A malaria vaccine protects Aotus monkeys against virulent Plasmodium falciparum infection

Prakash Srinivasan,Sachy Orr-Gonzalez,Louis H Miller,Andres G Lescano,Patrick E Duffy,Carmen Lucas,Carter Diggs,Ababacar Diouf,Lorraine Soisson,G Christian Baldeviano,Luis Lugo-Roman,Julio A Ventocilla,Carole A Long,Eileen Villasante,Kazutoyo Miura,Susan K Pierce,Daming Zhu,Karina P Leiva,David L Narum

doi:10.1038/s41541-017-0015-7

Abstract

The Plasmodium falciparum protein, apical membrane antigen 1 forms a complex with another parasite protein, rhoptry neck protein 2, to initiate junction formation with the erythrocyte and is essential for merozoite invasion during the blood stage of infection. Consequently, apical membrane antigen 1 has been a target of vaccine development but vaccination with apical membrane antigen 1 alone in controlled human malaria infections failed to protect and showed limited efficacy in field trials. Here we show that vaccination with AMA1–RON2L complex in Freund’s adjuvant protects Aotus monkeys against a virulent Plasmodium falciparum infection. Vaccination with AMA1 alone gave only partial protection, delaying infection in one of eight animals. However, the AMA1–RON2L complex vaccine completely protected four of eight monkeys and substantially delayed infection (>25 days) in three of the other four animals. Interestingly, antibodies from monkeys vaccinated with the AMA1–RON2L complex had significantly higher neutralizing activity than antibodies from monkeys vaccinated with AMA1 alone. Importantly, we show that antibodies from animals vaccinated with the complex have significantly higher neutralization activity against non-vaccine type parasites. We suggest that vaccination with the AMA1–RON2L complex induces functional antibodies that better recognize AMA1 as it appears complexed with RON2 during merozoite invasion. These data justify progression of this next generation AMA1 vaccine towards human trials.

Highlights

Malaria caused by Plasmodium falciparum (Pf) remains one of the most deadly infectious diseases in the world
RON2L binding to all required membrane antigen 1 (AMA1) was confirmed by surface plasmon resonance (SPR; Supplementary Fig. S1b)
Neutralization of GB4 parasites, expressing another heterologous AMA1 allele, was higher for pooled total IgG at 2.5 mg mL−1 from Group 3 than Group 2 animals (Supplementary Fig. S4a, b). These results suggest that the qualitative shift in the antibody response induced by the AMA1–RON2L complex enhanced the responses to functionally important conserved epitopes in AMA1

Summary

Introduction

Malaria caused by Plasmodium falciparum (Pf) remains one of the most deadly infectious diseases in the world. A recent study in Mali found no difference in time-to-infection in both children and adults, indicating no pre-erythrocytic immunity, but adults were significantly protected from clinical disease.[1] Interestingly, IgG purified from malaria-exposed adults are able to suppress growth of parasites when transferred to non-immune individuals,[2, 3] suggesting that antibodies play an important role in conferring clinical immunity. These observations indicate the possibility of developing a vaccine that would accelerate the acquisition of protective immunity to disease in children. Such a vaccine will have an enormous impact on reducing mortality and disease severity in children and pregnant women

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