Paper discussions

"Identification of highly-protective combinations of Plasmodium vivax recombinant proteins for vaccine development"

França et al. eLife 2017;6:e28673.

Paper presented by André Fonseca on 05/03/2021.

On the topic

Malaria is a health problem that still threatens millions of lives in the Tropics. Among the five Plasmodium species causing this disease, Plasmodium vivax is the second most prevalent worldwide and the most predominant in the Americas and Asia-Pacific regions. Due to its unique biology, P. vivax forms hypnozoites that can remain dormant for years and whose re-activation can cause relapsing blood-stage infections. P. vivax also have a shorter life cycle within the Anopheles female mosquitoes, which grants this malaria species to be less susceptible to common vector control measures. Therefore, vaccination is of particular interest to combat this parasite. Patients infected with P. vivax can develop protective immunity against clinical infections. This protective immunity is not yet fully understood, but antibody responses against different P. vivax antigens are thought to be essential to achieve such protective effect.

Brief summary

The discussed paper described a research effort to identify candidate P. vivax antigens for functional characterization. With this purpose, the study investigated the association between IgG antibody responses against 38 P. vivax recombinant antigens and the prospective risk of P. vivax malaria in a longitudinal cohort of young Papua New Guinean (PNG) children whose history of P. vivax infections was well characterized. A total of 264 children with age between 1 and 3 years old were enrolled in this study and followed up for 16 months with an active monitoring every two weeks. Finally, the study applied a novel methodology of simulated annealing algorithm to investigate the potential protective efficacy (PPE) of antibodies to multiple antigen-combinations and the antibody thresholds associated with protection.

The analysis suggested that high antibody levels to multiple antigens, including several novel proteins were strongly associated with malaria protection against P. vivax independently of individual differences in infection history, age, and transmission season. Additionally, combined antibody responses against five antigens had a PPE above 90%. Among these combinations, antibody responses against EBP, DBPII, RBP1a, CyRPA, and PVX_081550 were most frequently identified, with several of them requiring very low antibody levels to show a protective effect.

Our comment

From our discussion, there was a general consensus that this study was well conceived and it brought interesting insights to putative antigen targets for future vaccine development concerning P. vivax. Below we mention other aspects of this study that were raised in our discussion.

We appreciated the use of antibodies against antigens derived from the population under study, instead of antigens from a reference genome as done in a similar paper discussed by our group (go to this discussion). By selecting a panel of antigens that were found to be highly recognized by antibodies present in plasma samples from PNG children, the authors ensured antibody-specificity for the population under analysis. This aspect is expected to increase the chance of reproducible results if the study was repeated in the same population. Nevertheless, the antibody values reported throughout the study seemed particularly low. However, it may be explained by a (high) background signal subtracted from the raw antibody values.

In Table 1, the authors calculated the percentage of children with antibody levels higher than different quartiles of the antibody distribution for adults. We were expecting a higher percentage of children with antibody levels higher than these thresholds if the antibodies under analysis were highly protective. This shows that the antibody levels against different candidate antigens were far from the levels observed in adults.

The authors used negative binomial GEE models to analyse the association between IgG levels and prospective risk of P. vivax episodes. Notwithstanding citing several supporting papers, it would have helped the reader to provide a rationale to use these models.

Finally, the new annealing algorithm may be an interesting tool to analyse large datasets comprising antibodies against hundreds or thousands of different antigens. In theory, this algorithm allows to increase the chance of finding the best combination antibody targets for the future development of antimalarial vaccines. However, the use of an antibody panel consisting of 20 or 38 targets might be only useful in the context of a multivalent vaccine. Therefore, it is unclear how the identified combinations are directly translated to a future vaccine against P. vivax given that this malaria species is a high genetic diversity across malaria endemic areas.

More paper discussions can be found in the Archive.