Older Adults Mount Less Durable Humoral Responses to Two Doses of COVID-19 mRNA Vaccine but Strong Initial Responses to a Third Dose

Abstract

Background: Third coronavirus disease 2019 (COVID-19) vaccine doses are broadly recommended, but immunogenicity data remain limited, particularly in older adults.

Methods: We measured circulating antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor-binding domain, ACE2 displacement, and virus neutralization against ancestral and omicron (BA.1) strains from prevaccine up to 1 month following the third dose, in 151 adults aged 24-98 years who received COVID-19 mRNA vaccines.

Results: Following 2 vaccine doses, humoral immunity was weaker, less functional, and less durable in older adults, where a higher number of chronic health conditions was a key correlate of weaker responses and poorer durability. One month after the third dose, antibody concentrations and function exceeded post-second-dose levels, and responses in older adults were comparable in magnitude to those in younger adults at this time. Humoral responses against omicron were universally weaker than against the ancestral strain after both the second and third doses. Nevertheless, after 3 doses, anti-omicron responses in older adults reached equivalence to those in younger adults. One month after 3 vaccine doses, the number of chronic health conditions, but not age, was the strongest consistent correlate of weaker humoral responses.

Conclusions: Results underscore the immune benefits of third COVID-19 vaccine doses, particularly in older adults.

Keywords: ACE2 displacement; COVID-19; SARS-CoV-2; binding antibodies; humoral immunity; mRNA; older adults; omicron; vaccine; viral neutralization.

Figure 1.

Longitudinal antibody binding and neutralization responses to spike RBD following 1, 2, and 3 COVID-19 vaccine doses. A, Binding antibody responses to the SARS-CoV-2 spike RBD in serum, in HCW (blue circles) and older adults (orange circles) who were COVID-19 naive at study entry, as well as COVID-19 convalescent individuals (black circles) at 6 time points: prior to vaccination (pre-vax); 1 month following the first dose; 1, 3, and 6 months following the second dose; and 1 month following the third vaccine dose. Individuals with postvaccination infections are indicated by red dots at their first N-seropositive time point. Participant numbers are provided at the bottom of the plot. A thick horizontal red bar represents the median; thinner horizontal red bars represent the interquartile range. P values were computed using the Mann-Whitney U test (for comparisons between groups) or the Wilcoxon matched pairs test (for comparisons across time points within a group) and are uncorrected for multiple comparisons. B, As in (A) but for virus neutralization activity, defined as the lowest reciprocal plasma dilution at which neutralization was observed in all wells of a triplicate assay. Plasma samples showing neutralization in fewer than 3 wells at a 1/20 dilution were coded as LLOQ. The highest dilution tested was 1/2560, which corresponds to the ULOQ. Note that only a subset of prevaccine plasma samples was assayed for this activity. Abbreviations: conc, concentration; Conv, convalescent; COVID-19, coronavirus disease 2019; HCW, health care worker; LLOQ, lower limit of quantification; N, nucleocapsid; prevax, prevaccination; RBD, receptor-binding domain; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; ULOQ, upper limit of quantification.

Figure 2.

Decay rates of serum binding antibody responses to spike RBD following 2 COVID-19 vaccine doses. A, Temporal declines in serum binding antibody responses to spike RBD following 2 vaccine doses in HCW (blue) and older adults (orange) who were COVID-19 naive at study entry, as well as COVID-19 convalescent participants (black). Only participants with a complete longitudinal data series with no values above the ULOQ are shown. B, Binding antibody half-lives following 2 COVID-19 vaccine doses, calculated by fitting an exponential curve to each participant's data shown in (A). Participant numbers are indicated at the bottom of the plot. Red bars and whiskers represent the median and interquartile range. P values were computed using the Mann-Whitney U test and are uncorrected for multiple comparisons. Abbreviations: Ab, antibody; conc, concentration; Conv, convalescent; COVID-19, coronavirus disease 2019; CW, health care worker; RBD, receptor-binding domain; ULOQ, upper limit of quantification.

Figure 3.

Anti-omicron IgG binding and ACE2 displacement activities 1 month after the second and third COVID-19 vaccine doses. A, Binding IgG responses in plasma to the WT (ancestral Wuhan strain) and omicron S-RBD, measured using the MSD V-Plex assay, in HCW (blue circles) and older adults (orange circles) who remained COVID-19 naive throughout the study, as well as individuals with prior COVID-19 regardless of infection timing (COVID-19 convalescent; black circles) at 1 month after the second and third COVID-19 vaccine doses. Participant numbers are shown at the bottom of the plot. A thick horizontal red bar represents the median; thinner horizontal red bars represent the interquartile range. P values were computed using the Wilcoxon matched pairs test (for all within-group comparisons) or the Mann-Whitney U test (for between-group comparisons) and are uncorrected for multiple comparisons. B, As in (A) but for ACE2 displacement activity, measured using the V-plex SARS-CoV-2 (ACE2) assay, where results are reported in terms of % ACE2 displacement. Abbreviations: COVID-19, coronavirus disease 2019; HCW, health care worker; SD, Meso Scale Diagnostics; OM, omicron; postvax, postvaccination; S-RBD, spike receptor-binding domain; WT, wild type.

Figure 4.

Anti-omicron neutralization activities 1 month after the second and third COVID-19 vaccine doses. Neutralization activities, reported as the highest reciprocal plasma dilution at which neutralization was observed in all wells of a triplicate assay, against the WT (ancestral WA1/2020 strain) and omicron virus isolates, in a subset of HCW (blue circles) and older adults (orange circles) who remained COVID-19 naive throughout the study. Participant numbers are shown at the bottom of the plot. A thick horizontal red bar represents the median; thinner horizontal red bars represent the interquartile range. P values were computed using the Wilcoxon matched pairs test (for within-group comparisons) or the Mann-Whitney U test (for between-group comparisons) and are uncorrected for multiple comparisons. Abbreviations: COVID-19, coronavirus disease 2019; HCW, health care worker; LLOQ, lower limit of quantification; WT, wild type.