Molnupiravir inhibits SARS-CoV-2 variants including Omicron in the hamster model.

The recent emergence of the SARS-CoV-2 Omicron variant of concern (VOC) containing a heavily mutated spike protein capable of escaping preexisting immunity identifies a continued need for interventional measures. Molnupiravir (MK-4482), an orally administered nucleoside analog, has demonstrated efficacy against earlier SARS-CoV-2 lineages and was recently approved for SARS-CoV-2 infections in high-risk adults. Here we assessed the efficacy of MK-4482 against the earlier Alpha, Beta and Delta VOCs and Omicron in the hamster COVID-19 model. Omicron replication and associated lung disease in vehicle treated hamsters was reduced compared to the earlier VOCs. MK-4482 treatment inhibited virus replication in the lungs of Alpha, Beta and Delta VOC infected hamsters. Importantly, MK-4482 profoundly inhibited virus replication in the upper and lower respiratory tract of hamsters infected with the Omicron VOC. Consistent with its mutagenic mechanism, MK-4482 treatment had a more pronounced inhibitory effect on infectious titers compared to viral RNA genome load. Histopathologic analysis showed that MK-4482 treatment caused a concomitant reduction in the level of lung disease and viral antigen load in infected hamsters across all VOCs examined. Together, our data indicate the potential of MK-4482 as an effective antiviral against known SARS-CoV-2 VOCs, especially Omicron, and likely future SARS-CoV-2 variants

Lassa Virus Treatment Options

Lassa fever causes an approximate 5000 to 10,000 deaths annually in West Africa and cases have been imported into Europe and the Americas, challenging public health. Although Lassa virus was first described over 5 decades ago in 1969, no treatments or vaccines have been approved to treat or prevent infection. In this review, we discuss current therapeutics in the development pipeline for the treatment of Lassa fever, focusing on those that have been evaluated in humans or animal models. Several treatments, including the antiviral favipiravir and a human monoclonal antibody cocktail, have shown efficacy in preclinical rodent and non-human primate animal models and have potential for use in clinical settings. Movement of the promising preclinical treatment options for Lassa fever into clinical trials is critical to continue addressing this neglected tropical disease.</jats:p

SARS-CoV-2 reinfection prevents acute respiratory disease in Syrian hamsters but not replication in the upper respiratory tract

Human cases of SARS-CoV-2 reinfection have been documented throughout the pandemic, but are likely under-reported. In the current study, we use the Syrian hamster SARS-CoV-2 model to assess reinfection with homologous WA1 and heterologous B.1.1.7 (Alpha) and B.1.351 (Beta) SARS-CoV-2 variants over time. Upon primary infection with SARS-CoV-2 WA1, hamsters rapidly develop a strong and long-lasting humoral immune response. After reinfection with homologous and heterologous SARS-CoV-2 variants, this immune response protects hamsters from clinical disease, virus replication in the lower respiratory tract, and acute lung pathology. However, reinfection leads to SARS-CoV-2 replication in the upper respiratory tract with the potential for virus shedding. Our findings indicate that reinfection results in restricted SARS-CoV-2 replication despite substantial levels of humoral immunity, denoting the potential for transmission through reinfected asymptomatic individuals

Orally delivered MK-4482 inhibits SARS-CoV-2 replication in the Syrian hamster model

AbstractThe COVID-19 pandemic progresses unabated in many regions of the world. An effective antiviral against SARS-CoV-2 that could be administered orally for use following high-risk exposure would be of substantial benefit in controlling the COVID-19 pandemic. Herein, we show that MK-4482, an orally administered nucleoside analog, inhibits SARS-CoV-2 replication in the Syrian hamster model. The inhibitory effect of MK-4482 on SARS-CoV-2 replication is observed in animals when the drug is administered either beginning 12 h before or 12 h following infection in a high-risk exposure model. These data support the potential utility of MK-4482 to control SARS-CoV-2 infection in humans following high-risk exposure as well as for treatment of COVID-19 patients.</jats:p

Mastomys natalensis Has a Cellular Immune Response Profile Distinct from Laboratory Mice

The multimammate mouse (Mastomys natalensis; M. natalensis) has been identified as a major reservoir for multiple human pathogens including Lassa virus (LASV), Leishmania spp., Yersinia spp., and Borrelia spp. Although M. natalensis are related to well-characterized mouse and rat species commonly used in laboratory models, there is an absence of established assays and reagents to study the host immune responses of M. natalensis. As a result, there are major limitations to our understanding of immunopathology and mechanisms of immunological pathogen control in this increasingly important rodent species. In the current study, a large panel of commercially available rodent reagents were screened to identify their cross-reactivity with M. natalensis. Using these reagents, ex vivo assays were established and optimized to evaluate lymphocyte proliferation and cytokine production by M. natalensis lymphocytes. In contrast to C57BL/6J mice, lymphocytes from M. natalensis were relatively non-responsive to common stimuli such as phytohaemagglutinin P and lipopolysaccharide. However, they readily responded to concanavalin A stimulation as indicated by proliferation and cytokine production. In summary, we describe lymphoproliferative and cytokine assays demonstrating that the cellular immune responses in M. natalensis to commonly used mitogens differ from a laboratory-bred mouse strain.</jats:p

