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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

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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 5

B cell response to vaccination.

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B cell response to vaccination.
(A) RH5-specific antibody-secreting cell...
(A) RH5-specific antibody-secreting cell (ASC) responses were assessed by ex vivo enzyme-linked immunospot (ELISPOT) using RH5_FL protein and fresh peripheral blood mononuclear cells (PBMC) from the d63 time point. Individual and median responses are shown for each group and reported as RH5-specific ASC per million PBMC used in the assay (n = 8 for Group 2B and n = 7 for Group 2C because 1 sample was not tested in this group). (B) Correlation of the ASC response vs. the concentrations of serum anti–RH5_FL IgG measured at d84. Spearman’s rank correlation coefficient (rs) and P value are shown by Spearman’s rank correlation. (C) RH5-specific memory B cell (mBC) responses were assessed by ELISPOT assay using RH5_FL protein (n = 8 for Groups 2B and 2C). Frozen PBMC were thawed and underwent a 6-day polyclonal restimulation, during which ASC are derived from mBC, before testing in the assay. Individual and median responses are shown from the d84 and 140 time points and are reported as mBC-derived RH5-specific ASC per million cultured PBMC or as (D) % of total number IgG-secreting ASC (n = 7 for Group 2C at the d140 time point in D, otherwise n = 8). Groups 2B and 2C are coded by color and symbol.

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