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 4

Serum antibody response to vaccination.

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Serum antibody response to vaccination. Group 1 (n = 4), Group 2A (n = 4...
Group 1 (n = 4), Group 2A (n = 4), Group 2B (n = 8), Group 2C (n = 8). (A) Median anti–RH5_FL serum total IgG responses shown for all groups over time. Individual responses are shown in Supplemental Figure 3. Median and individual responses are shown at (B) d28, d84, and d140. The horizontal dotted line indicates the limit of detection of the assay. Statistical analysis using Kruskal-Wallis test with Dunn’s multiple comparison test. (C) Vaccine-induced responses shown for Groups 2B and 2C combined (n = 16) vs. responses following natural exposure in Ghanaian adults (n = 79) and Kenyan adults (n = 96); analysis by Kruskal-Wallis test with Dunn’s multiple comparison test. (D) Isotype profiles of serum antibody responses against RH5_FL were assessed by ELISA. Responses are shown at baseline (d0) and for all groups at d84. Individual and median responses are shown for IgG1 and IgG3; results for IgG2, IgG4, IgA, and IgM are shown in Supplemental Figure 5. (E) Avidity of serum IgG responses at d28 and d84 was assessed by sodium thiocyanate (NaSCN) displacement RH5_FL ELISA and is reported as the molar (M) concentration of NaSCN required to reduce the starting OD in the ELISA by 50% (IC50). Only samples with a positive response by anti–RH5_FL total IgG ELISA could be assayed for avidity. Symbols are coded according to group. *P < 0.05, **P < 0.01, ****P < 0.0001.