The Impact of Mutations in SARS-CoV-2 Spike on Viral Infectivity and Antigenicity.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global COVID-19 pandemic. Rapidly spreading SARS-CoV-2 variants may jeopardize newly introduced antibody and vaccine countermeasures. Here, using monoclonal antibodies (mAbs), animal immune sera, human convalescent sera and human sera from recipients of the BNT162b2 mRNA vaccine, we report the impact on antibody neutralization of a panel of authentic SARS-CoV-2 variants including a B.1.1.7 isolate, chimeric strains with South African or Brazilian spike genes and isogenic recombinant viral variants. Many highly neutralizing mAbs engaging the receptor-binding domain or N-terminal domain and most convalescent sera and mRNA vaccine-induced immune sera showed reduced inhibitory activity against viruses containing an E484K spike mutation. As antibodies binding to spike receptor-binding domain and N-terminal domain demonstrate diminished neutralization potency in vitro against some emerging variants, updated mAb cocktails targeting highly conserved regions, enhancement of mAb potency or adjustments to the spike sequences of vaccines may be needed to prevent loss of protection in vivo.

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Resistance of SARS-CoV-2 variants to neutralization by monoclonal and serum-derived polyclonal antibodies.

N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2.

The past several months have witnessed the emergence of SARS-CoV-2 variants with novel spike protein mutations that are influencing the epidemiological and clinical aspects of the COVID-19 pandemic. These variants can increase rates of virus transmission and/or increase the risk of reinfection and reduce the protection afforded by neutralizing monoclonal antibodies and vaccination. These variants can therefore enable SARS-CoV-2 to continue its spread in the face of rising population immunity while maintaining or increasing its replication fitness. The identification of four rapidly expanding virus lineages since December 2020, designated variants of concern, has ushered in a new stage of the pandemic. The four variants of concern, the Alpha variant (originally identified in the UK), the Beta variant (originally identified in South Africa), the Gamma variant (originally identified in Brazil) and the Delta variant (originally identified in India), share several mutations with one another as well as with an increasing number of other recently identified SARS-CoV-2 variants. Collectively, these SARS-CoV-2 variants complicate the COVID-19 research agenda and necessitate additional avenues of laboratory, epidemiological and clinical research.

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The biological and clinical significance of emerging SARS-CoV-2 variants.

The emergence of the highly transmissible B.1.1.529 Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is concerning for antibody countermeasure efficacy because of the number of mutations in the spike protein. In this study, we tested a panel of anti-receptor-binding domain monoclonal antibodies (mAbs) corresponding to those in clinical use by Vir Biotechnology (S309, the parent mAb of VIR-7831 (sotrovimab)), AstraZeneca (COV2-2196 and COV2-2130, the parent mAbs of AZD8895 and AZD1061), Regeneron (REGN10933 and REGN10987), Eli Lilly (LY-CoV555 and LY-CoV016) and Celltrion (CT-P59) for their ability to neutralize an infectious B.1.1.529 Omicron isolate. Several mAbs (LY-CoV555, LY-CoV016, REGN10933, REGN10987 and CT-P59) completely lost neutralizing activity against B.1.1.529 virus in both Vero-TMPRSS2 and Vero-hACE2-TMPRSS2 cells, whereas others were reduced (COV2-2196 and COV2-2130 combination, ~12-fold decrease) or minimally affected (S309). Our results suggest that several, but not all, of the antibodies in clinical use might lose efficacy against the B.1.1.529 Omicron variant. 

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An infectious SARS-CoV-2 B.1.1.529 Omicron virus escapes neutralization by therapeutic monoclonal antibodies

