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43600761.Pdf View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Radboud Repository PDF hosted at the Radboud Repository of the Radboud University Nijmegen The following full text is a publisher's version. For additional information about this publication click this link. http://hdl.handle.net/2066/153094 Please be advised that this information was generated on 2017-12-05 and may be subject to change. Impact of Malaria Preexposure on Antiparasite Cellular and Humoral Immune Responses after Controlled Human Malaria Infection Joshua M. Obiero,a* Seif Shekalaghe,b Cornelus C. Hermsen,a Maxmillian Mpina,b Else M. Bijker,a Meta Roestenberg,a* Karina Teelen,a Peter F. Billingsley,c B. Kim Lee Sim,c Eric R. James,c Claudia A. Daubenberger,d,e Stephen L. Hoffman,c b a a Salim Abdulla, Robert W. Sauerwein, Anja Scholzen Downloaded from Radboud University Medical Center, Department of Medical Microbiology, Nijmegen, The Netherlandsa; Ifakara Health Institute, Bagamoyo Research and Training Center, Bagamoyo, Tanzaniab; Sanaria Inc., Rockville, Maryland, USAc; Swiss Tropical and Public Health Institute, Department of Medical Parasitology and Infection Biology, Basel, Switzerlandd; University of Basel, Basel, Switzerlande To understand the effect of previous malaria exposure on antiparasite immune responses is important for developing successful immunization strategies. Controlled human malaria infections (CHMIs) using cryopreserved Plasmodium falciparum sporozo- ites provide a unique opportunity to study differences in acquisition or recall of antimalaria immune responses in individuals from different transmission settings and genetic backgrounds. In this study, we compared antiparasite humoral and cellular im- http://iai.asm.org/ mune responses in two cohorts of malaria-naive Dutch volunteers and Tanzanians from an area of low malarial endemicity, who were subjected to the identical CHMI protocol by intradermal injection of P. falciparum sporozoites. Samples from both trials were analyzed in parallel in a single center to ensure direct comparability of immunological outcomes. Within the Tanzanian cohort, we distinguished one group with moderate levels of preexisting antibodies to asexual P. falciparum lysate and another that, based on P. falciparum serology, resembled the malaria-naive Dutch cohort. Positive P. falciparum serology at baseline was associated with a lower parasite density at first detection by quantitative PCR (qPCR) after CHMI than that for Tanzanian volunteers with negative serology. Post-CHMI, both Tanzanian groups showed a stronger increase in anti-P. falciparum anti- body titers than Dutch volunteers, indicating similar levels of B-cell memory independent of serology. In contrast to the Dutch, on February 28, 2017 by UNIVERSITEITSBIBLIOTHEEK Tanzanians failed to increase P. falciparum-specific in vitro recall gamma interferon (IFN-␥) production after CHMI, and in- nate IFN-␥ responses were lower in P. falciparum lysate-seropositive individuals than in seronegative individuals. In conclu- sion, positive P. falciparum lysate serology can be used to identify individuals with better parasite control but weaker IFN-␥ re- sponses in circulating lymphocytes, which may help to stratify volunteers in future CHMI trials in areas where malaria is endemic. n 2012, Plasmodium falciparum malaria caused an estimated 207 where malaria is endemic, since it bypasses the need for infecting Imillion cases and 627,000 deaths, of which 90% occurred in local Anopheles mosquitoes with P. falciparum or importing P. children under 5 years of age and in pregnant women in sub- falciparum-infected mosquitoes to the trial site. The first PfSPZ Saharan Africa (1). Major control efforts have been implemented Challenge trial in malaria-naive Dutch volunteers demonstrated with some success (2, 3), but malaria eradication will likely require an infectivity rate of 83% after intradermal injections, indepen- a safe and highly protective vaccine. Subunit vaccines have thus far dent of the dose given (23). Recently, PfSPZ Challenge was used shown moderate efficacy at best. RTS,S is the only vaccine candi- for the first time during a CHMI trial in healthy adult male Tan- date in phase 3 trials but, despite averting substantial numbers of malaria cases (4), shows only 30 to 50% reduction in clinical dis- ease after 12 months depending on both age and malaria endemic- ity and even less after 18 months (5–7). These results stress the Received 10 December 2014 Returned for modification 26 January 2015 need for more effective second-generation vaccines. Key require- Accepted 9 March 2015 ments are not only the identification of novel immunogens but Accepted manuscript posted online 16 March 2015 also a better understanding of