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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.

SUBMITTER: Payne RO

PROVIDER: S-EPMC5752323 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Payne Ruth O RO Silk Sarah E SE Elias Sean C SC Miura Kazutoyo K Diouf Ababacar A Galaway Francis F de Graaf Hans H Brendish Nathan J NJ Poulton Ian D ID Griffiths Oliver J OJ Edwards Nick J NJ Jin Jing J Labbé Geneviève M GM Alanine Daniel Gw DG Siani Loredana L Di Marco Stefania S Roberts Rachel R Green Nicky N Berrie Eleanor E Ishizuka Andrew S AS Nielsen Carolyn M CM Bardelli Martino M Partey Frederica D FD Ofori Michael F MF Barfod Lea L Wambua Juliana J Murungi Linda M LM Osier Faith H FH Biswas Sumi S McCarthy James S JS Minassian Angela M AM Ashfield Rebecca R Viebig Nicola K NK Nugent Fay L FL Douglas Alexander D AD Vekemans Johan J Wright Gavin J GJ Faust Saul N SN Hill Adrian Vs AV Long Carole A CA Lawrie Alison M AM Draper Simon J SJ

JCI insight 20171102 21

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 ...[more]

PMID: 29093263

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Project description:BackgroundThe invasion of the red blood cells by Plasmodium falciparum merozoites involves the interplay of several proteins that are also targets for vaccine development. The proteins PfRh5-PfRipr-PfCyRPA-Pfp113 assemble into a complex at the apical end of the merozoite and are together essential for erythrocyte invasion. They have also been shown to induce neutralizing antibodies and appear to be less polymorphic than other invasion-associated proteins, making them high priority blood-stage vaccine candidates. Using available whole genome sequencing data (WGS) and new capillary sequencing data (CS), this study describes the genetic polymorphism in the Rh5 complex in P. falciparum isolates obtained from Kilifi, Kenya.Methods162 samples collected in 2013 and 2014 were genotyped by capillary sequencing (CS) and re-analysed WGS from 68 culture-adapted P. falciparum samples obtained from a drug trial conducted from 2005 to 2007. The frequency of polymorphisms in the merozoite invasion proteins, PfRh5, PfRipr, PfCyRPA and PfP113 were examined and where possible polymorphisms co-occurring in the same isolates.ResultsFrom a total 70 variants, including 2 indels, 19 SNPs [27.1%] were identified by both CS and WGS, while an additional 15 [21.4%] and 36 [51.4%] SNPs were identified only by either CS or WGS, respectively. All the SNPs identified by CS were non-synonymous, whereas WGS identified 8 synonymous and 47 non-synonymous SNPs. CS identified indels in repeat regions in the p113 gene in codons 275 and 859 that were not identified in the WGS data. The minor allele frequencies of the SNPs ranged between 0.7 and 34.9% for WGS and 1.1-29.6% for CS. Collectively, 12 high frequency SNPs (> 5%) were identified: four in Rh5 codon 147, 148, 203 and 429, two in p113 at codons 7 and 267 and six in Ripr codons 190, 259, 524, 985, 1003 and 1039.ConclusionThis study reveals that the majority of the polymorphisms are rare variants and confirms a low level of genetic polymorphisms in all proteins within the Rh5 complex.

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

Publications

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

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