Evaluation of drugs for potential repurposing against COVID-19 using a tier-based scoring system

Embargo removed due to subject matter

Bayesian estimation of Lassa virus epidemiological parameters: Implications for spillover prevention using wildlife vaccination

Lassa virus is a significant burden on human health throughout its endemic region in West Africa, with most human infections the result of spillover from the primary rodent reservoir of the virus, the natal multimammate mouse, M. natalensis. Here we develop a Bayesian methodology for estimating epidemiological parameters of Lassa virus within its rodent reservoir and for generating probabilistic predictions for the efficacy of rodent vaccination programs. Our approach uses Approximate Bayesian Computation (ABC) to integrate mechanistic mathematical models, remotely-sensed precipitation data, and Lassa virus surveillance data from rodent populations. Using simulated data, we show that our method accurately estimates key model parameters, even when surveillance data are available from only a relatively small number of points in space and time. Applying our method to previously published data from two villages in Guinea estimates the time-averaged R0 of Lassa virus to be 1.74 and 1.54 for rodent populations in the villages of Bantou and Tanganya, respectively. Using the posterior distribution for model parameters derived from these Guinean populations, we evaluate the likely efficacy of vaccination programs relying on distribution of vaccine-laced baits. Our results demonstrate that effective and durable reductions in the risk of Lassa virus spillover into the human population will require repeated distribution of large quantities of vaccine

Multiple DNA viruses identified in multimammate mouse (Mastomys natalensis) populations from across regions of sub-Saharan Africa

Abstract The multimammate mouse (Mastomys natalensis; M. natalensis) serves as the main reservoir for the zoonotic arenavirus Lassa virus (LASV), and this has led to considerable investigation into the distribution of LASV and other related arenaviruses in this host species. In contrast to the situation with arenaviruses, the presence of other viruses in M. natalensis remains largely unexplored. In this study, herpesviruses and polyomaviruses were identified and partially characterized by PCR methods, sequencing, and phylogenetic analysis. In tissues sampled from M. natalensis populations in Côte d'Ivoire and Mali, six new DNA viruses (four betaherpesviruses, one gammaherpesvirus and one polyomavirus) were identified. Phylogenetic analysis based on glycoprotein B amino acid sequences showed that the herpesviruses clustered with cytomegaloviruses and rhadinoviruses of multiple rodent species. The complete circular genome of the newly identified polyomavirus was amplified by PCR. Amino acid sequence analysis of the large T antigen or VP1 showed that this virus clustered with a known polyomavirus from a house mouse (species Mus musculus polyomavirus 1). These two polyomaviruses form a clade with other rodent polyomaviruses, and the newly identified virus represents the third known polyomavirus of M. natalensis. This study represents the first identification of herpesviruses and the discovery of a novel polyomavirus in M. natalensis. In contrast to arenaviruses, we anticipate that these newly identified viruses represent a low zoonotic risk due to the normally highly restricted specificity of members of these two DNA virus families to their individual mammalian host species.</jats:p

Combined molnupiravir-nirmatrelvir treatment improves the inhibitory effect on SARS-CoV-2 in macaques

The periodic emergence of SARS-CoV-2 variants of concern (VOCs) with unpredictable clinical severity and ability to escape preexisting immunity emphasizes the continued need for antiviral interventions. Two small molecule inhibitors, molnupiravir (MK-4482), a nucleoside analog, and nirmatrelvir (PF-07321332), a 3C-like protease inhibitor, have recently been approved as monotherapy for use in high-risk patients with COVID-19. As preclinical data are only available for rodent and ferret models, here we assessed the efficacy of MK-4482 and PF-07321332 alone and in combination against infection with the SARS-CoV-2 Delta VOC in the rhesus macaque COVID-19 model. Macaques were infected with the SARS-CoV-2 Delta variant and treated with vehicle, MK-4482, PF-07321332, or a combination of MK-4482 and PF-07321332. Clinical exams were performed at 1, 2, and 4 days postinfection to assess disease and virological parameters. Notably, use of MK-4482 and PF-07321332 in combination improved the individual inhibitory effect of both drugs, resulting in milder disease progression, stronger reduction of virus shedding from mucosal tissues of the upper respiratory tract, stronger reduction of viral replication in the lower respiratory tract, and reduced lung pathology. Our data strongly indicate superiority of combined MK-4482 and PF-07321332 treatment of SARS-CoV-2 infections as demonstrated in the closest COVID-19 surrogate model of human infection