Novel malaria multi-epitope vaccine design

Vaccines are expected to mimic and accelerate the acquisition of natural immunity, and vaccine development requires a basic understanding of how protective natural immunity develops. Candidate malaria vaccines that contain weakened live parasites have been shown to protect 100% of vaccinated individuals by induction of both antibody and cellular T cell responses against parasite antigens. Antibody responses are especially important against the blood stage infection, which is responsible for the clinical symptoms of the disease, while cellular responses are important against the liver stage parasite, which resides within the liver cells. Activation of T cells requires that parasite antigens are shown to these T cells by host molecules known as human leukocyte antigens (HLA), which are present on all nucleated host cells including liver cells. Different individuals have different HLA antigens and each HLA can recognize and display different portions of parasite antigens. HLA-displayed parasite antigens may contribute significantly to protection against malaria. Identification of portions of the parasite antigens that are recognized by host HLA antigens and are ultimately capable of eliciting immune responses that may correlate with protection is therefore key to effective malaria vaccine development. In this proposed study, the hypothesis to be tested is that HLA-displayed malaria antigens may inhibit the development of liver stage parasites and prevent blood stage infection and clinical malaria. Inclusion of only the conserved portions of parasite antigens is important since immune responses against variable portions are not effective against parasites that lack these antigen portions. White blood cells isolated from study subjects’ in an area of malaria transmission in Ghana will be used to assess cellular responses after stimulation with pools of parasite antigen fragments. The HLA antigens of these subjects will be determined and the parasite antigen epitopes that they bind to subject HLAs will be predicted using a bioinformatics algorithm. Predicted antigen epitopes within positive fragment pools that are conserved will be assessed for their ability to elicit cellular responses, confirming their immunologic significance. The vaccine will use a new technology called SAPN (self-assembling protein nanoparticles) that highly efficiently displays epitopes to the immune system. We will make four SAPN vaccines, each based on CSP, AMA1, TRAP or CelTOS epitopes that have been confirmed to bind to one or more of the five HLAs. Because there is no suitable animal model for human malaria, we will adapt the mouse malaria model. Mice will be transfected with two of these common human HLAs so they can present matched HLA-restricted epitopes. Protection will be tested using mouse malaria parasites that have been genetically modified to include CSP or CelTOS from the human malaria parasites; these parasites will infect HLA-transgenic mice, and the vaccine-induced responses may recognize the human malaria antigen inserts in the mouse parasites and confer protection against malaria in transgenic mice. If we can successfully demonstrate that these CSP and CelTOS SPAN vaccines induce protection, we will be able to quickly develop these vaccines for human testing, as another SAPN malaria vaccine is about to enter human trials.

Vaccines

Sep 2019 — Aug 2021

$523,986

Ghana