Biologically informed design of CD8+ T cell-dependent pre-erythrocytic stage malaria vaccines

Immunization with whole pre-erythrocytic (sporozoite and liver stage) Plasmodium falciparum (Pf) vaccines confers sterilizing immunity in human clinical trials. Replication-deficient vaccines, such as radiation- attenuated sporozoites infect the liver as sporozoites but do not develop into liver stage schizonts. Replication- competent vaccines, however, infect the liver and replicate as tissue schizonts. Multiple lines of evidence in animal models of malaria have shown that protection is dependent on antigen-specific CD8+ T cells that recognize liver stage-infected hepatocytes, leading to their elimination. Replication-competent parasite vaccination confers superior durable sterilizing immunity against infection, and this appears to be, in animal models, associated with broader and better CD8+ T cell responses. However, it remains largely unknown how the distinct molecular cell biological features of whole attenuated parasite vaccines drive differences in the priming of protective CD8+ T cells and of equal importance, which liver stage antigens are directly presented by wildtype liver stage-infected hepatocytes that are the targets of vaccine-elicited protective CD8+ T cells.

These critical knowledge gaps will be adressed by the project. Aim 1 will identify the distinct time points during which the demise of liver stage-infected hepatocytes results in optimal cross-presentation of liver stage antigens by antigen presenting cells to CD8+ T cells. For this, we will use the Plasmodium yoelii (Py) rodent malaria model to inform vaccine design of Pf, with which mechanistic host studies cannot be done. The project will also determine at what time points of wildtype liver stage development infected hepatocytes are most vulnerable to effector CD8+ T cell- mediated elimination. In concert with this, we will determine dynamic liver stage transcriptomes and proteomes throughout development and down-select the subset of liver stage proteins most prone to intrahepatocytic processing and MHC class I-restricted peptide presentation. Aim 2 will directly determine the MHC class I peptidome of Py and Pf presented on infected hepatocytes, specifically at timepoints of highest vulnerability and test their reactivity with whole parasite-vaccine-elicited CD8+ T cells. Reactive epitopes as well as nonreactive epitopes (covert epitopes) will be tested as vectored subunit vaccines in mice. As in Aim 1, mechanistic testing cannot be done in Pf and thus studies will be conducted on Py to guide the Pf work. Aim 3 will genetically engineer the ultimate Pf replication-competent parasite strain that is built with gene deletions and dominant negative transgenes of parasite origin and will also over-express protective CD8+ T cell epitopes that target liver stages at the point of their greatest vulnerability.

Project details

Product Development
Vaccines (Immune Correlates)

Feb 2021 — Jan 2026

$3.88M

United States