 1 and 2 trials ) a team led by investigators at the Malaria Research and Training Center (MRTC), Bamako, Mali; the Laboratory of Malaria Immunology and Vaccinology (LMIV), National Institute of Allergy and Infectious Diseases, National Institutes of Health; and Sanaria Inc. describes the durable protective efficacy against malaria shown by Sanaria ® PfSPZ Vaccine when administered to women prior to pregnancy. The two clinical trials, led by Dr. Halimatou Diawara (MRTC) and Dr. Sara Healy (LMIV), were conducted in Ouélessébougou, Mali from 2018-2021. For the first time, immunization with a malaria vaccine has been shown to protect mothers from malaria during pregnancy and to protect for two transmission seasons without booster doses of vaccine.

Malaria during pregnancy is an enormous problem. Plasmodium falciparum (Pf) infection during pregnancy causes up to an estimated 50,000 maternal deaths and 200,000 stillbirths in Africa each year. “Better protection for the mother and developing fetus is urgently needed” said Professor Abdoulaye Djimde, Director of the Malaria Research and Training Center at University of Bamako. “PfSPZ Vaccine has an excellent safety profile and our teams have worked with NIH and Sanaria partners over the years to demonstrate its efficacy in Mali, where seasonal malaria transmission is intense.”

This trial recruited women who were planning to get pregnant in the coming year. After immunization, birth control was stopped in most and the women were followed through two malaria transmission seasons over nearly two years. Those who became pregnant were followed throughout their pregnancies, and newborns were followed up to their first birthday to measure long-term outcomes. The study included two vaccine groups that received low and high doses of the vaccine, respectively (100 women per group) and a placebo group receiving normal saline (also 100 women).

PfSPZ Vaccine was well-tolerated and safe for both the mothers and their offspring, with no differences evident in the rate or severity of adverse events compared to placebo. Vaccine efficacy against infection with malaria parasites in the lower dose group was as high or higher during the second year (61%) as during the first year, without boosting, a first for a malaria vaccine. Over the two seasons, efficacy against infection with malaria parasites during pregnancy was 57% in this group. In the high dose group, efficacy against malaria infection was 86% during the first year in women who became pregnant.

An unexpected finding was that pregnancy was detected earlier in the vaccine group than placebo. Although this effect had marginal statistical significance, it suggested that malaria infection likely aborts many early pregnancies before they are detected.  By preventing these early infections, vaccinated women appeared to become pregnant sooner. This was actually noticed by several of the mothers: “The vaccine, I love it” said one participant; “since the start of the study I have not had malaria.” Another participant stated: “I was unable to conceive for three years after getting married, but during the study I got pregnant”.

Alassane Dicko, who leads the team in Mali, said that assessing the efficacy of PfSPZ Vaccine in women who wanted to become pregnant was the next logical and ethical step. “We were excited to see significant vaccine efficacy against Pf infection not only in the first year but through a second intense malaria transmission when administered pre-conception. This is a tremendous advance for protecting women against malaria before and during pregnancy.  We were also surprised to find an additional positive outcome, that pregnancies developed sooner in vaccinated participants.”

Sanaria founder and CEO, Stephen L. Hoffman, MD said, “Sanaria’s PfSPZ Vaccine has a long and excellent safety and tolerability record, and has shown strong and durable protection against Pf infection in multiple studies in Africa. The results of this study in women of child-bearing potential demonstrate clearly its potential to save the lives of women and their unborn babies in Africa.” Hoffman believes the vaccine will be best administered to adolescent girls prior to any pregnancies, who would then get boosted at the time of pregnancy. A full immunization series would be given to any pregnant women not previously immunized. The next step will be to demonstrate the safety and efficacy of PfSPZ Vaccine in pregnant women.

“While pregnant women are typically excluded from many clinical studies, given the scale of the problem and the profound effects of malaria on women of child-bearing potential, there is an ethical imperative to design and test interventions for this vulnerable group” said Rose Leke, Profesor, University of Cameroon, winner of the 2023 Virchow Prize for Global Health, and chair of the Gavi (Global Alliance for Vaccines and Immunizations) independent review committee. “ I applaud this research team for successfully pioneering the safe testing of PfSPZ Vaccine in young women and achieving such promising results on preventing malaria in pregnancy.”

About Sanaria Inc.: 
 Sanaria Inc. was founded in 2003. The Company's primary mission since the outset has been to develop and commercialize whole-parasite malaria vaccines that confer high-level, long-lasting protection against Plasmodium falciparum , the parasite responsible for most of the malaria-associated severe illness and death worldwide, as well as other parasites that cause human malaria. Sanaria Inc. seeks to use these vaccines to prevent malaria in individuals and eliminate the disease from entire populations in selected regions. Sanaria's corporate headquarters, administrative, research, development, and manufacturing operations are in Rockville, Maryland. The Company's website is www.sanaria.com

This news release contains certain forward-looking statements that involve known and unknown risks and uncertainties, which may cause actual results to differ materially from anticipated results or achievements expressed or implied by the statements made. Such statements include the availability of an effective vaccine, the expectations for eliminating malaria, and beliefs concerning the suitability of a successful vaccine. These forward-looking statements are further qualified by important factors that could cause actual results to differ materially from those in the forward-looking statements. These factors include, without limitation, the Company's ability to raise sufficient funds, the regulatory approval process, clinical trials results, the Company's patent portfolio, dependence on key personnel and other risks associated with vaccine development. For further information contact Alexander Hoffman, [email protected] , 301-770-3222.

The Lancet Infectious Diseases

Method of Research

Randomized controlled/clinical trial

Subject of Research

Article title.

Protection from malaria after pre-conception PfSPZ Vaccine

Article Publication Date

14-Aug-2024

COI Statement

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