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

Abstract

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

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

Results: Following two 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. Third doses boosted antibody binding and function to higher levels than second-doses, and induced responses in older adults that were comparable in magnitude to those in younger adults. Humoral responses against Omicron were universally weaker than against the ancestral strain after both second and third doses; nevertheless, after three doses, anti-Omicron responses in older adults reached equivalence to those in younger adults. After three vaccine doses, the number of chronic health conditions, but not age per se, was the strongest consistent correlate of weaker humoral responses.

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

Figure 1.. Longitudinal antibody binding and neutralization responses to spike RBD following one, two and three COVID-19 vaccine doses.

Panel 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 six timepoints: prior to vaccination (pre-vax), one month following the first dose, one, three and six months following the second dose, and one month following the third vaccine dose. Individuals with post-vaccination infections are indicated by red dots at their first N seropositive time point. Participant Ns are provided at the bottom of the plot. A thick horizontal red bar represents the median; thinner horizontal red bars represent the IQR. 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. ULOQ/LLOQ: upper/lower limit of quantification. Panel B: same as 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 three wells at a 1/20 dilution were coded as having a reciprocal dilution of 10, corresponding to the LLOQ in this assay. The highest dilution tested was 1/2560, which corresponds to the ULOQ. Note that only a subset of pre-vaccine plasma samples was assayed for this activity.

Figure 2:. Decay rates of serum binding antibody responses to spike RBD following two COVID-19 vaccine doses.

Panel A: Temporal declines in serum binding antibody responses to spike RBD following two 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 circles). ULOQ: upper limit of quantification. Only participants with a complete longitudinal data series with no values above the ULOQ are shown. Panel B: Binding antibody half-lives following two COVID-19 vaccine doses, calculated by fitting an exponential curve to each participant’s data shown in panel A. Participant Ns are indicated at the bottom of the plot. Red bars and whiskers represent the median and IQR. P-values were computed using the Mann-Whitney U-test and are uncorrected for multiple comparisons.

Figure 3:. Anti-Omicron IgG binding and ACE2 displacement activities one month after the second and third COVID-19 vaccine doses.

Panel A: Binding IgG responses in plasma to the wild-type (WT, ancestral Wuhan strain) and Omicron (OM) S-RBD, measured using the Meso Scale Diagnostics (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 one month after the second and third COVID-19 vaccine doses. Participant Ns are shown at the bottom of the plot. A thick horizontal red bar represents the median; thinner horizontal red bars represent the IQR. 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. Panel B: same as 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.

Figure 4:. Anti-Omicron neutralization activities one month after the second and third COVID-19 vaccine doses.

Neutralization activities, reported as the lowest reciprocal plasma dilution at which neutralization was observed in all wells of a triplicate assay, against the wild-type (WT, ancestral WA1/2020 strain) and Omicron (OM) virus isolates a subset of HCW (blue circles) and older adults (orange circles) who remained COVID-19 naive throughout the study. Participant Ns are shown at the bottom of the plot. A thick horizontal red bar represents the median; thinner horizontal red bars represent the IQR. 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.