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As the spread and evolution of SARS-CoV-2 continues, it is important to continue to not only work to prevent transmission but to develop improved antiviral treatments as well. The SARS-CoV-2 main protease (Mpro) has been established as a prominent druggable target. In the current study, investigators evaluate Mpro61 as a lead compound, utilizing structural studies, in vitro pharmacological profiling to examine possible off-target effects and toxicity, cellular studies, and testing in a male and female mouse model for SARS-CoV-2 infection.
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Researchers have used animal models that can replicate clinical and pathologic features of severe human coronavirus infections to develop novel vaccines and therapeutics in humans. The purpose of this review is to describe important animal models for COVID-19, with an emphasis on comparative pathology. The highlighted species included mice, ferrets, hamsters, and nonhuman primates. Knowledge gained from studying these animal models can help inform appropriate model selection for disease modeling, as well as for vaccine and therapeutic developments.
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Investigators compared acute SARS-CoV-2 infection in young and old rhesus macaques and baboons. Macaques had clinical signs of viral infection, mild to moderate pneumonitis and extra-pulmonary pathologies; both age groups recovered within 2 weeks. Baboons had prolonged viral RNA shedding and more lung inflammation compared with macaques; inflammation in bronchoalveolar lavage was increased in old versus young baboons. Macaques developed T-cell memory responses and bystander cytokine production.
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It is not clear why COVID-19 is deadly in some people and mild in others. To understand the underlying mechanism, investigators studied the contribution of CD4+ T cells in immune responses to SARS-CoV-2 infection. They analyzed single-cell transcriptomic data of >100,000 viral antigen-reactive CD4+ T cells from 40 COVID-19 patients.
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Animal models that recapitulate human COVID-19 disease are critical for understanding SARS-CoV-2 viral and immune dynamics, mechanisms of disease, and testing of vaccines and therapeutics. A group of male pigtail macaques (PTMs) were euthanized either 6- or 21-days after SARS-CoV-2 viral challenge and demonstrated mild-to-moderate COVID-19 disease.
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In aged diabetic female rhesus macaques, prophylactic administration of neutralizing monoclonal antibodies (mAbs) effectively limits SARS-CoV-2 replication in both the upper and lower respiratory tract, and decreases immune activation, including reducing interferon-induced chemokines and limiting effector CD4 T cell influx into the cerebrospinal fluid.
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Using the rhesus macaque model, researchers addressed whether natural immunity induced by the original SARS-CoV-2 WA1/2020 strain protects against re-challenge with B.1.1.7 and B.1.351, known as the alpha and beta variants of concern, respectively. The investigators infected rhesus macaques with WA1/2020 and re-challenged them on day 35 with WA1/2020 or with the alpha or beta variants. Natural immunity to WA1/2020 led to robust protection against re-challenge with WA1/2020, partial protection against beta, and an intermediate degree of protection against alpha.
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Using a rhesus macaque model (n=5 males per group), investigators tested a receptor binding domain (RBD) recombinant protein formulation COVID-19 vaccine candidate combined with an aluminum-based formulation of 3M’s Toll-like receptor 7 and 8 agonist 3M-052 (3M-052/Alum) and found the RBD+3M-052/Alum formulation produced a superior overall immune response than RBD+alum alone as demonstrated by higher SARS-CoV-2 neutralizing antibodies, improved Th1 biased CD4+ T cell reactions, and increased CD8+ T cell responses.
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It was poorly understood how mRNA vaccines against SARS-CoV-2 stimulate protective immune responses. To address this, researchers comprehensively profiled innate and adaptive immune responses of healthy volunteers vaccinated with the Pfizer-BioNTech mRNA vaccine (BNT162b2). Vaccination resulted in robust production of neutralizing antibodies against wild-type SARS-CoV-2, to a lesser extent, the beta variant, as well as significant increases in antigen-specific polyfunctional CD4+ and CD8+ T cells after the second dose.
