Advertisement

SARS-CoV-2 antibody kinetics eight months from COVID-19 onset: Persistence of spike antibodies but loss of neutralizing antibodies in 24% of convalescent plasma donors

      Highlights

      • Determining immune response against SARS-CoV-2 is essential for vaccine strategies.
      • 148 convalescent donors were evaluated at 8.3 months post initial COVID-19 symptoms.
      • Spike antibodies showed better persistence than nucleocapsid antibodies.
      • Neutralizing antibodies were detected in 76% of patients at the last time point.
      • Older age and hospitalization were associated with higher antibody levels.

      Abstract

      Elucidating the characteristics of human immune response against SARS-CoV-2 is of high priority and relevant for determining vaccine strategies. We report the results of a follow-up evaluation of anti-SARS-CoV-2 antibodies in 148 convalescent plasma donors who participated in a phase 2 study at a median of 8.3 months (range 6.8–10.5 months) post first symptom onset. Monitoring responses over time, we found contraction of antibody responses for all four antigens tested, with Spike antibodies showing higher persistence than Nucleocapsid antibodies. A piecewise linear random-effects multivariate regression analysis showed a bi-phasic antibody decay with a more pronounced decrease during the first 6 months post symptoms onset by analysis of two intervals. Interestingly, antibodies to Spike showed better longevity whereas their neutralization ability contracted faster. As a result, neutralizing antibodies were detected in only 76% of patients at the last time point. In a multivariate analysis, older age and hospitalization were independently associated with higher Spike, Spike-RBD, Nucleocapsid, N-RBD antibodies and neutralizing antibody levels. Results on persistence and neutralizing ability of anti-SARS-CoV-2 antibodies, especially against Spike and Spike-RBD, should be considered in the design of future vaccination strategies.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to European Journal of Internal Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Widge A.T.
        • Rouphael N.G.
        • Jackson L.A.
        • Anderson E.J.
        • Roberts P.C.
        • Makhene M.
        • et al.
        Durability of responses after SARS-CoV-2 mRNA-1273 vaccination.
        N Engl J Med. 2021; 384: 80-82
        • Anderson E.J.
        • Rouphael N.G.
        • Widge A.T.
        • Jackson L.A.
        • Roberts P.C.
        • Makhene M.
        • et al.
        Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults.
        N Engl J Med. 2020; 383: 2427-2438
        • Gavriatopoulou M.
        • Ntanasis-Stathopoulos I.
        • Korompoki E.
        • Fotiou D.
        • Migkou M.
        • Tzanninis I.G.
        • et al.
        Emerging treatment strategies for COVID-19 infection.
        Clin Exp Med. 2021; 21: 167-179
        • Psaltopoulou T.
        • Sergentanis T.N.
        • Pappa V.
        • Politou M.
        • Terpos E.
        • Tsiodras S.
        • et al.
        The emerging role of convalescent plasma in the treatment of COVID-19.
        Hemasphere. 2020; 4: e409
        • Wu F.
        • Liu M.
        • Wang A.
        • Lu L.
        • Wang Q.
        • Gu C.
        • et al.
        Evaluating the association of clinical characteristics with neutralizing antibody levels in patients who have recovered from mild COVID-19 in Shanghai, China..
        JAMA Intern Med. 2020; 180: 1356-1362
        • Hashem A.M.
        • Algaissi A.
        • Almahboub S.A.
        • Alfaleh M.A.
        • Abujamel T.S.
        • Alamri S.S.
        • et al.
        Early humoral response correlates with disease severity and outcomes in COVID-19 patients.
        Viruses. 2020; 12: 1390
        • Roltgen K.
        • Powell A.E.
        • Wirz O.F.
        • Stevens B.A.
        • Hogan C.A.
        • Najeeb J.
        • et al.
        Defining the features and duration of antibody responses to SARS-CoV-2 infection associated with disease severity and outcome.
        Sci Immunol. 2020; 5: eabe0240
        • Li K.
        • Huang B.
        • Wu M.
        • Zhong A.
        • Li L.
        • Cai Y.
        • et al.
        Dynamic changes in anti-SARS-CoV-2 antibodies during SARS-CoV-2 infection and recovery from COVID-19.
        Nat Commun. 2020; 11: 6044
        • Terpos E.
        • Politou M.
        • Sergentanis T.N.
        • Mentis A.
        • Rosati M.
        • Stellas D.
        • et al.
        Anti-SARS-CoV-2 antibody responses in convalescent plasma donors are increased in hospitalized patients; subanalyses of a phase 2 clinical study.
        Microorganisms. 2020; 8: 1885
        • Bajema K.L.
