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The emerging SARS-CoV-2 variants, commonly with many mutations in S1 subunit of spike (S) protein are weakening the efficacy of the current vaccines and antibody therapeutics. This calls for the variant-proof SARS-CoV-2 vaccines targeting the more conserved regions in S protein. Here, we designed a recombinant subunit vaccine, HR121, targeting the conserved HR1 domain in S2 subunit of S protein. HR121 consisting of HR1–linker1–HR2–linker2–HR1, is conformationally and functionally analogous to the HR1 domain present in the fusion intermediate conformation of S2 subunit. Immunization with HR121 in rabbits and rhesus macaques elicited highly potent cross-neutralizing antibodies against SARS-CoV-2 and its variants, particularly Omicron sublineages. Vaccination with HR121 achieved near-full protections against prototype SARS-CoV-2 infection in hACE2 transgenic mice, Syrian golden hamsters and rhesus macaques, and effective protection against Omicron BA.2 infection in Syrian golden hamsters. This study demonstrates that HR121 is a promising candidate of variant-proof SARS-CoV-2 vaccine with a novel conserved target in the S2 subunit for application against current and future SARS-CoV-2 variants.

Background Mucosal-associated invariant T (MAIT) cells are systemically depleted in human immunodeficiency virus type 1 (HIV-1) infected patients and are not replenished even after successful combined antiretroviral therapy (cART). This study aimed to identify the mechanism underlying MAIT cell depletion. Methods In the present study, we applied flow cytometry, single-cell RNA sequencing and immunohistochemical staining to evaluate the characteristics of pyroptotic MAIT cells in a total of 127 HIV-1 infected individuals, including 69 treatment-naive patients, 28 complete responders, 15 immunological non-responders, and 15 elite controllers, at the Fifth Medical Center of Chinese PLA General Hospital, Beijing, China. Results Single-cell transcriptomic profiles revealed that circulating MAIT cells from HIV-1 infected subjects were highly activated, with upregulation of pyroptosis-related genes. Further analysis revealed that increased frequencies of pyroptotic MAIT cells correlated with markers of systemic T-cell activation, microbial translocation, and intestinal damage in cART-naive patients and poor CD4+ T-cell recovery in long-term cART patients. Immunohistochemical staining revealed that MAIT cells in the gut mucosa of HIV-1 infected patients exhibited a strong active gasdermin-D (GSDMD, marker of pyroptosis) signal near the cavity side, suggesting that these MAIT cells underwent active pyroptosis in the colorectal mucosa. Increased levels of the proinflammatory cytokines interleukin-12 (IL-12) and IL-18 were observed in HIV-1 infected patients. In addition, activated MAIT cells exhibited an increased pyroptotic phenotype after being triggered by HIV-1 virions, T-cell receptor signals, IL-12 plus IL-18, and combinations of these factors, in vitro. Conclusions Activation-induced MAIT cell pyroptosis contributes to the loss of MAIT cells in HIV-1 infected patients, which could potentiate disease progression and poor immune reconstitution.

Characterization of eight novel full-length genomes of SARS-CoV-2 among imported COVID-19 cases from abroad in Yunnan, China Dear Editor: Recent correspondence in this Journal has highlighted the current threat posed by recently-emerging corona virus disease 2019 (COVID-19) in the world. 1 The COVID-19 is infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is characterized by fever, dry cough, weak, and so on. 2 , 3 SARS-CoV-2 has already caused a global pandemic. By 26 Apr, 2020, the spread of SARS-CoV-2 has led to more than 3.0 million infections and above 20 0,0 0 0 deaths; 4 thus, its outbreak has become a global public health problem. Recently, COVID-19 epidemic in China has been well controlled, whereas the risk of imported COVID-19 cases has increased dramatically. 5 As of April 26, 2020, a total of 1,636 abroad imported patients were reported in China. 6 However, limited studies on full-length genome characterization of SARS-CoV-2 from COVID-19 cases imported from abroad. Here, we characterized the genotype and mutation characteristics of SARS-CoV-2 isolated from eight imported cases from abroad in Yunnan, China. Eight COVID-19 patients imported from overseas were admitted to Yunnan Provincial Infectious Disease Hospital from March 15, 2020 to March 26, 2020. The epidemiological history and respiratory symptoms of the eight patients were summarized in Fig. 1 A and 1 B. The 8 patients include 4 males and 4 females, with ages ranging from 6 years to 70 years old. No patient has ever been to Wuhan city in China. Two cases YN_Im01 and YN_Im03 were from Spain to Yunnan, YN_Im02 from France, YN_Im04 from Cambodia, YN_Im05 from Sri Lanka, and YN_Im06-08, a family cluster of COVID-19 patients from the United States (Fig. 1 A). Six cases showed different degrees of respiratory symptoms before hospitalization. YN_Im06 was severe, YN_Im01, YN_Im05, YN_Im07, and YN_Im08 were moderate, YN_Im02 was mild, and YN_Im03 and YN_Im04 were asymptomatic according to the latest COVID-19 diagnostic criteria (5th edition) published by the National Health Commission of China (Fig. 1 B). So far, three main clades involving G, V, and S have been identified based on marker mutations in the complete SARS-CoV-2 genome according to the latest genotyping rules recommended by the GISAID databas. 7 G clade containing D614G variant in S protein is predominant in Europe, V clade possessing G251V mutation in ORF3 is more common in Asia and Europe, and S clade having L84S substitution in ORF8 is move prevalent in North America. 8 In this study, eight complete genome sequences of SARS-CoV-2 isolated from sputum samples were successfully amplified and sequenced with 38 overlapping fragments. Dataset comprise SARS-CoV-2 full-length sequences of representative clade G, V, and S as previously reported, and reference sequences with the highest sim