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      Signals of significantly increased vaccine breakthrough, decreased hospitalization rates, and less severe disease in patients with COVID-19 caused by the Omicron variant of SARS-CoV-2 in Houston, Texas

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          Abstract

          Genetic variants of SARS-CoV-2 continue to dramatically alter the landscape of the COVID-19 pandemic. The recently described variant of concern designated Omicron (B.1.1.529) has rapidly spread worldwide and is now responsible for the majority of COVID-19 cases in many countries. Because Omicron was recognized very recently, many knowledge gaps exist about its epidemiology, clinical severity, and disease course. A genome sequencing study of SARS-CoV-2 in the Houston Methodist healthcare system identified 4,468 symptomatic patients with infections caused by Omicron from late November 2021 through January 5, 2022. Omicron very rapidly increased in only three weeks to cause 90% of all new COVID-19 cases, and at the end of the study period caused 98% of new cases. Compared to patients infected with either Alpha or Delta variants in our healthcare system, Omicron patients were significantly younger, had significantly increased vaccine breakthrough rates, and were significantly less likely to be hospitalized. Omicron patients required less intense respiratory support and had a shorter length of hospital stay, consistent with on average decreased disease severity. Two patients with Omicron “stealth” sublineage BA.2 also were identified. The data document the unusually rapid spread and increased occurrence of COVID-19 caused by the Omicron variant in metropolitan Houston, and address the lack of information about disease character among US patients.

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          Considerable escape of SARS-CoV-2 Omicron to antibody neutralization

          The SARS-CoV-2 Omicron variant was first identified in November 2021 in Botswana and South Africa1-3. It has since spread to many countries and is expected to rapidly become dominant worldwide. The lineage is characterized by the presence of around 32 mutations in spike-located mostly in the N-terminal domain and the receptor-binding domain-that may enhance viral fitness and enable antibody evasion. Here we isolated an infectious Omicron virus in Belgium from a traveller returning from Egypt. We examined its sensitivity to nine monoclonal antibodies that have been clinically approved or are in development4, and to antibodies present in 115 serum samples from COVID-19 vaccine recipients or individuals who have recovered from COVID-19. Omicron was completely or partially resistant to neutralization by all monoclonal antibodies tested. Sera from recipients of the Pfizer or AstraZeneca vaccine, sampled five months after complete vaccination, barely inhibited Omicron. Sera from COVID-19-convalescent patients collected 6 or 12 months after symptoms displayed low or no neutralizing activity against Omicron. Administration of a booster Pfizer dose as well as vaccination of previously infected individuals generated an anti-Omicron neutralizing response, with titres 6-fold to 23-fold lower against Omicron compared with those against Delta. Thus, Omicron escapes most therapeutic monoclonal antibodies and, to a large extent, vaccine-elicited antibodies. However, Omicron is neutralized by antibodies generated by a booster vaccine dose.
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            Reduced neutralisation of SARS-CoV-2 omicron B.1.1.529 variant by post-immunisation serum

