Safety and Immunogenicity of Concomitant Administration and Combined Administration of Bivalent BNT162b2 COVID-19 Vaccine and Bivalent RSVpreF Respiratory Syncytial Virus Vaccine with or Without Quadrivalent Influenza Vaccine in Adults ≥ 65 Years of Age

Abstract

Concomitant administration may improve vaccination rates. This analysis of a phase 1/2 randomized study included 1073 healthy ≥65-year-olds who previously received ≥3 mRNA COVID-19 vaccine doses. Participants received concomitantly administered RSVpreF and bivalent BA.4/BA.5-adapted BNT162b2 vaccine (concomitant administration) with or without quadrivalent influenza vaccine (QIV), admixed combined RSVpreF + BNT162b2 vaccine (combined vaccine) with or without QIV, RSVpreF, BNT162b2, or QIV. Immunogenicity objectives included demonstrating the noninferiority of neutralizing antibody titers elicited by concomitant administration and combined vaccine compared with RSVpreF or BNT162b2 administered alone, and by concomitant administration and combined vaccine given with QIV compared with RSVpreF, BNT162b2, and QIV alone. Reactogenicity (≤7 days) and safety ≤1 month (adverse events (AEs)) and ≤6 months (serious AEs (SAEs)) after vaccination were assessed. Noninferiority for all immunogenicity comparisons was demonstrated. All vaccine groups were well tolerated; no new safety concerns were identified. Reactogenicity was mostly mild/moderate with rates generally similar across groups, except injection site pain and fatigue, which were less frequent with RSVpreF + placebo vs. other groups. AEs were infrequent, mostly mild/moderate, occurring at similar frequencies across groups. No AEs leading to study withdrawal or vaccine-related SAEs were reported. Favorable safety and tolerability alongside similar immunogenicity provide support for concomitant or combined use of RSVpreF and BNT162b2, with or without QIV, to help protect older adults from these important respiratory pathogens (NCT05886777).

Keywords: BNT162b2; QIV; RSVpreF; concomitant; immunogenicity; noninferiority; safety.

Figure 1

Study design (A) and objective and endpoints (B). HAI, hemagglutination inhibition assay; NT, neutralizing titer; QIV, quadrivalent influenza vaccine. In the first 2 groups, administration sites on the right arm were separated by 2.5 cm. Endpoints for the comparisons were RSV-A, RSV-B NTs (for RSVpreF); SARS-CoV-2 Omicron BA.4/BA.5 and ancestral-strain NTs (for BNT162b2); HAI titers for each strain contained in the QIV (for QIV).

Figure 2

Randomization and vaccine administration. QIV, quadrivalent influenza vaccine.

Figure 3

GMRs and GMTs 1 month after vaccination for the comparison of (A) RSVpreF concomitantly administered with BNT162b2 versus each vaccine administered alone and (B) RSVpreF concomitantly administered with both BNT162b2 and QIV versus each vaccine administered alone. Data are for the evaluable immunogenicity population. The LLOQ values were 10 for HAI titer, 242 for RSV-A NT50, 99 for RSV-B NT50, 71 for SARS-CoV-2 BA.4/BA.5 NT50, and 87 for SARS-CoV-2 ancestral strain. Assay results below the LLOQ were set to 0.5 × LLOQ. GMRs and 2-sided CIs were calculated by exponentiating the mean differences of the logarithms of the titers (assessed group minus comparator group) and the corresponding CIs based on the Student t distribution. Using a 2-fold noninferiority margin, success for the immunogenicity objectives was declared if the lower bound of the 2-sided 97.5% CI for the GMR was >0.5. The 2-fold noninferiority margin is denoted with the vertical black dashed line; the additional 1.5-fold noninferiority margin is denoted with the vertical gray dashed line. GMR, geometric mean ratio; GMT, geometric mean titer; HAI, hemagglutination inhibition; LLOQ, lower limit of quantitation; N, number of participants with valid and determinate assay results for the specified assay in the evaluable immunogenicity population; NT50, 50% neutralizing titer; RSV, respiratory syncytial virus; QIV, quadrivalent influenza vaccine.

