Determining the Time of Booster Dose Based on the Half-Life and Neutralization Titers against SARS-CoV-2 Variants of Concern in Fully Vaccinated Individuals

Abstract

Although mRNA-based COVID-19 vaccines reduce the risk of severe disease, hospitalization and death, vaccine effectiveness (VE) against infection and disease from variants of concern (VOC) wanes over time. Neutralizing antibodies (NAb) are surrogates of protection and are enhanced by a booster dose, but their kinetics and durability remain understudied. Current recommendation of a booster dose does not consider the existing NAb in each individual. Here, we investigated 50% neutralization (NT₅₀) titers against VOC among COVID-19-naive participants receiving the Moderna (n = 26) or Pfizer (n = 25) vaccine for up to 7 months following the second dose, and determined their half-lives. We found that the time it took for NT₅₀ titers to decline to 24, equivalent to 50% inhibitory dilution of 10 international units/mL, was longer in the Moderna (325/324/235/274 days for the D614G/alpha/beta/delta variants) group than in the Pfizer (253/252/174/226 days) group, which may account for the slower decline in VE of the Moderna vaccine observed in real-world settings and supports our hypothesis that measuring the NT₅₀ titers against VOC, together with information on NAb half-lives, can be used to dictate the time of booster vaccination. Our study provides a framework to determine the optimal time of a booster dose against VOC at the individual level. In response to future VOC with high morbidity and mortality, a quick evaluation of NAb half-lives using longitudinal serum samples from clinical trials or research programs of different primary-series vaccinations and/or one or two boosters could provide references for determining the time of booster in different individuals. IMPORTANCE Despite improved understanding of the biology of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), the evolutionary trajectory of the virus is uncertain, and the concern of future antigenically distinct variants remains. Current recommendations for a COVID-19 vaccine booster dose are primarily based on neutralization capacity, effectiveness against circulating variants of concern (VOC), and other host factors. We hypothesized that measuring neutralizing antibody titers against SARS-CoV-2 VOC together with half-life information can be used to dictate the time of booster vaccination. Through detailed analysis of neutralizing antibodies against VOC among COVID-19-naive vaccinees receiving either of two mRNA vaccines, we found that the time it took for 50% neutralization titers to decline to a reference level of protection was longer in the Moderna than in the Pfizer group, which supports our hypothesis. In response to future VOC with potentially high morbidity and mortality, our proof-of-concept study provides a framework to determine the optimal time of a booster dose at the individual level.

Keywords: half-life; mRNA vaccine; neutralizing antibodies; severe acute respiratory syndrome coronavirus 2; variants of concern.

FIG 1

NT₅₀ titers against SARS-CoV-2 D614G strain and VOC (alpha, beta, gamma, delta, and omicron) based on pseudovirus neutralization test among COVID-19 cases following natural infection (NI), COVID-19-naive, and COVID-19-recovered participants who had received Moderna or Pfizer vaccine. (A and B) COVID-19-naive (n = 33) (A) and COVID-19-recovered (n = 12) (B) participants at 3 weeks following Moderna or Pfizer vaccine. (C) COVID-19 cases at 3 weeks following NI (n = 11). (D) Comparison of NT₅₀ titers against VOC between the three groups. Data are the means of duplicates from one experiment. Dotted lines: NT₅₀ titer = 10. For box and whisker graphs in panels A to C: “number ×” = the median fold-reduction in NT₅₀ titers against each VOC compared with that against the D614G strain. *, P < 0.05 and ≥0.01; **, P < 0.01 and ≥0.001; ***, P < 0.001; Wilcoxon signed-rank test. In panel D, numbers = P values, two-tailed Mann-Whitney test between two groups. VOC are color-coded: green, D614G; purple, alpha; red, beta; blue, gamma; pink, delta; brown, omicron.

FIG 2

NT₅₀ titers against SARS-CoV-2 D614G strain and VOC (alpha, beta, gamma, and delta) based on pseudovirus neutralization test among COVID-19-naive participants receiving Moderna or Pfizer vaccine. (A to F) NT₅₀ titers at 3 weeks (A and B), 3 months (C and D) and 7 months (E and F) following two doses of mRNA vaccine. In panels A to F, “number ×” = mean fold-reduction in NT₅₀ titers against each VOC compared with that against the D614G strain. *, P < 0.05 and ≥0.01; **, P < 0.01 and ≥0.001; ***, P < 0.001; Wilcoxon signed-rank test. (G and H) NT₅₀ titers against the D614G and VOC declined over time within the Moderna (G) and Pfizer (H) groups. Numbers = P values, two-tailed Mann-Whitney test. Data are the means of duplicates from one experiment. Dotted lines: NT₅₀ titer = 10. Color code for each VOC is the same as in Fig. 1.

FIG 3

Decline of NT₅₀ titers against VOC in the Moderna and Pfizer groups. For sequential samples of the Moderna (A to D) and Pfizer (E to H) groups (n = 27 from 9 participants in each group), NT₅₀ titers were log-transformed and analyzed using an LME model to determine the half-life (t_1/2) of NAb against the D614G strain (A and E) and each VOC including the alpha (B and F), beta (C and G), and delta (D and H) variants for each individual. (I) Summary of the half-life of NAb for the Moderna and Pfizer groups. Data are the means of duplicates from one experiment. The decline of NT₅₀ titers against each VOC estimated by LME is shown in blue lines (lme4 package of R version 4.1.2). P values were based on the Wilcoxon rank-sum tests comparing the Moderna and Pfizer groups.

FIG 4

The time following the second dose of the Moderna or Pfizer vaccine it took NT₅₀ titers against each VOC to decline to 24. (A and B) Based on the half-life and NT₅₀ titer against each VOC on different sampling days, the time after the second dose required for the NT₅₀ titer to decline to 24 was calculated for a Moderna vaccinee (VX53) (A) and for each participant in the Moderna and Pfizer groups (B). ND = not determined because NT₅₀ titer < 24. Dashed lines, NT₅₀ titer = 24. (C and D) Comparison of the time required for NT₅₀ titers to decline to 24 for each VOC between the Moderna and Pfizer groups based on the 3-week samples (C) and all initial samples (D). Numbers = P values, two-tailed Mann-Whitney test. Color code for each VOC is the same as in Fig. 1.