Reduced Magnitude and Durability of Humoral Immune Responses to COVID-19 mRNA Vaccines Among Older Adults

Abstract

Background: The magnitude and durability of immune responses to coronavirus disease 2019 (COVID-19) mRNA vaccines remain incompletely characterized in the elderly.

Methods: Anti-spike receptor-binding domain (RBD) antibodies, angiotensin-converting enzyme 2 (ACE2) competition, and virus neutralizing activities were assessed in plasma from 151 health care workers and older adults (range, 24-98 years of age) 1 month following the first vaccine dose, and 1 and 3 months following the second dose.

Results: Older adults exhibited significantly weaker responses than younger health care workers for all humoral measures evaluated and at all time points tested, except for ACE2 competition activity after 1 vaccine dose. Moreover, older age remained independently associated with weaker responses even after correction for sociodemographic factors, chronic health condition burden, and vaccine-related variables. By 3 months after the second dose, all humoral responses had declined significantly in all participants, and remained significantly lower among older adults, who also displayed reduced binding antibodies and ACE2 competition activity towards the Delta variant.

Conclusions: Humoral responses to COVID-19 mRNA vaccines are significantly weaker in older adults, and antibody-mediated activities in plasma decline universally over time. Older adults may thus remain at elevated risk of infection despite vaccination.

Keywords: COVID-19; antibodies; humoral responses; mRNA vaccine; older adults; viral neutralization.

Figure 1.

Vaccine-induced binding antibody responses to spike are lower in older adults. A, Binding IgG responses to the SARS-CoV-2 spike RBD in plasma, measured by ELISA, following 1 dose of a COVID-19 mRNA vaccine, are shown for health care workers (blue circles) and older adults (orange circles) who were COVID-19 naive at study entry. The third group (N Sero+; grey circles) denotes convalescent participants with anti-N antibodies at study entry. Red bars and whiskers represent median and interquartile range, with group medians shown below. P values computed using the Mann-Whitney U test are shown above each comparison. B, Same data from the COVID-19–naive participants shown in A but plotted by age, and where symbols are colored based on the participants’ number of chronic health conditions, which remained significant in multivariable analyses (Table 2). Statistics were computed using ordinary least-squares regression (red dashed line). C and D, Same as A and B but for responses measured 1 month following 2 doses of mRNA vaccine. Abbreviations: BAU, binding antibody unit; ELISA, enzyme-linked immunosorbent assay; IgG, immunoglobulin G; N, nucleoprotein; RBD, receptor-binding domain; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 2.

Vaccine-induced ACE2 receptor competition activity is weaker in older adults. A, Ability of vaccine-induced plasma antibodies to displace soluble ACE2 receptor from spike RBD, measured by ELISA, following 1 dose of vaccine in COVID-19–naive health care workers (blue circles) and older adults (orange circles), as well as COVID-19–convalescent participants (N Sero+; grey circles). Values represent AU/mL calibrated against an external standard, reported in log₁₀ units. Red bars and whiskers represent median and interquartile range, with group medians shown below. P values computed using the Mann-Whitney U test are shown above each comparison. B, Same data from the COVID-19–naive participants shown in A but plotted by age, and colored by sex, which remained significant in multivariable analyses following 1 dose (Table 2). Statistics were computed using ordinary least-squares regression (red dashed line). C and D, Same as A and B but for responses measured 1 month following 2 doses of mRNA vaccine. Abbreviations: ACE2, angiotensin-converting enzyme 2; AU, arbitrary unit; COVID-19, coronavirus disease 2019; ELISA, enzyme-linked immunosorbent assay; RBD, receptor-binding domain; ULOQ, upper limit of quantification.

Figure 3.

Viral neutralization activity of vaccine-induced antibodies is weaker in older adults. A, Frequency of COVID-19–naive health care workers (blue) and older adults (orange), as well as convalescent participants (N Sero+; black) are shown as histograms. The proportion of participants in each group who displayed neutralizing activity against live SARS-CoV-2 (USA-WA1/2020 strain) in 3/3 wells at a 1:20 or higher plasma dilution is shown in the darkest color, while those displaying borderline activity (defined as neutralization in least 1 well at a 1:20 dilution) is shown in lighter color. Total number in each group is shown above each bar, with the number of participants displaying each activity shown within the bar. P values computed using Fisher exact test are shown above each comparison. B, Same data as the COVID-19 participants shown in A (where neutralization includes both yes and borderline categories) but plotted by age, and where neutralization is reported as the reciprocal log₂ dilution value. Samples that displayed no evidence of neutralization were coded as having a reciprocal dilution factor of 10 (3.32 log₂). Symbols are colored by vaccine received, which was significantly associated with neutralization activity after 1 dose (Table 2). Statistics were computed using ordinary least-squares regression. C and D, Same as A and B but for neutralization responses measured 1 month after 2 doses of mRNA vaccine and where neutralizing activity required inhibition of cytopathic effects in 3/3 wells at a 1:20 or higher plasma dilution. Abbreviations: COVID-19, coronavirus disease 2019; LLOQ, lower limit of quantification; Recip dil, reciprocal dilution; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; w/ nAb, with neutralizing antibodies.

Figure 4.

Older adults display lower magnitude and durability of antibody responses after vaccination. A, Binding IgG responses to spike RBD, measured by ELISA, 1 month after the first vaccine dose (1st, light green box), 1 month after the second vaccine dose (2nd, green box) and 3 months after this dose (3m, red box) are shown for HCW (blue) and older adults (orange) who were COVID-19–naive at study entry, and convalescent participants (N Sero+). Median values are displayed below each group. P values (computed using the Wilcoxon paired test for within-group comparisons, and the Mann-Whitney U test for between-group comparisons) are shown above each comparison performed. The number of pairs compared in the Wilcoxon paired test is shown below the relevant time points. B, ACE2 competition assay results in the same individuals, measured by ELISA. Values represent AU/mL calibrated against an external standard, reported in log₁₀ units. C, Virus neutralization assay results in the same individuals, displayed as the reciprocal log₂ plasma dilution. Note that some values are superimposed. Abbreviations: ACE2, angiotensin-converting enzyme 2; AU, arbitrary unit; BAU, binding antibody units; COVID-19, coronavirus disease 2019; ELISA, enzyme-linked immunosorbent assay; HCW, health care worker; IgG, immunoglobulin G; LLOQ, lower limit of quantification; RBD, receptor-binding domain; Recip dil, reciprocal dilution; ULOQ, upper limit of quantification.

Figure 5.

Cross-reactive antibody responses against the Delta variant after 2 doses of mRNA vaccine. A, Binding IgG antibody responses to spike RBD from the original Wuhan strain and the Delta variant, measured by ELISA, 1 month following the second vaccine dose (peak; green) and 3 months after this dose (durability; red) in HCW (blue) and older adults (orange) who were COVID-19 naive at study entry, and convalescent participants (N Sero+; grey). Median values are shown below each group. P values (computed using the Wilcoxon paired test for within-group comparisons, and the Mann-Whitney U test for between-group comparisons) are shown above each comparison performed. The number of pairs compared in the Wilcoxon paired test is shown below the relevant time points. B, ACE2 competition results in the same individuals, measured by ELISA. Values represent AU/mL calibrated against an external standard, reported in log₁₀ units. Abbreviations: ACE2, angiotensin-converting enzyme 2; AU, arbitrary unit; BAU, binding antibody units; COVID-19, coronavirus disease 2019; Delt, Delta; ELISA, enzyme-linked immunosorbent assay; HCW, health care worker; ns, not significant; RBD, receptor-binding domain; ULOQ, upper limit of quantification; Wuh, Wuhan.