Associations of Immunogenicity and Reactogenicity After Severe Acute Respiratory Syndrome Coronavirus 2 mRNA-1273 Vaccine in the COVE and TeenCOVE Trials

Abstract

Background: The reactogenicity and immunogenicity of coronavirus disease 2019 (COVID-19) vaccines are well studied. Little is known regarding the relationship between immunogenicity and reactogenicity of COVID-19 vaccines.

Methods: This study assessed the association between immunogenicity and reactogenicity after 2 mRNA-1273 (100 µg) injections in 1671 total adolescent and adult participants (≥12 years) from the primary immunogenicity sets of the blinded periods of the Coronavirus Efficacy (COVE) and TeenCOVE trials. Associations between immunogenicity through day 57 and solicited adverse reactions (ARs) after the first and second injections of mRNA-1273 were evaluated among participants with and without solicited ARs using linear mixed-effects models.

Results: mRNA-1273 reactogenicity in this combined analysis set was similar to that reported for these trials. The vaccine elicited high neutralizing antibody (nAb) geometric mean titers (GMTs) in evaluable participants. GMTs at day 57 were significantly higher in participants who experienced solicited systemic ARs after the second injection (1227.2 [1164.4-1293.5]) than those who did not (980.1 [886.8-1083.2], P = .001) and were associated with fever, chills, headache, fatigue, myalgia, and arthralgia. Significant associations with local ARs were not found.

Conclusions: These data show an association of systemic ARs with increased nAb titers following a second mRNA-1273 injection. While these data indicate systemic ARs are associated with increased antibody titers, high nAb titers were observed in participants after both injections, consistent with the immunogenicity and efficacy in these trials. These results add to the body of evidence regarding the relationship of immunogenicity and reactogenicity and can contribute toward the design of future mRNA vaccines.

Keywords: SARS-CoV-2; immunogenicity; mRNA-1273; reactogenicity; solicited adverse reactions.

Figure 1.

Trial profile immunogenicity analysis population. *The per-protocol immunogenicity subset consisted of randomly selected participants in the full analysis set (FAS) who received both planned injections (ie, received assigned treatment) with injection 2 received within 21–42 days after injection 1, had no virologic or serological evidence of SARS-CoV-2 at baseline, and had no major protocol deviations that impacted critical or key data. ^†Young adults from the COVE trial randomly selected for immunogenicity comparison in the TeenCOVE trial. ^§Fifteen samples from 18–25-year old participants selected from both immunogenicity sets. Abbreviations: COVE, Coronavirus Efficacy trial in adults; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TeenCOVE, phase 2/3 trial in adolescents.

Figure 2.

Solicited adverse reactions after first and second injections of mRNA-1273 vaccine. Percentages of participants in the immunogenicity subset (N = 1671) who had a solicited local or systemic reaction, within 7 days following injections 1 and 2 of mRNA-1273 100 µg, are shown. The maximum toxicity grade (grade 1 [mild], grade 2 [moderate], grade 3 [severe], and grade 4) is presented. Grade 4 fevers (>40.0°C/104.0°F) occurred in 1 and 3 participants after the first and second injections in the adult study, respectively, while no grade 4 events occurred in the adolescent study.

Figure 3.

Distribution of neutralizing antibody titers (ID₅₀) in mRNA-1273 vaccine recipients with and without adverse reactions. Neutralizing antibody titers (ID₅₀) by pseudovirus neutralizing antibody assay in log₁₀ scale at baseline (prior to injection 1), day 29 (prior to injection 2, 28 days post–injection 1), and day 57 (57 days post–injection 1, 28 days post–injection 2) after receipt of injections 1 and 2 of the mRNA-1273 vaccine in participants with (red) and without (blue) adverse reactions after 1 injection (A) and 2 injections (B). P values by linear mixed-effects models with Bonferroni multiplicity adjustment. Abbreviations: ID₅₀, 50% inhibitory dilution.

Figure 4.

Distribution of neutralizing antibody titers (ID₅₀) in mRNA-1273 vaccine recipients with and without individual systemic solicited events within 7 days after second injection. Neutralizing antibody titers (ID₅₀) by pseudovirus neutralizing antibody assay in log₁₀ scale at baseline, day 29, and day 57 after receipt of mRNA-1273 vaccine in participants with (red) and without (blue) individual systemic solicited events within 7 days after the second injection. P values by linear mixed-effects models with Bonferroni multiplicity adjustment. Abbreviation: ID₅₀, 50% inhibitory dilution.