Human-informed data-driven development of next-generation T cell vaccine against malaria

NIH Pandemic-Era Grants

Pandemic Era Grants

2022

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Principal Investigator: Denise L. Doolan
Organization: JAMES COOK UNIVERSITY OF NO QUEENSLAND
Fiscal Year: 2022
Award: $495,904
Funding agency: National Institute of Allergy and Infectious Diseases

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.

Terms: <Address><Adenoviridae><Adenoviruses><Agonist><Antibodies><Antibody Response><Antigen Targeting><Antigens><Attenuated><Blood erythrocyte><Body Tissues><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><Cell Body><Cells><Cessation of life><Characteristics><Chemoprophylaxis><Chlorochin><Chloroquine><Clinical><Clinical Evaluation><Clinical Testing><Complex><Computational Science><DNA><Data><Data Set><Dataset><Death><Deoxyribonucleic Acid><Development><Disease><Disorder><Erythrocytes><Erythrocytic><Genome><Goals><Human><Immune><Immune response><Immunes><Immunity><Immunization><Immunologic Sensitization><Immunologic Stimulation><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunology><Immunostimulation><In complete remission><Individual><Infection><Innate Immunity><Intravenous><Khingamin><LYT3><Lead><Link><Liposomal><Liposomes><Liver><Malaria><Malaria Vaccines><Malarial Vaccines><Marrow erythrocyte><Mediating><Mediator><Mediator of Activation><Mediator of activation protein><Memory><Messenger RNA><Mice><Mice Mammals><Modern Man><Multiomic Data><Murine><Mus><Native Immunity><Natural Immunity><Non-Specific Immunity><Nonspecific Immunity><Outcome><P falciparum><P. falciparum><P.falciparum><Paludism><Parasites><Pb element><Phase><Plasmodium><Plasmodium Infections><Plasmodium falciparum><Populations at Risk><Pre-Clinical Model><Preclinical Models><Proteins><Proteome><Public Health><RNA vaccine><RNA-based vaccine><Radiation><Red Blood Cells><Red Cell><Regimen><Risk><Selection Criteria><Site><Sporozoites><Sterility><T cell response><T memory cell><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><Targeted Research><Tissues><Transcend><Translational Research Enterprise><Transmission><Vaccination><Vaccine Antigen><Vaccines><Virulent><adaptive immunity><base><blood corpuscles><clinical development><clinical relevance><clinical test><clinically relevant><combinatorial><complete response><data integration><deliver vaccines><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><evaluate vaccines><heavy metal Pb><heavy metal lead><hepatic body system><hepatic organ system><host response><human model><immune system response><immunization strategy><immunogen><immunogenicity><immunoresponse><in silico><in vivo><innovate><innovation><innovative><mRNA><mRNA vaccine><mRNA-based vaccine><memory T lymphocyte><model of human><multiple omic data><new approaches><next generation><novel><novel approaches><novel strategies><novel strategy><pathogen><pre-clinical development><preclinical development><prevent><preventing><rational design><research clinical testing><response><screening><sterile><synergism><thymus derived lymphocyte><translation research enterprise><translational research program><transmission process><vaccination strategy><vaccine candidate><vaccine delivery><vaccine development><vaccine evaluation><vaccine platform><vaccine screening><vaccine testing><vaccines against malaria><vaccinology>