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 8

Vaccine-induced antibodies recognize conformational epitopes and inhibit interactions within the RH5 invasion complex.

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Vaccine-induced antibodies recognize conformational epitopes and inhibit...
(A) D0 and d84 sera for volunteers in Groups 2B and 2C (n = 16) were tested by ELISA against nondenatured RH5_FL protein (–) and the same protein following heat denaturation (+). Individual and median responses are shown. The 4BA7 and 2AC7 mAbs were included as controls that bind a linear vs. conformational epitope, respectively. **P < 0.01 according to Wilcoxon matched-pairs signed rank test. (B) D84 serum ELISA responses to RH5_FL and RH5ΔNL for volunteers in Groups 2B and 2C (n = 16) were analyzed for concordance by linear regression (solid line). r2 = 0.69; slope = 0.91 (95% CI, 0.56–1.27); Y intercept when X = 0.0 is 0.4 (95% CI, –2.7–3.6); X intercept when Y = 0.0 is –0.5 (95% CI, –6.0–2.3). Line of identity (X=Y) is also shown (dashed line).