Disclaimer: Early release articles are not considered as final versions. Any changes will be reflected in the online version in the month the article is officially released.
Volume 27, Number 8—August 2021
Delayed Antibody and T-Cell Response to BNT162b2 Vaccination in the Elderly, Germany
We detected delayed and reduced antibody and T-cell responses after BNT162b2 vaccination in 71 elderly persons (median age 81 years) compared with 123 healthcare workers (median age 34 years) in Germany. These data emphasize that nonpharmaceutical interventions for coronavirus disease remain crucial and that additional immunizations for the elderly might become necessary.
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has led to an urgent need for vaccines, particularly among persons at high risk for severe disease and death, such as the elderly (1). Efficacy against severe coronavirus disease (COVID-19) of mRNA vaccine BNT162b2 (Pfizer-BioNTech, https://www.pfizer.com) is reported to be >90% starting 7 days after the second vaccination; robust antibody and T-cell response has been demonstrated consistently across age groups (2–4). However, only 4.3% of participants in the BNT162b2 efficacy trial were >75 years of age (4). Given the elderly generally have weaker immune responses after vaccination, more detailed investigation is necessary (4,5).
In a prospective observational cohort study, we investigated SARS-CoV-2–specific antibodies, maturation of IgG avidity, and interferon-γ (IFN-γ) release of SARS-CoV-2–specific T cells in 2 cohorts of young and elderly BNT162b2-vaccinated persons (Table). Participants were recruited from 2 studies conducted at Charité–Universitätsmedizin Berlin, both conducted in accordance with the Declaration of Helsinki and Good Clinical Practice (https://www.ema.europa.eu/en/documents/scientific-guideline/ich-e-6-r2-guideline-good-clinical-practice-step-5_en.pdf) and approved by the local ethics committee (EA4/244/20 and EA4/245/20)
The first cohort consisted of 123 healthcare workers; median age was 34 (interquartile range [IQR] 20–64) years. The second cohort consisted of 71 elderly residents of an assisted living facility; median age was 81 (IQR 70–96) years. Blood samples were taken before the first vaccination (week 0), just before the second vaccination (week 3), and 4 weeks after the second vaccination (week 7). To discriminate between vaccine-induced antibody response and convalescent SARS-CoV-2 infection, we used the SeraSpot Anti-SARS-CoV-2 IgG microarray-based immunoassay including nucleocapsid and spike as antigens (Seramun Diagnostica GmbH, https://www.seramun.com) (Appendix). Ten of 123 healthcare workers and 1 of 71 elderly participants showed reactive anti-nucleocapsid or anti-spike IgG before the first vaccination and were excluded from further analyses.
At week 3, in the younger cohort, 93/107 (86.9%, 95% CI 79.2%–92.0%) participants showed reactive SARS-CoV-2 receptor-binding domain (RBD) IgG, compared with only 16/52 elderly participants (30.8%, 95% CI 19.9%–44.3%). At week 7, the antibody response rate had increased in both cohorts, to 112/113 in younger participants (99.1%, 95% CI 95.2%–100.0%) and 64/70 in the elderly cohort (91.4%, 95% CI 82.5%–96.0%) (Figure, panel A; Appendix Table). The comparison of SARS-CoV-2 RBD IgG levels demonstrated a significant difference in the 2 cohorts at both week 3 (p<0.0001) and week 7 (p = 0.0003) (Appendix Table), indicating a substantial delay and overall reduced antibody response in elderly participants. We observed similar kinetics and differences between cohorts for antibody responses to 2 further SARS-CoV-2 spike antigens: the S1 subdomain and the full spike protein (Appendix Table, Figure).
We further confirmed the delayed and reduced antibody response in the elderly by measurement of the functional neutralization capacity using the surrogate virus neutralization test (sVNT) cPass (medac GmbH, https://international.medac.de) (Appendix) (6). At week 3, only 24/52 elderly participants (46.2%, 95% CI 33.3%–59.5%) had neutralizing capacity in serum, compared with 97/107 younger participants (90.7%, 95% CI 83.7%–94.8%; p<0.0001 (Figure). In addition, the median sVNT titer for elderly participants was significantly lower than the young cohort (26.4% [IQR 6.8%–40.9%] vs. 60.2% [IQR 45.0%–76.4%]; p<0.0001) (Appendix Table). Although the neutralizing antibody response rate increased to 63/70 (90.0%, 95% CI 80.8%–95.1%) in elderly participants by week 7, the median sVNT titer remained significantly lower than in the younger cohort (89.6% [IQR 70.9%–95.2%] vs. 96.7% [IQR 95.6%–97.2%]; p<0.0001) (Appendix Table).