        • Wiegand R.E.
        • Cuffe K.
        • Patel S.V.
        • Iachan R.
        • Lim T.
        • et al.
        Estimated SARS-CoV-2 seroprevalence in the US as of September 2020.
        JAMA Intern Med. 2021; 181: 450-460
        • Gurgel R.Q.
        • de Sa L.C.
        • Souza D.R.V.
        • Martins A.F.
        • Matos I.L.S.
        • Lima A.G.A.
        • et al.
        SARS-CoV-2 has been circulating in northeastern Brazil since February 2020: evidence for antibody detection in asymptomatic patients.
        J Infect. 2021; 82: 186-230
        • Tsitsilonis O.E.
        • Paraskevis D.
        • Lianidou E.
        • Pierros V.
        • Akalestos A.
        • Kastritis E.
        • et al.
        Seroprevalence of antibodies against SARS-CoV-2 among the personnel and students of the National and Kapodistrian University of Athens, Greece: a preliminary report.
        Life (Basel). 2020; 10: 214
        • Trieu M.C.
        • Bansal A.
        • Madsen A.
        • Zhou F.
        • Saevik M.
        • Vahokoski J.
        • et al.
        SARS-CoV-2-specific neutralizing antibody responses in Norwegian Health Care workers after the first wave of COVID-19 pandemic: a prospective cohort study.
        J Infect Dis. 2021; 223: 589-599
        • Brochot E.
        • Demey B.
        • Touze A.
        • Belouzard S.
        • Dubuisson J.
        • Schmit J.L.
        • et al.
        Anti-spike, anti-nucleocapsid and neutralizing antibodies in SARS-CoV-2 inpatients and asymptomatic individuals.
        Front Microbiol. 2020; 11584251
        • Wellinghausen N.
        • Plonne D.
        • Voss M.
        • Ivanova R.
        • Frodl R.
        • Deininger S.
        SARS-CoV-2-IgG response is different in COVID-19 outpatients and asymptomatic contact persons.
        J Clin Virol. 2020; 130104542
        • Long Q.X.
        • Tang X.J.
        • Shi Q.L.
        • Li Q.
        • Deng H.J.
        • Yuan J.
        • et al.
        Clinical and immunological assessment of asymptomatic SARS-CoV-2 infections.
        Nat Med. 2020; 26: 1200-1204
        • Kwon J.S.
        • Kim J.Y.
        • Kim M.C.
        • Park S.Y.
        • Kim B.N.
        • Bae S.
        • et al.
        Factors of severity in patients with COVID-19: cytokine/chemokine concentrations, viral load, and antibody responses.
        Am J Trop Med Hyg. 2020; 103: 2412-2418
        • Ibarrondo F.J.
        • Fulcher J.A.
        • Goodman-Meza D.
        • Elliott J.
        • Hofmann C.
        • Hausner M.A.
        • et al.
        Rapid decay of anti-SARS-CoV-2 antibodies in persons with mild Covid-19.
        N Engl J Med. 2020; 383: 1085-1087
        • Terpos E.
        • Mentis A.
        • Dimopoulos M.A.
        Loss of anti-SARS-CoV-2 antibodies in mild Covid-19.
        N Engl J Med. 2020; 383: 1695
        • Kutsuna S.
        • Asai Y.
        • Matsunaga A.
        Loss of anti-SARS-CoV-2 antibodies in mild Covid-19.
        N Engl J Med. 2020; 383: 1695-1696
        • Gudbjartsson D.F.
        • Norddahl G.L.
        • Melsted P.
        • Gunnarsdottir K.
        • Holm H.
        • Eythorsson E.
        • et al.
        Humoral immune response to SARS-CoV-2 in Iceland.
        N Engl J Med. 2020; 383: 1724-1734
        • Bolke E.
        • Matuschek C.
        • Fischer J.C.
        Loss of anti-SARS-CoV-2 antibodies in mild Covid-19.
        N Engl J Med. 2020; 383: 1694-1695
        • Colson P.
        • Finaud M.
        • Levy N.
        • Lagier J.C.
        • Raoult D.
        Evidence of SARS-CoV-2 re-infection with a different genotype.
        J Infect. 2021; 82: 84-123
        • Tillett R.L.
        • Sevinsky J.R.
        • Hartley P.D.
        • Kerwin H.
        • Crawford N.
        • Gorzalski A.
        • et al.
        Genomic evidence for reinfection with SARS-CoV-2: a case study.
        Lancet Infect Dis. 2021; 21: 52-58
        • Hall V.
        • Foulkes S.
        • Charlett A.
        • Atti A.
        • Monk E.J.M.
