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      SARS‐CoV‐2 Omicron variant: Immune escape and vaccine development

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          Abstract

          New genetic variants of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) constantly emerge through unmitigated spread of the virus in the ongoing Coronavirus disease 2019 pandemic. Omicron (B.1.1.529), the latest variant of concern (VOC), has so far shown exceptional spread and infectivity and has established itself as the dominant variant in recent months. The SARS‐CoV‐2 spike glycoprotein is a key component for the recognition and binding to host cell angiotensin‐converting enzyme 2 receptors. The Omicron variant harbors a cluster of substitutions/deletions/insertions, and more than 30 mutations are located in spike. Some noticeable mutations, including K417N, T478K, N501Y, and P681H, are shared with the previous VOCs Alpha, Beta, Gamma, or Delta variants and have been proven to be associated with higher transmissibility, viral infectivity, and immune evasion potential. Studies have revealed that the Omicron variant is partially resistant to the neutralizing activity of therapeutic antibodies and convalescent sera, which poses significant challenges for the clinical effectiveness of the current vaccines and therapeutic antibodies. We provide a comprehensive analysis and summary of the epidemiology and immune escape mechanisms of the Omicron variant. We also suggest some therapeutic strategies against the Omicron variant. This review, therefore, aims to provide information for further research efforts to prevent and contain the impact of new VOCs during the ongoing pandemic.

          Abstract

          Omicron (B.1.1.529), the latest variant of concern, is partially resistant to the neutralizing activity of therapeutic antibodies and convalescent sera, which poses significant challenges for the clinical effectiveness of the current vaccines and therapeutic antibodies. We provide a comprehensive analysis and summary of the epidemiology and immune escape mechanisms of the Omicron variant. We also suggest some therapeutic strategies against the Omicron variant.

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          Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

          Abstract Background Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle–encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19. Methods This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with SARS-CoV-2. Results The trial enrolled 30,420 volunteers who were randomly assigned in a 1:1 ratio to receive either vaccine or placebo (15,210 participants in each group). More than 96% of participants received both injections, and 2.2% had evidence (serologic, virologic, or both) of SARS-CoV-2 infection at baseline. Symptomatic Covid-19 illness was confirmed in 185 participants in the placebo group (56.5 per 1000 person-years; 95% confidence interval [CI], 48.7 to 65.3) and in 11 participants in the mRNA-1273 group (3.3 per 1000 person-years; 95% CI, 1.7 to 6.0); vaccine efficacy was 94.1% (95% CI, 89.3 to 96.8%; P<0.001). Efficacy was similar across key secondary analyses, including assessment 14 days after the first dose, analyses that included participants who had evidence of SARS-CoV-2 infection at baseline, and analyses in participants 65 years of age or older. Severe Covid-19 occurred in 30 participants, with one fatality; all 30 were in the placebo group. Moderate, transient reactogenicity after vaccination occurred more frequently in the mRNA-1273 group. Serious adverse events were rare, and the incidence was similar in the two groups. Conclusions The mRNA-1273 vaccine showed 94.1% efficacy at preventing Covid-19 illness, including severe disease. Aside from transient local and systemic reactions, no safety concerns were identified. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.)
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            Effectiveness of Covid-19 Vaccines against the B.1.617.2 (Delta) Variant

