Evolution of SARS-CoV-2 immune responses in nursing home residents following full dose of the Comirnaty® COVID-19 vaccine
Authors: Estela Giménez, Juan Alberola, Ignacio Torres, Eliseo Albert, María Jesús Alcaraz, Pilar Botija, Paula Amat, María José Remigia, María José Beltrán, Celia Rodado, Dixie Huntley, Beatriz Olea, David Navarro
Journal: Journal of Infection (2021)

Dear Editor, We read with interest the studies published by Tré-Hardy and colleagues 1Tré-Hardy M. Cupaiolo R. Wilmet A. Beukinga I. Blairon L Waning antibodies in SARS-CoV-2 naïve vaccinees: results of a three-month interim analysis of ongoing immunogenicity and efficacy surveillance of the mRNA-1273 vaccine in healthcare workers.J Infect. 2021; 83: 381-412Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar,2Tré-Hardy M. Cupaiolo R. Wilmet A. Antoine-Moussiaux T. Della Vecchia A. Horeanga A. et al.Six-month interim analysis of ongoing immunogenicity surveillance of the mRNA-1273 vaccine in healthcare workers: a third dose is expected.J Infect. 2021; S0163–4453 (-3): 00433Google Scholar in the Journal of Infection showing a marked and significant decrease in serum SARS-CoV-2-Spike(S) antibody levels in healthcare workers at 3 and 6 months after complete vaccination with the mRNA-1273 vaccine (Spikevax). Real-world experience has shown mRNA COVID-19 vaccines to be effective in reducing incidence of both asymptomatic and symptomatic SARS-CoV-2 infections and related deaths in nursing home residents,3White E.M. Yang X. Blackman C. Feifer R.A. Gravenstein S. Mor V. Incident SARS-CoV-2 infection among mRNA-vaccinated and unvaccinated nursing home residents.N Engl J Med. 2021; 385: 474-476Crossref PubMed Scopus (62) Google Scholar congruent with their ability to elicit robust virus-specific T and B cell immune responses in this population group.4Torres I. Albert E. Giménez E. Alcaraz M.J. Botija P. Amat P. et al.B and T cell immune responses elicited by the Comirnaty COVID-19 vaccine in nursing-home residents.Clin Microbiol Infect. 2021; S1198–743X: 00332-00333Google Scholar,5Salmerón Ríos S. Mas Romero M. Cortés Zamora E.B. Tabernero Sahuquillo M.T. Romero Rizos L. Sánchez-Jurado P.M. et al.Immunogenicity of the BNT162b2 vaccine in frail or disabled nursing home residents: COVID-A study.J Am Geriatr Soc. 2021; 69: 1441-1447Crossref PubMed Scopus (60) Google Scholar Nevertheless, maintaining seemingly protective immune responses in these individuals over time may be compromised by the concurrence of older age, frailty and co-morbidities. To shed light on this issue, here we assessed SARS-CoV-2-Spike (S)-targeted antibody and functional T cell responses at around 6 months after vaccination with Comirnaty® (Pfizer–BioNTech) in a previously recruited cohort.4Torres I. Albert E. Giménez E. Alcaraz M.J. Botija P. Amat P. et al.B and T cell immune responses elicited by the Comirnaty COVID-19 vaccine in nursing-home residents.Clin Microbiol Infect. 2021; S1198–743X: 00332-00333Google Scholar Out of 53 nursing home residents enrolled in a previous study 4Torres I. Albert E. Giménez E. Alcaraz M.J. Botija P. Amat P. et al.B and T cell immune responses elicited by the Comirnaty COVID-19 vaccine in nursing-home residents.Clin Microbiol Infect. 2021; S1198–743X: 00332-00333Google Scholar with data on B and T cell immunity at a median of 17.5 days (range, 14−35 days) after second vaccine dose (baseline sample), 46 (44 females; median age, 89 years; range, 60−100; Supplementary Table 1) were reassessed (follow-up sample) at a median of 195 days (range, 179−195 days). The remaining 7 patients either died (n = 4; in no case attributable to COVID-19) or lacked the follow-up specimen (n = 3). Blood specimens were collected in sodium heparin tubes (Beckton Dickinson, U.K. Ltd., UK). Informed consent was obtained from participants. The study was approved by the Hospital Clínico Universitario INCLIVA Research Ethics Committee (February 2021). Total antibodies (IgG and IgM) against SARS-CoV-2-S protein receptor binding domain (RBD) and the nucleoprotein (N) were measured by Roche Elecsys® electrochemiluminescence sandwich immunoassays (Roche Diagnostics, Pleasanton, CA, USA). Antibody levels measured by the former assay correlate strongly with neutralizing antibody titers.6Higgins V. Fabros A. Kulasingam V. Quantitative measurement of anti-SARS-CoV-2 antibodies: analytical and clinical evaluation.J Clin Microbiol. 