Biology subjects

Noyce, R. S.

Publications and source records attributed to Noyce, R. S..

5 recordsLinked to original sources

bioRxiv2026

The selection for cidofovir-resistant mutant vaccinia viruses is inhibited by coinfecting cidofovir-sensitive wildtypes

Recent years have seen two outbreaks of zoonotic mpox, highlighting the need for additional therapies to treat these infections and curb the spread of the virus. However, there are only two antiviral drugs available for treating mpox, and drug resistance is a potential threat to intervention. Here we investigate how drug resistance emerges in a population of viruses where the sensitive wildtype strain vastly outnumbers the drug-resistant mutant. Using cidofovir treatment and resistance as a model system during vaccinia virus infection, we found that cidofovir-resistant poxviruses rapidly outcompete cidofovir-sensitive viruses when the two strains replicate in complete isolation. However, when the two strains infect the same cell, the drug-resistant virus lost its competitive advantage over the sensitive strain. We found that when the two viruses replicate in separate cells treated with cidofovir, the resistant strain displays faster genome replication kinetics compared to the sensitive strain. However, when the two viruses replicate in the same drug-treated cell, the strains replicated at the same rate. This showed that the drug-resistance trait was functionally shared between the two genetically-distinct strains, allowing the sensitive strain to parasitize the growth advantage of the resistant strain and preventing the rapid outgrowth of the resistant strain. These observations suggest that poxvirus coinfections negatively affect the selection for a rare trait like cidofovir-resistance. Considering that poxviruses actively prevent superinfection, we hypothesize that superinfection exclusion could maintain fitness in a population and facilitate the outgrowth of rare, advantageous traits in poxvirus populations.

microbiology↗

bioRxiv2024

Oncolytic vaccinia virus as a precision cancer vaccine platform

Oncolytic viruses are immunotherapeutic agents that selectively replicate in and kill tumour cells with the goal of promoting anti-cancer immune responses. Vaccinia virus (VACV) is a strong oncolytic virus candidate as it infects a wide range of cancer cells, is amenable to genetic tailoring and induces potent, long-lasting immunity. Here, we examine the use of genetically engineered oncolytic VACVs (oVACV) to express a variety of MHC-I complexes and the co-stimulatory ligand CD80 to stimulate anti-tumour CD8+ T cell responses in two syngeneic cancer models. Tumour antigen specific CD8+ T cells were detected in both the tumour and spleen following oVACV treatment, demonstrating the ability to induce tumour targeted T cell responses with viral therapy. oVACV expression of peptide-MHC-I complexes enhanced the efficacy of primary tumour clearance with tumour specific antigen targeting showing the greatest efficacy. Initial tumour clearance following treatment with oVACVs led to variable anti-tumour immune memory depending on the tumour model. Depletion of CD8+ T cells prevented therapeutic efficacy of oVACV while combination with PD-L1 immune checkpoint blockade enhanced tumour clearance. Overall, we demonstrate the ability to generate an oncolytic virus capable of inducing recognition and elimination of tumour cells through VACV-mediated expression of defined peptide-MHC-I complexes.

immunology↗

bioRxiv2023

Immunogenicity and Efficacy of TNX-1800, A Live Virus Recombinant Poxvirus Vaccine Candidate, Against SARS-CoV-2 Challenge in Nonhuman Primates

TNX-1800 is a synthetically derived live chimeric Horsepox Virus (rcHPXV) vaccine expressing Wuhan SARS-CoV-2 spike (S) protein. The primary objective of this study was to evaluate the immunogenicity and efficacy of TNX-1800 in two nonhuman primate species challenged with USA-WA1/2020 SARS-CoV-2. TNX-1800 vaccination was well tolerated, as indicated by the lack of serious adverse events or significant changes in clinical parameters. A single dose of TNX-1800 generated robust humoral responses in African Green Monkeys and Cynomolgus Macaques, as measured by the total binding anti-SARS-CoV-2 S IgG and neutralizing antibody titers against the USA-WA1/2020 strain. In Cynomolgus Macaques, a single dose of TNX-1800 induced a strong interferon-gamma (IFN-{gamma}) mediated T cell response, promoting both pathogen clearance in the upper and lower airways and generation of systemic neutralizing antibody response against WA strain SARS-CoV-2. Future studies will assess the efficacy of TNX-1800 against newly emerging variants and demonstrate its safety in humans.

immunology↗

bioRxiv2023

Immunogenicity and tolerability of a SARS-CoV-2 TNX-1800, a live recombinant poxvirus vaccine candidate, in Syrian Hamsters and New Zealand White Rabbits.

TNX-1800 is a preclinical stage synthetic derived live chimeric horsepox virus vaccine that comprises an engineered SARS-CoV-2 spike (S) gene expression cassette. The objectives of this study were to assess the immunogenicity and tolerability of TNX-1800 administration in Syrian golden hamsters and New Zealand white rabbits. Animals were vaccinated via percutaneous inoculation and evaluated for dose tolerance and immunogenicity at three different dose levels. The 28-day study data showed that the single percutaneous administration of three TNX-1800 vaccine dose levels was well tolerated in both hamsters and rabbits. For all dose levels, rabbits had more dermal observations than hamsters at the same dose levels. Vaccine-induced viral load four weeks post-dosing was below the detection level for both species.

immunology↗

bioRxiv2021

Booster vaccines protect hamsters with waning immunity from Delta VOC infection, disease, and transmission

Waning immunity to COVID-19 vaccination is associated with increased risk of breakthrough infection, especially with highly transmissible variants of concern (VOC). Booster vaccination generates rapid immune recall in humans, which real-world observational studies suggest protects against VOC infection and associated disease, and modeling studies suggest could mitigate community spread. We directly tested the impact of booster vaccination on protection against Delta VOC infection, disease, and transmission to naive cohorts in golden Syrian hamsters. Animals with waning immunity to bnt162b2 generated rapid immune recall and strong protection against upper- and lower-respiratory tract infection when boosted with bnt126b2, mRNA-1273 or AZD1222. Boosting with either mRNA vaccine generated moderate protection against lung inflammation and virus transmission to unvaccinated animals. Our data support booster vaccination as a tool to address emerging VOC in the COVID-19 pandemic. One-Sentence SummaryA booster vaccine delivered 9 months after primary bnt162b2 vaccination protects hamsters from Delta VOC infection, disease, and transmission.

immunology↗