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BMC Medicine
Published in: BMC Medicine 1/2017

Open Access 01-12-2017 | Research article

Modest heterologous protection after Plasmodium falciparum sporozoite immunization: a double-blind randomized controlled clinical trial

Authors: Jona Walk, Isaie J. Reuling, Marije C. Behet, Lisette Meerstein-Kessel, Wouter Graumans, Geert-Jan van Gemert, Rianne Siebelink-Stoter, Marga van de Vegte-Bolmer, Thorsten Janssen, Karina Teelen, Johannes H. W. de Wilt, Quirijn de Mast, André J. van der Ven, Ernest Diez Benavente, Susana Campino, Taane G. Clark, Martijn A. Huynen, Cornelus C. Hermsen, Else M. Bijker, Anja Scholzen, Robert W. Sauerwein

Published in: BMC Medicine | Issue 1/2017

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Abstract

Background

A highly efficacious vaccine is needed for malaria control and eradication. Immunization with Plasmodium falciparum NF54 parasites under chemoprophylaxis (chemoprophylaxis and sporozoite (CPS)-immunization) induces the most efficient long-lasting protection against a homologous parasite. However, parasite genetic diversity is a major hurdle for protection against heterologous strains.

Methods

We conducted a double-blind, randomized controlled trial in 39 healthy participants of NF54-CPS immunization by bites of 45 NF54-infected (n = 24 volunteers) or uninfected mosquitoes (placebo; n = 15 volunteers) against a controlled human malaria infection with the homologous NF54 or the genetically distinct NF135.C10 and NF166.C8 clones. Cellular and humoral immune assays were performed as well as genetic characterization of the parasite clones.

Results

NF54-CPS immunization induced complete protection in 5/5 volunteers against NF54 challenge infection at 14 weeks post-immunization, but sterilely protected only 2/10 and 1/9 volunteers against NF135.C10 and NF166.C8 challenge infection, respectively. Post-immunization plasma showed a significantly lower capacity to block heterologous parasite development in primary human hepatocytes compared to NF54. Whole genome sequencing showed that NF135.C10 and NF166.C8 have amino acid changes in multiple antigens targeted by CPS-induced antibodies. Volunteers protected against heterologous challenge were among the stronger immune responders to in vitro parasite stimulation.

Conclusions

Although highly protective against homologous parasites, NF54-CPS-induced immunity is less effective against heterologous parasite clones both in vivo and in vitro. Our data indicate that whole sporozoite-based vaccine approaches require more potent immune responses for heterologous protection.

Trial registration

This trial is registered in clinicaltrials.gov, under identifier NCT02098590.
Appendix
Available only for authorised users
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Metadata
Title
Modest heterologous protection after Plasmodium falciparum sporozoite immunization: a double-blind randomized controlled clinical trial
Authors
Jona Walk
Isaie J. Reuling
Marije C. Behet
Lisette Meerstein-Kessel
Wouter Graumans
Geert-Jan van Gemert
Rianne Siebelink-Stoter
Marga van de Vegte-Bolmer
Thorsten Janssen
Karina Teelen
Johannes H. W. de Wilt
Quirijn de Mast
André J. van der Ven
Ernest Diez Benavente
Susana Campino
Taane G. Clark
Martijn A. Huynen
Cornelus C. Hermsen
Else M. Bijker
Anja Scholzen
Robert W. Sauerwein
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2017
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-017-0923-4

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