            Background The B.1.617.2 (delta) variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19), has contributed to a surge in cases in India and has now been detected across the globe, including a notable increase in cases in the United Kingdom. The effectiveness of the BNT162b2 and ChAdOx1 nCoV-19 vaccines against this variant has been unclear. Methods We used a test-negative case–control design to estimate the effectiveness of vaccination against symptomatic disease caused by the delta variant or the predominant strain (B.1.1.7, or alpha variant) over the period that the delta variant began circulating. Variants were identified with the use of sequencing and on the basis of the spike ( S ) gene status. Data on all symptomatic sequenced cases of Covid-19 in England were used to estimate the proportion of cases with either variant according to the patients’ vaccination status. Results Effectiveness after one dose of vaccine (BNT162b2 or ChAdOx1 nCoV-19) was notably lower among persons with the delta variant (30.7%; 95% confidence interval [CI], 25.2 to 35.7) than among those with the alpha variant (48.7%; 95% CI, 45.5 to 51.7); the results were similar for both vaccines. With the BNT162b2 vaccine, the effectiveness of two doses was 93.7% (95% CI, 91.6 to 95.3) among persons with the alpha variant and 88.0% (95% CI, 85.3 to 90.1) among those with the delta variant. With the ChAdOx1 nCoV-19 vaccine, the effectiveness of two doses was 74.5% (95% CI, 68.4 to 79.4) among persons with the alpha variant and 67.0% (95% CI, 61.3 to 71.8) among those with the delta variant. Conclusions Only modest differences in vaccine effectiveness were noted with the delta variant as compared with the alpha variant after the receipt of two vaccine doses. Absolute differences in vaccine effectiveness were more marked after the receipt of the first dose. This finding would support efforts to maximize vaccine uptake with two doses among vulnerable populations. (Funded by Public Health England.)
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              The reproductive number of COVID-19 is higher compared to SARS coronavirus

