{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T11:19:22Z","timestamp":1779189562775,"version":"3.51.4"},"update-to":[{"DOI":"10.12688\/wellcomeopenres.14909.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2019,11,14]],"date-time":"2019-11-14T00:00:00Z","timestamp":1573689600000}}],"reference-count":59,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2019,11,14]],"date-time":"2019-11-14T00:00:00Z","timestamp":1573689600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000769","name":"University of Oxford","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000769","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["107499"],"award-info":[{"award-number":["107499"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["wellcomeopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Wellcome Open Res"],"abstract":"<ns4:p>\n                    Malaria remains a major public health burden despite approval for implementation of a partially effective pre-erythrocytic malaria vaccine. There is an urgent need to accelerate development of a more effective multi-stage vaccine. Adults in malaria endemic areas may have substantial immunity provided by responses to the blood stages of malaria parasites, but field trials conducted on several blood-stage vaccines have not shown high levels of efficacy. \u00a0We will use the controlled human malaria infection (CHMI) models with malaria-exposed volunteers to identify correlations between immune responses and parasite growth rates\n                    <ns4:italic>in vivo<\/ns4:italic>\n                    . \u00a0Immune responses more strongly associated with control of parasite growth should be prioritized to accelerate malaria vaccine development. We aim to recruit up to 200 healthy adult volunteers from areas of differing malaria transmission in Kenya, and after confirming their health status through clinical examination and routine haematology and biochemistry, we will comprehensively characterize immunity to malaria using &gt;100 blood-stage antigens. We will administer 3,200 aseptic, purified, cryopreserved\n                    <ns4:italic>Plasmodium falciparum<\/ns4:italic>\n                    sporozoites (PfSPZ Challenge) by direct venous inoculation. Serial quantitative polymerase chain reaction to measure parasite growth rate\n                    <ns4:italic>in vivo<\/ns4:italic>\n                    will be undertaken. Clinical and laboratory monitoring will be undertaken to ensure volunteer safety. In addition, we will also explore the perceptions and experiences of volunteers and other stakeholders in participating in a malaria volunteer infection study. Serum, plasma, peripheral blood mononuclear cells and whole blood will be stored to allow a comprehensive assessment of adaptive and innate host immunity. We will use CHMI in semi-immune adult volunteers to relate parasite growth outcomes with antibody responses and other markers of host immunity.\n                  <\/ns4:p>\n                  <ns4:p>\n                    <ns4:bold>Registration:<\/ns4:bold>\n                    ClinicalTrials.gov identifier\n                    <ns4:ext-link xmlns:ns3=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" ns3:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/study\/NCT02739763\">NCT02739763<\/ns4:ext-link>\n                    .\n                  <\/ns4:p>","DOI":"10.12688\/wellcomeopenres.14909.2","type":"journal-article","created":{"date-parts":[[2019,11,14]],"date-time":"2019-11-14T12:10:09Z","timestamp":1573733409000},"page":"155","update-policy":"https:\/\/doi.org\/10.12688\/wellcomeopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Controlled Human Malaria Infection in Semi-Immune Kenyan Adults (CHMI-SIKA): a study protocol to investigate in vivo Plasmodium falciparum malaria parasite growth in the context of pre-existing immunity"],"prefix":"10.12688","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0321-7128","authenticated-orcid":false,"given":"Melissa C.","family":"Kapulu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricia","family":"Njuguna","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mainga M.","family":"Hamaluba","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"CHMI-SIKA Study Team","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2560","published-online":{"date-parts":[[2019,11,14]]},"reference":[{"key":"ref-1","article-title":"World Malaria Report 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Kublin","year":"2017","journal-title":"Sci Transl Med."