ABSTRACT
Mass vaccination schemes have been launched for COVID-19 worldwide. However, recent studies have revealed that SARS-CoV-2 Omicron and its sub-lineages efficiently evade humoral immunity from vaccination or previous infection. Therefore, it is of great importance to investigate the contribution of cellular immunity against infection of emerging variants of SARS-CoV-2 in the context of vaccine-induced immunity. By using C57BL/6J and K18-hACE2 mouse models, we demonstrated that BNT162b2 induces robust protective immunity in B-cell deficient (μMT) mice. We further demonstrated that this protection is attributed to the cellular immunity mediated by robust IFN-γ production. In addition, we revealed that SARS-CoV-2 Omicron BA.1 could also induce strong cellular responses in vaccinated μMT mice upon viral challenge, which highlights the significance of cellular immunity against the ever-emerging SARS-CoV-2 variants that evade antibody-mediated immunity. Overall, our study provides evidence that BNT162b2 can induce significant protective immunity in mice that are unable to produce antibodies.
Subject(s)
COVID-19 , Lymphoma, B-CellABSTRACT
It has been reported that multiple SARS-CoV-2 variants of concerns (VOCs) including B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta) can reduce neutralisation by antibodies, resulting in vaccine breakthrough infections. Virus-antiserum neutralisation assays are typically performed to monitor potential vaccine breakthrough strains. However, such experimental-based methods are slow and cannot instantly validate whether newly emerging variants can break through current vaccines or therapeutic antibodies. To address this, we sought to establish a computational model to predict the antigenicity of SARS-CoV-2 variants by sequence alone and in real time. In this study, we firstly identified the relationship between the antigenic difference transformed from the amino acid sequence and the antigenic distance from the neutralisation titres. Based on this correlation, we obtained a computational model for the receptor binding domain (RBD) of the spike protein to predict the fold decrease in virus-antiserum neutralisation titres with high accuracy (~0.79). Our predicted results were comparable with experimental neutralisation titres of variants, including B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), B.1.429 (Epsilon), P.1 (Gamma), B.1.526 (Iota), B.1.617.1 (Kappa), and C.37 (Lambda), as well as SARS-CoV. Here, we firstly predicted the fold of decrease of B.1.1.529 (Omicron) as 17.4-fold less susceptible to neutralisation. We visualised all 1521 SARS-CoV-2 lineages to indicate variants including B.1.621 (Mu), B.1.630, B.1.633, B.1.649, and C.1.2, which can induce vaccine breakthrough infections in addition to reported VOCs B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta), and B.1.1.529 (Omicron). Our study offers a quick approach to predict the antigenicity of SARS-CoV-2 variants as soon as they emerge. Furthermore, this approach can facilitate future vaccine updates to cover all major variants. An online version can be accessed at http://jdlab.online .
Subject(s)
Breakthrough PainABSTRACT
SARS-CoV-2 Omicron emerged in November 2021 and is rapidly spreading among the human populations. The variant contains 34 changes in its spike protein including 15 substitutions at the receptor-binding domain (RBD). While recent reports reveal that the Omicron variant can robustly escape from vaccine and therapeutic neutralization antibodies, the pathogenicity of the virus remains unknown. Here, we investigate the virological features and pathogenesis of the Omicron variant using in vitro and in vivo models. Our results demonstrate that the replication of the Omicron variant is dramatically attenuated in Calu3 and Caco2 but not in VeroE6 cells. Further mechanistic investigations reveal that the Omicron variant is deficient in transmembrane serine protease 2 (TMPRSS2) usage in comparison to that of WT, Alpha, Beta, and Delta variant, which explained its inefficient replication in Calu3 and Caco2 cells. Importantly, the replication of the Omicron variant is markedly attenuated in both the upper and lower respiratory tract of infected K18-hACE2 mice in comparison to that of WT and Delta variant, which results in its dramatically ameliorated lung pathology. When compared with SARS-CoV-2 WT, Alpha, Beta, and Delta variant, infection by the Omicron variant causes the least body weight loss and mortality rate. Overall, our study demonstrates that the Omicron variant is significantly attenuated in virus replication and pathogenicity in comparison with WT and previous variants. Our data suggest the current global vaccination strategy has forced SARS-CoV-2 into a new evolutionary trajectory towards reduced replication fitness in exchange of better immune escape. These findings are critical for setting policy in the pandemic control and disease management of COVID-19.
Subject(s)
COVID-19ABSTRACT
Mice are not susceptible to wildtype SARS-CoV-2 infection. Emerging SARS-CoV-2 variants including B.1.1.7, B.1.351, P.1, and P.3 contain mutations in spike, which have been suggested to associate with an increased recognition of mouse ACE2, raising the postulation that they may have evolved to expand species tropism to rodents. Here, we investigated the capacity of B.1.1.7 and other emerging SARS-CoV-2 variants in infecting mouse (Mus musculus) and rats (Rattus norvegicus) under in vitro and in vivo settings. Our results show that B.1.1.7 and P.3, but not B.1 or wildtype SARS-CoV-2, can utilize mouse and rat ACE2 for virus entry in vitro. High infectious virus titers, abundant viral antigen expression, and pathological changes are detected in the nasal turbinate and lung of B.1.1.7-inocluated mice and rats. Together, these results reveal that the current predominant circulating SARS-CoV-2 variant, B.1.1.7, has gained the capability to expand species tropism to rodents.
Subject(s)
COVID-19ABSTRACT
The ongoing coronavirus disease 2019 (COVID-19) pandemic is a serious threat to global public health, and imposes severe burdens on the entire human society. The severe acute respiratory syndrome (SARS) coronavirus-2 (SARS-CoV-2) can cause severe respiratory illness and death. Currently, there are no specific antiviral drugs that can treat COVID-19. Several vaccines against SARS-CoV-2 are being actively developed by research groups around the world. The surface S (spike) protein and the highly expressed internal N (nucleocapsid) protein of SARS-CoV-2 are widely considered as promising candidates for vaccines. In order to guide the design of an effective vaccine, we need experimental data on these potential epitope candidates. In this study, we mapped the immunodominant (ID) sites of S protein using sera samples collected from recently discharged COVID-19 patients. The SARS-CoV-2 S protein-specific antibody levels in the sera of recovered COVID-19 patients were strongly correlated with the neutralising antibody titres. We used epitope mapping to determine the landscape of ID sites of S protein, which identified nine linearized B cell ID sites. Four out of the nine ID sites were found in the receptor-binding domain (RBD). Further analysis showed that these ID sites are potential high-affinity SARS-CoV-2 antibody binding sites. Peptides containing two out of the nine sites were tested as vaccine candidates against SARS-CoV-2 in a mouse model. We detected epitope-specific antibodies and SARS-CoV-2-neutralising activity in the immunised mice. This study for the first time provides human serological data for the design of vaccines against COVID-19.