scholarly journals Neutralization of ancestral SARS-CoV-2 and variants Alpha, Beta, Gamma, Delta, Zeta and Omicron by mRNA vaccination and infection-derived immunity through homologous and heterologous variants

2021 ◽  
Author(s):  
Meriem Bekliz ◽  
Kenneth Adea ◽  
Pauline Vetter ◽  
Christiane S Eberhardt ◽  
Krisztina Hosszu-Fellous ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Immune Escape ◽  
Neutralization Assay ◽  
Significant Loss ◽  
Antigenic Relationship ◽  
Double Dose ◽  
Gamma Delta ◽  
Breakthrough Infection ◽  
Neutralizing Capacity ◽  
Alpha Beta

Emerging SARS-CoV-2 variants of concern/interest (VOC/VOI) raise questions about effectiveness of neutralizing antibodies derived from infection or vaccination. As the population immunity to SARS-CoV-2 has become more complex due to prior infection and/or vaccination, understanding the antigenic relationship between variants is needed. Here, we have assessed in total 104 blood specimens from convalescent individuals after infection with early-pandemic SARS-CoV-2 (pre-VOC) or with Alpha, Beta, Gamma or Delta, post-vaccination after double-dose mRNA-vaccination and break through infections due to Delta or Omicron. Neutralization against seven authentic SARS-CoV-2 isolates (B.1, Alpha, Beta, Gamma, Delta, Zeta, Omicron) was assessed by plaque-reduction neutralization assay. We found highest neutralization titers against the homologous (previously infecting) variant, with lower neutralization efficiency against heterologous variants. Significant loss of neutralization for Omicron was observed but to a varying degree depending on previously infecting variant (23.0-fold in Beta-convalescence up to 56.1-fold in Alpha-convalescence), suggesting that infection-derived immunity varies, but independent of the infecting variant is only poorly protective against Omicron. Of note, Zeta VOI showed also pronounced escape from neutralization of up to 28.2-fold in Alpha convalescent samples. Antigenic mapping reveals both Zeta and Omicron as separate antigenic clusters. Double dose vaccination showed robust neutralization for Alpha, Beta, Gamma, Delta and Zeta, with fold-change reduction of only 2.8 (for Alpha) up to 6.9 (for Beta). Escape from neutralization for Zeta was largely restored in vaccinated individuals, while Omicron still showed a loss of neutralization of 85.7-fold compared to pre-VOC SARS-CoV-2. Combined immunity from infection followed by vaccination or vaccine breakthrough infection showed highest titers and most robust neutralization for heterologous variants. Breakthrough infection with Delta showed only 12.5-fold reduced neutralization for Omicron, while breakthrough infection with Omicron showed only a 1.5-fold loss for Delta, suggests that infection with antigenically different variants can boost immunity for antigens closer to the vaccine strain. Antigenic cartography showed also a tendency towards broader neutralizing capacity for heterologous variants. We conclude that the complexity of background immunity needs to be taken into account when assessing new VOCs. Development towards separate serotypes such as Zeta was already observed before Omicron emergence, thus other factors than just immune escape must contribute to Omicrons rapid dominance. However, combined infection/vaccination immunity could ultimately lead to broad neutralizing capacity also against non-homologous variants.

scholarly journals Vaccine-breakthrough infection by the SARS-CoV-2 Omicron variant elicits broadly cross-reactive immune responses

2021 ◽  
Author(s):  
Runhong Zhou ◽  
Kelvin Kai-Wang To ◽  
Qiaoli Peng ◽  
Jacky Man-Chun Chan ◽  
Haode Huang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Preventive Strategies ◽  
Gamma Delta ◽  
Breakthrough Infection ◽  
Host Immune Responses ◽  
Cell Responses ◽  
Booster Vaccine ◽  
Ic50 Values ◽  
The Mean

Highly transmissible SARS-CoV-2 Omicron variant has posted a new crisis for COVID-19 pandemic control. Within a month, Omicron is dominating over Delta variant in several countries probably due to immune evasion. It remains unclear whether vaccine-induced memory responses can be recalled by Omicron infection. Here, we investigated host immune responses in the first vaccine-breakthrough case of Omicron infection in Hong Kong. We found that the breakthrough infection rapidly recruited potent cross-reactive broad neutralizing antibodies (bNAbs) against current VOCs, including Alpha, Beta, Gamma, Delta and Omicron, from unmeasurable IC50 values to mean 1:2929 at around 9-12 days, which were higher than the mean peak IC50 values of BioNTech-vaccinees. Cross-reactive spike- and nucleocapsid-specific CD4 and CD8 T cell responses were detected. Similar results were also obtained in the second vaccine-breakthrough case of Omicron infection. Our preliminary findings may have timely implications to booster vaccine optimization and preventive strategies of pandemic control.

