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

TY - JOUR

T1 - Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions

AU - Payne, Ruth O

AU - Silk, Sarah E

AU - Elias, Sean C

AU - Miura, Kazutoyo

AU - Diouf, Ababacar

AU - Galaway, Francis

AU - de Graaf, Hans

AU - Brendish, Nathan J

AU - Poulton, Ian D

AU - Griffiths, Oliver J

AU - Edwards, Nick J

AU - Jin, Jing

AU - Labbé, Geneviève M

AU - Alanine, Daniel Gw

AU - Siani, Loredana

AU - Di Marco, Stefania

AU - Roberts, Rachel

AU - Green, Nicky

AU - Berrie, Eleanor

AU - Ishizuka, Andrew S

AU - Nielsen, Carolyn M

AU - Bardelli, Martino

AU - Partey, Frederica D

AU - Ofori, Michael F

AU - Barfod, Lea

AU - Wambua, Juliana

AU - Murungi, Linda M

AU - Osier, Faith H

AU - Biswas, Sumi

AU - McCarthy, James S

AU - Minassian, Angela M

AU - Ashfield, Rebecca

AU - Viebig, Nicola K

AU - Nugent, Fay L

AU - Douglas, Alexander D

AU - Vekemans, Johan

AU - Wright, Gavin J

AU - Faust, Saul N

AU - Hill, Adrian Vs

AU - Long, Carole A

AU - Lawrie, Alison M

AU - Draper, Simon J

PY - 2017/11/2

Y1 - 2017/11/2

N2 - 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.

AB - 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.

U2 - 10.1172/jci.insight.96381

DO - 10.1172/jci.insight.96381

M3 - Journal article

C2 - 29093263

SN - 2379-3708

VL - 2

JO - JCI insight

JF - JCI insight

IS - 21

M1 - e96381

ER -