Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions
Ruth O. Payne, … , Alison M. Lawrie, Simon J. Draper
Ruth O. Payne, … , Alison M. Lawrie, Simon J. Draper
Published November 2, 2017
Citation Information: JCI Insight. 2017;2(21):e96381. https://doi.org/10.1172/jci.insight.96381.
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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 9

Vaccine-induced antibodies inhibit interactions within the RH5 invasion complex.

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Vaccine-induced antibodies inhibit interactions within the RH5 invasion ...
(A) D0 and d84 Group 2B sera (n = 7) and Group 2C sera (n = 8) were tested for their ability to inhibit the interaction between proteins from the RH5 invasion complex by AVEXIS. Dilution of each test serum sample is shown starting at 1:10. Results with various assay controls also shown (no serum for RH5-Basigin, and anti-AMA1 for RH5-CyRPA and RH5-P113). Each point represents the mean of duplicate or triplicate wells. (B) Correlation of blocking activity for each interaction using d84 sera from Groups 2B and 2C (n = 15) against anti–RH5_FL serum IgG responses measured by ELISA. Blocking activity was calculated for each individual sample from the data in panel A as the ratio of the Abs 485 nm at 1:10 serum dilution divided by the Abs 485 nm at the highest serum dilution tested. Spearman’s rank correlation coefficient (rs) and P value(Spearman’s rank correlation) are shown.