To characterize the maturation of IgG avidity in all 16 elderly and 30 randomly selected younger participants who were seroreactive at week 3, we applied a modified SARS-CoV-2 S1 IgG ELISA (Euroimmun, https://www.euroimmun.com) (Appendix Figure 2). The delayed antibody response in the elderly is reflected in results: at week 7, only 8/16 elderly (50.0%, 95% CI 28.0%–72.0%) exhibited high S1 IgG avidity indices (>60) compared with 28/30 young participants (93.3%, 95% CI 78.7%–98.8%) (Figure, panel C). Consequently, the median relative avidity index of IgG was significantly higher in the younger cohort than the elderly cohort (76.2% [IQR 67.6%–82.9%] vs. 59.3% [IQR 55.3%–68.9%]; p = 0.0002) (Figure, panel C).
In addition to antibody responses, we assessed SARS-CoV-2 spike-specific T cell responses by an IFN-γ release assay (IGRA) (Euroimmun) (Appendix) of S1 peptide-stimulated T cells at week 7. The proportion of persons with IGRA results above the defined threshold (Appendix) was significantly lower in the elderly than in younger participants (51.2% [95% CI 36.8%–65.4%] vs. 84.5% [95% CI 74.4%–91.1%]; p = 0.0002). Accordingly, median S1-induced IFN-γ release was significantly decreased in the elderly compared to younger participants (707.3 mIU/mL [IQR 216–1,392] vs. 2184 mIU/mL [IQR 1,274–2,484]; p<0.0001) (Figure, panel D). In contrast, we detected no significant difference in IFN-γ release after mitogen stimulation between the 2 cohorts, indicating no general impairment of IFN-γ responses in the elderly (p = 0.77) (Figure, panel D; Appendix Table).
In summary, vaccination with BNT162b2 induces both arms of adaptive immunity: SARS-CoV-2–specific antibodies and SARS-CoV-2–specific T cells. However, we observed delayed and less robust cellular and humoral immune response among the elderly than among younger adults. A limitation of our study is the lack of data on other COVID-19 vaccines. Furthermore, we cannot exclude that underlying diseases or medications, which are more common in the elderly (Table), might impair the vaccine-induced immune response. For example, patients on dialysis have significantly lower antibody response than vaccinated same-age patients not on dialysis (E. Schrezenmeier et al., unpub. data, http://medrxiv.org/lookup/doi/10.1101/2021.03.31.21254683).
Our data are supported by other real-world observations suggesting a delayed and reduced immunogenicity of BNT162b2 in the elderly (5,7; D.A. Collier et al., unpub. data, http://medrxiv.org/lookup/doi/10.1101/2021.02.03.21251054). In line with our observations for BNT162b2, an effect of age-dependent decrease of immune function, referred to as immunosenescence, is well known and contributes to increased prevalence of infectious disease and vaccine failure in the elderly (8). A lower vaccine-induced immune response to influenza and hepatitis B viruses is well documented (9,10); however, such data are scarce for mRNA vaccines.
Of note, vaccination with 2 doses of BNT162b2 might not fully prevent SARS-CoV-2 outbreaks among elderly persons in congregate settings, such as long-term care facilities, possibly because of delayed and reduced immune response. However, vaccination protects against severe disease (11–13).
Although the immune response of elderly participants 4 weeks after the second dose of BNT162b2 nearly reached the level of younger participants, a small fraction of elderly participants did not demonstrate robust antibody and T-cell response. However, the immunologic correlates of protection remain unknown, and identification of persons with no or incomplete protection after vaccination remains challenging. Therefore, strategies focused solely on vaccination of high-risk groups might be insufficient to protect those at risk for severe disease. For the elderly, vaccination of caregivers and close contacts should be prioritized. Moreover, a booster vaccination, altered vaccine dose, or different COVID-19 vaccines should be considered for the elderly if further evidence demonstrates high rates of breakthrough infections despite 2-dose BNT162b2 vaccination.
These results are particularly relevant for vaccination strategies focused on broad administration of the first dose of a 2-dose vaccine while postponing the second vaccination. This practice might leave a relevant proportion of elderly with comparatively low levels of immunity for a prolonged period, emphasizing the need for nonpharmaceutical interventions, such as mask use and regular testing.
Dr. Schwarz is a postdoctoral researcher in the Institute of Virology, Charité–Universitätsmedizin Berlin, Berlin, Germany. Her research interests include infectious disease surveillance and immunologic testing.
