RESUMO
Clinically licensed COVID-19 vaccines ameliorate viral infection by inducing vaccinee production of neutralizing antibodies that bind to the SARS-CoV-2 Spike protein to inhibit viral cellular entry (Walsh et al., 2020; Baden et al., 2021), however the clinical effectiveness of these vaccines is transitory as viral variants arise that escape antibody neutralization (Tregoning et al., 2021; Willett et al., 2022). Vaccines that solely rely upon a T cell response to combat viral infection could be transformational because they can be based on highly conserved short peptide epitopes that hold the potential for pan-variant immunity, but a mRNA-LNP T cell vaccine has not been shown to be sufficient for effective antiviral prophylaxis. Here we show that a mRNA-LNP vaccine based on highly conserved short peptide epitopes activates a CD8+ and CD4+ T cell response that prevents mortality in HLA-A*02:01 transgenic mice infected with the SARS-CoV-2 Beta variant of concern (B.1.351). In mice vaccinated with the T cell vaccine, 24% of the nucleated cells in lung were CD8+ T cells on day 7 post infection. This was 5.5 times more CD8+ T cell infiltration of the lungs in response to infection compared to the Pfizer-BioNTech Comirnaty(R) vaccine. Between days 2 and 7 post infection, the number of CD8+ T cells in the lung increased in mice vaccinated with the T cell vaccine and decreased in mice vaccinated with Comirnaty(R). The T cell vaccine did not produce neutralizing antibodies, and thus our results demonstrate that SARS-CoV-2 viral infection can be controlled by a T cell response alone. Our results suggest that further study is merited for pan-variant T cell vaccines, and that T cell vaccines may be relevant for individuals that cannot produce neutralizing antibodies or to help mitigate Long COVID.
RESUMO
Lipid nanoparticle (LNP)-based drug delivery systems have become the most clinically advanced non-viral delivery technology. LNPs can encapsulate and deliver a wide variety of bioactive agents, including the small molecule drugs, proteins and peptides, and nucleic acids. However, as the physicochemical properties of small- and macromolecular cargos can vary drastically, every LNP carrier system needs to be carefully tailored in order to deliver the cargo molecules in a safe and efficient manner. Our group applied the combinatorial library synthesis approach and in vitro and in vivo screening strategy for the development of LNP delivery systems for drug delivery. In this Review, we highlight our recent progress in the design, synthesis, characterization, evaluation, and optimization of combinatorial LNPs with novel structures and properties for the delivery of small- and macromolecular therapeutics both in vitro and in vivo. These delivery systems have enormous potentials for cancer therapy, antimicrobial applications, gene silencing, genome editing, and more. We also discuss the key challenges to the mechanistic study and clinical translation of new LNP-enabled therapeutics.
RESUMO
New strains of SARS-CoV-2 have emerged, including B.1.351 and P.1, that demonstrate increased transmissibility and the potential of rendering current SARS-CoV-2 vaccines less effective. A concern is that existing SARS-CoV-2 spike subunit vaccines produce neutralizing antibodies to three dimensional spike epitopes that are subject to change during viral drift. Here we provide an initial report on the hypothesis that adaptive T cell based immunity may provide a path for a pan-COVID-19 vaccine that is resilient to viral drift. T cell based adaptive immunity can be based on short peptide sequences selected from the viral proteome that are less subject to drift, and can utilize multiple such epitopes to provide redundancy in the event of drift. We find that SARS-CoV-2 peptides contained in a mRNA-LNP T cell vaccine for SARS-CoV-2 are immunogenic in mice transgenic for the human HLA-A*02:01 gene. We plan to test the efficacy of this vaccine with SARS-CoV-2 B.1.351 challenge trials with HLA-A*02:01 mice.