Immunogenicity of Extended mRNA SARS-CoV-2 Vaccine Dosing Intervals

Standard dosing intervals for BNT162b2 and mRNA-1273 SARS-CoV-2 vaccines are 21 and 28 days, respectively.¹ Data suggest improved effectiveness of ChAdOx1 adenoviral² and other nonreplicating vaccines³ with increased dosing intervals, but little data exist for mRNA vaccines. This study investigated the immunogenicity of extended mRNA vaccine dosing intervals.

The COVID-19 Occupational Risks, Seroprevalence and Immunity among Paramedics in Canada cohort study (approved by the University of British Columbia and University of Toronto research ethics boards) recruited Canadian paramedics (January 25 to July 14, 2021), with written consent. Participants who provided a blood sample at enrollment or between 170 to 190 days after the first dose and had received 2 mRNA vaccine doses were eligible for this analysis. Participants with documented COVID-19 were excluded.

We relied on observed variability of vaccine intervals and timing of enrollment relative to vaccination to select participants with different vaccine intervals and performed 2 separate investigations, with different approaches to timing of blood samples. The first investigation compared antibody levels at comparable time intervals after the second dose. For the short (≤28 days) vs medium (42-49 days) vaccine dosing interval comparison, 30 samples (collected at enrollment) from each group were selected based on similar second vaccine-to-sample-collection intervals and were matched by vaccine type, age, sex, and comorbidities (eAppendix in the Supplement). The second investigation compared antibody levels sampled at a standardized interval (170-190 days) after the first dose. For the short (≤36 days) vs long (100-120 days) comparison, 30 samples from each group were selected, matching by the same characteristics.

The primary outcome was the reciprocal of neutralizing antibody titers against a live Wuhan strain (eAppendix in the Supplement). Secondary outcomes included IgG antibodies to the spike protein and receptor-binding domain (RBD) using a multiplex assay (V-PLEX COVID-19 Coronavirus Panel 2 [IgG] Kit; Meso Scale Diagnostics); antibodies to spike protein using a monoplex assay (Elecsys Anti-SARS-CoV-2 S assay; Roche); and inhibition of angiotensin-converting enzyme 2 (ACE-2) binding to RBD from Wuhan, Alpha, Beta, Delta, and Gamma variants (V-PLEX COVID-19 Coronavirus Panel 11 [ACE2] Kit).

Outcomes were reported as geometric mean (geometric SD [GSD]) compared with the Wilcoxon matched-pair signed rank test using IBM SPSS. A 2-sided P < .05 was considered statistically significant.

For the first investigation, the mean age for the short (dosing interval range, 18-28 days) group was 39 years (43% women); 70% received BNT162b2 and 30% mRNA-1273; for the medium (range, 42-49 days) group, the mean age was 41 years (47% women); 60% received BNT162b2 and 40% mRNA-1273. Comparing immunogenicity based on time after the second vaccine dose (matched at a mean of 56 days [SD, 26 days]), the viral neutralization geometric mean was 54.6 (GSD, 3.0) for the short group vs 230.8 (GSD, 2.0) for the medium group (P < .001). Spike and RBD IgG antibodies measured with the multiplex assay are presented in Figure 1. The spike antibody concentrations measured using the monoplex assay for the short group were 1697 U/mL (GSD, 1.7 U/mL) vs 2476 U/mL (GSD, 1.0 U/mL) for the medium group (P < .001). The ACE-2 inhibition for the Beta variant was 11.2 U/mL (GSD, 1.6 U/mL) for the short group vs 14.7 U/mL (GSD, 1.8 U/mL) for the medium group (P = .04). See Figure 1 for the Delta variant results. The comparisons of the Wuhan, Alpha, and Gamma variants were not statistically significant.

