[R01] Circularization of RNA to improve the durability of the vaccine immune response
Ente: National Institute of Allergy and Infectious Diseases
Scadenza: 2030-04-30
Importo max: 798.400 EUR
Paese: US
Descrizione
ABSTRACT
mRNA vaccines are one of the most promising vaccine platforms available to rapidly deploy in response
to emerging viral infections. However, the duration of the protective antibody response induced by these vaccines
is limited, even after multiple vaccine doses. The rapid decay of the antibody response to mRNA vaccines
necessitates frequent revaccinations.
The immunogenicity of vaccines based on conventional mRNA may be reduced due to triggering TLR 3,
7 and 8, and RIG-I receptors resulting in strong induction of the innate immune response. This leads to
expression and activation of protein kinase R and 2’-5’-oligoadenylate synthetase, which in turn leads to
suppression of translation. As circular RNA does not have termini, it stimulates innate immune responses
weaker. Moreover, circular RNA has the advantage of prolonged expression due to resistance to exonucleases.
A protein produced from circular RNA is detectable in serum or at a site of injection for a much longer period of
time as compared to linear mRNA. Extended antigen availability to mimic the natural kinetics of antigen delivery
during viral infections has shown to be highly effective in potentiating germinal center responses to immunogens.
Hantaviruses are globally emerging pathogens; the New World hantaviruses Andes virus (ANDV) and
Sin Nombre virus cause hantavirus cardiopulmonary syndrome with a case fatality rate up to 40%. A recent
outbreak of ANDV demonstrated transmission through direct contact with infected individuals but also airborne
human-to-human, highlighting the significant pandemic potential of this virus.
The proposal is based on extensive preliminary data which show that ANDV linear mRNA vaccine
platforms are protective against ANDV challenge in the 100% lethal hamster model. The proposal is aimed at
testing the hypothesis that the innovative circular RNA vaccine construct against ANDV will elicit the most potent
adaptive immune response including diversity and magnitude of germinal center responses, long lived plasma
cells, memory B cells, and T cell responses. This will be achieved by pursuing the following Specific Aims: 1) To
investigate circular RNA vaccine platform, in comparison with linear mRNA, for the ability to induce innate
immune responses, 2) To investigate the effects of circular RNA vaccine platform, in comparison with linear
mRNA, on the induction of adaptive immune response, 3) To investigate immunological mechanisms of
protection by circular RNA in vivo. To accomplish these aims, molecular, virological, and immunological
expertise and access to biocontainment will be employed.
The proposed in-depth investigation of the immune mechanisms of protection of circular RNA, in
comparison with linear mRNA platforms will facilitate development of vaccines based on this innovative platform.
Furthermore, the proposal will result in an innovative circular RNA-based vaccine against ANDV that is suitable
for clinical development and can serve as a
Istituzione: UNIVERSITY OF TEXAS MED BR GALVESTON
PI: Robert Koehler Abbott, Alexander Bukreyev
Progetto: 5R01AI184768-02
Settori: National Institute of Allergy and Infectious Diseases
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