Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions
Ruth O. Payne, et al.
Ruth O. Payne, et al.
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Research Article Infectious disease Vaccines

Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions

Abstract

The development of a highly effective vaccine remains a key strategic goal to aid the control and eventual eradication of Plasmodium falciparum malaria. In recent years, the reticulocyte-binding protein homolog 5 (RH5) has emerged as the most promising blood-stage P. falciparum candidate antigen to date, capable of conferring protection against stringent challenge in Aotus monkeys. We report on the first clinical trial to our knowledge to assess the RH5 antigen — a dose-escalation phase Ia study in 24 healthy, malaria-naive adult volunteers. We utilized established viral vectors, the replication-deficient chimpanzee adenovirus serotype 63 (ChAd63), and the attenuated orthopoxvirus modified vaccinia virus Ankara (MVA), encoding RH5 from the 3D7 clone of P. falciparum. Vaccines were administered i.m. in a heterologous prime-boost regimen using an 8-week interval and were well tolerated. Vaccine-induced anti-RH5 serum antibodies exhibited cross-strain functional growth inhibition activity (GIA) in vitro, targeted linear and conformational epitopes within RH5, and inhibited key interactions within the RH5 invasion complex. This is the first time to our knowledge that substantial RH5-specific responses have been induced by immunization in humans, with levels greatly exceeding the serum antibody responses observed in African adults following years of natural malaria exposure. These data support the progression of RH5-based vaccines to human efficacy testing.

Authors

Ruth O. Payne, Sarah E. Silk, Sean C. Elias, Kazutoyo Miura, Ababacar Diouf, Francis Galaway, Hans de Graaf, Nathan J. Brendish, Ian D. Poulton, Oliver J. Griffiths, Nick J. Edwards, Jing Jin, Geneviève M. Labbé, Daniel G.W. Alanine, Loredana Siani, Stefania Di Marco, Rachel Roberts, Nicky Green, Eleanor Berrie, Andrew S. Ishizuka, Carolyn M. Nielsen, Martino Bardelli, Frederica D. Partey, Michael F. Ofori, Lea Barfod, Juliana Wambua, Linda M. Murungi, Faith H. Osier, Sumi Biswas, James S. McCarthy, Angela M. Minassian, Rebecca Ashfield, Nicola K. Viebig, Fay L. Nugent, Alexander D. Douglas, Johan Vekemans, Gavin J. Wright, Saul N. Faust, Adrian V.S. Hill, Carole A. Long, Alison M. Lawrie, Simon J. Draper

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Figure 6

Functional GIA induced by ChAd63-MVA RH5 vaccination.

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Functional GIA induced by ChAd63-MVA RH5 vaccination. (A) In vitro growt...
(A) In vitro growth inhibition activity (GIA) of purified IgG was assessed at 10 mg/ml against 3D7 clone P. falciparum parasites. Individual data and medians are shown for each group at d84 (G1, n = 4; G2A, n = 4; G2B, n = 8; G2C, n = 8); pooled sera were used for each group (n = 4) at baseline (d0). (B) Dilution series of purified IgG from Group 2B and 2C d84 samples. (C) Relationship between GIA data from the dilution series shown in B and concentration of anti–RH5_FL purified IgG used in the assay as measured by ELISA. The EC50 (concentration of anti-RH5_FL polyclonal IgG that gives 50% GIA, dashed line) was 8.2 μg/ml (95% CI, 7.2–9.5 μg/ml); nonlinear regression curve is shown (solid line, r2 = 0.90, n = 74). Two volunteers (1 in Group 2B and 1 in 2C) showed a reproducibly higher EC50 of 3.3 μg/ml (95% CI, 2.8–3.9 μg/ml); nonlinear regression curve is shown (dotted line, r2 = 0.99, n = 10). (D) Purified IgG from Group 2B and 2C d84 samples, plus 1 pooled d0 preimmunization sample, were tested at 10 mg/ml against a panel of 8 other laboratory-adapted parasite lines and short-term culture-adapted parasite isolates. GIA for each parasite and test sample is plotted against corresponding GIA against 3D7 clone parasites on the x axis.