Acquisition, maintenance and adaptation of invasion inhibitory antibodies against Plasmodium falciparum invasion ligands involved in immune evasion.

Muyideen K Tijani,Alex B Odaibo,Chiaka I Anumudu,Mats Wahlgren,Oluwatoyin A Babalola,Olajumoke A Morenikeji,Christine Langer,Kristina E M Persson,James G Beeson,Michael C Asuzu,Roseangela I Nwuba,Linda Reiling,Adanze O Asinobi

doi:10.1371/journal.pone.0182187

Abstract

Erythrocyte-binding antigens (EBAs) and P. falciparum reticulocyte-binding homologue proteins (PfRhs) are two important protein families that can vary in expression and utilization by P. falciparum to evade inhibitory antibodies. We evaluated antibodies at repeated time-points among individuals living in an endemic region in Nigeria over almost one year against these vaccine candidates. Antibody levels against EBA140, EBA175, EBA181, PfRh2, PfRh4, and MSP2, were measured by ELISA. We also used parasites with disrupted EBA140, EBA175 and EBA181 genes to show that all these were targets of invasion inhibitory antibodies. However, antigenic targets of inhibitory antibodies were not stable and changed substantially over time in most individuals, independent of age. Antibodies levels measured by ELISA also varied within and between individuals over time and the antibodies against EBA181, PfRh2 and MSP2 declined more rapidly in younger individuals (≤15 years) compared with older (>15). The breadth of high antibody responses over time was more influenced by age than by the frequency of infection. High antibody levels were associated with a more stable invasion inhibitory response, which could indicate that during the long process of formation of immunity, many changes not only in levels but also in functional responses are needed. This is an important finding in understanding natural immunity against malaria, which is essential for making an efficacious vaccine.

Highlights

An estimated 3.4 billion people are at risk of malaria worldwide and about 429,000 deaths due to malaria were reported in the year 2015 alone [1]
Previous studies suggest that phenotypic variation based on selective expression of members of the erythrocyte-binding antigen (EBAs) and P. falciparum reticulocyte-binding homologue (PfRhs) invasion ligands families is an important immune evasion mechanism utilized by the parasite [11]
Variation in invasion inhibitory antibodies against P. falciparum pairwise comparison of parasite prevalence showed significant differences only between February and all the months except August

Summary

Introduction

An estimated 3.4 billion people are at risk of malaria worldwide and about 429,000 deaths due to malaria were reported in the year 2015 alone [1]. There is not yet a highly efficacious vaccine for malaria and the final results from the phase 3 trial of the most advanced malaria vaccine, RTS,S, showed only modest efficacy [2]. Mechanisms through which P. falciparum is able to cause repeated infections appear to be at least partly mediated by its ability to vary invasion ligand expression and use, as well as through antigenic diversity of key immune targets [10]. Previous studies suggest that phenotypic variation based on selective expression of members of the erythrocyte-binding antigen (EBAs) and P. falciparum reticulocyte-binding homologue (PfRhs) invasion ligands families is an important immune evasion mechanism utilized by the parasite [11]

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Conclusion