scholarly journals Superior immunity that allows neutralization of all SARS-CoV-2 variants of concern develops in COVID-19 convalescents and naïve individuals after three vaccinations

2022 ◽  
Author(s):  
Ulrike Protzer ◽  
Paul Wratil ◽  
Marcel Stern ◽  
Alina Priller ◽  
Annika Willmann ◽  
...  
Keyword(s):  
Immune Escape ◽  
Neutralizing Antibody ◽  
Antibody Responses ◽  
Immune Protection ◽  
Breakthrough Infection ◽  
High Quality ◽  
Antibody Avidity ◽  
Neutralization Capacity ◽  
Neutralizing Capacity ◽  
Antibody Dynamics

Abstract Infection-neutralizing antibody responses after SARS-CoV-2 infection or COVID-19 vaccination are an essential part of antiviral immunity. This immune protection is challenged by the occurrence of SARS-CoV-2 variants of concern (VoCs) with immune escape properties, such as omicron (B.1.1.529) that is rapidly spreading worldwide. Here, we report neutralizing antibody dynamics in a longitudinal cohort of COVID-19 convalescent and naïve individuals vaccinated with mRNA BNT162b2 by quantifying anti-SARS-CoV-2-spike antibodies and determining their avidity and neutralization capacity. A superior infection-neutralizing capacity against all VoCs, including omicron, developed by either two vaccinations of convalescents, or a third vaccination or breakthrough infection of twice-vaccinated naïve individuals. These three consecutive spike antigen exposures resulted in an increasing neutralization capacity per anti-spike antibody unit and were paralleled by stepwise increases in antibody avidity. In conclusion, an infection/vaccination-induced hybrid immunity or a triple immunization induces high-quality antibodies resulting in superior neutralization capacity against VoCs, including omicron.

scholarly journals B.1.617.3 SARS CoV-2 spike E156G/Δ157-158 mutations contribute to reduced neutralization sensitivity and increased infectivity

2021 ◽  
Author(s):  
Tarun Mishra ◽  
Garima Joshi ◽  
Atul Kumar ◽  
Rishikesh Dalavi ◽  
Pankaj Pandey ◽  
...  
Keyword(s):  
Immune Evasion ◽  
Neutralizing Antibodies ◽  
Immune Escape ◽  
Coding Region ◽  
Rt Pcr ◽  
Breakthrough Infection ◽  
Neutralization Sensitivity ◽  
Spike Gene ◽  
Spike Coding ◽  
The Usa

SARS CoV-2 variants raise significant concerns due to their ability to cause vaccine breakthrough infections. Here, we sequence-characterized the spike gene, isolated from a breakthrough infection, that corresponded to B.1.617.3 lineage. Delineating the functional impact of spike mutations using reporter pseudoviruses (PV) revealed that N-terminal domain (NTD)-specific E156G/Δ157-158 contributed to increased infectivity and reduced sensitivity to ChAdOx1 nCoV-19 vaccine (CovishieldTM)-elicited neutralizing antibodies. A six-nucleotide deletion (467-472) in the spike coding region introduced this change in the NTD. We confirmed the presence of E156G/Δ157-158 in the RT-PCR-positive cases concurrently screened, in addition to other circulating spike (S1) mutations like T19R, T95I, L452R, E484Q, and D614G. Notably, E156G/Δ157-158 was present in more than 85% of the sequences reported from the USA, UK, and India in August 2021. The spike PV bearing combination of E156G/Δ157-158 and L452R further promoted infectivity and conferred immune evasion. Additionally, increased cell-to-cell fusion was observed when spike harbored E156G/Δ157-158, L452R, and E484Q, suggesting a combinatorial effect of these mutations. Notwithstanding, the plasma from a recovered individual robustly inhibited mutant spike PV, indicating the increased breadth of neutralization post-recovery. Our data highlights the importance of spike NTD-specific changes in determining infectivity and immune escape of variants.

scholarly journals A noncompeting pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2