              Introduction In Wuhan, China, a novel and alarmingly contagious primary atypical (viral) pneumonia broke out in December 2019. It has since been identified as a zoonotic coronavirus, similar to SARS coronavirus and MERS coronavirus and named COVID-19. As of 8 February 2020, 33 738 confirmed cases and 811 deaths have been reported in China. Here we review the basic reproduction number (R 0) of the COVID-19 virus. R 0 is an indication of the transmissibility of a virus, representing the average number of new infections generated by an infectious person in a totally naïve population. For R 0 > 1, the number infected is likely to increase, and for R 0 < 1, transmission is likely to die out. The basic reproduction number is a central concept in infectious disease epidemiology, indicating the risk of an infectious agent with respect to epidemic spread. Methods and Results PubMed, bioRxiv and Google Scholar were accessed to search for eligible studies. The term ‘coronavirus & basic reproduction number’ was used. The time period covered was from 1 January 2020 to 7 February 2020. For this time period, we identified 12 studies which estimated the basic reproductive number for COVID-19 from China and overseas. Table 1 shows that the estimates ranged from 1.4 to 6.49, with a mean of 3.28, a median of 2.79 and interquartile range (IQR) of 1.16. Table 1 Published estimates of R 0 for 2019-nCoV Study (study year) Location Study date Methods Approaches R 0 estimates (average) 95% CI Joseph et al. 1 Wuhan 31 December 2019–28 January 2020 Stochastic Markov Chain Monte Carlo methods (MCMC) MCMC methods with Gibbs sampling and non-informative flat prior, using posterior distribution 2.68 2.47–2.86 Shen et al. 2 Hubei province 12–22 January 2020 Mathematical model, dynamic compartmental model with population divided into five compartments: susceptible individuals, asymptomatic individuals during the incubation period, infectious individuals with symptoms, isolated individuals with treatment and recovered individuals R 0 = \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}$\beta$\end{document} / \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}$\alpha$\end{document} \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}$\beta$\end{document} = mean person-to-person transmission rate/day in the absence of control interventions, using nonlinear least squares method to get its point estimate \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{upgreek} \usepackage{mathrsfs} \setlength{\oddsidemargin}{-69pt} \begin{document} }{}$\alpha$\end{document} = isolation rate = 6 6.49 6.31–6.66 Liu et al. 3 China and overseas 23 January 2020 Statistical exponential Growth, using SARS generation time = 8.4 days, SD = 3.8 days Applies Poisson regression to fit the exponential growth rateR 0 = 1/M(−𝑟)M = moment generating function of the generation time distributionr = fitted exponential growth rate 2.90 2.32–3.63 Liu et al. 3 China and overseas 23 January 2020 Statistical maximum likelihood estimation, using SARS generation time = 8.4 days, SD = 3.8 days Maximize log-likelihood to estimate R 0 by using surveillance data during a disease epidemic, and assuming the secondary case is Poisson distribution with expected value R 0 2.92 2.28–3.67 Read et al. 4 China 1–22 January 2020 Mathematical transmission model assuming latent period = 4 days and near to the incubation period Assumes daily time increments with Poisson-distribution and apply a deterministic SEIR metapopulation transmission model, transmission rate = 1.94, infectious period =1.61 days 3.11 2.39–4.13 Majumder et al. 5 Wuhan 8 December 2019 and 26 January 2020 Mathematical Incidence Decay and Exponential Adjustment (IDEA) model Adopted mean serial interval lengths from SARS and MERS ranging from 6 to 10 days to fit the IDEA model, 2.0–3.1 (2.55) / WHO China 18 January 2020 / / 1.4–2.5 (1.95) / Cao et al. 6 China 23 January 2020 Mathematical model including compartments Susceptible-Exposed-Infectious-Recovered-Death-Cumulative (SEIRDC) R = K 2 (L × D) + K(L + D) + 1L = average latent period = 7,D = average latent infectious period = 9,K = logarithmic growth rate of the case counts 4.08 / Zhao et al. 7 China 10–24 January 2020 Statistical exponential growth model method adopting serial interval from SARS (mean = 8.4 days, SD = 3.8 days) and MERS (mean = 7.6 days, SD = 3.4 days) Corresponding to 8-fold increase in the reporting rateR 0 = 1/M(−𝑟)𝑟 =intrinsic growth rateM = moment generating function 2.24 1.96–2.55 Zhao et al. 7 China 10–24 January 2020 Statistical exponential growth model method adopting serial interval from SARS (mean = 8.4 days, SD = 3.8 days) and MERS (mean = 7.6 days, SD = 3.4 days) Corresponding to 2-fold increase in the reporting rateR 0 = 1/M(−𝑟)𝑟 =intrinsic growth rateM = moment generating function 3.58 2.89–4.39 Imai (2020) 8 Wuhan January 18, 2020 Mathematical model, computational modelling of potential epidemic trajectories Assume SARS-like levels of case-to-case variability in the numbers of secondary cases and a SARS-like generation time with 8.4 days, and set number of cases caused by zoonotic exposure and assumed total number of cases to estimate R 0 values for best-case, median and worst-case 1.5–3.5 (2.5) / Julien and Althaus 9 China and overseas 18 January 2020 Stochastic simulations of early outbreak trajectories Stochastic simulations of early outbreak trajectories were performed that are consistent with the epidemiological findings to date 2.2 Tang et al. 10 China 22 January 2020 Mathematical SEIR-type epidemiological model incorporates appropriate compartments corresponding to interventions Method-based method and Likelihood-based method 6.47 5.71–7.23 Qun Li et al. 11 China 22 January 2020 Statistical exponential growth model Mean incubation period = 5.2 days, mean serial interval = 7.5 days 2.2 1.4–3.9 Averaged 3.28 CI, Confidence interval. Figure 1 Timeline of the R 0 estimates for the 2019-nCoV virus in China The first studies initially reported estimates of R 0 with lower values. Estimations subsequently increased and then again returned in the most recent estimates to the levels initially reported (Figure 1). A closer look reveals that the estimation method used played a role. The two studies using stochastic methods to estimate R 0, reported a range of 2.2–2.68 with an average of 2.44. 1 , 9 The six studies using mathematical methods to estimate R 0 produced a range from 1.5 to 6.49, with an average of 4.2. 2 , 4–6 , 8 , 10 The three studies using statistical methods such as exponential growth estimated an R 0 ranging from 2.2 to 3.58, with an average of 2.67. 3 , 7 , 11 Discussion Our review found the average R 0 to be 3.28 and median to be 2.79, which exceed WHO estimates from 1.4 to 2.5. The studies using stochastic and statistical methods for deriving R 0 provide estimates that are reasonably comparable. However, the studies using mathematical methods produce estimates that are, on average, higher. Some of the mathematically derived estimates fall within the range produced the statistical and stochastic estimates. It is important to further assess the reason for the higher R 0 values estimated by some the mathematical studies. For example, modelling assumptions may have played a role. In more recent studies, R 0 seems to have stabilized at around 2–3. R 0 estimations produced at later stages can be expected to be more reliable, as they build upon more case data and include the effect of awareness and intervention. It is worthy to note that the WHO point estimates are consistently below all published estimates, although the higher end of the WHO range includes the lower end of the estimates reviewed here. R 0 estimates for SARS have been reported to range between 2 and 5, which is within the range of the mean R 0 for COVID-19 found in this review. Due to similarities of both pathogen and region of exposure, this is expected. On the other hand, despite the heightened public awareness and impressively strong interventional response, the COVID-19 is already more widespread than SARS, indicating it may be more transmissible. Conclusions This review found that the estimated mean R 0 for COVID-19 is around 3.28, with a median of 2.79 and IQR of 1.16, which is considerably higher than the WHO estimate at 1.95. These estimates of R 0 depend on the estimation method used as well as the validity of the underlying assumptions. Due to insufficient data and short onset time, current estimates of R 0 for COVID-19 are possibly biased. However, as more data are accumulated, estimation error can be expected to decrease and a clearer picture should form. Based on these considerations, R 0 for COVID-19 is expected to be around 2–3, which is broadly consistent with the WHO estimate. Author contributions J.R. and A.W.S. had the idea, and Y.L. did the literature search and created the table and figure. Y.L. and A.W.S. wrote the first draft; A.A.G. drafted the final manuscript. All authors contributed to the final manuscript. Conflict of interest None declared.
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                Author and article information