For the second investigation, the mean age was 41 years (60% women); 87% received BNT162b2 and 13% mRNA-1273 for both the short (range, 21-36 days) and long (range, 102-118 days) groups. Comparing immunogenicity based on time after the first vaccine dose (mean, 179 days [SD, 4.0 days] for the short group and 180 days [SD, 5.7 days] for the long group), the viral neutralization geometric mean was 41.8 (GSD, 2.8) for the short group vs 302.3 (GSD, 2.4) for the long group (P < .001). The multiplex IgG antibodies are presented in Figure 2. For the short vs long groups, the geometric mean monoplex spike antibodies were 928.4 U/mL (GSD, 2.1 U/mL) vs 1154 U/mL (GSD, 5.0 U/mL; P = .002). The geometric means for ACE-2 inhibition for the Alpha variant were 7.7 U/mL (GSD, 1.7 U/mL) vs 22.8 U/mL (GSD, 2.3 U/mL; P < .001); for the Beta variant, 5.4 U/mL (GSD, 3.1 U/mL) vs 15.5 U/mL (GSD, 2.0 U/mL; P < .001), and for the Gamma variant, 4.9 U/mL (GSD, 1.5 U/mL) vs 14.3 U/mL (GSD, 2.1 U/mL; P < .001). Results for the Wuhan and Delta variants are presented in Figure 2.

Longer mRNA vaccine dosing intervals demonstrated improved immunogenicity, which was consistent when responses were measured based on timing of the first or second dose. These data suggest that extending dosing intervals may be particularly advantageous against the Delta variant.

A delayed second-dose strategy could yield faster partial protection to a larger proportion of the population when vaccine supplies are limited. Modeling studies have estimated overall decreased mortality with delayed second doses when accounting for partial protection provided after 1 dose, even without taking into consideration the potential benefits of delayed second doses on long-term vaccine effectiveness.^4,5 However, the trade-off of lower individual immune protection after 1 dose may be unfavorable in at-risk groups or settings where COVID-19 prevalence is high.

Limitations include lack of randomization, small sample size, and focus on middle-aged adults. Although antibody neutralization correlates with disease protection,⁶ studies should validate whether extending vaccine dosing intervals leads to more sustained vaccine protection.

Corresponding Author: Brian Grunau, MD, MHSc, British Columbia Resuscitation Research Collaborative, 1190 Hornby St, Fourth Floor, Vancouver, BC V6Z 2K5, Canada (brian.grunau@ubc.ca).

Accepted for Publication: November 18, 2021.

Published Online: December 3, 2021. doi:10.1001/jama.2021.21921

Author Contributions: Drs Grunau and Lavoie had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Grunau, Goldfarb, Asamoah-Boaheng, Kirkham, Demers, Lavoie.

Acquisition, analysis, or interpretation of data: Grunau, Asamoah-Boaheng, Golding, Kirkham, Demers, Lavoie.

Drafting of the manuscript: Grunau, Asamoah-Boaheng, Lavoie.

Critical revision of the manuscript for important intellectual content: Goldfarb, Asamoah-Boaheng, Golding, Kirkham, Demers, Lavoie.

Statistical analysis: Asamoah-Boaheng, Lavoie.

Obtained funding: Grunau, Goldfarb, Kirkham, Demers, Lavoie.

Administrative, technical, or material support: Goldfarb, Golding, Kirkham, Demers.

Supervision: Grunau, Goldfarb, Kirkham, Lavoie.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was supported by funding from the government of Canada, through the COVID-19 Immunity Task Force.

Role of the Funder/Sponsor: The government of Canada had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank Mohammad Ehsanul Karim, PhD (School of Population and Public Health, University of British Columba), for providing statistical expertise; Paul N. Levett, PhD, and Martin Petric, PhD (British Columbia Centre for Disease Control), for performing live virus neutralization testing; Richard Armour, MSc (British Columbia Emergency Health Services), for assisting with participant enrollment; and Vilte Barakauskas, PhD (British Columbia Children’s and Women’s Hospital), for managing specimens. No compensation was received for their contributions to this work.