The unprecedented public health and economic impact of the COVID-19 pandemic caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been met with an equally unprecedented scientific response. Much of this response has focused, appropriately, on the mechanisms of SARS-CoV-2 entry into host cells, and in particular the binding of the spike (S) protein to its receptor, angiotensin-converting enzyme 2 (ACE2), and subsequent membrane fusion. This Review provides the structural and cellular foundations for understanding the multistep SARS-CoV-2 entry process, including S protein synthesis, S protein structure, conformational transitions necessary for association of the S protein with ACE2, engagement of the receptor-binding domain of the S protein with ACE2, proteolytic activation of the S protein, endocytosis and membrane fusion. We define the roles of furin-like proteases, transmembrane protease, serine 2 (TMPRSS2) and cathepsin L in these processes, and delineate the features of ACE2 orthologues in reservoir animal species and S protein adaptations that facilitate efficient human transmission. We also examine the utility of vaccines, antibodies and other potential therapeutics targeting SARS-CoV-2 entry mechanisms. Finally, we present key outstanding questions associated with this critical process.

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Mechanisms of SARS-CoV-2 entry into cells.

http://www.cell.com/article/S0092867421014963/pdf

mRNA-based COVID-19 vaccine boosters induce neutralizing immunity against SARS-CoV-2 Omicron variant

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.

We provide two methods for monitoring reinfection trends in routine surveillance data to identify signatures of changes in reinfection risk and apply these approaches to data from South Africa’s severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic to date. Although we found no evidence of increased reinfection risk associated with circulation of the Beta (B.1.351) or Delta (B.1.617.2) variants, we did find clear, population-level evidence to suggest immune evasion by the Omicron (B.1.1.529) variant in previously infected individuals in South Africa. Reinfections occurring between 1 November 2021 and 31 January 2022 were detected in individuals infected in all three previous waves, and there has been an increase in the risk of having a third infection since mid-November 2021. Description Omicron and reinfection risk So far, our experience with pandemic coronavirus has been that the emergence of new variants is not detected until there has been substantial community transmission. Early in November 2021, South African scientists spotted reinfections consistent with the timing of the emergence of the Omicron variant (B.1.1.529). In a population largely untouched by vaccines but widely infected, Pulliam et al. found that Beta or Delta variants rarely caused reinfection. However, after 31 October 2021, individuals were found who had had three experiences of infection (see the Perspective by Zelner and Eisenberg). The culprit was the rapidly emerging Omicron variant, with multiple mutations in the Spike protein. This variant’s chief advantage is its ability to evade naturally acquired immunity. Fortunately, the Omicron variant does not fully evade vaccine-derived immunity, but only those privileged to have been vaccinated can benefit. —CA Analysis of routine surveillance data from South Africa indicates that the Omicron variant of SARS-CoV-2 evades immunity from prior infection. INTRODUCTION Globally, there have been more than 404 million cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with 5.8 million confirmed deaths as of February 2022. South Africa has experienced four waves of SARS-CoV-2 transmission, with the second, third, and fourth waves being driven by the Beta, Delta, and Omicron variants, respectively. A key question with the emergence of new variants is the extent to which they are able to reinfect those who have had a prior natural infection. RATIONALE We developed two approaches to monitor routine epidemiological surveillance data to determine whether SARS-CoV-2 reinfection risk has changed through time in South Africa in the context of the emergence of the Beta (B.1.351), Delta (B.1.617.2), and Omicron (B.1.1.529) variants. We analyzed line-list data on positive tests for SARS-CoV-2 with specimen receipt dates between 4 March 2020 and 31 January 2022 collected through South Africa’s National Notifiable Medical Conditions Surveillance System. Individuals having sequential positive tests at least 90 days apart were considered to have suspected reinfections. Our routine monitoring of reinfection risk included comparison of reinfection rates with the expectation under a null model (approach 1) and estimation of the time-varying hazards of infection and reinfection throughout the epidemic (approach 2) based on model-based reconstruction of the susceptible populations eligible for primary and second infections. RESULTS A total of 105,323 suspected reinfections were identified among 2,942,248 individuals with laboratory-confirmed SARS-CoV-2 who had a positive test result at least 90 days before 31 January 2022. The number of reinfections observed through the end of the third wave in September 2021 was consistent with the null model of no change in reinfection risk (approach 1). Although increases in the hazard of primary infection were observed after the introduction of both the Beta and Delta variants, no corresponding increase was observed in the reinfection hazard (approach 2). Contrary to expectation, the estimated hazard ratio for reinfection versus primary infection was lower during waves driven by the Beta and Delta variants than for the first wave: the relative hazard ratio for wave 2 versus wave 1 was 0.71 [95% confidence interval (95% CI): 0.60 to 0.85]; the relative hazard ratio for wave 3 versus wave 1 was 0.54 (95% CI: 0.45 to 0.64). By contrast, the recent spread of the Omicron variant has been associated with an increase in reinfection hazard coefficient. The estimated relative hazard ratio for reinfection versus primary infection versus wave 1 was 1.75 (95% CI: 1.48 to 2.10) for the period of Omicron emergence (1 November 2021 to 30 November 2021) and 1.70 (95% CI: 1.44 to 2.04) for wave 4 versus wave 1. Individuals with identified reinfections since 1 November 2021 had experienced primary infections in all three prior waves, and an increase in third infections has been detected since mid-November 2021. Many individuals experiencing third infections had second infections during the third (Delta) wave that ended in September 2021, strongly suggesting that these infections resulted from immune evasion rather than waning immunity. CONCLUSION Population-level evidence suggests that the Omicron variant is associated with a marked ability to evade immunity from prior infection. In contrast, there is no population-wide epidemiological evidence of immune escape associated with the Beta or Delta variants. This finding has important implications for public health planning, particularly in countries such as South Africa with high rates of immunity from prior infection. The further development of methods to track reinfection risk during pathogen emergence, including refinements to assess the impact of waning immunity, account for vaccine-derived protection, and monitor the risk of multiple reinfections, will be important for future pandemic preparedness. SARS-CoV-2 reinfection patterns in South Africa. South Africa has experienced four waves of SARS-CoV-2 transmission, each driven by the emergence of a new variant. Reinfection of previously infected individuals was relatively rare through the end of the third wave. Methods developed in South Africa to monitor reinfection trends led to the early detection of increased reinfection risk associated with the Omicron variant.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8995029

