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Q&A: Developing an effective malaria vaccine
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According to WHO, progress against malaria has stalled and the disease remains a global health concern, causing more than 200 million illnesses and 435,000 deaths in 90 countries in 2017.
In a recent review, James G. Beeson, MBBS, PhD, deputy director and head of malaria research at the Burnet Institute and adjunct professor at Monash University, both in Australia, and colleagues noted that WHO has prioritized the development of a malaria vaccine with more than 75% efficacy against clinical malaria that is suitable for use in all malaria-endemic areas by 2030.
Writing in the Science Translational Medicine, Beeson and colleagues explained that developing a vaccine with sustained high efficacy is an “enduring challenge.”
“Although there has been major recent progress in malaria vaccine development, substantial challenges remain for achieving highly efficacious and durable vaccines against Plasmodium falciparum and Plasmodium vivax malaria,” they wrote. “Greater knowledge of mechanisms and key targets of immunity are needed to accomplish this goal, together with new strategies for generating potent, long-lasting, functional immunity against multiple antigens.”
Infectious Disease News spoke with Beeson and co-author Michelle Boyle, PhD, researcher at the Burnet Institute, about the challenges and strategies for developing a suitable malaria vaccine. – by Marley Ghizzone
How important is it to have an effective malaria vaccine?
Malaria continues to be one of the most important causes of death and illness globally. A highly effective malaria vaccine would be a major benefit in achieving malaria elimination in many regions throughout the world. The need for an effective malaria vaccine is highlighted by the spread of antimalarial drug resistance, and mosquito resistance to insecticides and other control measures, which are challenging malaria control elimination efforts. Vaccines have proved to be a very effective and affordable tool for the control and prevention of a range of other infectious diseases. To be highly effective, a malaria vaccine would need to have high efficacy (protect a high proportion of people who receive the vaccine) and be long-lasting so that protection is provided for at least 2 years before requiring a booster.
WHO and other organizations have established a goal of developing vaccines with at least 75% efficacy against clinical malaria by 2030. Realistically speaking, is that doable?
We are confident that achieving a vaccine with 75% efficacy is achievable in the long term. The key question is whether it is achievable by 2030. Achieving that time line depends on progress with current development strategies. The most advanced vaccine, known as RTS,S, demonstrated significant but modest efficacy in large phase 3 trials. Approaches are being explored to increase the efficacy of this vaccine or modify that vaccine to make it more efficacious, such as by adding other antigens or changing the formulation or dosing. If these strategies were successful, it may lead to a highly effective vaccine in the near term. On the other hand, if different strategies and antigens are required to achieve the 75% efficacy level, the timeline for achieving this may be longer. However, it is important to emphasize that a vaccine with an efficacy of around 50% would still have major public health benefit, and this is a level of efficacy achieved with some vaccines effective against other pathogens.
In your review, you discuss three vaccine strategies that have been tested for efficacy in human trials — pre-erythrocytic, blood stage and transmission blocking. What are the advantages and drawbacks of each?
A vaccine that is highly effective against the pre-erythrocytic stages would be ideal because it would prevent initial infection, and thereby prevent the subsequent development of malaria disease (which occurs during blood stage replication) and transmission to mosquitoes. However, achieving vaccines with very high efficacy against these stages has proved very challenging. The advantage of blood-stage vaccines is that they induce immune responses that prevent the development of clinical malaria illness, including severe disease and deaths. A challenge for vaccine development at this stage is that many target antigens are polymorphic, enabling evasion of immune responses. Transmission-blocking vaccines do not directly protect vaccinated individuals from malaria infection or illness but instead prevent malaria transmission. The aim of these vaccines is to reduce malaria transmission in populations and contribute to malaria control and elimination, and these vaccines or their components would be used in combination with vaccines targeting the pre-erythrocytic and blood stages that protect people from clinical illness. It is likely that a combination of vaccine components targeting pre-erythrocytic stages, blood-stage replication, and transmission blocking might be required for highly efficacious vaccines to advance malaria elimination. However, relatively limited data exist to understand how multistage vaccines should be formulated to be most effective and further research to understand this is a priority.
How can we improve the efficacy of malaria vaccines?
Potential strategies to improve vaccine efficacy are discussed in detail in our review. In summary, priorities for achieving higher efficacy include identification of optimal strategies for the generation of highly potent functional immunity, which depends on a strong knowledge of mechanisms and targets of protective responses. Further, optimized selection of antigens (or combinations of antigens) that mediate protective immunity is required, as well as developing strategies to overcome parasite polymorphisms and prevent vaccine escape. Research findings suggest that vaccine-induced responses are lower in malaria-exposed populations compared with malaria-naive populations, suggesting malaria exposure has an impact on the generation of effective immunity. Understanding the basis for this may be crucial for achieving greater vaccine efficacy.
It is important to consider that current vaccines have relatively short-lived efficacy, and the identification of strategies or vaccine components that generate longer lived immunity would increase the protective effect of vaccines and make implementation more cost effective and logistically less demanding. Therefore, this needs to be a priority for research.
What would future implementation of a malaria vaccine look like? Would there still be a need for other interventions?
The main target group for vaccines globally is young children, although there is also a substantial burden of malaria among adolescents and adults in many regions. Therefore, malaria vaccines would ideally have dosing and timing regimens that could be integrated into the extended program of immunization (EPI). Coformulation of a malaria vaccine with other vaccines would be an advantage. Greater durability of malaria vaccine efficacy with less frequent booster doses would reduce demands on health care systems and provide flexibility for integration into the EPI. Increased vaccine thermostability to accommodate interruptions in the cold chain would allow implementation under the new WHO controlled temperature chain, which can facilitate better coverage and reduce costs.
In most settings, implementation of malaria vaccines will occur together with other control interventions, including insecticide-treated bed nets, spraying of residual insecticides indoors, intermittent preventive malaria treatment or chemoprophylaxis, and interventions such as mass drug administration or screen-and-treat campaigns.
Reference:
Beeson JG, et al. Sci Transl Med. 2019;doi:10.1126/scitranslmed.aau1458.
Disclosures: The authors report no relevant financial disclosures.