In addition to the lack of an immune correlate of protection that would permit down-selection of vaccine candidates before expensive efficacy trials, several other factors have impeded malaria vaccine development. Chief among these impediments are the size and plasticity of the P. falciparum
genome, which has about 23 million bases of DNA organized into 14 chromosomes and about 5,000 genes (8
). This is orders of magnitude larger than the genomes of most of the viruses and bacteria for which vaccines have been successfully developed. Through mechanisms that are poorly understood, many of these genes are differentially expressed during the various stages of the highly complex life cycle in vertebrate hosts and mosquitoes (). Adding further complexity, mutation during mitotic reproduction in the haploid liver and blood stages and genetic recombination during the diploid sexual reproductive stages in the mosquito result in extensive genetic diversity that is driven by selection pressure from the immune system, as well as by drugs and, when they are deployed, potentially by vaccines (9
). All of this complexity and diversity greatly complicates the choice of candidate antigens for vaccine development and raises doubt that monovalent single-antigen vaccines will provide broad cross-protection.
At least 18 different forms of one leading blood-stage antigen (10
) and >200 variants of another (11
) have been documented in a single African village. If vaccines targeting these antigens generate immune responses that are in-sufficiently cross-protective, vaccines based on just one or two genetic variants are unlikely to be broadly efficacious (9
). To date, the choices of which variants of target antigens to include in malaria vaccines have not been made in consideration of the frequencies of these variants in natural populations. Careful molecular epidemiological studies are beginning to pinpoint which of the many polymorphisms in some of these antigens are the most important determinants of strain-specific natural immunity (10
), and this approach may help inform the design of polyvalent or chimeric vaccines that protect against diverse parasite strains (9
Immunization with stage-specific vaccines typically protects against only that life-cycle stage, hence the notion of vaccines that specifically prevent infection, disease, or transmission by targeting the different stages. A highly efficacious pre-erythrocytic vaccine would prevent not only infection but also disease and transmission (3
); however, even a single surviving sporozoite could theoretically result in infection, disease, and transmission. This is because of the parasite’s ability to multiply rapidly—one sporozoite gives rise to tens of thousands of merozoites, and each merozoite multiplies roughly tenfold in 48 h, quickly resulting in billions of parasites circulating in the body. The fully sterile protection that would be required to completely prevent infection is a dauntingly high bar for a vaccine to clear. However, the ability of a partially efficacious pre-erythrocytic vaccine to reduce the risk of clinical malaria illness (12
) supports the idea that there is some benefit from slowing the rate of parasite reproduction short of complete prevention of blood-stage infection. A so-called “leaky vaccine,” perhaps better thought of as an injectable bed-net, could be a valuable tool for malaria control.
Most successful vaccines prevent infection or illness with pathogens that naturally result in strong and long-lasting immune protection after a single exposure. As described above, naturally acquired protective immunity to malaria is hard-won and short-lived. An effective malaria vaccine will need to produce stronger and faster immune responses than those that develop under even the most intense, continuous natural exposure to malaria. A vaccine intended to prevent infection will need to surpass natural immunity, which gradually protects against clinical illness but does not completely prevent infection.
Finally, because the host immune response contributes to malaria pathogenesis, a vaccine could theoretically increase the risk of harmful inflammatory responses to subsequent infection, especially a vaccine directed against the blood stages responsible for pathology. Vigilance for untoward inflammatory responses to malaria vaccines or to postvaccination malaria infection is an important aspect of clinical malaria vaccine development, especially for blood-stage vaccines.