"New antigens for a multicomponent blood-stage malaria vaccine"

Osier, F. H. et al (2014). Sci Transl Med 6:247ra102.

Paper presented by André Fonseca on 11/12/2020.

On the topic

According to the 2020 World Malaria Report published by the World Health Organization, malaria had caused 229 million cases and 409,000 deaths worldwide in 2019. These numbers highlight the severity of the disease, which is still a global health problem. Several strategies have been proposed to tackle malaria control. Among those, the development of vaccines against the blood-stage form of the Plasmodium falciparum has become a popular research topic. This interest arises mainly because proteins displayed at the merozoite’s surface constitute prime immune targets due to their repeated presentation to the host immune system. However, due to the inability to produce natively folded recombinant antigens in immunological studies, only a few antigens have been translated to candidates for testing in clinical trials.

Brief summary

The discussed study overcame the constraints of constructing natively fold recombinant antigens by generating a large library of biochemically active merozoite surface and secreted full-length ectodomain proteins. Based on this achievement, a systematic examination of antibody reactivity against these proteins was performed in a cohort of 286 Kenyan children with the objective of determining their potential in protecting against clinical malaria. This analysis found antibodies against less-known antigens with superior or equivalent potential protective efficacy to the handful of current leading malaria vaccine candidates. It also identified five antibody combinations that could predict clinical malaria in the Kenyan children with 100% accuracy. Such findings suggested that highly effective vaccination can be achieved by eliciting antibody responses against these antigens.

Our comment

After our Journal Club, there are three key points worth of discussion.

The first one is the use of the Modified Poisson regression which is typically used for for incidence or count data. This modelling choice was not well explained given that the study did not include such type of data. We argue that standard logistic regression could have been applied instead. This modelling approach has the advantage to allow interpreting the results in terms of odds ratio.

Another point of the discussion was the graphical representation of the data. In Figures 2B and C referring to the number of protective antibodies, it is unnecessary to overlay Normal density probability functions in intrinsically count data.

Finally, the most important aspect of the discussion was related to the proteins from the 3D7 parasite reference genome used in the study. Interestingly, the 3D7 parasite line is known to have a West Africa origin. Given this fact, this proof-of-principle study should have been conducted in a country from this area. This contrast with the choice of Kenya, a country located in East Africa. where different P. falciparum parasites might be in circulation and under selection. Therefore, we predict that the findings of the study might not be highly reproducible.

Figure 2B and C

The number of protective antibodies is intrinsically count data. Estimated Normal density functions do not make sense in these data as they predict negative values for the number of protective antibodies.

More paper discussions can be found in the Archive.