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JCI Insight. 2017 Nov 2;2(21). pii: 96381. doi: 10.1172/jci.insight.96381.

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

Author information

1
The Jenner Institute, University of Oxford, Oxford, United Kingdom.
2
Laboratory of Malaria and Vector Research, NIAID/NIH, Rockville, Maryland, USA.
3
Cell Surface Signalling Laboratory, Wellcome Trust Sanger Institute, Cambridge, United Kingdom.
4
NIHR Wellcome Trust Clinical Research Facility, University Hospital Southampton NHS Foundation Trust and Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
5
ReiThera SRL (formerly Okairos SRL), Viale Città d'Europa, Rome, Italy.
6
Clinical Biomanufacturing Facility, University of Oxford, Oxford, United Kingdom.
7
Centre for Medical Parasitology, Department of Immunology and Microbiology (ISIM), Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
8
Department of Immunology, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana.
9
KEMRI Centre for Geographic Medicine Research, Kilifi, Kenya.
10
QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.
11
European Vaccine Initiative, UniversitätsKlinikum Heidelberg, Heidelberg, Germany.
12
GSK Vaccines, Wavre, Belgium.

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.

PMID:
29093263
PMCID:
PMC5752323
DOI:
10.1172/jci.insight.96381
[Indexed for MEDLINE]
Free PMC Article

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