H5N1 COBRA hemagglutinin (HA) sequences, termed human COBRA-2 HA, were constructed through layering of HA sequences from viruses isolated from humans collected between 2004-2007 using only clade 2 strains. These COBRA HA proteins, when expressed on the surface of virus-like particles (VLP), elicited protective immune responses in mice, ferrets, and non-human primates. However, these vaccines were not as effective at inducing neutralizing antibodies against newly circulating viruses. Therefore, COBRA HA-based vaccines were updated in order to elicit protective antibodies against the current circulating clades of H5Nx viruses. Next-generation COBRA HA vaccines were designed to encompass the newly emerging viruses circulating in wild avian populations. HA amino acid sequences from avian and human H5 influenza viruses isolated between 2011-2017 were downloaded from the GISAID (Global Initiative on Sharing All Influenza Data). Mice were vaccinated with H5 COBRA rHA that elicited antibodies with hemagglutinin inhibition (HAI) activity against H5Nx viruses from five clades. The H5 COBRA rHA vaccine, termed IAN8, elicited protective immune responses against mice challenged with A/Sichuan/26621/2014 and A/Vietnam/1203/2004. This vaccine elicited antibodies with HAI activity against viruses from clades 2.2, 2.3.2.1, 2.3.4.2, 2.2.1 and 2.2.2. Lungs from vaccinated mice had decreased viral titers and the levels of cellular infiltration in mice vaccinated with IAN-8 rHA were similar to mice vaccinated with wild-type HA comparator vaccines or mock vaccinated controls. Overall, these next-generation H5 COBRA HA vaccines elicited protective antibodies against both historical H5Nx influenza viruses, as well as currently circulating clades of H5N1, H5N6, and H5N8 influenza viruses.

Next-Generation Computationally Designed Influenza Hemagglutinin Vaccines Protect against H5Nx Virus Infections.

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Critical roles of chemokines and cytokines in antiviral innate immune responses during rabies virus infection

To construct a expression plasmid containing the full-length cDNA of rabies virus, four overlapped fragments covering full length cDNA of rabies virus street stain HN10 were cloned into pVAX1 sequentially in the genome except for the G-L noncoding region which was replaced with GFP gene. The plasmid containing the full-length viral cDNA was flanked by hammerhead ribozyme (HamRz) and hepatitis delta ribozyme (HdvRz) sequences and arranged under the control of the cytomegalovirus (CMV) promoter. The constructed plasmid could be directly used for the following procedure of producing the recombinant rabies virus street HN10.

[Construction and analysis of full-length cDNA clone of rabies virus street strain].

Pathogenicity of rabies viruses isolated in China: two fixed strains and a street strain.

Objective Analysis the epidemiological characteristics on rabies cases occurred in Guangxi from 2004 to 2008 and summarize the result of healthy-dog infection rabies virus investigation from 2006 to 2008.Exploring the high-occurrence and correlated factors on rabies in Guangxi.Methods Data collected from the National Disease Surveillance System and the National Active Surveillance System for Rabies from 2004 to 2008 and Data of healthy-dog infection rabies virus investigation from 2006 to 2008 were analyzed.Results The total rabies cases were 2463 in Guangxi from 2004-2008 and average incidence rate was 0.98 per 100 thousand per year.There were 95 counties had rabies case reported,anyway more than 10 cases occurred county number was declined while less than 5 cases rose year by year.The rabies case incidence area was expanded and the cases in middle and west area of Guangxi rose significantly.Rabies cases were reported whole year and no seasonal peak.Human rabies eases mainly were farmers,students and children.Yanger than 20 years old and elder 40 years old were the highest age groups in the population of the investigation,83.79% cases were attacked by dogs.78.5% cases classification category Ⅲ.83.17% cases had exposed on the upper and lower limbs,10.56% exposed to the head,face or neck.But 67.88% cases did not received any PEP and only 18.31% cases vaccinated and 3.63% category Ⅲ exposure cases combined administration of RIG.The incubation median was 60 days.The rabies virus infection rate among randomly collection healthy-dog brain samples from 2006 to 2008 was 1.92%,0.93% and 0.89%.Conclusion Unsuccessful and inadequate PEP of patients were the main factors leading to the high-occurrence of human rabies in Guangxi.And there axe a lot of infection rabies virus healthy-dogs alive in Guangxi also as a high-occurrence factor.

Key words: 
Rabies; SEER program; Epidemiologic studies

Ying Huang

Papers

Next-Generation Computationally Designed Influenza Hemagglutinin Vaccines Protect against H5Nx Virus Infections.

Critical roles of chemokines and cytokines in antiviral innate immune responses during rabies virus infection

[Construction and analysis of full-length cDNA clone of rabies virus street strain].

Pathogenicity of rabies viruses isolated in China: two fixed strains and a street strain.

Analysis of human rabies high-occurrence factors in Guangxi from 2004 to 2008.