2021; 59 (-20): e03149Crossref PubMed Scopus (101) Google Scholar Cryopreserved plasma (-20 °C) specimens were thawed and assayed in singlets within 15 days after collection. Plasma specimens were diluted (1/10) for antibody quantitation when appropriate. SARS‐CoV‐2‐S-reactive IFNγ‐producing‐CD8+ and CD4+ T cells were enumerated in whole blood by flow cytometry for ICS (BD Fastimmune, BD‐Beckton Dickinson and Company‐Biosciences, San Jose, CA) as previously described.4Torres I. Albert E. Giménez E. Alcaraz M.J. Botija P. Amat P. et al.B and T cell immune responses elicited by the Comirnaty COVID-19 vaccine in nursing-home residents.Clin Microbiol Infect. 2021; S1198–743X: 00332-00333Google Scholar Of the 46 residents, 10 (21.7%) had evidence of SARS-CoV-2 infection at baseline, as determined by both RT-PCR on nasopharyngeal specimens and detection of N-specific antibodies. No additional residents developed N-specific antibodies between sampling times. Data on SARS-CoV-2-RBD antibody levels were available for 45 participants. All 43 residents who tested positive at baseline also displayed detectable responses at follow-up, although overall, antibody levels were found to decrease significantly, by a median of 4.8 fold (range, 1.1−39) [median of 2249 IU/ml at baseline vs. median 307 IU/ml at follow-up, P < 0.001 (Fig. 1A)]. One of the two remaining residents developed SARS-CoV-2-S-specific antibodies (8 IU/ml) between sampling times. Antibodies waning was documented more frequently (P < 0.001) in SARS-CoV-2 naïve (29/35) than in recovered (1/10) residents (Fig. 1B). These observations were not unexpected as they have also been made in other population groups, including younger individuals seemingly with few or no comorbidities, at comparable timeframes 2Tré-Hardy M. Cupaiolo R. Wilmet A. Antoine-Moussiaux T. Della Vecchia A. Horeanga A. et al.Six-month interim analysis of ongoing immunogenicity surveillance of the mRNA-1273 vaccine in healthcare workers: a third dose is expected.J Infect. 2021; S0163–4453 (-3): 00433Google Scholar,7Naaber P. Tserel L. Kangro K. Sepp E. Jürjenson V. Adamson A. et al.Dynamics of antibody response to BNT162b2 vaccine after six months: a longitudinal prospective study.Lancet Reg Health Eur. 2021; (Sep 6)100208Abstract Full Text Full Text PDF PubMed Scopus (386) Google Scholar,8Dimeglio C. Herin F. Miedougé M. Da-Silva I. Porcheron M. Martin-Blondel G. et al.One year later: SARS-CoV-2 immune response and vaccination of healthcare workers post-infection.J Infect. 2021; 83: 381-412Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar after full vaccination with mRNA vaccines. Data on T cell responses were available for 46 participants. Overall, detectable SARS-CoV-2-S IFN-γ T cells (either CD8+, CD4+ or both) were documented in 82.6% (38/46) and 73.9% (34/46) of residents at baseline and follow-up, respectively (P = 0.01). The corresponding figures for SARS-CoV-2-S IFN-γ CD8+ T cells were 72% (33/46) and 52.1% (24/46). As shown in Fig. 2A, 8 of 13 residents testing negative at baseline later acquired detectable responses, albeit at low frequencies (median, 0.08%; range, 0.01−0.21%), whereas SARS-CoV-2-S IFN-γ CD8+ T cells were no longer detectable at follow-up in 16 out of 33 residents who tested positive