protection-related immune re- Citation Obiero JM, Shekalaghe S, Hermsen CC, Mpina M, Bijker EM, Roestenberg M, Teelen K, Billingsley PF, Sim BKL, James ER, Daubenberger CA, Hoffman SL, sponses. This includes the effect of previous malaria exposure on Abdulla S, Sauerwein RW, Scholzen A. 2015. Impact of malaria preexposure on immune responses upon reexposure or vaccination (8, 9). antiparasite cellular and humoral immune responses after controlled human During the past 3 decades, controlled human malaria infection malaria infection. Infect Immun 83:2185–2196. doi:10.1128/IAI.03069-14. (CHMI) trials have become an indispensable tool not only in as- Editor: J. H. Adams sessing the efficacy of candidate vaccines (10, 11) but also in eval- Address correspondence to Robert W. Sauerwein, [email protected], uating immune responses induced by exposure to the malaria par- or Anja Scholzen, [email protected]. asite (12–15). CHMI trials have so far been performed in countries * Present address: Joshua M. Obiero, University of California Irvine, Department of Medicine, Division of Infectious Diseases, Irvine, California, USA; Meta were malaria is not endemic in previously unexposed individuals Roestenberg, Leiden University Medical Center, Department of Infectious (11, 16–19). A logical next step is to study the potential differences Diseases, Leiden, The Netherlands. in the acquisition, maintenance, or recall of immune responses in Supplemental material for this article may be found at http://dx.doi.org/10.1128 individuals from different transmission settings and genetic back- /IAI.03069-14. grounds (20, 21). The availability of aseptic, purified, cryopre- Copyright © 2015, American Society for Microbiology. All Rights Reserved. served, live P. falciparum sporozoites (PfSPZs; PfSPZ Challenge) doi:10.1128/IAI.03069-14 (22) opens up opportunities to carry out CHMI trials in countries May 2015 Volume 83 Number 5 Infection and Immunity iai.asm.org 2185 Obiero et al. zanian volunteers, resulting in similar infection rates (24). As a isolation lysis buffer to serve as an internal control. For quantification of follow-up, we here present results of the malaria-specific humoral PhHV, the primers GGGCGAATCACAGATTGAATC and GCGGTTCC and cellular immune responses in Tanzanians and Dutch volun- AAACGTACCAA and the probe Cy5-TTTTTATGTGTCCGCCACCATC teers who were inoculated intradermally with the same number of TGGATC were used. live PfSPZs during these CHMI studies. P. falciparum (NF54 strain) standard curves for both qPCR assays were prepared in Nijmegen by titration of ring-stage-infected red blood cells (RBC) in uninfected human blood. The two qPCR assays in both sites MATERIALS AND METHODS were confirmed to yield the same results when quantifying the P. falcipa- Human ethics statement. The Dutch trial (23) was approved by the Cen- rum content in sequential samples from four CHMI volunteers. tral Committee for Research Involving Human Subjects of The Nether- Parasite material for immunological analysis. The P. falciparum Downloaded from lands (NL31858.091.10) and registered at Clinicaltrials.gov, identifier NF54 strain used in both CHMI trials is the parental strain of the 3D7 NCT 01086917. The Tanzanian trial (24) was approved by institutional clone (27 ). P. falciparum (NF54 strain) blood-stage parasites were cul- review boards of the Ifakara Health Institute (IHI/IRB/No25), the Na- tured in RPMI 1640 containing 10% human Aϩ serum and a 5% hemat- tional Institute for Medical Research Tanzania (NIMR/HQ/R.8a/Vol.IX/ ocrit erythrocyte suspension in a semiautomated culture system and reg- 1217), the Ethikkommission beider Basel (EKBB), Basel, Switzerland ularly screened for mycoplasma contamination. For in vitro stimulation (EKBB 319/11), and the Tanzanian Food and Drug Administration (ref- assays, asynchronous parasites harvested at a parasitemia of approxi- erence no. CE.57/180/04A/50) and registered at Clinicaltrials.gov, identi- mately 10 to 20% were purified by centrifugation on a 63% Percoll density fier NCT 01540903. All study teams complied with the Declaration of gradient to obtain mature asexual stages. This resulted in concentrations Helsinki and good clinical practice, including monitoring of data, and all of parasitemia levels of about 80 to 90%, consisting of more than 95% http://iai.asm.org/ volunteers gave written informed consent. schizonts/mature trophozoites. P. falciparum-infected RBC (PfRBC) were Clinical trial design. Samples for immunological analysis were ob- washed twice in RPMI, cryopreserved in glycerol-containing freeze me- tained from two CHMI trials (23, 24). dium, and used upon thawing in stimulation assays. Mock-cultured unin- The first trial, performed at Radboud University Medical Center,
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