Waning of 2-Dose BNT162b2 and mRNA-1273 Vaccine Effectiveness Against Symptomatic SARS-CoV-2 Infection Accounting for Depletion-of-Susceptibles Bias

Abstract

Concerns about the duration of protection conferred by coronavirus disease 2019 (COVID-19) vaccines have arisen in postlicensure evaluations. "Depletion of susceptibles," a bias driven by differential accrual of infection among vaccinated and unvaccinated individuals, may obscure vaccine effectiveness (VE) estimates, hindering interpretation. We enrolled California residents who received molecular SARS-CoV-2 tests in a matched, test-negative design, case-control study to estimate VE of mRNA-based COVID-19 vaccines between February 23 and December 5, 2021. We analyzed waning protection following 2 vaccine doses using conditional logistic regression models. Additionally, we used data from a population-based serological study to adjust for "depletion-of-susceptibles" bias and estimated VE for 3 doses, by time since second dose receipt. Pooled VE of BNT162b2 and mRNA-1273 against symptomatic SARS-CoV-2 infection was 91.3% (95% confidence interval (CI): 83.8, 95.4) at 14 days after second-dose receipt and declined to 50.8% (95% CI: 19.7, 69.8) at 7 months. Adjusting for depletion-of-susceptibles bias, we estimated VE of 53.2% (95% CI: 23.6, 71.2) at 7 months after primary mRNA vaccination series. A booster dose of BN162b2 or mRNA-1273 increased VE to 95.0% (95% CI: 82.8, 98.6). These findings confirm that observed waning of protection is not attributable to epidemiologic bias and support ongoing efforts to administer additional vaccine doses to mitigate burden of COVID-19.

Keywords: COVID-19; SARS-CoV-2; bias; depletion of susceptibles; vaccination; vaccine effectiveness.

Figure 1

Descriptive attributes of California residents seeking testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, enrolled between February to December 2021. Distribution of the days elapsed between vaccination and SARS-CoV-2 testing among individuals who received 2 doses of either BNT162b2 (Pfizer/BioNTech, New York, New York) or mRNA-1273 (Moderna, Cambridge, Massachusetts). Plots show the distribution of BNT162b2 (A) and mRNA-1273 (B), for which second doses are recommended ≥21 and ≥28 days after first dose, respectively, and distribution of the days elapsed between participants’ date of full vaccination for cases testing positive for SARS-CoV-2 (C) and controls testing negative (D). Participants were considered fully vaccinated if they were tested ≥14 days after their second dose of mRNA-1273 or BNT162b2.

Figure 2

Two-dose vaccine effectiveness against symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection over time, California, February to December 2021. Estimates from a conditional logistic regression model matching cases and controls on age group, sex, region, and week of SARS-CoV-2 testing are shown for vaccine effectiveness of 2 doses of BNT162b2 (Pfizer/BioNTech, New York, New York) or mRNA-1273 (Moderna, Cambridge, Massachusetts) by days since participants were fully vaccinated. Shaded areas denote 95% confidence intervals around point estimates. Numerical estimates plotted in this figure are presented in Web Table 4. Model estimates a 40.2% (95% confidence interval: 17.5, 73.7) reduction in vaccine effectiveness over 7 months.

Figure 3

Two-dose vaccine effectiveness against symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection over time within distinct participant strata, California, February to December 2021. Vaccine effectiveness estimates are partitioned for 2 doses by time since participants were considered fully vaccinated, for BNT162b2 (Pfizer/BioNTech, New York, New York) recipients (A), mRNA-1273 (Moderna, Cambridge, Massachusetts) recipients (B), participants aged 13–49 years (C), participants aged ≥50 years (D), participants with no self-reported preexisting conditions (E), and participants who self-reported any preexisting conditions (F). Comorbid conditions within the participant sample are enumerated in Web Table 2. Estimates obtained via conditional logistic regression models matching cases and controls on age group, sex, region, and week of SARS-CoV-2 testing. Shaded areas denote 95% confidence intervals (CIs) around point estimates. Model estimates a 7-month reduction of 40.5% (95% CI: 17.6, 73.2) for BNT-162b2 (A); 40.4% (95% CI: 17.7, 74.2) for mRNA-1723 (B); 34.9% (95% CI: 14.4, 64.0) for participants under 50 years of age (C); 42.6% (95% CI: 10.2, 103.3) for participants over 50 years of age (D); 33.1% (95% CI: 10.3, 69.1) for those who are healthy with no preexisting conditions (E); and 53.0% (95% CI: −4.1, 143.4) for those with preexisting conditions (F).

Figure 4

Two-dose vaccine effectiveness against symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by interval between receipt of first and second doses, California, February to December 2021. Two-dose vaccine effectiveness estimates presented as of 14 days after second dose receipt, according to the length of the interval between receipt of first and second doses. Estimates were obtained via conditional logistic regression models matching cases and controls on age group, sex, region, and week of SARS-CoV-2 testing. Shaded areas denote 95% confidence intervals around point estimates. Longer-term vaccine effectiveness for 2 doses plotted according to the length of the interdose interval in Web Figure 3.

Figure 5

Two-dose vaccine effectiveness against symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection as of December 2021 by time since second dose receipt, correcting for depletion-of-susceptibles bias, in a hypothetical cohort. “Naive” (bias-uncorrected) estimates of 2-dose vaccine effectiveness from Figure 2 (gray) were overlaid with bias-corrected estimates (blue) accounting for unreported infections among vaccinated and unvaccinated persons, as listed in Web Table 5, for hypothetical cohorts of individuals offered vaccination 1–7 months prior to December 2021. Rows and columns correspond to differing assumptions about the proportion of individuals who remained uninfected at the time vaccination was offered to them, among the vaccinated and unvaccinated, respectively. Scenarios considered include: 100% uninfected among the vaccinated and the unvaccinated when offered vaccination (A), 90% uninfected among the unvaccinated and 100% uninfected among the vaccinated (B), 80% uninfected among the unvaccinated and 100% uninfected among the vaccinated (C), 100% uninfected among the unvaccinated and 90% uninfected among the vaccinated (D), 90% uninfected among the unvaccinated and the vaccinated (E), 80% uninfected among the unvaccinated and 90% uninfected among the vaccinated (F), 100% uninfected among the vaccinated and 80% uninfected among the unvaccinated (G), 90% uninfected among the vaccinated and 80% uninfected among the unvaccinated (H), and 80% uninfected among the vaccinated and the unvaccinated (I). Corresponding numerical estimates are presented in Web Table 5.