Science ◽  
2020 ◽  
Vol 368 (6496) ◽  
pp. 1274-1278 ◽  
Author(s):  
Yan Wu ◽  
Feiran Wang ◽  
Chenguang Shen ◽  
Weiyu Peng ◽  
Delin Li ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Immune Escape ◽  
Complex Structure ◽  
Structural Basis ◽  
Virus Binding ◽  
Angiotensin Converting Enzyme 2 ◽  
Binding Interface ◽  
Neutralizing Capacity ◽  
Rational Vaccine Design ◽  
Therapeutic Study

Neutralizing antibodies could potentially be used as antivirals against the coronavirus disease 2019 (COVID-19) pandemic. Here, we report isolation of four human-origin monoclonal antibodies from a convalescent patient, all of which display neutralization abilities. The antibodies B38 and H4 block binding between the spike glycoprotein receptor binding domain (RBD) of the virus and the cellular receptor angiotensin-converting enzyme 2 (ACE2). A competition assay indicated different epitopes on the RBD for these two antibodies, making them a potentially promising virus-targeting monoclonal antibody pair for avoiding immune escape in future clinical applications. Moreover, a therapeutic study in a mouse model validated that these antibodies can reduce virus titers in infected lungs. The RBD-B38 complex structure revealed that most residues on the epitope overlap with the RBD-ACE2 binding interface, explaining the blocking effect and neutralizing capacity. Our results highlight the promise of antibody-based therapeutics and provide a structural basis for rational vaccine design.

scholarly journals Human neutralizing antibodies for SARS-CoV-2 prevention and immunotherapy

2021 ◽  
Author(s):  
Dongyan Zhou ◽  
Runhong Zhou ◽  
Zhiwei Chen
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Neutralizing Antibodies ◽  
Immune Escape ◽  
Passive Immunization ◽  
Clinical Development ◽  
Vaccine Research ◽  
Breakthrough Infection ◽  
Clinical Benefits

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). SARS-CoV-2 has been spreading worldwide since December 2019, resulting in the ongoing COVID-19 pandemic with 237 million infections and 4.8 million deaths by 11 October 2021. While there are great efforts of global vaccination, ending this pandemic has been challenged by issues of exceptionally high viral transmissibility, re-infection, vaccine-breakthrough infection, and immune escape variants of concerns. Besides the record-breaking speed of vaccine research and development, antiviral drugs including SARS-CoV-2-specific human neutralizing antibodies (HuNAbs) have been actively explored for passive immunization. In support of HuNAb-based immunotherapy, passive immunization using convalescent patients’ plasma have generated promising evidence on clinical benefits for both mild and severe COVID-19 patients. Since the source of convalescent plasma is limited, the discovery of broadly reactive HuNAbs may have significant impacts on the fight against the COVID-19 pandemic. In this review, therefore, we discuss the current technologies of gene cloning, modes of action, in vitro and in vivo potency and breadth, and clinical development for potent SARS-CoV-2-specific HuNAbs.

scholarly journals A non-competing pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2

2020 ◽  
Author(s):  
Yan Wu ◽  
Feiran Wang ◽  
Chenguang Shen ◽  
Weiyu Peng ◽  
Delin Li ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Neutralizing Antibodies ◽  
Immune Escape ◽  
Structural Basis ◽  
Cellular Receptor ◽  
Virus Binding ◽  
Reduction Activity ◽  
Binding Interface ◽  
Neutralizing Capacity

AbstractNeutralizing antibodies could be antivirals against COVID-19 pandemics. Here, we report the isolation of four human-origin monoclonal antibodies from a convalescent patient in China. All of these isolated antibodies display neutralization abilities in vitro. Two of them (B38 and H4) block the binding between RBD and vial cellular receptor ACE2. Further competition assay indicates that B38 and H4 recognize different epitopes on the RBD, which is ideal for a virus-targeting mAb-pair to avoid immune escape in the future clinical applications. Moreover, therapeutic study on the mouse model validated that these two antibodies can reduce virus titers in the infected mouse lungs. Structure of RBD-B38 complex revealed that most residues on the epitope are overlapped with the RBD-ACE2 binding interface, which explained the blocking efficacy and neutralizing capacity. Our results highlight the promise of antibody-based therapeutics and provide the structural basis of rational vaccine design.One Sentence SummaryA pair of human neutralizing monoclonal antibodies against COVID-19 compete cellular receptor binding but with different epitopes, and with post-exposure viral load reduction activity.

scholarly journals Neutralization of VOCs including Delta one year post COVID-19 or vaccine

