The University of Southampton
University of Southampton Institutional Repository
Warning ePrints Soton is experiencing an issue with some file downloads not being available. We are working hard to fix this. Please bear with us.

Reduced blood-stage malaria growth and immune correlates in humans following RH5 vaccination

Reduced blood-stage malaria growth and immune correlates in humans following RH5 vaccination
Reduced blood-stage malaria growth and immune correlates in humans following RH5 vaccination
Background: development of an effective vaccine against the pathogenic blood-stage infection of human malaria has proved challenging, and no candidate vaccine has affected blood-stage parasitemia following controlled human malaria infection (CHMI) with blood-stage Plasmodium falciparum.

Methods: we undertook a phase I/IIa clinical trial in healthy adults in the United Kingdom of the RH5.1 recombinant protein vaccine, targeting the P. falciparum reticulocyte-binding protein homolog 5 (RH5), formulated in AS01B adjuvant. We assessed safety, immunogenicity, and efficacy against blood-stage CHMI. Trial registered at ClinicalTrials.gov, NCT02927145.

Findings: the RH5.1/AS01B formulation was administered using a range of RH5.1 protein vaccine doses (2, 10, and 50 μg) and was found to be safe and well tolerated. A regimen using a delayed and fractional third dose, in contrast to three doses given at monthly intervals, led to significantly improved antibody response longevity over ∼2 years of follow-up. Following primary and secondary CHMI of vaccinees with blood-stage P. falciparum, a significant reduction in parasite growth rate was observed, defining a milestone for the blood-stage malaria vaccine field. We show that growth inhibition activity measured in vitro using purified immunoglobulin G (IgG) antibody strongly correlates with in vivo reduction of the parasite growth rate and also identify other antibody feature sets by systems serology, including the plasma anti-RH5 IgA1 response, that are associated with challenge outcome.

Conclusions: our data provide a new framework to guide rational design and delivery of next-generation vaccines to protect against malaria disease.

