Comparative Effectiveness of Alternative Intervals between First and Second Doses of the mRNA COVID-19 Vaccines: a Trial Emulation Approach

ImportancemRNA COVID-19 vaccines require two primary doses. The optimal timing of second dose administration with respect to vaccine effectiveness of the primary series has not been thoroughly evaluated and has implications for vaccination strategies. ObjectiveTo assess whether the effectiveness of mRNA COVID-19 vaccines (Pfizer-BioNTech and Moderna) against SARS-CoV-2 infection differs by varying intervals between the first and second doses of the primary series among the general population. DesignWe employed a trial emulation approach (clone-censor weight analysis) to estimate the risk of SARS-CoV-2 infection after the first dose administration under the scenario where the total study population had followed each of the following interdose intervals: recommended by the Food and Drug Administration (FDA) (17-25 days for Pfizer-BioNTech; 24-32 days for Moderna), late-but-allowable (26-42 days for Pfizer-BioNTech; 33-49 days for Moderna), and late ([≥]43 days for Pfizer-BioNTech; [≥]50 days for Moderna). SettingGeorgia, USA. ParticipantsIndividuals who received [≥]1 dose of mRNA COVID-19 vaccines in Georgia between December 13, 2020 and March 16, 2022. ExposureDosing protocols based on the timing of the second dose administration. Main Outcomes and MeasuresSARS-CoV-2 infection was defined as a positive result by a real-time reverse transcriptase PCR or antigen test. The follow-up period began the day after the first dose administration and ended at the earliest of SARS-CoV-2 infection, protocol nonadherence, or end of study. ResultsIn the short-term, the cumulative risk of SARS-CoV-2 infection was lowest under the FDA-recommended protocol (risk ratio (RR) on Day 50 after the first dose administration compared to the FDA-recommended protocol: 1.08 [95% confidence interval 1.07-1.10] under the late-but-allowable and 1.14 [1.12-1.16] under the late protocol). Longer-term, the late-but-allowable protocol resulted in the lowest risk (RR on Day 120: 0.83 [0.82-0.84] for the late-but-allowable and 1.10 [1.08-1.12] for the late protocol). The late protocol consistently yielded the highest risk among all protocols. Conclusions and RelevanceDelaying the timing of the second dose administration by a week may provide stronger protection against SARS-CoV-2 infection, but a longer delay would increase the risk of infection. KEY POINTSO_ST_ABSQuestionC_ST_ABSDoes the effectiveness of mRNA COVID-19 vaccines differ by intervals between the first and second doses of the primary series? FindingsThis study of >6 million mRNA COVID-19 vaccine recipients in Georgia, US used a trial emulation approach to compare the risk of SARS-CoV-2 infection under three protocols based on the timing of the second dose ("recommended," "late-but-allowable," and "late"). The late-but-allowable protocol led to the lowest cumulative risk in a long term. MeaningDelaying the receipt of the second dose by a week may decrease the risk of SARS-CoV-2 infection, but a longer delay would increase the risk.