2021 ◽  
Author(s):  
Sebastian Havervall ◽  
Ulrika Marking ◽  
Max Gordon ◽  
Henry Ng ◽  
Nina Greilert-Norin ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Wide Spread ◽  
Wild Type ◽  
Policy Makers ◽  
Full List ◽  
Low Resource Settings ◽  
Neutralizing Capacity ◽  
Alpha Beta ◽  
One Year ◽  
Type Infection

Background: SARS-CoV-2 variants, such as Alpha, Beta, Gamma and Delta, are raising concern about the efficiency of neutralizing antibodies (NAb) induced by wild-type infection or vaccines based on the wild-type spike. Methods: We determined IgG and NAb against SARS-CoV-2 variants one year following mild wild-type infection (n=104) and two-dose regimens with BNT162b2 (BNT/BNT) (n=67), ChAdOx1 (ChAd/ChAd) (n=82), or heterologous ChAdOx1 followed by BNT162b2 (ChAd/BNT) (n=116). Findings: Wild type spike IgG and NAb remained detectable in 80% (83/104) of unvaccinated participants one year post mild infection. The neutralizing capacity was similar against wild type (reference), Alpha (0.95 (0.92-0.98) and Delta 1.03 (0.95-1.11) but significantly reduced against Beta (0.54 (0.48-0.60)) and Gamma 0.51 (0.44-0.61). Similarly, BNT/BNT and ChAd/ChAd elicited sustained capacity against Alpha and Delta (1.01 (0.78-1.31) and 1.03 (0.95-1.11)) and (0.96 (0.84-1.09) and 0.82 (0.61-1.10) respectively), with reduced capacity against Beta (0.67 (0.50-0.88) and 0.53 (0.40-0.71)) and Gamma (0.12 (0.06-0.27) and 0.54 (0.37-0.80)). A similar trend was found following ChAd/BNT (0.74 (0.66-0.83) and 0.70 (0.50-0.97) against Alpha and Delta and 0.29 (0.20-0.42) and 0.13 (0.08-0.20) against Beta and Gamma). Interpretation: Persistent neutralization of the wide-spread Alpha and Delta variants one year after wild-type infection may aid vaccine policy makers in low-resource settings when prioritizing vaccine supply. The reduced capacity of neutralizing Beta and Gamma strains, but not the Alpha and Delta strains following both infection and three different vaccine regimens argues for caution against Beta and Gamma-exclusive mutations in the efforts to optimize next generation SARS-CoV-2 vaccines. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section

scholarly journals Diminished neutralization responses towards SARS-CoV-2 Omicron VoC after mRNA or vector-based COVID-19 vaccinations

2021 ◽  
Author(s):  
Henning Jacobsen ◽  
Monika Strengert ◽  
Henrike Maass ◽  
Mario Alberto Ynga Durand ◽  
Barbora Kessel ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Immune Escape ◽  
Significant Risk ◽  
Neutralization Assay ◽  
The Novel ◽  
Wild Type ◽  
Neutralization Activity ◽  
Novel Variant

Background: SARS-CoV-2 variants accumulating immune escape mutations provide a significant risk to vaccine-induced protection. The novel variant of concern Omicron (B.1.1.529) has to date the largest number of amino acid alterations in its Spike protein. Thus, it may efficiently escape recognition by neutralizing antibodies, allowing breakthrough infections in convalescent and vaccinated individuals. Aims: We analysed neutralization activity after vaccination with all mRNA-, vector- or heterologous immunization schemes currently available in Europe at peak response and in a longitudinal follow-up with BNT162b2 vaccinees to define immune escape potential of the Omicron VoC. Methods: We tested sera by in vitro neutralization assay towards SARS-CoV-2 B.1, Omicron, Beta and Delta pseudotypes Results: All vaccines apart from Ad26.CoV2.S showed high levels of responder rates (93.3-100%) towards SARS-CoV-2 wild-type, but some reductions in neutralizing Beta and Delta VoC pseudotypes. The novel Omicron variant had the biggest impact, both in terms of response rates and neutralization titres among responders. Only mRNA-1273 showed a 100% response rate to Omicron and induced the highest titres of neutralizing antibodies, followed by heterologous prime-boost approaches. Homologous BNT162b2 vaccination or vector-based formulations with AZD1222 or Ad26.CoV2.S performed less well with peak responder rates of 33%, 50% and 9%, respectively. However, Omicron responder rates in BNT162b2 recipients were maintained in our six month longitudinal follow-up and even slightly increased to 47%, indicating cross-protection against Omicron is maintained over time. Conclusions: Overall, our data strongly argues for urgent booster doses in individuals who were previously vaccinated with BNT162b2, or a vector-based immunization scheme.

