Kinetics of the SARS-CoV-2 Antibody Avidity Response Following Infection and Vaccination

Laura Garcia, Tom Woudenberg, Jason Rosado, Adam H Dyer, Françoise Donnadieu, Delphine Planas, Timothée Bruel, Olivier Schwartz, Thierry Prazuck, Aurélie Velay, Samira Fafi-Kremer, Isabella Batten, Conor Reddy, Emma Connolly, Matt McElheron, Sean P Kennelly, Nollaig M Bourke, Michael T White, Stéphane Pelleau, Laura Garcia, Tom Woudenberg, Jason Rosado, Adam H Dyer, Françoise Donnadieu, Delphine Planas, Timothée Bruel, Olivier Schwartz, Thierry Prazuck, Aurélie Velay, Samira Fafi-Kremer, Isabella Batten, Conor Reddy, Emma Connolly, Matt McElheron, Sean P Kennelly, Nollaig M Bourke, Michael T White, Stéphane Pelleau

Abstract

Serological assays capable of measuring antibody responses induced by previous infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been critical tools in the response to the COVID-19 pandemic. In this study, we use bead-based multiplex assays to measure IgG and IgA antibodies and IgG avidity to five SARS-CoV-2 antigens (Spike (S), receptor-binding domain (RBD), Nucleocapsid (N), S subunit 2, and Membrane-Envelope fusion (ME)). These assays were performed in several cohorts of healthcare workers and nursing home residents, who were followed for up to eleven months after SARS-CoV-2 infection or up to six months after vaccination. Our results show distinct kinetic patterns of antibody quantity (IgG and IgA) and avidity. While IgG and IgA antibody levels waned over time, with IgA antibody levels waning more rapidly, avidity increased with time after infection or vaccination. These contrasting kinetic patterns allow for the estimation of time since previous SARS-CoV-2 infection. Including avidity measurements in addition to antibody levels in a classification algorithm for estimating time since infection led to a substantial improvement in accuracy, from 62% to 78%. The inclusion of antibody avidity in panels of serological assays can yield valuable information for improving serosurveillance during SARS-CoV-2 epidemics.

Trial registration: ClinicalTrials.gov NCT04325646 NCT04262921 NCT04441684 NCT04750720.

Keywords: SARS-CoV-2; antibody; avidity; kinetics; multiplex; serology; time since infection.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
IgG antibody kinetics following SARS-CoV-2 infection or vaccination with BNT162b2. IgG antibodies to five SARS-CoV-2 antigens were measured in serum samples using a bead-based multiplex Luminex assay. (First row) Healthcare workers from hospitals in Strasbourg and Paris were followed longitudinally after PCR-confirmed SARS-CoV-2 infection. (Middle row) Healthcare workers from a hospital in Orléans were followed longitudinally after receiving two doses of Pfizer BNT162b2 vaccine. (Bottom row) Residents of a nursing home in Dublin were followed after receiving two doses of Pfizer BNT162b2 vaccine. Individuals with “history of past infection” correspond to individuals with recorded SARS-CoV-2 infection before vaccination and are represented with blue dots. Individuals with no history of past infection are in green. Time is denoted as weeks post-vaccination. Thicker dots represent the median of each group. Black arrows indicate the date of the second vaccine injection.
Figure 2
Figure 2
Kinetics of IgG avidity following SARS-CoV-2 infection or vaccination with BNT162b2. IgG avidity to five SARS-CoV-2 antigens was measured in serum samples using a bead-based multiplex Luminex assay. (First row) Healthcare workers from hospitals in Strasbourg and Paris were followed longitudinally following PCR-confirmed SARS-CoV-2 infection. (Middle row) Healthcare workers from a hospital in Orléans were followed longitudinally after receiving two doses of Pfizer BNT162b2 vaccine. (Bottom row) Residents of a nursing home in Dublin were followed after receiving two doses of Pfizer BNT162b2 vaccine. Individuals with “history of past infection” correspond to individuals with recorded SARS-CoV-2 infection before vaccination and are represented with blue dots. Individuals with no history of past infection are in green. Time is denoted as weeks post-vaccination. Thicker dots represent the median of each group. Black arrows indicate the date of the second vaccine injection. The avidity indexes of anti-Nucleocapsid and anti-Membrane-Envelope IgG are not shown for unvaccinated individuals, as well as data points for anti-spike (whole spike, RBD and S2) IgG of nursing home residents with no prior history of infection before vaccination.
Figure 3
Figure 3
Serological markers of time since infection. Anti-SARS-CoV-2 IgG levels and avidity were measured in samples from individuals with recent (within the previous 3 months, red) and older (6–9 months ago, blue) naturally acquired SARS-CoV-2 infection.
Figure 4
Figure 4
Predictions of time since infection without (a) and with (b) avidity measurements. Predictions are derived from random forest regression models, with point estimates in blue and 95% uncertainty intervals as vertical bars. (a) Predictions without avidity measurements from a random forest model with 6 biomarkers: NP IgA, S IgA, NP IgG, S2 IgA, RBD IgA and S2 IgG. (b) Predictions with avidity measurements from a random forest model with 6 biomarkers: NP avidity, NP IgA, NP IgG, S avidity, RBD avidity and S2 avidity.