        • Simmons R.
        • et al.
        SARS-CoV-2 infection rates of antibody-positive compared with antibody-negative health-care workers in England: a large, multicentre, prospective cohort study (SIREN).
        Lancet. 2021; 397 (2020110920228551): 1459-1469
        • Robbiani D.
        • Gaebler C.
        • Muecksch F.
        • Lorenzi J.
        • Wang Z.
        • Cho A.
        • et al.
        Convergent antibody responses to SARS-CoV-2 in convalescent individuals.
        Nature. 2020; 584: 437-442
        • Bates D.M.
        • Chambers J.M
        Nonlinear models. Chapter 10 of statistical models.
        Wadsworth & Brooks/Cole, 1992 (in S eds J. M. Chambers and T. J. Hastie)
        • Bates D.M.
        • Watts D.G.
        Nonlinear regression analysis and its applications.
        Wiley, 1988
        • Dan J.M.
        • Mateus J.
        • Kato Y.
        • Hastie K.M.
        • Yu E.D.
        • Faliti C.E.
        • et al.
        Immunological memory to SARS-CoV-2 assessed for up to 8 months after infection.
        Science. 2021; 371: eabf4063
        • Grzelak L.
        • Velay A.
        • Madec Y.
        • Gallais F.
        • Staropoli I.
        • Schmidt-Mutter C.
        • et al.
        Sex differences in the evolution of neutralizing antibodies to SARS-CoV-2.
        J Infect Dis. 2021; https://doi.org/10.1093/infdis/jiab127
        • Klein S.L.
        • Pekosz A.
        • Park H.S.
        • Ursin R.L.
        • Shapiro J.R.
        • Benner S.E.
        • et al.
        Sex, age, and hospitalization drive antibody responses in a COVID-19 convalescent plasma donor population.
        J Clin Invest. 2020; 130: 6141-6150
        • Mehew J.
        • Johnson R.
        • Roberts D.
        • Harvala H.
        Convalescent plasma for COVID-19: male gender, older age and hospitalisation associated with high neutralising antibody levels, England, 22 April to 12 May 2020.
        Euro Surveill. 2020; 25: 2001754
        • Muecksch F.
        • Wise H.
        • Batchelor B.
        • Squires M.
        • Semple E.
        • Richardson C.
        • et al.
        Longitudinal serological analysis and neutralizing antibody levels in Coronavirus Disease 2019 convalescent patients.
        J Infect Dis. 2021; 223: 389-398
        • Beaudoin-Bussieres G.
        • Laumaea A.
        • Anand S.P.
        • Prevost J.
        • Gasser R.
        • Goyette G.
        • et al.
        Decline of humoral responses against SARS-CoV-2 spike in convalescent individuals.
        mBio. 2020; 11: e02590-20
        • Perreault J.
        • Tremblay T.
        • Fournier M.J.
        • Drouin M.
        • Beaudoin-Bussieres G.
        • Prevost J.
        • et al.
        Waning of SARS-CoV-2 RBD antibodies in longitudinal convalescent plasma samples within 4 months after symptom onset.
        Blood. 2020; 136: 2588-2591
        • Figueiredo-Campos P.
        • Blankenhaus B.
        • Mota C.
        • Gomes A.
        • Serrano M.
        • Ariotti S.
        • et al.
        Seroprevalence of anti-SARS-CoV-2 antibodies in COVID-19 patients and healthy volunteers up to 6 months post disease onset.
        Eur J Immunol. 2020; 50: 2025-2040
        • Gaebler C.
        • Wang Z.
        • Lorenzi J.C.C.
        • Muecksch F.
        • Finkin S.
        • Tokuyama M.
        • et al.
        Evolution of antibody immunity to SARS-CoV-2.
        Nature. 2021; 591: 639-644
        • Tan Y.
        • Liu F.
        • Xu X.
        • Ling Y.
        • Huang W.
        • Zhu Z.
        • et al.
        Durability of neutralizing antibodies and T-cell response post SARS-CoV-2 infection.
        Front Med. 2020; 14: 746-751
        • Yang O.O.
        • Ibarrondo F.J.
        Loss of anti-SARS-CoV-2 antibodies in mild Covid-19. Reply.
        N Engl J Med. 2020; 383: 1697-1698
        • Huang A.T.
        • Garcia-Carreras B.
        • Hitchings M.D.T.
        • Yang B.
        • Katzelnick L.C.
        • Rattigan S.M.
        • et al.
        A systematic review of antibody mediated immunity to coronaviruses: kinetics, correlates of protection, and association with severity.
        Nat Commun. 2020; 11: 4704
        • Lin Q.
