TY - JOUR
T1 - Modest heterologous protection after Plasmodium falciparum sporozoite immunization
T2 - A double-blind randomized controlled clinical trial
AU - Walk, Jona
AU - Reuling, Isaie J.
AU - Behet, Marije C.
AU - Meerstein-Kessel, Lisette
AU - Graumans, Wouter
AU - van Gemert, Geert Jan
AU - Siebelink-Stoter, Rianne
AU - van de Vegte-Bolmer, Marga
AU - Janssen, Thorsten
AU - Teelen, Karina
AU - de Wilt, Johannes H.W.
AU - de Mast, Quirijn
AU - van der Ven, André J.
AU - Diez Benavente, Ernest
AU - Campino, Susana
AU - Clark, Taane G.
AU - Huynen, Martijn A.
AU - Hermsen, Cornelus C.
AU - Bijker, Else M.
AU - Scholzen, Anja
AU - Sauerwein, Robert W.
N1 - Funding Information:
This study was funded by the Bill and Melinda Gates Foundation, grant ID number OPP1080385. The funder agreed with the study design as proposed by the authors and had no role in the collection, analysis or interpretation of the data, the preparation of the report, or decision to publish. MCB is supported by a Nijmegen Institute for Infection, Inflammation and Immunity (N4i) PhD scholarship. JW, IJR, MCB, and RWS had full access to all study data with final responsibility to submit the report for publication.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/9/13
Y1 - 2017/9/13
N2 - 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 14weeks 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.
AB - 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 14weeks 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.
KW - Controlled human malaria infection
KW - Heterologous protection
KW - Immune responses
KW - Malaria
KW - Plasmodium falciparum
KW - Sporozoite
KW - Vaccine
UR - http://www.scopus.com/inward/record.url?scp=85029415530&partnerID=8YFLogxK
U2 - 10.1186/s12916-017-0923-4
DO - 10.1186/s12916-017-0923-4
M3 - Article
C2 - 28903777
AN - SCOPUS:85029415530
SN - 1741-7015
VL - 15
JO - BMC Medicine
JF - BMC Medicine
IS - 1
M1 - 168
ER -