The identification of the Omicron (B.1.1.529.1 or BA.1) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Botswana in November 2021¹ immediately caused concern owing to the number of alterations in the spike glycoprotein that could lead to antibody evasion. We² and others^3–6 recently reported results confirming such a concern. Continuing surveillance of the evolution of Omicron has since revealed the rise in prevalence of two sublineages, BA.1 with an R346K alteration (BA.1+R346K, also known as BA.1.1) and B.1.1.529.2 (BA.2), with the latter containing 8 unique spike alterations and lacking 13 spike alterations found in BA.1. Here we extended our studies to include antigenic characterization of these new sublineages. Polyclonal sera from patients infected by wild-type SARS-CoV-2 or recipients of current mRNA vaccines showed a substantial loss in neutralizing activity against both BA.1+R346K and BA.2, with drops comparable to that already reported for BA.1 (refs. ^2,3,5,6). These findings indicate that these three sublineages of Omicron are antigenically equidistant from the wild-type SARS-CoV-2 and thus similarly threaten the efficacies of current vaccines. BA.2 also exhibited marked resistance to 17 of 19 neutralizing monoclonal antibodies tested, including S309 (sotrovimab)⁷, which had retained appreciable activity against BA.1 and BA.1+R346K (refs. ^2–4,6). This finding shows that no authorized monoclonal antibody therapy could adequately cover all sublineages of the Omicron variant, except for the recently authorized LY-CoV1404 (bebtelovimab).

Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe disease in human with an overall case-fatality rate of >35%. Effective antivirals are crucial for improving the clinical outcome of MERS. Although a number of repurposed drugs, convalescent-phase plasma, antiviral peptides, and neutralizing antibodies exhibit anti-MERS-CoV activity in vitro, most are not readily available or have not been evaluated in nonhuman primates. We assessed 3 repurposed drugs with potent in vitro anti-MERS-CoV activity (mycophenolate mofetil [MMF], lopinavir/ritonavir, and interferon-β1b) in common marmosets with severe disease resembling MERS in humans. The lopinavir/ritonavir-treated and interferon-β1b-treated animals had better outcome than the untreated animals, with improved clinical (mean clinical scores ↓50.9%–95.0% and ↓weight loss than the untreated animals), radiological (minimal pulmonary infiltrates), and pathological (mild bronchointerstitial pneumonia) findings, and lower mean viral loads in necropsied lung (↓0.59–1.06 log₁₀ copies/glyceraldehyde 3-phosphate dehydrogenase [GAPDH]; P < .050) and extrapulmonary (↓0.11–1.29 log₁₀ copies/GAPDH; P < .050 in kidney) tissues. In contrast, all MMF-treated animals developed severe and/or fatal disease with higher mean viral loads (↑0.15–0.54 log₁₀ copies/GAPDH) than the untreated animals. The mortality rate at 36 hours postinoculation was 67% (untreated and MMF-treated) versus 0–33% (lopinavir/ritonavir-treated and interferon-β1b-treated). Lopinavir/ritonavir and interferon-β1b alone or in combination should be evaluated in clinical trials. MMF alone may worsen MERS and should not be used.

Middle East respiratory syndrome coronavirus (MERS-CoV) infection caused severe pneumonia and multiorgan dysfunction and had a higher crude fatality rate (around 50% vs 10%) than SARS coronavirus (SARS-CoV) infection. To understand the pathogenesis, we studied viral replication, cytokine/chemokine response, and antigen presentation in MERS-CoV–infected human monocyte–derived macrophages (MDMs) versus SARS-CoV–infected MDMs. Only MERS-CoV can replicate in MDMs. Both viruses were unable to significantly stimulate the expression of antiviral cytokines (interferon α [IFN-α] and IFN-β) but induced comparable levels of tumor necrosis factor α and interleukin 6. Notably, MERS-CoV induced significantly higher expression levels of interleukin 12, IFN-γ, and chemokines (IP-10/CXCL-10, MCP-1/CCL-2, MIP-1α/CCL-3, RANTES/CCL-5, and interleukin 8) than SARS-CoV. The expression of major histocompatibility complex class I and costimulatory molecules were significantly higher in MERS-CoV–infected MDMs than in SARS-CoV–infected cells. MERS-CoV replication was validated by immunostaining of infected MDMs and ex vivo lung tissue. We conclusively showed that MERS-CoV can establish a productive infection in human macrophages. The aberrant induction of inflammatory cytokines/chemokines could be important in the disease pathogenesis.

Middle East respiratory syndrome (MERS) is associated with a mortality rate of >35%. We previously showed that MERS coronavirus (MERS-CoV) could infect human macrophages and dendritic cells and induce cytokine dysregulation. Here, we further investigated the interplay between human primary T cells and MERS-CoV in disease pathogenesis. Importantly, our results suggested that MERS-CoV efficiently infected T cells from the peripheral blood and from human lymphoid organs, including the spleen and the tonsil. We further demonstrated that MERS-CoV infection induced apoptosis in T cells, which involved the activation of both the extrinsic and intrinsic apoptosis pathways. Remarkably, immunostaining of spleen sections from MERS-CoV–infected common marmosets demonstrated the presence of viral nucleoprotein in their CD3⁺ T cells. Overall, our results suggested that the unusual capacity of MERS-CoV to infect T cells and induce apoptosis might partly contribute to the high pathogenicity of the virus.

Human intestinal tract as an alternative route to acquire MERS-CoV infection.