From a genome-wide screen of RNAi molecules against SARS-CoV-2 to a validated broad-spectrum and potent prophylaxis.

Expanding the arsenal of prophylactic approaches against SARS-CoV-2 is of utmost importance, specifically those strategies that are resistant to antigenic drift in Spike. Here, we conducted a screen of over 16,000 RNAi triggers against the SARS-CoV-2 genome, using a massively parallel assay to identify hyper-potent siRNAs. We selected Ten candidates for in vitro validation and found five siRNAs that exhibited hyper-potent activity (IC50 < 20 pM) and strong blockade of infectivity in live-virus experiments. We further enhanced this activity by combinatorial pairing of the siRNA candidates and identified cocktails that were active against multiple types of variants of concern (VOC). We then examined over 2,000 possible mutations in the siRNA target sites by using saturation mutagenesis and confirmed broad protection of the leading cocktail against future variants. Finally, we demonstrated that intranasal administration of this siRNA cocktail effectively attenuates clinical signs and viral measures of disease in the gold-standard Syrian hamster model. Our results pave the way for the development of an additional layer of antiviral prophylaxis that is orthogonal to vaccines and monoclonal antibodies.

Recommending COVID-19 vaccination for adolescents in primary care.

BACKGROUND: COVID-19 vaccines are available for adolescents in the United States, but many parents are hesitant to have their children vaccinated. The advice of primary care professionals strongly influences vaccine uptake. OBJECTIVE: We examined the willingness of primary care professionals (PCPs) to recommend COVID-19 vaccination for adolescents. METHODS: Participants were a national sample of 1,047 US adolescent primary care professionals. They participated in an online survey in early 2021, after a COVID-19 vaccine had been approved for adults but before approval for adolescents. Respondents included physicians (71%), advanced practice providers (17%), and nurses (12%). We identified correlates of willingness to recommend COVID-19 vaccination for adolescents using logistic regression. RESULTS: The majority (89%) of respondents were willing to recommend COVID-19 vaccination for adolescents, with advanced practice providers and nurses being less likely than paediatricians to recommend vaccination (84% vs. 94%, aOR 0.47, 95% CI 0.23-0.92). Respondents who had received at least one dose of a COVID-19 vaccine were more likely to recommend adolescent vaccination (92% vs. 69%, aOR 4.20, 95% CI 2.56-6.87) as were those with more years in practice (94% vs. 88%, aOR 2.93, 95% CI 1.79-4.99). Most respondents (96%) said they would need some measure of support in order to provide COVID-19 vaccination to adolescents, with vaccine safety and efficacy information being the most commonly cited need (80%). CONCLUSION: Adolescent primary care professionals were generally willing to recommend COVID-19 vaccination. However, most indicated a need for additional resources to be able to administer COVID-19 vaccines at their clinic.

mRNA-1273 or mRNA-Omicron boost in vaccinated macaques elicits similar B cell expansion, neutralizing responses, and protection from Omicron.

SARS-CoV-2 Omicron is highly transmissible and has substantial resistance to neutralization following immunization with ancestral spike-matched vaccines. It is unclear whether boosting with Omicron-matched vaccines would enhance protection. Here, nonhuman primates that received mRNA-1273 at weeks 0 and 4 were boosted at week 41 with mRNA-1273 or mRNA-Omicron. Neutralizing titers against D614G were 4,760 and 270 reciprocal ID50 at week 6 (peak) and week 41 (preboost), respectively, and 320 and 110 for Omicron. 2 weeks after the boost, titers against D614G and Omicron increased to 5,360 and 2,980 for mRNA-1273 boost and 2,670 and 1,930 for mRNA-Omicron, respectively. Similar increases against BA.2 were observed. Following either boost, 70%-80% of spike-specific B cells were cross-reactive against WA1 and Omicron. Equivalent control of virus replication in lower airways was observed following Omicron challenge 1 month after either boost. These data show that mRNA-1273 and mRNA-Omicron elicit comparable immunity and protection shortly after the boost.

Protection from SARS-CoV-2 Delta one year after mRNA-1273 vaccination in rhesus macaques coincides with anamnestic antibody response in the lung.

mRNA-1273 vaccine efficacy against SARS-CoV-2 Delta wanes over time; however, there are limited data on the impact of durability of immune responses on protection. Here, we immunized rhesus macaques and assessed immune responses over 1 year in blood and upper and lower airways. Serum neutralizing titers to Delta were 280 and 34 reciprocal ID50 at weeks 6 (peak) and 48 (challenge), respectively. Antibody-binding titers also decreased in bronchoalveolar lavage (BAL). Four days after Delta challenge, the virus was unculturable in BAL, and subgenomic RNA declined by ∼3-log10 compared with control animals. In nasal swabs, sgRNA was reduced by 1-log10, and the virus remained culturable. Anamnestic antibodies (590-fold increased titer) but not T cell responses were detected in BAL by day 4 post-challenge. mRNA-1273-mediated protection in the lungs is durable but delayed and potentially dependent on anamnestic antibody responses. Rapid and sustained protection in upper and lower airways may eventually require a boost.