Funding: this study was supported by USAID, UK MRC, Wellcome Trust, NIAID, and the NIHR Oxford-BRC.
2666-6359
701-719.e19
Minassian, Angela M.
93984419-d2e6-48fc-ad3c-9126d9a19e7c
Silk, Sarah
cd15636e-1e31-400b-af5c-ddfba66da60b
Barrett, Jordan
f795694f-78eb-4e70-a118-221a8ea87ed3
Nielsen, Carolyn
6d5161fa-1ef4-4aeb-a4ee-ee6c02e45ba0
Miura, Kazutoyo
f6ce0c45-4398-42db-9800-e7eede2a4bea
Diouf, Ababacar
701e038e-840e-4d3f-8f4a-3dbe08ada45c
Loos, Carolin
9162211d-adbe-472f-a5d2-7a4cc5a07f5e
Fallon, Jonathan
3a7316bd-eb34-413b-9a95-198464325b9f
Michell, Ashlin
ad8639c1-3895-4a24-80db-e75289d34e7d
White, Michael
65ef35c8-bfe9-46bd-b066-b59c7ecb8f7c
Edwards, Nick
973b95b7-f5b3-4ab2-9f94-1ce6436a5b96
Poulton, Ian
8b164f18-db46-4e29-b50f-d0d0bf690e20
Mitton, Celia
b5cca43b-aaac-4743-8bd7-a997f77f379e
Payne, Ruth O.
af14315a-cd57-4c77-b2bc-4d03d0daf6d7
Marks, Michael
91d7c45a-1af5-408a-b966-4c29dae6e8af
Maxwell-Scott, Hector
e622605e-fdce-4bfd-a2af-0e999ff93a91
Querol-Rubiera, Antonio
adfba78e-8bec-4107-b84d-ff72b11baeb1
Bisnauthsing, Karen
52c5102d-245e-4f95-ba58-3b35cb022389
Batra, Rahul
bb8ff98c-7d8e-4383-80c4-c0eab7cb095b
Ogrina, Tatiana
03af3246-54c8-48a5-b0a2-84c96992938c
Brendish, Nathan
a8a4189e-01eb-4ab3-933e-a24cd188a4d7
Themistocleous, Yrene
20689b85-e02b-4fbc-b8b8-96440ed269f7
Rawlinson, Thomas
a5e056c3-85cd-4dfc-a85f-760d915ae14c
Ellis, Katherine
da169763-3d02-4c8c-b204-bea56a6e132f
Quinkert, Doris
f14ee2d6-c0e7-42d6-a50d-354d19df9cb2
Baker, Megan
38ed5218-d01a-455a-afbf-6d44eea44417
Lopez Ramon, Raquel
33063878-68d4-4773-9326-948ef8d71a06
Barfod, Lea
8032edca-d714-4f2a-8045-8f43dfe58906
Folegatti, Pedro M.
23e5cd74-8076-45e5-9d16-9856641e1e01
Silman, Daniel
3959d4fd-bf62-4276-9c01-18b770341280
Datoo, Mehreen
e453bf20-c34b-4b5f-b482-4dd3c1d5b9b7
Taylor, Iona
50b5860e-c50b-4fed-9760-c336ab2766ad
Jin, Jing
2de3bc78-4e6c-49c6-8ef9-67cf0abb4347
Pulido, David
d4c47e57-fe1d-4756-a90e-916cb5f162b7
Douglas, Alexander
b5f60d6c-dc69-49a5-920b-1b02ba1f34d6
de Jongh, Willem
48237544-9640-4c3b-acc5-4dada37f7dde
Smith, Robert
45e68a98-dbe1-4491-b116-8cb2acb6e6f2
Berrie, Eleanor
6837def4-0ec8-4395-9eeb-8a3c9ea4401e
Noe, Amy
37871935-5e49-4d39-961c-f55310a6cf82
Diggs, Carter
4690a293-9a8a-4c29-b4eb-7709ae3abfe8
Soisson, Lorraine
8d4ca3c7-cb0f-4366-82ce-12bf92ab2309
Ashfield, Rebecca
8543235a-8e08-4be5-bc93-d62ecd213ee4
Faust, Saul
f97df780-9f9b-418e-b349-7adf63e150c1
Goodman, Anna L.
6541cbb8-783d-4470-8235-a6595320c267
Lawrie, Alison M.
dd354ff4-6d60-4029-af83-ae6d233eb2af
Nugent, Fay L
c526acc8-fa2b-4052-8004-9d1721fc1bc7
Alter, Galit
2742863e-d5cf-4419-b922-9679afa2bc4b
Long, Carole A.
0a762300-9d7a-47d0-b086-78676f736540
Draper, Simon J.
e874c36e-5bad-4acf-8f55-41fa7c871464
Minassian, Angela M.
93984419-d2e6-48fc-ad3c-9126d9a19e7c
Silk, Sarah
cd15636e-1e31-400b-af5c-ddfba66da60b
Barrett, Jordan
f795694f-78eb-4e70-a118-221a8ea87ed3
Nielsen, Carolyn
6d5161fa-1ef4-4aeb-a4ee-ee6c02e45ba0
Miura, Kazutoyo
f6ce0c45-4398-42db-9800-e7eede2a4bea
Diouf, Ababacar
701e038e-840e-4d3f-8f4a-3dbe08ada45c
Loos, Carolin
9162211d-adbe-472f-a5d2-7a4cc5a07f5e
Fallon, Jonathan
3a7316bd-eb34-413b-9a95-198464325b9f
Michell, Ashlin
ad8639c1-3895-4a24-80db-e75289d34e7d
White, Michael
65ef35c8-bfe9-46bd-b066-b59c7ecb8f7c
Edwards, Nick
973b95b7-f5b3-4ab2-9f94-1ce6436a5b96
Poulton, Ian
8b164f18-db46-4e29-b50f-d0d0bf690e20
Mitton, Celia
b5cca43b-aaac-4743-8bd7-a997f77f379e
Payne, Ruth O.
af14315a-cd57-4c77-b2bc-4d03d0daf6d7
Marks, Michael
91d7c45a-1af5-408a-b966-4c29dae6e8af
Maxwell-Scott, Hector
e622605e-fdce-4bfd-a2af-0e999ff93a91
Querol-Rubiera, Antonio
adfba78e-8bec-4107-b84d-ff72b11baeb1
Bisnauthsing, Karen
52c5102d-245e-4f95-ba58-3b35cb022389
Batra, Rahul
bb8ff98c-7d8e-4383-80c4-c0eab7cb095b
Ogrina, Tatiana
03af3246-54c8-48a5-b0a2-84c96992938c
Brendish, Nathan
a8a4189e-01eb-4ab3-933e-a24cd188a4d7
Themistocleous, Yrene
20689b85-e02b-4fbc-b8b8-96440ed269f7
Rawlinson, Thomas
a5e056c3-85cd-4dfc-a85f-760d915ae14c
Ellis, Katherine
da169763-3d02-4c8c-b204-bea56a6e132f
Quinkert, Doris
f14ee2d6-c0e7-42d6-a50d-354d19df9cb2
Baker, Megan
38ed5218-d01a-455a-afbf-6d44eea44417
Lopez Ramon, Raquel
33063878-68d4-4773-9326-948ef8d71a06
Barfod, Lea
8032edca-d714-4f2a-8045-8f43dfe58906
Folegatti, Pedro M.
23e5cd74-8076-45e5-9d16-9856641e1e01
Silman, Daniel
3959d4fd-bf62-4276-9c01-18b770341280
Datoo, Mehreen
e453bf20-c34b-4b5f-b482-4dd3c1d5b9b7
Taylor, Iona
50b5860e-c50b-4fed-9760-c336ab2766ad
Jin, Jing
2de3bc78-4e6c-49c6-8ef9-67cf0abb4347
Pulido, David
d4c47e57-fe1d-4756-a90e-916cb5f162b7
Douglas, Alexander
b5f60d6c-dc69-49a5-920b-1b02ba1f34d6
de Jongh, Willem
48237544-9640-4c3b-acc5-4dada37f7dde
Smith, Robert
45e68a98-dbe1-4491-b116-8cb2acb6e6f2
Berrie, Eleanor
6837def4-0ec8-4395-9eeb-8a3c9ea4401e
Noe, Amy
37871935-5e49-4d39-961c-f55310a6cf82
Diggs, Carter
4690a293-9a8a-4c29-b4eb-7709ae3abfe8
Soisson, Lorraine
8d4ca3c7-cb0f-4366-82ce-12bf92ab2309
Ashfield, Rebecca
8543235a-8e08-4be5-bc93-d62ecd213ee4
Faust, Saul
f97df780-9f9b-418e-b349-7adf63e150c1
Goodman, Anna L.
6541cbb8-783d-4470-8235-a6595320c267
Lawrie, Alison M.
dd354ff4-6d60-4029-af83-ae6d233eb2af
Nugent, Fay L
c526acc8-fa2b-4052-8004-9d1721fc1bc7
Alter, Galit
2742863e-d5cf-4419-b922-9679afa2bc4b
Long, Carole A.
0a762300-9d7a-47d0-b086-78676f736540
Draper, Simon J.
e874c36e-5bad-4acf-8f55-41fa7c871464

