The recent emergence of B.1.1.529, the Omicron variant1,2, has raised concerns of escape from protection by vaccines and therapeutic antibodies. A key test for potential countermeasures against B.1.1.529 is their activity in preclinical rodent models of respiratory tract disease. Here, using the collaborative network of the SARS-CoV-2 Assessment of Viral Evolution (SAVE) programme of the National Institute of Allergy and Infectious Diseases (NIAID), we evaluated the ability of several B.1.1.529 isolates to cause infection and disease in immunocompetent and human ACE2 (hACE2)-expressing mice and hamsters. Despite modelling data indicating that B.1.1.529 spike can bind more avidly to mouse ACE2 (refs. 3,4), we observed less infection by B.1.1.529 in 129, C57BL/6, BALB/c and K18-hACE2 transgenic mice than by previous SARS-CoV-2 variants, with limited weight loss and lower viral burden in the upper and lower respiratory tracts. In wild-type and hACE2 transgenic hamsters, lung infection, clinical disease and pathology with B.1.1.529 were also milder than with historical isolates or other SARS-CoV-2 variants of concern. Overall, experiments from the SAVE/NIAID network with several B.1.1.529 isolates demonstrate attenuated lung disease in rodents, which parallels preliminary human clinical data.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for an unprecedented global pandemic of COVID-19. Animal models are urgently needed to study the pathogenesis of COVID-19 and to screen vaccines and treatments. We show that African green monkeys (AGMs) support robust SARS-CoV-2 replication and develop pronounced respiratory disease, which may more accurately reflect human COVID-19 cases than other nonhuman primate species. SARS-CoV-2 was detected in mucosal samples, including rectal swabs, as late as 15 days after exposure. Marked inflammation and coagulopathy in blood and tissues were prominent features. Transcriptome analysis demonstrated stimulation of interferon and interleukin-6 pathways in bronchoalveolar lavage samples and repression of natural killer cell-and T cell-associated transcripts in peripheral blood. Despite a slight waning in antibody titers after primary challenge, enhanced antibody and cellular responses contributed to rapid clearance after re-challenge with an identical strain. These data support the utility of AGM for studying COVID-19 pathogenesis and testing medical countermeasures.

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The SARS-CoV-2 omicron variant emerged in November 2021 and consists of several mutations within the spike. We used serum from mRNA vaccinated individuals to measure neutralization activity against omicron in a live-virus assay. Following 2-4 weeks after primary series of vaccinations, we observed a 30-fold reduction in neutralizing activity against Omicron. Six months after the initial two vaccine doses, sera from naïve vaccinated subjects showed no neutralizing activity against omicron. In contrast, COVID-19 recovered individuals six months after receiving the primary series of vaccinations show a 22-fold reduction with majority of the subjects retaining neutralizing antibody responses. In naïve individuals following a booster shot (3rd dose), we observed a 14-fold reduction in neutralizing activity against omicron and over 90% of subjects show neutralizing activity. These findings show that a 3rd dose is required to provide robust neutralizing antibody responses against the omicron variant.

12Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for an unprecedented global 13 pandemic of COVID-19. Animal models are urgently needed to study the pathogenesis of COVID-19 and to 14 screen candidate vaccines and treatments. Nonhuman primates (NHP) are considered the gold standard model 15 for many infectious pathogens as they usually best reflect the human condition. Here, we show that African green 16 monkeys support a high level of SARS-CoV-2 replication and develop pronounced respiratory disease that may 17 be more substantial than reported for other NHP species including cynomolgus and rhesus macaques. In 18 addition, SARS-CoV-2 was detected in mucosal samples of all animals including feces of several animals as late 19 as 15 days after virus exposure. Importantly, we show that virus replication and respiratory disease can be 20 produced in African green monkeys using a much lower and more natural dose of SARS-CoV-2 than has been 21 employed in other NHP studies. 42varying degrees of non-lethal illness when the virus was delivered into the respiratory tract of these animals [7-43 13]. While each of these models has utility in the study of COVID-19, NHPs have the closest physiological 44 resemblance to humans allowing a better comparison of host responses to infection. This genetic similarity has 45 also contributed to the increased availability of reagents to perform in-depth analyses of the immune response. 46Recently, the first studies evaluating the pathogenic potential of SARS-CoV-2 in cynomolgus and rhesus 47 macaques were performed. Rhesus macaques developed pneumonia and clinical signs whereas disease in 48 cynomolgus macaques was fairly mild indicating the former appears to better reflect more severe cases of 49 . These results suggest certain NHP species may serve as better models than others for 50 4 coronavirus infections. For SARS, the disease caused by SARS-CoV-1, African green monkeys (AGMs) were 51 found to support the highest level of viral replication, followed by cynomolgus macaques and rhesus macaques 52 when all three species were challenged in parallel [14]. Only AGMs had notable replication in the lower 53 respiratory tract following SARS-CoV-1 inoculation; necropsy of these animals indicated focal interstitial 54 mononuclear inflammatory infiltrates and edema in the lung consistent with human SARS. As SARS-CoV-1 and 55 SARS-CoV-2 share the same putative host receptor angiotensin-converting enzyme 2 (ACE2) [15, 16], we 56 reasoned that AGMs might serve as a useful model for COVID-19. 57Here, we infected AGMs with a low passage isolate of SARS-CoV-2 (SARS-CoV-2/INMI1- 58Isolate/2020/Italy) and evaluated their potential as a model for COVID-19. SARS-CoV-2/INMI1-Isolate/2020/Italy 59 was isolated from the first clinical case in Italy [17] and is the first V clade virus (GISAID) to be experimentally 60 inoculated into NHPs. We demonstrate AGMs mimic several aspects of human disease including a high degree 61 of viral replication and severe pulmonary lesions. T...

Despite the development and deployment of antibody and vaccine countermeasures, rapidly-spreading SARS-CoV-2 variants with mutations at key antigenic sites in the spike protein jeopardize their efficacy. The recent emergence of B.1.1.529, the Omicron variant1,2, which has more than 30 mutations in the spike protein, has raised concerns for escape from protection by vaccines and therapeutic antibodies. A key test for potential countermeasures against B.1.1.529 is their activity in pre-clinical rodent models of respiratory tract disease. Here, using the collaborative network of the SARS-CoV-2 Assessment of Viral Evolution (SAVE) program of the National Institute of Allergy and Infectious Diseases (NIAID), we evaluated the ability of multiple B.1.1.529 Omicron isolates to cause infection and disease in immunocompetent and human ACE2 (hACE2) expressing mice and hamsters. Despite modeling and binding data suggesting that B.1.1.529 spike can bind more avidly to murine ACE2, we observed attenuation of infection in 129, C57BL/6, and BALB/c mice as compared with previous SARS-CoV-2 variants, with limited weight loss and lower viral burden in the upper and lower respiratory tracts. Although K18-hACE2 transgenic mice sustained infection in the lungs, these animals did not lose weight. In wild-type and hACE2 transgenic hamsters, lung infection, clinical disease, and pathology with B.1.1.529 also were milder compared to historical isolates or other SARS-CoV-2 variants of concern. Overall, experiments from multiple independent laboratories of the SAVE/NIAID network with several different B.1.1.529 isolates demonstrate attenuated lung disease in rodents, which parallels preliminary human clinical data.

SARS-CoV-2 Omicron is highly transmissible and has substantial resistance to antibody neutralization following immunization with ancestral spike-matched vaccines. It is unclear whether boosting with Omicron-specific vaccines would enhance immunity and 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 antibody titers against D614G were 4760 and 270 reciprocal ID50 at week 6 (peak) and week 41 (pre-boost), respectively, and 320 and 110 for Omicron. Two weeks after boost, titers against D614G and Omicron increased to 5360 and 2980, respectively, for mRNA-1273 and 2670 and 1930 for mRNA-Omicron. Following either boost, 70-80% of spike-specific B cells were cross-reactive against both WA1 and Omicron. Significant and equivalent control of virus replication in lower airways was observed following either boost. Therefore, an Omicron boost may not provide greater immunity or protection compared to a boost with the current mRNA-1273 vaccine.