Retained avidity despite reduced cross-binding and cross-neutralizing antibody levels to Omicron after SARS-COV-2 wild-type infection or mRNA double vaccination

The rapid evolution of SARS-CoV-2 has posed a challenge to long-lasting immunity against the novel virus. Apart from neutralizing function, binding antibodies induced by vaccination or infection play an important role in containing the infection. To determine the proportion of wild-type (WT)–generated antibodies recognizant of more recent variants, plasma samples from either SARS-CoV-2 WT-infected (n = 336) or double-mRNA (Comirnaty)–vaccinated individuals (n = 354, age and sex matched to the convalescent group) were analyzed for binding antibody capacity against the S1 protein of the BA.1 omicron variant. Overall, 38.59% (95% CI, 37.01– 40.20) of WT-generated antibodies recognized Omicron BA.1 S1 protein [28.83% (95% CI, 26.73–30.91) after infection and 43.46% (95% CI, 41.61–45.31) after vaccination; p < 0.001]. Although the proportion of WT-generated binding and neutralizing antibodies also binding to BA.1 is substantially reduced, the avidity of the remaining antibodies against the Omicron variant was non-inferior to that of the ancestral virus: Omicron: 39.7% (95% CI: 38.1–41.3) as compared to the avidity to WT: 27.0% (95% CI, 25.5–28.4), respectively (p < 0.001). Furthermore, we noticed a modestly yet statistically significant higher avidity toward the Omicron epitopes among the vaccinated group (42.2%; 95% CI, 40.51–43.94) as compared to the convalescent counterparts (36.4%; 95% CI, 33.42–38.76) (p = 0.003), even after adjusting for antibody concentration. Our results suggest that an aspect of functional immunity against the novel strain was considerably retained after WT contact, speculatively counteracting the impact of immune evasion toward neutralization of the strain. Higher antibody levels and cross-binding capacity among vaccinated individuals suggest an advantage of repeated exposure in generating robust immunity.

[1]  K. Becker,et al.  Immune response after two doses of the BNT162b2 COVID-19 vaccine and risk of SARS-CoV-2 breakthrough infection in Tyrol, Austria: an open-label, observational phase 4 trial , 2023, The Lancet. Microbe.

[2]  W. Borena,et al.  Characterizing SARS-CoV-2 neutralization profiles after bivalent boosting using antigenic cartography , 2023, medRxiv.

[3]  Clarissa M Koch,et al.  SARS-CoV-2 elicits non-sterilizing immunity and evades vaccine-induced immunity: implications for future vaccination strategies , 2023, European Journal of Epidemiology.

[4]  C. Watanabe,et al.  Antibody Avidity Maturation Following Recovery From Infection or the Booster Vaccination Grants Breadth of SARS-CoV-2 Neutralizing Capacity , 2022, The Journal of infectious diseases.

[5]  C. Davis,et al.  Cross-neutralization and viral fitness of SARS-CoV-2 Omicron sublineages , 2022, bioRxiv.

[6]  D. Grill,et al.  Longitudinal antibody titer, avidity, and neutralizing responses after SARS-CoV-2 infection , 2022, Heliyon.

[7]  J. Bhiman,et al.  Clinical severity of SARS-CoV-2 Omicron BA.4 and BA.5 lineages compared to BA.1 and Delta in South Africa , 2022, Nature Communications.

[8]  H. Wardemann,et al.  Sterilizing immunity: Understanding COVID-19 , 2022, Immunity.

[9]  Micah Thornton,et al.  BNT162b2-induced neutralizing and non-neutralizing antibody functions against SARS-CoV-2 diminish with age , 2022, Cell reports.

[10]  A. Ruello,et al.  Antibody Avidity and Neutralizing Response against SARS-CoV-2 Omicron Variant after Infection or Vaccination , 2022, Journal of immunology research.

[11]  S. Weaver,et al.  Cross-neutralization and cross-protection among SARS-CoV-2 viruses bearing different variant spikes , 2022, Signal Transduction and Targeted Therapy.

[12]  H. Vennema,et al.  Antigenic cartography using sera from sequence-confirmed SARS-CoV-2 variants of concern infections reveals antigenic divergence of Omicron , 2022, Immunity.

[13]  M. Mavrouli,et al.  Comparative Characterization of Human Antibody Response Induced by BNT162b2 Vaccination vs. SARS-CoV-2 Wild-Type Infection , 2022, Vaccines.

[14]  P. Willeit,et al.  Six-Month Follow-Up of Immune Responses after a Rapid Mass Vaccination against SARS-CoV-2 with BNT162b2 in the District of Schwaz/Austria , 2022, Viruses.

[15]  A. Galvani,et al.  The durability of natural infection and vaccine-induced immunity against future infection by SARS-CoV-2 , 2022, Proceedings of the National Academy of Sciences of the United States of America.