Minassian, Angela M., Silk, Sarah, Barrett, Jordan, Nielsen, Carolyn, Miura, Kazutoyo, Diouf, Ababacar, Loos, Carolin, Fallon, Jonathan, Michell, Ashlin, White, Michael, Edwards, Nick, Poulton, Ian, Mitton, Celia, Payne, Ruth O., Marks, Michael, Maxwell-Scott, Hector, Querol-Rubiera, Antonio, Bisnauthsing, Karen, Batra, Rahul, Ogrina, Tatiana, Brendish, Nathan, Themistocleous, Yrene, Rawlinson, Thomas, Ellis, Katherine, Quinkert, Doris, Baker, Megan, Lopez Ramon, Raquel, Barfod, Lea, Folegatti, Pedro M., Silman, Daniel, Datoo, Mehreen, Taylor, Iona, Jin, Jing, Pulido, David, Douglas, Alexander, de Jongh, Willem, Smith, Robert, Berrie, Eleanor, Noe, Amy, Diggs, Carter, Soisson, Lorraine, Ashfield, Rebecca, Faust, Saul, Goodman, Anna L., Lawrie, Alison M., Nugent, Fay L, Alter, Galit, Long, Carole A. and Draper, Simon J. (2021) Reduced blood-stage malaria growth and immune correlates in humans following RH5 vaccination. Med, 2 (6), 701-719.e19. (doi:10.1016/j.medj.2021.03.014).

