Why is it difficult to develop a malaria vaccine?

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Research into the development of a malaria vaccine has been in the works for decades, but why have we still not developed a viable vaccine? As it turns out, there are many obstacles that need to be overcome in order to do so. But doing so remains critical since malaria infection only provides partial, not lifelong immunity.

The most cited obstacle to developing a malaria vaccine involves targeting the complex life cycle of the malaria parasite. The life cycle includes 1) the pre-erythrocytic stage, in which the malaria parasite enters a human through an infectious bite and moves towards the liver 2) the erythrocytic state, in which the parasite invades blood cells and multiplies until the cells burst, and 3) the sexual stage, in which gametes of the parasite fuse inside a female mosquito and produce the infectious forms of the parasite that spread via subsequent bites to other individuals. Vaccine development aims to target these stages. 

Some vaccines that are being developed to target the pre-erythrocytic stage of malaria parasites aim to stop the spread of the infectious parasite shortly after a bite. This proves to be very difficult as the parasite spreads to the liver less than an hour after a bite. Triggering an immune response with a vaccine to act on the parasite in this short window is difficult to achieve.

Photo: Stages of the malaria life cycle that are the target of vaccine development

Nonetheless, one of the most promising candidates to date is the pre-erythrocytic RTS,S malaria vaccine, which has achieved partial immunity in some humans and has averted some severe malaria cases. However, early testing of the vaccine indicated diminishing vaccine efficacy with time. This can be attributed to the fact that the vaccine induced antibodies are short lived and can diminish in the absence of actual malaria exposure. 

Attenuated, or weakened, whole vaccines have been assessed for their ability to generate antibodies to the pre-erythrocytic stage, but remains logistically challenging despite promising data on protection. Current live-attenuated whole sporozoite vaccines require storage at very cold storage and liquid nitrogen transport. Given the need for malaria protection in many developing regions where reliable cold storage is not feasible during large vaccine campaigns, this platform is not feasible for many regions where protection is most needed. Further, the current whole sporozoite vaccines are administered intravenously which is not as approachable for large scale vaccine campaigns as an intramuscular delivery.

There are also challenges to developing an erythrocytic or “blood stage” vaccine. Extensive genetic diversity of the antigens of the blood stage has made it challenging to target. Developing a vaccine that provides cross-reactive immunity across the five different species of the Plasmodium parasite is a hurdle for developing an effective erythrocytic vaccine.

Transmission blocking vaccines (TBVs) target antigens associated with the sexual stage of the parasite. The goal of this vaccine approach is to stimulate antibodies that limit the production of new infectious sporozoites, to block mosquito acquisition of the parasite during blood meals from malaria infected individuals. While this type of vaccine does not protect the recipient, they may protect communities by limiting transmission by mosquitoes.

Finding opportune ways to elicit a robust immune response to a complicated life cycle with a vaccine has remained a challenge in the decades of malaria research. The future of malaria vaccines entails identifying new antigens, understanding what immune response best correlates to protection, and how to pharmacologically supplement vaccine efficacy.

While vaccines targeting any of these individual stages has not yet been successful, perhaps future success will be achieved by vaccines that combine antigens from multiple stages of the malaria parasite life cycle. Researchers may also need to identify new antigens that can be targeted with vaccines that will yield higher levels of immunity in vaccinated populations. Finding ideal antigens can be challenging because over 5,000 proteins are expressed at different points over the life cycle of the malaria parasite and which of these antigens elicit the most protective immune response remains unclear.

In addition to finding ideal antigens to target, a remaining challenge in the field is the lack of clear immune correlates of protection. Without this data to inform research, vaccine developers are unable to understand what concentration of antibodies and cellular immune responses correlate to immunity of each of antigens of the different life cycles.

It has been observed that the vaccine induced responses are lower in individuals of malaria exposed populations than in malaria naive populations. Prior malaria infection may lead to chronic malaria infection which may alter B cell functionality, the cell type that secretes antibodies, thereby restricting the antibody response elicited from vaccination. As vaccine candidates are developed another important consideration to boost the potency and longevity of the immune response elicited by vaccination is the use of pharmacological substances called adjuvants. Another unique challenge in malaria vaccine research is that current adjuvants have been found to induce moderate antibodies and poor immune responsesthus hindering malaria vaccine efficacy. Development of new adjuvants are needed to boost the immunity elicited by the malaria vaccines developed, especially for malaria-exposed populations.

There are many challenges to developing an effective malaria vaccine, but the scientific community continues to strive for their 2030 goal to license a malaria vaccine with at least 75% efficacy and reduce transmission through widespread vaccination campaigns. 

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