Figure 4

GMRs and GMTs 1 month after vaccination for the comparison of (A) combined (RSVpreF + BNT162b2) vaccine concomitantly administered with placebo versus each vaccine administered alone and (B) combined (RSVpreF + BNT162b2) vaccine concomitantly administered with QIV versus each vaccine administered alone. Data are for the evaluable immunogenicity population. The LLOQ values were 10 for HAI titer, 242 for RSV-A NT50, 99 for RSV-B NT50, 71 for SARS-CoV-2 BA.4/BA.5 NT50, and 87 for SARS-CoV-2 ancestral strain. Assay results below the LLOQ were set to 0.5 × LLOQ. GMRs and 2-sided CIs were calculated by exponentiating the mean differences of the logarithms of the titers (assessed group minus comparator group) and the corresponding CIs based on the Student t distribution. Using a 2-fold noninferiority margin, success for the immunogenicity objectives was declared if the lower bound of the 2-sided 97.5% CI for the GMR was >0.5. The noninferiority margin is denoted with the vertical black dashed line; the additional 1.5-fold noninferiority margin is denoted with the vertical gray dashed line. GMR, geometric mean ratio; GMT, geometric mean titer; HAI, hemagglutination inhibition; LLOQ, lower limit of quantitation; N, number of participants with valid and determinate assay results for the specified assay in the evaluable immunogenicity population; NT50, 50% neutralizing titer; RSV, respiratory syncytial virus; QIV, quadrivalent influenza vaccine.

Figure 5

Local reactions. Results are for the electronic diary (e-diary) safety population (i.e., all participants who received the study intervention with ≥1 day of e-diary data transmitted). Severity grading of the specific local reaction is provided in Table S1. Local reactions were assessed at the injection site on the right arm. Numbers above the bars indicate the percentage of participants in each group reporting the specified event (rounded to whole numbers). RSVpreF/BNT, RSVpreF concomitantly administered with BNT162b2 (n = 157) in the right arm and placebo administered in the left arm; RSVpreF/BNT with QIV, RSVpreF concomitantly administered with BNT162b2 in the right arm with QIV administered in the left arm (n = 158); RSVpreF, RSVpreF administered in the right arm and placebo in the left arm (n = 152); BNT, BNT162b2 administered in the right arm and placebo in the left arm (n = 150); QIV, QIV administered in the right arm and placebo in the left arm (n = 149); Combined (RSVpreF + BNT) with QIV, combined (RSVpreF + BNT162b2) vaccine administered in the right arm and QIV administered in the left arm (n = 154); Combined (RSVpreF + BNT), combined (RSVpreF + BNT162b2) vaccine administered in the right arm and placebo in the left arm (n = 153); QIV, quadrivalent influenza vaccine.

Figure 6

Systemic events. Results are for the electronic diary (e-diary) safety population (i.e., all participants who received the study intervention with ≥1 day of e-diary data transmitted). Severity grading of the specific systemic event is provided in Table S1. Numbers above the bars indicate the percentage of participants in each group reporting the specified event (rounded to whole numbers). RSVpreF/BNT, RSVpreF concomitantly administered with BNT162b2 (n = 157) in the right arm and placebo administered in the left arm; RSVpreF/BNT with QIV, RSVpreF concomitantly administered with BNT162b2 in the right arm with QIV administered in the left arm (n = 158); RSVpreF, RSVpreF administered in the right arm and placebo in the left arm (n = 152); BNT, BNT162b2 administered in the right arm and placebo in the left arm (n = 150); QIV, QIV administered in the right arm and placebo in the left arm (n = 149); Combined (RSVpreF + BNT) with QIV, combined (RSVpreF + BNT162b2) vaccine administered in the right arm and QIV administered in the left arm (n = 154); Combined (RSVpreF + BNT), combined (RSVpreF + BNT162b2) vaccine administered in the right arm and placebo in the left arm (n = 153); QIV, quadrivalent influenza vaccine.