References

    1. Wheatley A.K., Juno J.A., Wang J.J., Selva K.J., Reynaldi A., Tan H.-X., Lee W.S., Wragg K.M., Kelly H.G., Esterbauer R., et al. Evolution of Immune Responses to SARS-CoV-2 in Mild-Moderate COVID-19. Nat. Commun. 2021;12:1162. doi: 10.1038/s41467-021-21444-5.
    1. Gallais F., Gantner P., Bruel T., Velay A., Planas D., Wendling M.-J., Bayer S., Solis M., Laugel E., Reix N., et al. Evolution of Antibody Responses up to 13 Months after SARS-CoV-2 Infection and Risk of Reinfection. EBio Med. 2021;71:103561. doi: 10.1016/j.ebiom.2021.103561.
    1. Pelleau S., Woudenberg T., Rosado J., Donnadieu F., Garcia L., Obadia T., Gardais S., Elgharbawy Y., Velay A., Gonzalez M., et al. Kinetics of the Severe Acute Respiratory Syndrome Coronavirus 2 Antibody Response and Serological Estimation of Time Since Infection. J. Infect. Dis. 2021;224:1489–1499. doi: 10.1093/infdis/jiab375.
    1. Slifka M.K., Antia R., Whitmire J.K., Ahmed R. Humoral Immunity Due to Long-Lived Plasma Cells. Immunity. 1998;8:363–372. doi: 10.1016/S1074-7613(00)80541-5.
    1. Tang F., Quan Y., Xin Z.-T., Wrammert J., Ma M.-J., Lv H., Wang T.-B., Yang H., Richardus J.H., Liu W., et al. Lack of Peripheral Memory B Cell Responses in Recovered Patients with Severe Acute Respiratory Syndrome: A Six-Year Follow-up Study. J. Immunol. 2011;186:7264–7268. doi: 10.4049/jimmunol.0903490.
    1. Tas J.M.J., Mesin L., Pasqual G., Targ S., Jacobsen J.T., Mano Y.M., Chen C.S., Weill J.-C., Reynaud C.-A., Browne E.P., et al. Visualizing Antibody Affinity Maturation in Germinal Centers. Science. 2016;351:1048–1054. doi: 10.1126/science.aad3439.
    1. Shlomchik M.J., Weisel F. Germinal Center Selection and the Development of Memory B and Plasma Cells. Immunol. Rev. 2012;247:52–63. doi: 10.1111/j.1600-065X.2012.01124.x.
    1. Bergeri I., Whelan M., Ware H., Subissi L., Nardone A., Lewis H.C., Li Z., Ma X., Valenciano M., Cheng B., et al. Global Epidemiology of SARS-CoV-2 Infection: A Systematic Review and Meta-Analysis of Standardized Population-Based Seroprevalence Studies, Jan 2020-Dec 2021. medRxiv. 2022 doi: 10.1101/2021.12.14.21267791.
    1. Ainsworth M., Andersson M., Auckland K., Baillie J.K., Barnes E., Beer S., Beveridge A., Bibi S., Blackwell L., Borak M., et al. Performance Characteristics of Five Immunoassays for SARS-CoV-2: A Head-to-Head Benchmark Comparison. Lancet Infect. Dis. 2020;20:1390–1400. doi: 10.1016/S1473-3099(20)30634-4.
    1. Yang Y., Yang M., Peng Y., Liang Y., Wei J., Xing L., Guo L., Li X., Li J., Wang J., et al. Longitudinal Analysis of Antibody Dynamics in COVID-19 Convalescents Reveals Neutralizing Responses up to 16 Months after Infection. Nat. Microbiol. 2022;7:423–433. doi: 10.1038/s41564-021-01051-2.
    1. Drouot L., Hantz S., Jouen F., Velay A., Lamia B., Veber B., Sibilia J., Lotellier M., Candon S., Alain S., et al. Evaluation of Humoral Immunity to SARS-CoV-2: Diagnostic Value of a New Multiplex Addressable Laser Bead Immunoassay. Front. Microbiol. 2020;11:603931. doi: 10.3389/fmicb.2020.603931.
