New viral vectors for infectious diseases and cancer.

https://www.mdpi.com/2076-393X/8/4/680/pdf

Development and Applications of Viral Vectored Vaccines to Combat Zoonotic and Emerging Public Health Threats.

Therapeutic vaccination regimens inducing clinically effective tumor-specific CD8+ T lymphocyte (CTL) responses are an unmet medical need. We engineer two distantly related arenaviruses, Pichinde virus and lymphocytic choriomeningitis virus, for therapeutic cancer vaccination. In mice, life-replicating vector formats of these two viruses delivering a self-antigen in a heterologous prime-boost regimen induce tumor-specific CTL responses up to 50% of the circulating CD8 T cell pool. This CTL attack eliminates established solid tumors in a significant proportion of animals, accompanied by protection against tumor rechallenge. The magnitude of CTL responses is alarmin driven and requires combining two genealogically distantly related arenaviruses. Vector-neutralizing antibodies do not inhibit booster immunizations by the same vector or by closely related vectors. Rather, CTL immunodominance hierarchies favor vector backbone-targeted responses at the expense of self-reactive CTLs. These findings establish an arenavirus-based immunotherapy regimen that allows reshuffling of immunodominance hierarchies and breaking self-directed tolerance for efficient tumor control.

/pdf/heterologous-arenavirus-vector-prime-boost-overrules-self-fccqb125q4.pdf

Heterologous arenavirus vector prime-boost overrules self-tolerance for efficient tumor-specific CD8 T cell attack.

Efficient and safe induction of CD8 + T cell responses is a desired characteristic of vaccines against intracellular pathogens. To achieve this, a new generation of safe vaccines is being developed accommodating single, dominant antigens of pathogens of interest. In particular, the selection of such antigens is challenging, since due to HLA polymorphism the ligand specificities and immunodominance hierarchies of pathogen-specific CD8 + T cell responses differ throughout the human population. A recently discovered mechanism of proteasome-mediated CD8 + T cell epitope generation, i.e., by proteasome-catalyzed peptide splicing (PCPS), expands the pool of peptides and antigens, presented by MHC class I HLA molecules. On the cell surface, one-third of the presented self-peptides are generated by PCPS, which coincides with one-fourth in terms of abundance. Spliced epitopes are targeted by CD8 + T cell responses during infection and, like non-spliced epitopes, can be identified within antigen sequences using a novel in silico strategy. The existence of spliced epitopes, by enlarging the pool of peptides available for presentation by different HLA variants, opens new opportunities for immunotherapies and vaccine design.

/pdf/an-unexpected-major-role-for-proteasome-catalyzed-peptide-1y8cmuupdj.pdf

An Unexpected Major Role for Proteasome-Catalyzed Peptide Splicing in Generation of T Cell Epitopes: Is There Relevance for Vaccine Development?

Background Given the continuing coronavirus disease 2019 (COVID-19) pandemic and much of the U.S. implementing social distancing due to the lack of alternatives, there has been a push to develop a vaccine to eliminate the need for social distancing. Methods In 2020, we developed a computational model of the U.S. simulating the spread of COVID-19 coronavirus and vaccination. Results Simulation experiments revealed that when vaccine efficacy exceeded 70%, coverage exceeded 60%, and vaccination occurred on day 1, the attack rate dropped to 22% with daily cases not exceeding 3.2 million (reproductive rate, R0, 2.5). When R0 was 3.5, the attack rate dropped to 41% with daily cases not exceeding 14.4 million. Increasing coverage to 75% when vaccination occurred by day 90 resulted in 5% attack rate and daily cases not exceeding 258,029when R0 was 2.5 and a 26% attack rate and maximum daily cases of 22.6 million when R0 was 3.5. When vaccination did not occur until day 180, coverage (i.e., those vaccinated plus those otherwise immune) had to reach 100%. A vaccine with an efficacy between 40% and 70% could still obviate the need for other measures under certain circumstances such as much higher, and in some cases, potentially unachievable, vaccination coverages. Conclusion Our study found that to either prevent or largely extinguish an epidemic without any other measures (e.g., social distancing), the vaccine has to have an efficacy of at least 70%.

https://www.medrxiv.org/content/medrxiv/early/2020/05/30/2020.05.29.20117184.full.pdf

How efficacious must a COVID-19 coronavirus vaccine be to prevent or stop an epidemic by itself

Development of novel replication-defective lymphocytic choriomeningitis virus vectors expressing SIV antigens.

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Development of novel replication-defective lymphocytic choriomeningitis virus vectors expressing SIV antigens.