scholarly journals Infectivity and immune escape of the new SARS-CoV-2 variant of interest Lambda

2021 ◽  
Author(s):  
M&oacutenica L. Acevedo ◽  
Luis Alonso-Palomares ◽  
Andr&eacutes Bustamante ◽  
Aldo Gaggero ◽  
Fabio Paredes ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Immune Escape ◽  
Neutralization Assay ◽  
Spike Protein ◽  
Pseudotyped Virus ◽  
South American ◽  
Virus Neutralization Assay ◽  
Alpha Variant ◽  
Vaccination Campaigns ◽  
The Impact

Background: The newly described SARS-CoV-2 lineage C.37 was recently classified as a variant of interest by the WHO (Lambda variant) based on its high circulation rates in South American countries and the presence of critical mutations in the spike protein. The impact of such mutations in infectivity and immune escape from neutralizing antibodies are entirely unknown. Methods: We performed a pseudotyped virus neutralization assay and determined the impact of the Lambda variant on infectivity and immune escape using plasma samples from healthcare workers (HCW) from two centers in Santiago, Chile who received the two-doses scheme of the inactivated virus vaccine CoronaVac. Results: We observed an increased infectivity mediated by the Lambda spike protein that was even higher than that of the D614G (lineage B) or the Alpha and Gamma variants. Compared to the Wild type (lineage A), neutralization was decreased by 3.05-fold for the Lambda variant while it was 2.33-fold for the Gamma variant and 2.03-fold for the Alpha variant. Conclusions: Our results indicate that mutations present in the spike protein of the Lambda variant of interest confer increased infectivity and immune escape from neutralizing antibodies elicited by CoronaVac. These data reinforce the idea that massive vaccination campaigns in countries with high SARS-CoV-2 circulation must be accompanied by strict genomic surveillance allowing the identification of new isolates carrying spike mutations and immunology studies aimed to determine the impact of these mutations in immune escape and vaccines breakthrough.

scholarly journals CD147 antibody specifically and effectively inhibits infection and cytokine storm of SARS-CoV-2 and its variants delta, alpha, beta, and gamma

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Jiejie Geng ◽  
Liang Chen ◽  
Yufeng Yuan ◽  
Ke Wang ◽  
Youchun Wang ◽  
...  
Keyword(s):  
Viral Entry ◽  
Neutralizing Antibodies ◽  
Immune Escape ◽  
Mapk Pathway ◽  
Cytokine Storm ◽  
Cytokines And Chemokines ◽  
Signaling Axis ◽  
Alpha Beta ◽  
New Perspective ◽  
Stat Pathway

AbstractSARS-CoV-2 mutations contribute to increased viral transmissibility and immune escape, compromising the effectiveness of existing vaccines and neutralizing antibodies. An in-depth investigation on COVID-19 pathogenesis is urgently needed to develop a strategy against SARS-CoV-2 variants. Here, we identified CD147 as a universal receptor for SARS-CoV-2 and its variants. Meanwhile, Meplazeumab, a humanized anti-CD147 antibody, could block cellular entry of SARS-CoV-2 and its variants—alpha, beta, gamma, and delta, with inhibition rates of 68.7, 75.7, 52.1, 52.1, and 62.3% at 60 μg/ml, respectively. Furthermore, humanized CD147 transgenic mice were susceptible to SARS-CoV-2 and its two variants, alpha and beta. When infected, these mice developed exudative alveolar pneumonia, featured by immune responses involving alveoli-infiltrated macrophages, neutrophils, and lymphocytes and activation of IL-17 signaling pathway. Mechanistically, we proposed that severe COVID-19-related cytokine storm is induced by a “spike protein-CD147-CyPA signaling axis”: Infection of SARS-CoV-2 through CD147 initiated the JAK-STAT pathway, which further induced expression of cyclophilin A (CyPA); CyPA reciprocally bound to CD147 and triggered MAPK pathway. Consequently, the MAPK pathway regulated the expression of cytokines and chemokines, which promoted the development of cytokine storm. Importantly, Meplazumab could effectively inhibit viral entry and inflammation caused by SARS-CoV-2 and its variants. Therefore, our findings provided a new perspective for severe COVID-19-related pathogenesis. Furthermore, the validated universal receptor for SARS-CoV-2 and its variants can be targeted for COVID-19 treatment.

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