    1. Guarino C., Larson E., Babasyan S., Rollins A., Joshi L.R., Laverack M., Parrilla L., Plocharczyk E., Diel D.G., Wagner B. Development of a Quantitative COVID-19 Multiplex Assay and Its Use for Serological Surveillance in a Low SARS-CoV-2 Incidence Community. PLoS ONE. 2022;17:e0262868. doi: 10.1371/journal.pone.0262868.
    1. Brochot E., Souplet V., Follet P., Ponthieu P., Olivier C., Even G., Audebert C., Malbec R. A Multiplex Serological Assay for the Characterization of IgG Immune Response to SARS-CoV-2. PLoS ONE. 2022;17:e0262311. doi: 10.1371/journal.pone.0262311.
    1. Li F.F., Liu A., Gibbs E., Tanunliong G., Marquez A.C., Gantt S., Frykman H., Krajden M., Morshed M., Prystajecky N.A., et al. A Novel Multiplex Electrochemiluminescent Immunoassay for Detection and Quantification of Anti-SARS-CoV-2 IgG and Anti-Seasonal Endemic Human Coronavirus IgG. J. Clin. Virol. 2022;146:105050. doi: 10.1016/j.jcv.2021.105050.
    1. Chawla A., Murphy G., Donnelly C., Booth C.L., Johnson M., Parry J.V., Phillips A., Geretti A.M. Human Immunodeficiency Virus (HIV) Antibody Avidity Testing To Identify Recent Infection in Newly Diagnosed HIV Type 1 (HIV-1)-Seropositive Persons Infected with Diverse HIV-1 Subtypes. J. Clin. Microbiol. 2007;45:415–420. doi: 10.1128/JCM.01879-06.
    1. Prince H.E., Lapé-Nixon M. Role of Cytomegalovirus (CMV) IgG Avidity Testing in Diagnosing Primary CMV Infection during Pregnancy. Clin. Vaccine Immunol. 2014;21:1377–1384. doi: 10.1128/CVI.00487-14.
    1. Agbede O.O., Adeyemi O.O., Olatinwo A.W.O. Significance of IgG-Avidity in Antenatal Rubella Diagnosis. J. Fam. Reprod. Health. 2013;7:131–137.
    1. Mercader S., Garcia P., Bellini W.J. Measles Virus IgG Avidity Assay for Use in Classification of Measles Vaccine Failure in Measles Elimination Settings. Clin. Vaccine Immunol. 2012;19:1810–1817. doi: 10.1128/CVI.00406-12.
    1. Sowers S.B., Rota J.S., Hickman C.J., Mercader S., Redd S., McNall R.J., Williams N., McGrew M., Walls M.L., Rota P.A., et al. High Concentrations of Measles Neutralizing Antibodies and High-Avidity Measles IgG Accurately Identify Measles Reinfection Cases. Clin. Vaccine Immunol. 2016;23:707–716. doi: 10.1128/CVI.00268-16.
    1. Grzelak L., Velay A., Madec Y., Gallais F., Staropoli I., Schmidt-Mutter C., Wendling M.-J., Meyer N., Planchais C., Rey D., et al. Sex Differences in the Evolution of Neutralizing Antibodies to Severe Acute Respiratory Syndrome Coronavirus 2. J. Infect. Dis. 2021;224:983–988. doi: 10.1093/infdis/jiab127.
    1. Dyer A.H., Noonan C., McElheron M., Batten I., Reddy C., Connolly E., Pierpoint R., Murray C., Leonard A., Higgins C., et al. Previous SARS-CoV-2 Infection, Age, and Frailty Are Associated With 6-Month Vaccine-Induced Anti-Spike Antibody Titer in Nursing Home Residents. J. Am. Med. Dir. Assoc. 2022;23:434–439. doi: 10.1016/j.jamda.2021.12.001.
    1. Liaw A., Wiener M. Classification and Regression by RandomForest. Comput. Sci. 2007;2:18–22.
    1. Koerber N., Priller A., Yazici S., Bauer T., Cheng C.-C., Mijočević H., Wintersteller H., Jeske S., Vogel E., Feuerherd M., et al. Dynamics of Spike-and Nucleocapsid Specific Immunity during Long-Term Follow-up and Vaccination of SARS-CoV-2 Convalescents. Nat. Commun. 2022;13:153. doi: 10.1038/s41467-021-27649-y.
