Vaccinating with the genome: a Sisyphean task?
This paper from 2009 is highly worth reading. It speaks about the difficulties of going from a sequenced genome to solving real problems (not GWAS), be it finding diseases mechanisms or developing effective malaria vaccine, as in the case of the linked paper. Genomes of both the malaria parasite and its mosquito vector were assembled in 2001, but the only vaccines under consideration even today are based on research done in the early 1990s.
Human trials of subunit vaccines against the asexual blood stage of malaria are yielding disappointing results, supporting the premise that a single recombinant protein will not be particularly efficacious and that additional proteins must be added. The genome sequence of Plasmodium falciparum offers a large number of additional candidates, but which should be chosen? Various criteria have been suggested to rank the additional candidates, but in the absence of even a partially effective asexual-stage vaccine, the criteria remain unvalidated. These issues are discussed here, together with some suggestions as to how the development of an asexual-stage vaccine could be progressed.
Why is it so difficult to develop vaccines despite having the sequenced genome? The researchers realized that genome was only a tiny piece of the puzzle. It had been extremely difficult to figure out the functions of most genes, especially in highly AT-rich Plasmodium genome. Even doing experiments that were routine for model organisms (such as making transgenics) turned out to be difficult to establish in newly sequenced organisms.
There are two positive developments.
1. CRISPR/cas9 technology (discussed in detail in our chemistry blog) made it easy to develop transgenics.
2. The following paper is a potential success story of post-genomic era that may lead to developing new malaria vaccines in future.
Current vaccine strategies against the asexual blood stage of Plasmodium falciparum are mostly focused on well-studied merozoite antigens that induce immune responses after natural exposure, but have yet to induce robust protection in any clinical trial. Here we compare human-compatible viral- vectored vaccines targeting ten different blood-stage antigens. We show that the full-length P. falciparum reticulocyte-binding protein homologue 5 (PfRH5) is highly susceptible to cross-strain neutralizing vaccine-induced antibodies, out-performing all other antigens delivered by the same vaccine platform. We find that, despite being susceptible to antibody, PfRH5 is unlikely to be under substantial immune selection pressure; there is minimal acquisition of anti-PfRH5 IgG antibodies in malaria-exposed Kenyans. These data challenge the widespread beliefs that any merozoite antigen that is highly susceptible to immune attack would be subject to significant levels of antigenic polymorphism, and that erythrocyte invasion by P. falciparum is a degenerate process involving a series of parallel redundant pathways.