We thank Marie Luisa Schmidt, Patricia Tscheak, Julia Tesch, Johanna Riege, Petra Mackeldanz, Felix Walper, Jörn Ilmo Beheim-Schwarzbach, Tobias Bleicker, Sevda Senaydin, Doris Steuer, André Solarek, Viktoria Schenkel, Ute Gläser, Anne-Sophie Sinnigen, Carolin Rubisch, Nadine Olk, Lisbeth Hasler, Angela Sanchez-Rezza, Paolo Kroneberg, Alexandra Horn, Lara Bardtke, Kai Pohl, Daniel Wendisch, Philipp Georg, Denise Treue, Dana Briesemeister, Jenny Schlesinger, Luisa Kegel, Annelie Richter, Ben Al-Rim, Birgit Maeß, Hana Hastor, Maria Rönnefarth, and Alexander Krannich for excellent assistance and biobanking of samples
Parts of this work were supported by grants from the Berlin Institute of Health (BIH). This study was further supported by the German Ministry of Research through the projects VARIPath (01KI2021) to V.M.C., and NaFoUniMedCovid19-COVIM, FKZ: 01KX2021 to L.E.S., F.K., C.D., and V.M.C., and by the RECOVER project (European Union Horizon 2020 research and innovation program; GA101003589) to C.D. T.C.J. is in part funded through NIAID-NIH CEIRS contract HHSN272201400008C. V.M.C. is a participant in the BIH–Charite Clinician Scientist Program funded by the Charite–Universitätsmedizin Berlin and BIH.
V.M.C. is named together with Euroimmun GmbH on a patent application filed recently regarding SARS-CoV-2 diagnostics via antibody testing.
- Brown AE, Heinsbroek E, Kall MM, Allen H, Beebeejaun K, Blomquist P, et al.; PHE COVID-19 Mortality Working Group. Epidemiology of confirmed COVID-19 deaths in adults, England, March–December 2020. Emerg Infect Dis. 2021;27:1468–71.
- Walsh EE, Frenck RW Jr, Falsey AR, Kitchin N, Absalon J, Gurtman A, et al. Safety and immunogenicity of two RNA-based Covid-19 vaccine candidates. N Engl J Med. 2020;383:2439–50.
- Dagan N, Barda N, Kepten E, Miron O, Perchik S, Katz MA, et al. BNT162b2 mRNA Covid-19 vaccine in a nationwide mass vaccination setting. N Engl J Med. 2021;384:1412–23.
- Polack FP, Thomas SJ, Kitchin N, Absalon J, Gurtman A, Lockhart S, et al.; C4591001 Clinical Trial Group. Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. 2020;383:2603–15.
- Van Praet JT, Vandecasteele S, De Roo A, De Vriese AS, Reynders M. Humoral and cellular immunogenicity of the BNT162b2 mRNA Covid-19 Vaccine in nursing home residents. Clin Infect Dis. 2021;
ciab300; Epub ahead of print.
- Tan CW, Chia WN, Qin X, Liu P, Chen MI-C, Tiu C, et al. A SARS-CoV-2 surrogate virus neutralization test based on antibody-mediated blockage of ACE2-spike protein-protein interaction. Nat Biotechnol. 2020;38:1073–8.
- Müller L, Andrée M, Moskorz W, Drexler I, Walotka L, Grothmann R, et al. Age-dependent immune response to the Biontech/Pfizer BNT162b2 COVID-19 vaccination. Clin Infect Dis. 2021;
ciab381; Epub ahead of print.
- Crooke SN, Ovsyannikova IG, Poland GA, Kennedy RB. Immunosenescence and human vaccine immune responses. Immun Ageing. 2019;16:25.
- Fisman DN, Agrawal D, Leder K. The effect of age on immunologic response to recombinant hepatitis B vaccine: a meta-analysis. Clin Infect Dis. 2002;35:1368–75.
- McElhaney JE, Verschoor CP, Andrew MK, Haynes L, Kuchel GA, Pawelec G. The immune response to influenza in older humans: beyond immune senescence. Immun Ageing. 2020;17:10.
- Cavanaugh AM, Fortier S, Lewis P, Arora V, Johnson M, George K, et al. COVID-19 outbreak associated with a SARS-CoV-2 R.1 lineage variant in a skilled nursing facility after vaccination program—Kentucky, March 2021. MMWR Morb Mortal Wkly Rep. 2021;70:639–43.
- Teran RA, Walblay KA, Shane EL, Xydis S, Gretsch S, Gagner A, et al. Postvaccination SARS-CoV-2 infections among skilled nursing facility residents and staff members—Chicago, Illinois, December 2020–March 2021. MMWR Morb Mortal Wkly Rep. 2021;70:632–8.
- Tober-Lau P, Schwarz T, Hillus D, Spieckermann J, Helbig ET, Lippert LJ, et al. Outbreak of SARS-CoV-2 B.1.1.7 lineage after vaccination in long-term care facility, Germany, February–March 2021.[ [Epub ahead of print]. Emerg Infect Dis. 2021; (
Suggested citation for this article: Schwarz T, Tober-Lau P, Hillus D, Helbig ET, Lippert LJ, Thibeault C, et al. Delayed antibody and T-cell response to BNT162b2 vaccination in the elderly, Germany. Emerg Infect Dis. 2021 Aug [date cited]. https://doi.org/10.3201/eid2708.211145
Original Publication Date: June 08, 2021
1These authors contributed equally to this article.
2These senior authors contributed equally to this article.