Cellular immunity in Tanzanian volunteers upon malaria vaccination and controlled human malaria infection

Abstract

Despite considerable efforts and achievements, malaria continues to be one of the most devastating infectious diseases in the world. Clearly, an effective vaccine against malaria would help to reduce disease burden and support elimination programs. This year, the malaria vaccine RTS,S/AS01 will be rolled out in three countries of sub-Saharan Africa, representing a milestone in malaria vaccine development. However, RTS,S induced only partial and short- lived protection when assessed in large-scale clinical trials in infants and children of sub-Saharan Africa, highlighting the need for more effective vaccines. Conversely, it has been known for a long time that sterile protection against malaria can be achieved by administration of large amounts of radiation-attenuated sporozoites. The Sanaria PfSPZ Vaccine consists of radiation-attenuated, aseptic, purified, cryopreserved Plasmodium falciparum sporozoites (PfSPZ). This vaccination approach has induced up to 100% protection during clinical trials in malaria-naive, US volunteers. At the same time, development of the PfSPZ Vaccine also enabled the use of non-attenuated cryopreserved PfSPZ in controlled human malaria infection (CHMI) to assess vaccine efficacy. Together, these tools are not only promising for vaccine development, but also offer a unique opportunity to study the human immune response to P. falciparum in a highly controlled setting in sub-Saharan Africans, the population most strongly affected by malaria. Thus, the aims of this thesis were: First, to study the cellular immune response towards RTS,S, the most advanced subunit malaria vaccine in a paediatric phase III clinical trial in Tanzania. Second, to assess safety, immunogenicity and protective efficacy of the PfSPZ Vaccine, a live-attenuated malaria vaccine, in a phase I clinical trial in adult Tanzanians. Third, to develop an analysis pipeline that allows for unbiased detection of ex vivo phenotypic alterations of T-cell subsets measured by multicolour flow cytometry. Fourth, to analyse the immune response of unconventional T cells towards PfSPZ vaccination and CHMI in Tanzanian volunteers in a comprehensive and unbiased approach.