[16]  E. Connolly,et al.  Kinetics of the SARS-CoV-2 Antibody Avidity Response Following Infection and Vaccination , 2022, Viruses.

[17]  G. Alter,et al.  Correlates of protection against SARS‐CoV‐2 infection and COVID‐19 disease , 2022, Immunological reviews.

[18]  C. Steves,et al.  Symptom prevalence, duration, and risk of hospital admission in individuals infected with SARS-CoV-2 during periods of omicron and delta variant dominance: a prospective observational study from the ZOE COVID Study , 2022, The Lancet.

[19]  Jeffrey M. Wilson,et al.  Trajectory of IgG to SARS-CoV-2 After Vaccination With BNT162b2 or mRNA-1273 in an Employee Cohort and Comparison With Natural Infection , 2022, Frontiers in Immunology.

[20]  J. Dushoff,et al.  Increased risk of SARS-CoV-2 reinfection associated with emergence of Omicron in South Africa , 2022, Science.

[21]  J. Knight,et al.  SARS-CoV-2-specific antibody and T-cell responses 1 year after infection in people recovered from COVID-19: a longitudinal cohort study , 2022, The Lancet Microbe.

[22]  D. Kaufmann,et al.  Evolution of Anti-RBD IgG Avidity following SARS-CoV-2 Infection , 2022, Viruses.

[23]  A. Tkachuk,et al.  Avidity of IgG to SARS-CoV-2 RBD as a Prognostic Factor for the Severity of COVID-19 Reinfection , 2022, Viruses.

[24]  G. Lozanski,et al.  Neutralizing antibody responses elicited by SARS-CoV-2 mRNA vaccination wane over time and are boosted by breakthrough infection , 2022, Science Translational Medicine.

[25]  X. Daniell,et al.  Mapping SARS-CoV-2 antigenic relationships and serological responses , 2022, bioRxiv.

[26]  A. Casadevall,et al.  Mucosal Vaccines, Sterilizing Immunity, and the Future of SARS-CoV-2 Virulence , 2022, Viruses.

[27]  Hamed Khakzad,et al.  Spike-Dependent Opsonization Indicates Both Dose-Dependent Inhibition of Phagocytosis and That Non-Neutralizing Antibodies Can Confer Protection to SARS-CoV-2 , 2022, Frontiers in Immunology.

[28]  D. von Laer,et al.  SARS-CoV-2 Omicron Variant Neutralization in Serum from Vaccinated and Convalescent Persons , 2022, The New England journal of medicine.

[29]  A. Schäffer,et al.  Large-Scale Study of Antibody Titer Decay following BNT162b2 mRNA Vaccine or SARS-CoV-2 Infection , 2021, Vaccines.

[30]  Jordan J. Clark,et al.  Activity of convalescent and vaccine serum against SARS-CoV-2 Omicron , 2021, Nature.

[31]  T. Ndung’u,et al.  Omicron extensively but incompletely escapes Pfizer BNT162b2 neutralization , 2021, Nature.

[32]  P. Maes,et al.  Considerable escape of SARS-CoV-2 Omicron to antibody neutralization , 2021, Nature.

[33]  Fei Shao,et al.  Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies , 2021, bioRxiv.

[34]  A. Telenti,et al.  Broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift , 2021, Nature.

[35]  Xiawei Wei,et al.  SARS‐CoV‐2 Omicron variant: Characteristics and prevention , 2021, MedComm.

[36]  Lindsay N. Carpp,et al.  Immune correlates analysis of the mRNA-1273 COVID-19 vaccine efficacy clinical trial , 2021, Science.

[37]  D. Wesemann,et al.  Antibody Dynamics and Durability in Coronavirus Disease-19 , 2021, Clinics in Laboratory Medicine.

[38]  J. Mascola,et al.  Durability of mRNA-1273 vaccine–induced antibodies against SARS-CoV-2 variants , 2021, Science.

[39]  H. Ulmer,et al.  Persistence of immunity to SARS-CoV-2 over time in the ski resort Ischgl , 2021, EBioMedicine.

[40]  K. Bates,et al.  Marked increase in avidity of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) antibodies 7-8 months after infection is not diminished in old age. , 2021, The Journal of infectious diseases.

[41]  K. Hedman,et al.  Comparison of approaches for IgG avidity calculation and a new highly sensitive and specific method with broad dynamic range. , 2021, International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases.

[42]  A. Fiore-Gartland,et al.  Evidence for antibody as a protective correlate for COVID-19 vaccines , 2021, Vaccine.

[43]  M. Nussenzweig,et al.  Evolution of antibody immunity to SARS-CoV-2 , 2021, Nature.

[44]  D. von Laer,et al.  Comparison of Four SARS-CoV-2 Neutralization Assays , 2020, Vaccines.