Phase 1/2 Randomized Study of the Immunogenicity, Safety, and Tolerability of a Respiratory Syncytial Virus Prefusion F Vaccine in Adults With Concomitant Inactivated Influenza Vaccine

Abstract

Background: Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in older adults and adults with comorbidities. An effective vaccine is needed. An investigational bivalent prefusion F vaccine (RSVpreF) was assessed in healthy adults.

Methods: This phase 1/2 study randomized adults 18-85 years old to receive placebo or 60, 120, or 240 µg RSVpreF (with or without aluminum hydroxide) alone or concomitantly with seasonal inactivated influenza vaccine (SIIV). Safety and immunogenicity were assessed.

Results: In older adults, reactogenicity events were predominantly mild or moderate among RSVpreF recipients; adverse events through 1 month postvaccination were similar across formulations. Coadministration with SIIV did not appear to affect safety among younger or older adults. All RSVpreF formulations with or without concomitant SIIV elicited robust RSV serum-neutralizing responses in adults aged 50-85 years 1 month postvaccination. Neutralizing titers 1 and 12 months postvaccination were 6.9-14.9 and 2.9-4.5 times, respectively, those before vaccination. SIIV immune responses trended lower when coadministered with RSVpreF.

Conclusions: RSVpreF formulations administered alone or with SIIV were well tolerated and highly immunogenic in older adults, supporting the potential for RSVpreF to protect older adults from RSV disease.

Clinical trials registration: NCT03529773.

Keywords: F protein; immunogenicity; older adults; respiratory syncytial virus; safety; vaccine.

Figure 1.

Disposition of participants 50–85 years of age in the sentinel (A) and expanded (B) cohorts. Participants who did not receive seasonal inactivated influenza vaccine (SIIV) concomitantly with the respiratory syncytial virus (RSV) vaccine received it 1 month later. ^aOne participant randomized to the 60-µg bivalent RSV prefusion F vaccine (RSVpreF) + SIIV group did not receive vaccination. ^bOne participant randomized to the 120-µg RSVpreF + SIIV group was instead administered RSVpreF 240 µg + aluminum hydroxide + SIIV; this participant is included in the population to which the participant was randomized. Abbreviations: AE, adverse event; Al(OH)₃, aluminum hydroxide; f/u, follow-up; PV1, post–vaccination 1; RSV, respiratory syncytial virus; RSVpreF, bivalent respiratory syncytial virus prefusion F vaccine; SIIV, seasonal inactivated influenza vaccine.

Figure 2.

Percentages of expanded cohort participants reporting individual local reactions (A) or systemic events (B) by severity within 14 days postvaccination. Total number of participants = 40–43 per group. 60 = 60 µg bivalent respiratory syncytial virus prefusion F vaccine (RSVpreF); 120 = 120 µg RSVpreF; 240 = 240 µg RSVpreF. Abbreviations: A, aluminum hydroxide; P, placebo; RSVpreF, bivalent respiratory syncytial virus prefusion F vaccine; S, seasonal inactivated influenza vaccine.

Figure 3.

Respiratory syncytial virus (RSV) neutralizing geometric mean titers before and 1 month post–vaccination 1 for RSV subgroups A and B among expanded cohort participants aged 18–49 years (A) and 65–85 years (B). Neutralizing titer geometric mean fold rises from prevaccination to 1 month postvaccination are indicated above each pair of bars. Total number of participants: 38–41 per group (18–49 years) and 38–43 per group (65–85 years). Abbreviations: Al(OH)₃, aluminum hydroxide; GMFR, geometric mean fold rise; GMT, geometric mean titer; m, month; RSV, respiratory syncytial virus; SIIV, seasonal inactivated influenza vaccine.

Figure 4.

Respiratory syncytial virus (RSV) neutralizing titer geometric mean fold rises through 12 months post–vaccination 1 compared with prevaccination for RSV subgroups A and B in participants aged 18–49 years (A) and 65–85 years (B) in the expanded cohort. Abbreviations: Al(OH)₃, aluminum hydroxide; GMFR, geometric mean fold rise; RSV, respiratory syncytial virus; RSVpreF, bivalent respiratory syncytial virus prefusion F vaccine; SIIV, seasonal inactivated influenza vaccine.

Figure 5.

Hemagglutination inhibition (HAI) geometric mean titers to A/H3N2/Singapore (A), A/H1N1/Michigan (B), B/Colorado (C), and B/Phuket (D) at 1 month after seasonal inactivated influenza vaccine (SIIV) in participants aged 18–49 and 65–85 years receiving either SIIV concomitantly with bivalent respiratory syncytial virus prefusion F vaccine (RSVpreF) (RSVpreF + SIIV) or SIIV 1 month after RSVpreF (SIIV alone) in the expanded cohort (evaluable influenza immunogenicity population). Total number of participants = 31–41 per group. Geometric mean ratios at 1 month after SIIV for concomitant (RSVpreF + SIIV) to sequential (SIIV alone) administration are shown above each bar. Participants 18–49 years of age received quadrivalent SIIV containing A/H3N2/Singapore, A/H1N1/Michigan, B/Colorado, and B/Phuket; participants 65–85 years of age received high-dose trivalent SIIV containing A/H3N2/Singapore, A/H1N1/Michigan, and B/Colorado. Abbreviations: Al(OH)₃, aluminum hydroxide; GMR, geometric mean ratio; GMT, geometric mean titer; HAI, hemagglutination inhibition; RSVpreF, bivalent respiratory syncytial virus prefusion F vaccine; SIIV, seasonal inactivated influenza vaccine.

Figure 6.

Seasonal inactivated influenza vaccine (SIIV) neutralizing geometric mean titers (GMTs) (A/H3N2/Singapore) and hemagglutination inhibition (HAI) GMTs (A/H3N2/Singapore, A/H1N1/Michigan, B/Colorado, B/Phuket) at 1 month after SIIV in participants aged 18–49 years (A) and 65–85 years (B) in the expanded cohort (evaluable influenza immunogenicity population). Total number of participants = 34–41 per group. Geometric mean ratios at 1 month after SIIV for bivalent respiratory syncytial virus prefusion F vaccine (RSVpreF) + SIIV to SIIV alone (ie, 1 month after placebo), to SIIV after RSVpreF, and to pooled SIIV after RSVpreF and SIIV alone are shown above each bar. Participants 18–49 years of age received quadrivalent SIIV containing A/H3N2/Singapore, A/H1N1/Michigan, B/Colorado, and B/Phuket; participants 65–85 years of age received high-dose trivalent SIIV containing A/H3N2/Singapore, A/H1N1/Michigan, and B/Colorado. Abbreviations: Al(OH)₃, aluminum hydroxide; GMR, geometric mean ratio; GMT, geometric mean titer; HAI, hemagglutination inhibition; NT, neutralization titer; RSVpreF, bivalent respiratory syncytial virus prefusion F vaccine; SIIV, seasonal inactivated influenza vaccine.