        • Zhu L.
        • Ni Z.
        • Meng H.
        • You L.
        Duration of serum neutralizing antibodies for SARS-CoV-2: lessons from SARS-CoV infection.
        J Microbiol Immunol Infect. 2020; 53: 821-822
        • Fenwick C.
        • Croxatto A.
        • Coste A.T.
        • Pojer F.
        • Andre C.
        • Pellaton C.
        • et al.
        Changes in SARS-CoV-2 spike versus nucleoprotein antibody responses impact the estimates of infections in population-based seroprevalence studies.
        J Virol. 2021; 95: e01828-20
        • Wajnberg A.
        • Amanat F.
        • Firpo A.
        • Altman D.R.
        • Bailey M.J.
        • Mansour M.
        • et al.
        Robust neutralizing antibodies to SARS-CoV-2 infection persist for months.
        Science. 2020; 370: 1227-1230
        • Crawford K.H.D.
        • Dingens A.S.
        • Eguia R.
        • Wolf C.R.
        • Wilcox N.
        • Logue J.K.
        • et al.
        Dynamics of neutralizing antibody titers in the months after SARS-CoV-2 infection.
        J Infect Dis. 2021; 223: 197-205
        • Sokal A.
        • Chappert P.
        • Barba-Spaeth G.
        • Roeser A.
        • Fourati S.
        • Azzaoui I.
        • et al.
        Maturation and persistence of the anti-SARS-CoV-2 memory B cell response.
        Cell. 2021; 184: 1201-13e14
        • Sherina N.
        • Piralla A.
        • Du L.
        • Wan H.
        • Kumagai-Braesch M.
        • Andrell J.
        • et al.
        Persistence of SARS-CoV-2-specific B and T cell responses in convalescent COVID-19 patients 6-8 months after the infection.
        Med (N Y). 2021; 2: 281-295.e4
        • Cao W.C.
        • Liu W.
        • Zhang P.H.
        • Zhang F.
        • Richardus J.H.
        Disappearance of antibodies to SARS-associated coronavirus after recovery.
        N Engl J Med. 2007; 357: 1162-1163
        • Payne D.C.
        • Iblan I.
        • Rha B.
        • Alqasrawi S.
        • Haddadin A.
        • Al Nsour M.
        • et al.
        Persistence of antibodies against middle east respiratory syndrome coronavirus.
        Emerg Infect Dis. 2016; 22: 1824-1826
        • Hartley G.E.
        • Edwards E.S.J.
        • Aui P.M.
        • Varese N.
        • Stojanovic S.
        • McMahon J.
        • et al.
        Rapid generation of durable B cell memory to SARS-CoV-2 spike and nucleocapsid proteins in COVID-19 and convalescence.
        Science Immunol. 2020; 5: eabf8891
        • Kremsner P.
        • Mann P.
        • Bosch J.
        • Fendel R.
        • Gabor J.J.
        • Kreidenweiss A.
        • et al.
        Phase 1 assessment of the safety and immunogenicity of an mRNA- Lipid nanoparticle vaccine candidate against SARS-CoV-2 in human volunteers.
        medRxiv. 2020; (2020110920228551)
        • Scepanovic P.
        • Alanio C.
        • Hammer C.
        • Hodel F.
        • Bergstedt J.
        • Patin E.
        • et al.
        Human genetic variants and age are the strongest predictors of humoral immune responses to common pathogens and vaccines.
        Genome Med. 2018; 10: 59
        • Qu J.
        • Wu C.
        • Li X.
        • Zhang G.
        • Jiang Z.
        • Li X.
        • et al.
        Profile of immunoglobulin G and IgM antibodies against severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2).
        Clin Infect Dis. 2020; 71: 2255-2258
        • Chen X.
        • Pan Z.
        • Yue S.
        • Yu F.
        • Zhang J.
        • Yang Y.
        • et al.
        Disease severity dictates SARS-CoV-2-specific neutralizing antibody responses in COVID-19.
        Signal Transduct Target Ther. 2020; 5: 180
        • Wang X.
        • Guo X.
        • Xin Q.
        • Pan Y.
        • Hu Y.
        • Li J.
        • et al.
        Neutralizing antibodies responses to SARS-CoV-2 in COVID-19 inpatients and convalescent patients.
        Clin Infect Dis. 2020; 71: 2688-2694
        • Markmann A.J.
        • Giallourou N.
        • Bhowmik D.R.
        • Hou Y.J.
        • Lerner A.
        • Martinez D.R.
        • et al.
        Sex disparities and neutralizing antibody durability to SARS-CoV-2 infection in convalescent individuals.
        medRxiv. 2021;