Record type: Article

Abstract

Background: development of an effective vaccine against the pathogenic blood-stage infection of human malaria has proved challenging, and no candidate vaccine has affected blood-stage parasitemia following controlled human malaria infection (CHMI) with blood-stage Plasmodium falciparum.

Methods: we undertook a phase I/IIa clinical trial in healthy adults in the United Kingdom of the RH5.1 recombinant protein vaccine, targeting the P. falciparum reticulocyte-binding protein homolog 5 (RH5), formulated in AS01B adjuvant. We assessed safety, immunogenicity, and efficacy against blood-stage CHMI. Trial registered at ClinicalTrials.gov, NCT02927145.

Findings: the RH5.1/AS01B formulation was administered using a range of RH5.1 protein vaccine doses (2, 10, and 50 μg) and was found to be safe and well tolerated. A regimen using a delayed and fractional third dose, in contrast to three doses given at monthly intervals, led to significantly improved antibody response longevity over ∼2 years of follow-up. Following primary and secondary CHMI of vaccinees with blood-stage P. falciparum, a significant reduction in parasite growth rate was observed, defining a milestone for the blood-stage malaria vaccine field. We show that growth inhibition activity measured in vitro using purified immunoglobulin G (IgG) antibody strongly correlates with in vivo reduction of the parasite growth rate and also identify other antibody feature sets by systems serology, including the plasma anti-RH5 IgA1 response, that are associated with challenge outcome.

Conclusions: our data provide a new framework to guide rational design and delivery of next-generation vaccines to protect against malaria disease.

Funding: this study was supported by USAID, UK MRC, Wellcome Trust, NIAID, and the NIHR Oxford-BRC.

Text
1-s2.0-S2666634021001161-main (1) - Version of Record
Available under License Creative Commons Attribution.
Download (4MB)

More information

Accepted/In Press date: 25 March 2021
Published date: 19 April 2021

Identifiers

Local EPrints ID: 449413
URI: http://eprints.soton.ac.uk/id/eprint/449413
ISSN: 2666-6359
PURE UUID: 9c4c6378-30b4-4114-b9da-419370ec3b06
ORCID for Nathan Brendish: ORCID iD orcid.org/0000-0002-9589-4937
ORCID for Saul Faust: ORCID iD orcid.org/0000-0003-3410-7642

Catalogue record

Date deposited: 27 May 2021 16:31
Last modified: 26 Nov 2021 03:21

Export record

Altmetrics

Contributors

Author: Angela M. Minassian
Author: Sarah Silk
Author: Jordan Barrett
Author: Carolyn Nielsen
Author: Kazutoyo Miura
Author: Ababacar Diouf
Author: Carolin Loos
Author: Jonathan Fallon
Author: Ashlin Michell
Author: Michael White
Author: Nick Edwards
Author: Ian Poulton
Author: Celia Mitton
Author: Ruth O. Payne
Author: Michael Marks
Author: Hector Maxwell-Scott
Author: Antonio Querol-Rubiera
Author: Karen Bisnauthsing
Author: Rahul Batra
Author: Tatiana Ogrina
Author: Nathan Brendish ORCID iD
Author: Yrene Themistocleous
Author: Thomas Rawlinson
Author: Katherine Ellis
Author: Doris Quinkert
Author: Megan Baker
Author: Raquel Lopez Ramon
Author: Lea Barfod
Author: Pedro M. Folegatti
Author: Daniel Silman
Author: Mehreen Datoo
Author: Iona Taylor
Author: Jing Jin
Author: David Pulido
Author: Alexander Douglas
Author: Willem de Jongh
Author: Robert Smith
Author: Eleanor Berrie
Author: Amy Noe
Author: Carter Diggs
Author: Lorraine Soisson
Author: Rebecca Ashfield
Author: Saul Faust ORCID iD
Author: Anna L. Goodman
Author: Alison M. Lawrie
Author: Fay L Nugent
Author: Galit Alter
Author: Carole A. Long
Author: Simon J. Draper

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×