Monday, April 29, 2024
4/29/2024
PA-19-077 DOOLAN: PROJECT SUMMARY Malaria remains a global public health problem with nearly half of the world's population at risk. An effective malaria vaccine would prevent almost half a million deaths and over 200 million clinical cases each year and help eradicate the disease. The most effective experimental malaria vaccination regimens to date are radiation- attenuated sporozoites (RAS; PfSPZ) and infectious sporozoites administered under chemoprophylaxis (CPS). Protective immunity is believed to be mediated by CD8+ T cells which attack the parasite during the pre- erythrocytic (PE) liver-stage of infection. However, the key antigens underlying this protection are largely unknown. We have developed and applied a proteome-wide T cell screening approach to identify the subset of key antigens targeted by T cell responses from the complete Plasmodium falciparum parasite proteome. We have shown that the antigens preferentially recognized by T cells are distinct from antibody targets. Here, we will characterize and credential highly ranked pre-erythrocytic P. falciparum T cell antigens from our unique dataset, focusing on those that are categorized as exclusively T cell targets, since T cells directed against liver- stage antigens are considered the primary immune effectors required for sterile immunity against malaria which prevents disease and stops transmission. Our selection criteria will consider extent of sequence conservation across Plasmodium strains and species, to target a vaccine that confers strain transcending and cross-species protection. We will use clinically relevant selection criteria governed by the capacity of the antigen to protect against virulent P. yoelii parasite challenge in established preclinical models and to be recognized by recall Plasmodium-specific immune responses in protective human models. We will use two innovative vaccine delivery platforms selected for capacity to induce robust and sustained T cell responses, with a specific focus on the induction of liver-specific resident memory T cells (Trm) targeting the putative site of immune action. Our selected regimens include “Prime-Target” comprising a DNA prime followed by adenovirus boost delivered intravenously to target the liver, and a liposomal mRNA vaccine platform with an incorporated agonist (cA) to activate NKT cells and link innate and adaptive immunity; both platforms can induce sustained T cell responses and are capable of protecting mice against sporozoite challenge. We will assign priorities for vaccine development according to their credentials, evaluate combinations for synergy, and down-select for clinical development the set of antigens that have a maximum likelihood of inducing robust and sustained protective immunity against malaria in humans. The optimal vaccine candidate defined with this preclinical development strategy could be transitioned directly to clinical development with the ultimate goal of deploying in the field an effective rationally-designed genome-based vaccine that would induce durable T-cell mediated protection and ameliorate disease in all at-risk individuals.
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