    1. Li M., Liu J., Lu R., Zhang Y., Du M., Xing M., Wu Z., Kong X., Zhu Y., Zhou X., et al. Longitudinal Immune Profiling Reveals Dominant Epitopes Mediating Long-Term Humoral Immunity in COVID-19-Convalescent Individuals. J. Allergy Clin. Immunol. 2022;149:1225–1241. doi: 10.1016/j.jaci.2022.01.005.
    1. Kurano M., Morita Y., Nakano Y., Yokoyama R., Shimura T., Qian C., Xia F., He F., Zheng L., Ohmiya H., et al. Response Kinetics of Different Classes of Antibodies to SARS-CoV2 Infection in the Japanese Population: The IgA and IgG Titers Increased Earlier than the IgM Titers. Int. Immunopharmacol. 2022;103:108491. doi: 10.1016/j.intimp.2021.108491.
    1. Feng S., Phillips D.J., White T., Sayal H., Aley P.K., Bibi S., Dold C., Fuskova M., Gilbert S.C., Hirsch I., et al. Correlates of Protection against Symptomatic and Asymptomatic SARS-CoV-2 Infection. Nat. Med. 2021;27:2032–2040. doi: 10.1038/s41591-021-01540-1.
    1. Gilbert P.B., Montefiori D.C., McDermott A.B., Fong Y., Benkeser D., Deng W., Zhou H., Houchens C.R., Martins K., Jayashankar L., et al. Immune Correlates Analysis of the MRNA-1273 COVID-19 Vaccine Efficacy Clinical Trial. Science. 2022;375:43–50. doi: 10.1126/science.abm3425.
    1. Khoury D.S., Cromer D., Reynaldi A., Schlub T.E., Wheatley A.K., Juno J.A., Subbarao K., Kent S.J., Triccas J.A., Davenport M.P. Neutralizing Antibody Levels Are Highly Predictive of Immune Protection from Symptomatic SARS-CoV-2 Infection. Nat. Med. 2021;27:1205–1211. doi: 10.1038/s41591-021-01377-8.
    1. Bauer G. The Potential Significance of High Avidity Immunoglobulin G (IgG) for Protective Immunity towards SARS-CoV-2. Int. J. Infect. Dis. 2021;106:61–64. doi: 10.1016/j.ijid.2021.01.061.
    1. Dobaño C., Sanz H., Sorgho H., Dosoo D., Mpina M., Ubillos I., Aguilar R., Ford T., Díez-Padrisa N., Williams N.A., et al. Concentration and Avidity of Antibodies to Different Circumsporozoite Epitopes Correlate with RTS,S/AS01E Malaria Vaccine Efficacy. Nat. Commun. 2019;10:2174. doi: 10.1038/s41467-019-10195-z.
    1. Usinger W.R., Lucas A.H. Avidity as a Determinant of the Protective Efficacy of Human Antibodies to Pneumococcal Capsular Polysaccharides. Infect. Immun. 1999;67:2366–2370. doi: 10.1128/IAI.67.5.2366-2370.1999.
    1. Tauzin A., Gendron-Lepage G., Nayrac M., Anand S.P., Bourassa C., Medjahed H., Goyette G., Dubé M., Bazin R., Kaufmann D.E., et al. Evolution of Anti-RBD IgG Avidity Following SARS-CoV-2 Infection. Viruses. 2022;14:532. doi: 10.3390/v14030532.
    1. Glück V., Tydykov L., Mader A.-L., Warda A.-S., Bertok M., Weidlich T., Gottwald C., Köstler J., Salzberger B., Wagner R., et al. Humoral Immunity in Dually Vaccinated SARS-CoV-2-Naïve Individuals and in Booster-Vaccinated COVID-19-Convalescent Subjects. Infection. 2022 doi: 10.1007/s15010-022-01817-8.
    1. Koehler M., Ray A., Moreira R.A., Juniku B., Poma A.B., Alsteens D. Molecular Insights into Receptor Binding Energetics and Neutralization of SARS-CoV-2 Variants. Nat. Commun. 2021;12:6977. doi: 10.1038/s41467-021-27325-1.

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