                Contributors
                kang.zhang@gmail.com
                xiaweiwei@scu.edu.cn
                Journal
                MedComm (2020)
                MedComm (2020)
                10.1002/(ISSN)2688-2663
                MCO2
                MedComm
                John Wiley and Sons Inc. (Hoboken )
                2688-2663
                16 March 2022
                March 2022
                : 3
                : 1 ( doiID: 10.1002/mco2.v3.1 )
                : e126
                Affiliations
                [ 1 ] Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of Biotherapy and Cancer Center National Clinical Research Center for Geriatrics West China Hospital Sichuan University Chengdu Sichuan China
                [ 2 ] Center for Biomedicine and Innovations Faculty of Medicine Macau University of Science and Technology Macau China
                Author notes
                [*] [* ] Correspondence

                Kang Zhang, Center for Biomedicine and Innovations, Faculty of Medicine, Macau University of Science and Technology, Macau, China.

                Email: kang.zhang@ 123456gmail.com

                Xiawei Wei, Laboratory of Aging Research and Cancer Drug Target, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan 610041, China.

                Email: xiaweiwei@ 123456scu.edu.cn

                Author information
                https://orcid.org/0000-0003-3426-2730
                https://orcid.org/0000-0002-6513-6422
                Article
                MCO2126
                10.1002/mco2.126
                8925644
                35317190
                12431176-43dc-465f-b2b5-a38b1c48dee3
                © 2022 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 02 March 2022
                : 22 February 2022
                : 02 March 2022
                Page count
                Figures: 5, Tables: 2, Pages: 17, Words: 10794
                Funding
                Funded by: National Science Foundation for Excellent Young Scholars
                Award ID: 32122052
                Funded by: National Natural Science Foundation Regional Innovation, and Development
                Award ID: U19A2003
                Categories
                Review
                Reviews
                Custom metadata
                2.0
                March 2022
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.1.2 mode:remove_FC converted:16.03.2022

                immune escape,omicron variant,spike,vaccine development
                immune escape, omicron variant, spike, vaccine development

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