Comparative Effectiveness of Alternative Intervals between First and Second Doses of the mRNA COVID-19 Vaccines: a Trial Emulation Approach
Authors: Shioda Kayoko , Breskin Alexander , Harati Pravara , Chamberlain Allison , Lopman Benjamin A , Rogawski McQuade Elizabeth T. 
Published: March 2023

Importance

mRNA 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.

Objective

To 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.

Design

We 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).

Setting

Georgia, USA.

Participants

Individuals who received ≥1 dose of mRNA COVID-19 vaccines in Georgia between December 13, 2020 and March 16, 2022.

Exposure

Dosing protocols based on the timing of the second dose administration.

Main Outcomes and Measures

SARS-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.

Results

In 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 Relevance

Delaying 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 POINTS

Question

Does the effectiveness of mRNA COVID-19 vaccines differ by intervals between the first and second doses of the primary series?

Findings

This 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.

Meaning

Delaying 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.