            According to WHO, SARS-CoV-2 is estimated to have caused 265 million infections and more than 5 million deaths over the past 2 years. Current vaccines are based on the original SARS-CoV-2 strain and are designed primarily to raise an antibody response against the spike protein (S), although elicited T-cell responses can also contribute to protection from severe disease. The SARS-CoV-2 RNA polymerase is intrinsically error prone, which results in mutation to the viral genome. In the past year, several variants containing multiple mutations in S have been reported: alpha (B.1.1.7), beta (B.1.351), gamma (P.1), and delta (B.1.617.2). These variants contain mutations in the receptor binding motif, a small 25 amino acid patch at the tip of S that mediates interaction with the ACE2 receptor (one mutation in alpha, three in beta and gamma, and two in delta). These changes can lead to increased transmissibility by increasing affinity to ACE2 (by seven times for alpha, 19 times for both beta and gamma, and double for delta) 1 or lead to immune escape. First alpha and then delta variants spread globally causing successive waves of infection, while large localised outbreaks were caused in southern Africa by the beta variant and in South America by the gamma variant. At present, delta is estimated to have caused more than 99% of infections worldwide; however, a new variant of concern, omicron (B.1.1.529), was reported first in South Africa on Nov 24, 2021, 2 but has since been reported in multiple countries. Early reports from South Africa suggest that omicron is highly transmissible, in a population where 60–80% already show serological evidence of previous infection or vaccination, suggesting that omicron is able to break through natural and vaccine-induced immunity; although early reports do not indicate more severe disease. Omicron contains a large number of mutations in S compared with previous variants of concern, mostly concentrated around the receptor binding motif: 30 amino acid substitutions, deletion of six residues, and insertion of three residues. 1 Mutations are also present at other sites (receptor binding domain and N-terminal domain) which might affect neutralising antibodies. There is concern that omicron will lead to increased propensity to infect individuals who have received vaccines, whose antigens are based on the original S sequence. Here, we report the results of neutralisation assays using an isolate of omicron obtained from an infected case in the UK. Neutralisation assays were done on sera from individuals from the immunology cohort of the Com-COV2 study, 3 who were seronegative at enrolment (defined by anti-nucleocapsid IgG). Participants were vaccinated with two doses of Oxford–AstraZeneca's ChAdOx1 nCoV-19 (ChAd; n=22), or two doses of Pfizer–BioNTech's BNT162b2 (BNT; n=21) with a priming interval of 8–11 (median 9) weeks. Samples were obtained 28 days (range 25–32) following the second immunisation (appendix p 1). 3 Live virus neutralisation titres against omicron are compared with titres against Victoria, an early pandemic SARS-CoV-2 strain, together with titres against beta and delta variants. Neutralising titres on sera from participants who had received homologous ChAd dropped to below the detectable threshold in all but one participant (figure A, B ). Median neutralising titres on sera from participants who had received homologous BNT reduced by 29·8 fold from 1609 (Victoria strain) to 54 (omicron variant), with one participant dropping below the detection threshold. In most cases, samples that did not neutralise with 50% focus reduction neutralisation titres at a dilution of less than 1/20 showed some residual neutralising activity (figure 1C). Figure Neutralisation assays of SARS-CoV-2 omicron Neutralisation of victoria, beta, delta, and omicron using ChAd serum (A) and BNT serum (B). Median values are indicated above each column. The data underpinning the victoria, beta, and delta neutralisation have been previously reported. 4 The horizontal dotted line indicates half the value of the lower limit of detection. The red horizontal lines in (A) and (B) represent the assay limit of detection and the red numbers represent the median values of the FRNT50. (C) Percent neutralisation at serum dilution of 1/20 for those sera which did not achieve FRNT50 at 1/20. ChAd=ChAdOx1 nCoV-19. BNT=BNT162b2. FRNT50=50% focus reduction neutralisation titres. In summary, there was a substantial decrease in neutralisation titre in recipients of both homologous ChAd and BNT primary courses, with evidence of some recipients not neutralising at all. This reduction in neutralisation titre will probably be more pronounced at later timepoints. These data, although derived from a relatively small sample size, are consistent with published data from datasets of similar size.4, 5, 6 Together, the findings suggest that omicron is more antigenically distant from the original SARS-CoV-2 vaccine strain than the previously most distant strains, beta and delta. Preliminary data from the UK Health Security Agency 7 have shown reduced effectiveness against symptomatic infection after two doses of ChAd or BNT, suggesting a result of increased breakthrough infections in previously infected or double vaccinated individuals, which could drive a further wave of infection. The effect on disease severity is unknown, although there is currently no evidence of increased potential to cause severe disease, hospitalisation, or death. It could be that other aspects of the immune response such as non-neutralising antibodies and cellular immunity, which are not expected to be as severely affected by this variant, could confer a degree of protection against severe disease. However, it should be noted that higher transmission will inevitably lead to increased numbers of cases and a greater burden on health systems, even without proportional changes in severity. Possessing a high starting neutralisation titre against early pandemic strains gives a higher level of neutralisation of omicron, which could be obtained by deploying third booster doses of vaccine. There is some reassurance that a third dose of a COVID-19 vaccine does indeed increase vaccine effectiveness against the omicron variant, 7 and testing of samples from Cov-BOOST 8 will provide further information on the immunology underlying this. Together, these findings will provide further understanding of the potential for a boosting strategy as a control measure for omicron infection and transmission. Should omicron, as expected, become the dominant strain worldwide, given its antigenic distance from ancestral strains, it could be necessary to produce vaccines tailored to omicron; however, these might be unlikely to give protection against previous strains. This development might stimulate consideration of a switch from the current monovalent vaccine strategy towards multivalent formulations currently used in seasonal influenza vaccines. In the meantime, reaching people who are unvaccinated with current vaccines is a priority, in order to reduce transmission levels and the potential for severe disease in people who are immunologically naive.
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              Is Open Access

              Genomic characterization and Epidemiology of an emerging SARS-CoV-2 variant in Delhi, India

              Delhi, the national capital of India, has experienced multiple SARS-CoV-2 outbreaks in 2020 and reached population seropositivity of over 50% by 2021. During April 2021, the city became overwhelmed by COVID-19 cases and fatalities, as a new variant B.1.617.2 (Delta) replaced B.1.1.7 (Alpha). A Bayesian model explains the growth advantage of Delta through a combination of increased transmissibility and reduced sensitivity to immune responses generated against earlier variants (median estimates; ×1.5-fold, 20% reduction). Seropositivity of an employee and family cohort increased from 42% to 87.5% between March and July 2021, with 27% reinfections, as judged by increased antibody concentration after a previous decline. The likely high transmissibility and partial evasion of immunity by the Delta variant contributed to an overwhelming surge in Delhi.
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                Author and article information

                Journal
                Am J Pathol
                Am J Pathol
                The American Journal of Pathology
                Published by Elsevier Inc. on behalf of the American Society for Investigative Pathology.
                0002-9440
                1525-2191
                3 February 2022
                3 February 2022
                Affiliations
                []Laboratory of Human Molecular and Translational Human Infectious Diseases
                []Laboratory of Antibody Discovery and Accelerated Protein Therapeutics, Center for Infectious Diseases, Houston Methodist Research Institute and Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, Texas;
                [§ ]Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York;
                []Consortium for Advanced Science and Engineering, University of Chicago, Chicago, Illinois;
                [∗∗ ]Computing, Environment and Life Sciences, Argonne National Laboratory, Lemont, Illinois;
                Author notes
                [†† ]Address correspondence to James M. Musser, M.D., Ph.D., Department of Pathology and Genomic Medicine, Houston Methodist Research Institute, 6565 Fannin Street, Suite B490, Houston, Texas 77030. Tel: 713.441.5890,
                [∗]

                Contributed equally;

                Article
                S0002-9440(22)00044-X
                10.1016/j.ajpath.2022.01.007
                8812084
                35123975
                3312072b-a992-4570-baef-1cf646db5511
                © 2022 Published by Elsevier Inc. on behalf of the American Society for Investigative Pathology.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 4 January 2022
                : 18 January 2022
                : 20 January 2022
                Categories
                Regular Article

                Pathology
                Pathology

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