}],"container-title":["Wellcome Open 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status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/wellcomeopenres.17028.r37058, Alister G. Craig, Department of Tropical Disease Biology, Liverpool School of Tropical Medicine, Liverpool, UK, 18 Nov 2019, version 2, indexed","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-155\/v2#referee-response-37058","order":0,"name":"referee-response-37058","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/wellcomeopenres.16254.r34926, Salim Abdulla, Ifakara Health Institute, Dar es Salaam, Tanzania, 11 Mar 2019, version 1, 1 approved, 1 approved with reservations","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-155\/v1#referee-response-34926","order":1,"name":"referee-response-34926","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Melissa Kapulu<\/b>; \n<i>Posted: 30 Oct 2019<\/i>;  The use of the standard CHMI procedures as well as the social science component will further develop this approach for testing new candidate malaria diagnostics, drugs, vaccines and extend the application of the CHMI model into the exploration of the correlates of malaria immunity that is still not very well known.  &nbsp;We thank the reviewer for their comment.  It will be good for the investigators to provide a list of the specific antigens of interest in this study and describe a bit better how this approach of using CHMI platform to select for those antibodies that have been associated with reduced replication will be identified, different from previous work in which antibodies were similarly screened and episodes of parasitaemia monitored. Is the value of the CHMI only about removing the heterogeneity of malaria exposure in the assessment?  &nbsp;We have added the reference to the recently published KILCHIP paper Kamuyu et al 2018 describing the antigens. We anticipate that using the CHMI model in the context of pre-existing immunity will help identify potential antigens that could be prioritised for vaccine development. Heterogeneity of exposure is one of the factors that confounds analyses of association between immune responses and outcomes in the field. The CHMI model provides a \u201cclean\u201d system where individuals are equally exposed to a known quantity and genotype of parasites. The known timing of exposure also allows us to calculate the liver to blood inoculum in relation to parasite growth which would not be possible in cohort studies in the field.  It will be good for the investigators to comment on the choice of using CHMI with Sporozoite Challenge inoculation approach while the interest is in blood stage antigens and a blood stage Challenge model exist that would have given a more uniform blood stage parasitaemia. I assume that one of the reasons apart from ease of procedures, is the breath of assessments that can be done using the Sporozoite Challenge approach. Example, pre-patent periods can be assessed as an indicator of liver stage activity.&nbsp;The investigators will take blood samples also during the liver stage replication of the parasites and hence using a battery of immunological assays already proposed to be done, be able to assess both pre-exiting as well as newly expressed antibodies for both liver stage as well as blood stage during the follow up period. How this information will be used to identify priority antigens is not very clear in the manuscript. Furthermore, observed high antibody titres does not always translate into effect in reducing replication so how are the other factors going to be teased out.  We refer to our answer to reviewer number 1 comment 3 regarding the use of sporozoites. We agree with the reviewer that high antibody titres do not necessarily translate to a reduction in symptoms or effects on parasite growth. We will examine a wide range of antibody responses, in order to identify the limitations of seeking to explain outcomes with a single response.  Is any work going to be done to identify novel antigens during this process?  The antigens described on the microarray (Kamuyu et al 2018) include both previously characterized and uncharacterised and novel antigens. The use of this chip with these antigens is to examine their potential as vaccine candidates at the blood stage with complementary work on functional assays. There are plans to further use the sample set generated to identify \u201cnovel\u201d antigens involved in the pre-erythrocytic and transmission stages of the parasite.","URL":"https:\/\/wellcomeopenresearch.org\/articles\/3-155\/v2#referee-comment-3990","order":2,"name":"referee-comment-3990","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This work is supported by a Wellcome Trust grant (107499) and the study is sponsored The University of Oxford. The University of Oxford will sponsor the study and provide insurance for the trial. The University of Oxford has a specialist insurance policy in place which would operate in the event of any participant suffering harm as a result of their involvement in the research. Sanaria, Inc. has product insurance for non-negligent harm arising as a result of exposure to PfSPZ. KEMRI-WTRP Clinical Trials Facility will provide indemnity for clinical negligence. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":3,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}