Phase II/III Double-Blind Study Evaluating Safety and Immunogenicity of a Single Intramuscular Booster Dose of the Recombinant SARS-CoV-2 Vaccine "Patria" (AVX/COVID-12) Using an Active Newcastle Disease Viral Vector (NDV) during the Omicron Outbreak in Healthy Adults with Elevated Baseline Antibody Titers from Prior COVID-19 and/or SARS-CoV-2 Vaccination (preprint)

Background: The urgent need for safe, effective, and economical coronavirus disease 2019 (COVID-19) vaccines, especially for booster campaigns targeting vulnerable populations, prompted the development of the AVX/COVID-12 vaccine candidate. AVX/COVD-12 is based in a Newcastle disease virus La Sota (NDV-LaSota) recombinant viral vector. This vaccine expresses a stabilized version of the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), specifically the ancestral Wuhan strain. The study aimed to assess its safety, immunogenicity, and potential efficacy as an anti-COVID-19 booster vaccine. Methods: In a phase II/III clinical trial conducted from November 9, 2022, to September 11, 2023, a total of 4,056 volunteers were enrolled. Participants received an intramuscular booster dose of either AVX/COVID-12 or AZ/ChAdOx-1-S vaccines. Safety, immunogenicity, and potential efficacy were assessed through various measures, including neutralizing antibody titers, interferon (IFN)-γ-producing CD4+ T cells, and CD8+ T cells. The evaluation also involved immunobridging, utilizing the AZ/ChAdOx-1-S vaccine as an active comparator, and monitoring the incidence of COVID-19 cases. Findings: The AVX/COVID-12 vaccine induced neutralizing antibodies against both the ancestral SARS-CoV-2 and the BA.2 and BA.5 Omicron variants. The geometric mean ratio of neutralizing antibody titers between individuals immunized with the AVX/COVID-12 vaccine and those with the AZ/ChAdOx-1-S vaccine at 14 days is 0.96, with a confidence interval (CI) of 0.85-1.06. The outcome aligns with the non-inferiority criterion recommended by the World Health Organization (WHO), indicating a lower limit of the CI greater than or equal to 0.67. Induction of IFN-γ-producing CD8+ T cells at day 14 post-immunization was exclusively observed in the AVX/COVID-12 group. Finally, a trend suggested a potentially lower incidence of COVID-19 cases in AVX/COVID-12 boosted volunteers compared to AZ/ChAdOx-1-S recipients. Conclusion: The AVX/COVID-12 vaccine proved safe, well-tolerated, and immunogenic. AVX/COVID-12 meets the WHO non-inferiority standard compared to AZ/ChAdOx-1-S. These results strongly advocate for AVX/COVID-12 as a viable booster dose, supporting its utilization in the population.

REGEN-COV Antibody Cocktail Clinical Outcomes Study in Covid-19 Outpatients (preprint)

Background: REGEN-COV antibody cocktail (casirivimab with imdevimab) rapidly reduced viral load and decreased medically-attended visits in the phase 1/2 portion of this trial; REGEN-COV, retains activity in vitro against emerging SARS-CoV-2 variants of concern. Methods: The phase 3 portion of this adaptive, randomized, master protocol, included 4,057 Covid-19 outpatients with one or more risk factors for severe disease. Patients were randomized to a single treatment of intravenous placebo, or various doses of REGEN-COV, and followed for 28 days. The prespecified hierarchical analysis first compared REGEN-COV 2400mg dose vs concurrent placebo, then compared the 1200mg dose vs concurrent placebo, for endpoints assessing risk of hospitalization or death, and time to symptom resolution. Safety was evaluated in all treated patients. Results: Both REGEN-COV 2400mg and 1200mg significantly reduced Covid-19-related hospitalization or all-cause death compared to placebo (71.3% reduction [1.3% vs 4.6%; p<0.0001] and 70.4% reduction [1.0% vs 3.2%; p=0.0024], respectively). The median time to resolution of Covid-19 symptoms was 4 days shorter in both dose arms vs placebo (10 vs 14 days; p<0.0001). Efficacy of REGEN-COV was consistent across subgroups, including patients who were SARS-CoV-2 serum antibody-positive at baseline. REGEN-COV more rapidly reduced viral load than placebo. Serious adverse events occurred more frequently in the placebo group (4.0%) than in the 1200mg (1.1%) and 2400mg (1.3%) groups and grade [≥]2 infusion-related reactions were infrequent (<0.3% in all groups). Conclusions: Treatment with REGEN-COV was well-tolerated and significantly reduced Covid-19-related hospitalization or all-cause death, rapidly resolved symptoms, and reduced viral load. (Funded by Regeneron Pharmaceuticals and the Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services; ClinicalTrials.gov number, NCT04425629.)