Diverse outcomes of controlled human malaria infection originate from host-intrinsic immune variation and not var gene switching

Falciparum malaria is clinically heterogeneous and the relative contribution of parasite and host in shaping disease severity remains unclear. We explored the interaction between inflammation and parasite variant surface antigen (VSA) expression, asking whether this relationship underpins the variation observed in controlled human malaria infection (CHMI). We uncovered marked heterogeneity in the response of naive hosts to blood challenge; some volunteers remained quiescent, others triggered interferon-stimulated inflammation and some showed transcriptional evidence of myeloid cell suppression. Significantly, only inflammatory volunteers experienced hallmark symptoms of malaria. When we tracked temporal changes in parasite VSA expression to ask whether variants associated with severe disease preferentially expand in naive hosts (as predicted by current theory) we found that var gene profiles were unchanged after 10-days of infection. The diverse outcomes of CHMI therefore depend upon human immune variation and there is no evidence for switching or selection of var genes in naive hosts. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial NCT02044198, [NCT02905019][1] ### Funding Statement KM is the recipient of a Medical Research Council PhD studentship (grant no. G40270). AJR is funded by the Medical Research Council (programme grant no. MR/M003906/1) and the Wellcome Sanger Institute is funded by the Wellcome Trust (grant WT206194). AOT is the recipient of a Wellcome Trust PhD studentship (grant no. 203783/Z/16/Z). MPB is part of the Wellcome Centre for Integrative Parasitology (grant no. 104111/Z/14/Z). SJD is the recipient of a Wellcome Trust Senior Fellowship (grant no. 106917/Z/15/Z) and is a Lister Institute Research Prize Fellow. JAR is supported by the Wellcome Trust (grant no. 084226). And PJS is the recipient of a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant no. 107668/Z/15/Z). The clinical trials were originally funded by the PATH Malaria Vaccine Initiative, US Agency for International Development (USAID) and the European Union Seventh Framework Programme (FP7/2007-2013) under the grant agreement for MultiMalVax (number 305282). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: NCT02044198: UK NHS Research Ethics Service (Oxfordshire Research Ethics Committee A, ref. 13/SC/0596) Western Institutional Review Board (WIRB) in the USA (ref. 20131985) UK Medicines and Healthcare products Regulatory Agency (MHRA) (ref. 21584/0326/001-0001) [NCT02905019][1]: UK NHS Research Ethics Service (South Central Berkshire Research Ethics Committee, ref. 16/SC/0261) UK MHRA (ref. 21584/0360/001-0001) All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All datasets are publicly available using the accession numbers below: Blood challenge human microarray dataset (NCBI GEO): GSE132050 Mosquito challenge human RNA-sequencing dataset (EBI ArrayExpress): EGAS00001003766 and EGAD00001005790 Blood challenge metabolomics dataset (MetaboLights): MTBLS1188 Parasite RNA-sequencing dataset (blood and mosquito challenge) (EBI ENA): ERP116360 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02905019&atom=%2Fmedrxiv%2Fearly%2F2020%2F09%2F07%2F2020.09.04.20188144.atom