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

Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions
Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions
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.
2379-3708
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Vekemans, Johan
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Faust, Saul N.
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Galaway, Francis
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De Graaf, Hans
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Brendish, Nathan
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Jin, Jing
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Labbe, Genevieve M.
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Siani, Loredana
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Berrie, Eleanor
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Ishizuka, Andrew
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Nielsen, Carolyn M.
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Barfod, Lea
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Wambua, Juliana
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Biswas, Sumi
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Minassian, Angela M.
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Ashfield, Rebecca
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Nugent, Fay L.
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Douglas, Alexander D.
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Vekemans, Johan
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Wright, Gavin J.
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Faust, Saul N.
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Hill, Adrian V.S.
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Long, Carole A.
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Lawrie, Alison M.
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Draper, Simon J.
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Payne, Ruth O., Silk, Sarah, Elias, Sean, Miura, Kazutoyo, Diouf, Ababacar, Galaway, Francis, De Graaf, Hans, Brendish, Nathan, Poulton, Ian D., Griffiths, Oliver J., Edwards, Nick J., Jin, Jing, Labbe, Genevieve M., Alanine, Daniel G.W., Siani, Loredana, Di Marco, Stefania, Roberts, Rachel, Green, Nicky, Berrie, Eleanor, Ishizuka, Andrew, Nielsen, Carolyn M., Bardelli, Martino, Partey, Frederica D., Ofori, Michael F., Barfod, Lea, Wambua, Juliana, Murungi, Linda M., Osier, Faith H., Biswas, Sumi, McCarthy, James S., Minassian, Angela M., Ashfield, Rebecca, Viebig, Nicola K., Nugent, Fay L., Douglas, Alexander D., Vekemans, Johan, Wright, Gavin J., Faust, Saul N., Hill, Adrian V.S., Long, Carole A., Lawrie, Alison M. and Draper, Simon J. (2017) Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions. JCI Insight, 2 (21), [e96381]. (doi:10.1172/jci.insight.96381).

Record type: Article

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.

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Accepted/In Press date: 5 October 2017
e-pub ahead of print date: 2 November 2017
Published date: November 2017

Identifiers

Local EPrints ID: 417223
URI: http://eprints.soton.ac.uk/id/eprint/417223
ISSN: 2379-3708
PURE UUID: bd3fb28b-fe5e-46e1-b837-8963c74a33c0
ORCID for Nathan Brendish: ORCID iD orcid.org/0000-0002-9589-4937
ORCID for Saul N. Faust: ORCID iD orcid.org/0000-0003-3410-7642

Catalogue record

Date deposited: 26 Jan 2018 17:30
Last modified: 02 Nov 2024 03:01

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Contributors

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

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