at baseline. SARS-CoV-2-S IFN-γ CD4+ T cells were detected in 26% (12/46) and 65.2% (30/46) of residents at baseline and follow-up, respectively. Nineteen participants developed CD4+ T cell responses between testing time points (median, 0.1%; range, 0.03–1.14%), whereas one out of 12 with detectable responses at baseline had lost this at follow-up (Fig. 2B). The likelihood of having detectable SARS-CoV-2 IFN-γ CD8+ and CD4+ T at follow-up was higher (P = 0.03 and P = 0.5) in SARS-CoV-2 recovered (8/10 and 7/10, respectively) than in naïve residents (9/36 and 25/36, respectively). For those with detectable responses at both time points, overall, SARS-CoV-2-S IFN-γ CD8+ T cell frequencies decreased significantly (P = 0.001) over time whereas the opposite (P = 0.01) was seen for CD4+ T cells (Fig. 2C). Interestingly, the resident lacking anti-RBD antibodies at follow-up had detectable SARS-CoV-2-S CD4+ T cell responses. In this regard, collectively, the above data suggested that SARS-CoV-2-S IFN-γ CD4+ T cells may develop later than CD8+ T cells in nursing home residents. Supplementary Table 2 shows the combined results for all immunological parameters. No correlation, as evaluated by the Spearman rank test, was found between anti-RBD antibody levels and SARS-CoV-2-S IFN-γ CD4+ (Rho=-0.015; P = 0.94) and CD8+ (Rho:-0.18; P = 0.87) T cells. Limitations of the current study are the relatively small sample size and lack of a control group; regarding the latter, most of the 17 controls included in our previous study 4Torres I. Albert E. Giménez E. Alcaraz M.J. Botija P. Amat P. et al.B and T cell immune responses elicited by the Comirnaty COVID-19 vaccine in nursing-home residents.Clin Microbiol Infect. 2021; S1198–743X: 00332-00333Google Scholar were unfortunately not available for follow-up sampling. Secondly, neutralization assays were not carried out. In summary, our data revealed that a large percentage of nursing home residents displayed detectable SARS-CoV-2-S-reactive antibodies and T cell responses, respectively, by around 6 months after complete vaccination with Comirnaty® COVID-19 vaccine, although these generally declined over time. Whether these mid-term immune responses suffice to prevent COVID-19 remains to be determined. Our data also suggested that a booster (third) dose, which has been proposed for elderly people 9Krause P.R. Fleming T.R. Peto R. Longini I.M. Figueroa J.P. Sterne J.A.C. et al.Considerations in boosting COVID-19 vaccine immune responses.Lancet. 2021; https://doi.org/10.1016/S0140-6736(21)02046-8Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar may be delayed beyond 6 months in fully vaccinated COVID-19 recovered residents. Estela Giménez: Methodology, Validation. Juan Alberola: Methodology, Validation. Ignacio Torres: Methodology, Validation. Eliseo Albert: Methodology, Validation. María Jesús Alcaraz: Methodology, Validation. Pilar Botija: . Paula Amat: Methodology, Validation. María José Remigia: Methodology, Validation. María José Beltrán: . Celia Rodado: . Dixie Huntley: Methodology, Validation. Beatriz Olea: Methodology, Validation. David Navarro: Conceptualization, Supervision. The authors declare no conflicts of interest. We are grateful to all personnel who work at nursing home residences affiliated to the Clínico-Malvarrosa Health Department and at Clinic University Hospital, in particular to those at the Microbiology laboratory, for their commitment in the fight against COVID-19. Ignacio Torres holds a Río Hortega Contract (CM20/00090) from the Carlos III Health Institute. Eliseo Albert holds a Juan Rodés Contract (JR20/00011) from the Carlos III Health Institute. Estela Giménez holds a Juan Rodés Contract (JR18/00053) from the Carlos III Health Institute. This work received no public or private funds. 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