Increased risk of SARS-CoV-2 reinfection associated with emergence of Omicron in South Africa

Abstract SARS-CoV-2 Omicron subvariants BA.2.12.1 and BA.4/5 have surged notably to become dominant in the United States and South Africa, respectively 1,2 . These new subvariants carrying further mutations in their spike proteins raise concerns that they may further evade neutralizing antibodies, thereby further compromising the efficacy of COVID-19 vaccines and therapeutic monoclonals. We now report findings from a systematic antigenic analysis of these surging Omicron subvariants. BA.2.12.1 is only modestly (1.8-fold) more resistant to sera from vaccinated and boosted individuals than BA.2. However, BA.4/5 is substantially (4.2-fold) more resistant and thus more likely to lead to vaccine breakthrough infections. Mutation at spike residue L452 found in both BA.2.12.1 and BA.4/5 facilitates escape from some antibodies directed to the so-called class 2 and 3 regions of the receptor-binding domain 3 . The F486V mutation found in BA.4/5 facilitates escape from certain class 1 and 2 antibodies but compromises the spike affinity for the viral receptor. The R493Q reversion mutation, however, restores receptor affinity and consequently the fitness of BA.4/5. Among therapeutic antibodies authorized for clinical use, only bebtelovimab retains full potency against both BA.2.12.1 and BA.4/5. The Omicron lineage of SARS-CoV-2 continues to evolve, successively yielding subvariants that are not only more transmissible but also more evasive to antibodies. 

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Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4 and BA.5

The SARS-CoV-2 B.1.617 lineage was identified in October 2020 in India1–5. Since then, it has become dominant in some regions of India and in the UK, and has spread to many other countries6. The lineage includes three main subtypes (B1.617.1, B.1.617.2 and B.1.617.3), which contain diverse mutations in the N-terminal domain (NTD) and the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein that may increase the immune evasion potential of these variants. B.1.617.2—also termed the Delta variant—is believed to spread faster than other variants. Here we isolated an infectious strain of the Delta variant from an individual with COVID-19 who had returned to France from India. We examined the sensitivity of this strain to monoclonal antibodies and to antibodies present in sera from individuals who had recovered from COVID-19 (hereafter referred to as convalescent individuals) or who had received a COVID-19 vaccine, and then compared this strain with other strains of SARS-CoV-2. The Delta variant was resistant to neutralization by some anti-NTD and anti-RBD monoclonal antibodies, including bamlanivimab, and these antibodies showed impaired binding to the spike protein. Sera collected from convalescent individuals up to 12 months after the onset of symptoms were fourfold less potent against the Delta variant relative to the Alpha variant (B.1.1.7). Sera from individuals who had received one dose of the Pfizer or the AstraZeneca vaccine had a barely discernible inhibitory effect on the Delta variant. Administration of two doses of the vaccine generated a neutralizing response in 95% of individuals, with titres three- to fivefold lower against the Delta variant than against the Alpha variant. Thus, the spread of the Delta variant is associated with an escape from antibodies that target non-RBD and RBD epitopes of the spike protein. The SARS-CoV-2 Delta variant partially evades neutralization by several monoclonal antibodies and by sera from individuals who have had COVID-19, but two doses of anti-COVID-19 vaccines still generate a strong neutralizing response.

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Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization.

The SARS-CoV-2 B.1.617 lineage emerged in October 2020 in India1-6. It has since then become dominant in some indian regions and further spread to many countries. The lineage includes three main subtypes (B1.617.1, B.1617.2 and B.1.617.3), which harbour diverse Spike mutations in the N-terminal domain (NTD) and the receptor binding domain (RBD) which may increase their immune evasion potential. B.1.617.2 is believed to spread faster than the other versions. Here, we isolated infectious B.1.617.2 from a traveller returning from India. We examined its sensitivity to monoclonal antibodies (mAbs) and to antibodies present in sera from COVID-19 convalescent individuals or vaccine recipients, in comparison to other viral lineages. B.1.617.2 was resistant to neutralization by some anti-NTD and anti-RBD mAbs, including Bamlanivimab, which were impaired in binding to the B.1.617.2 Spike. Sera from convalescent patients collected up to 12 months post symptoms and from Pfizer Comirnaty vaccine recipients were 3 to 6 fold less potent against B.1.617.2, relative to B.1.1.7. Sera from individuals having received one dose of AstraZeneca Vaxzevria barely inhibited B.1.617.2. Thus, B.1.617.2 spread is associated with an escape to antibodies targeting non-RBD and RBD Spike epitopes.

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Julien Le Guen

Papers

Reduced sensitivity of SARS-CoV-2 variant Delta to antibody neutralization.

Reduced sensitivity of infectious SARS-CoV-2 variant B.1.617.2 to monoclonal antibodies and sera from convalescent and vaccinated individuals