Efficacy, Immunogenicity, and Safety of the Bivalent Respiratory Syncytial Virus (RSV) Prefusion F Vaccine in Older Adults Over 2 RSV Seasons

Abstract

Background

Respiratory syncytial virus (RSV) is an important cause of lower respiratory tract illness (LRTI) in older adults. RSV prefusion F (RSVpreF) is a bivalent stabilized prefusion F vaccine containing RSV-A and RSV-B antigens. In this phase 3 trial in persons aged ≥60 years, RSVpreF demonstrated vaccine efficacy (VE) of 88.9% and 77.8% against RSV-associated LRTI with ≥3 symptoms at the end of RSV seasons 1 and 2, respectively. We describe final safety and efficacy results and present immunogenicity data.

Methods

This study was conducted over 2 RSV seasons. Participants were randomized (1:1) to RSVpreF 120-µg or placebo. A secondary objective was to describe RSVpreF immunogenicity 1 month post-vaccination and before season 2 visits in participants from the United States and Japan.

Results

One-month post-vaccination neutralization titer geometric mean fold rise (GMFR) was 12.1 for combined RSV-A/RSV-B. Geometric mean titers decreased at the preseason 2 visit but remained substantially higher than baseline (RSV-A/RSV-B GMFR = 4.7). One month post-vaccination, GMFRs for RSV-A/RSV-B neutralizing responses were 12.0 to 13.0 for subgroups stratified by age (60–69, 70–79, ≥80 years). RSV-A/RSV-B GMFRs in participants with prespecified chronic conditions were generally similar to those without (range, 11.4–14.4). A consistent favorable safety profile and durable VE were seen through 2 RSV seasons.

Conclusions

High RSV neutralizing titers were observed 1 month after RSVpreF vaccination in persons aged ≥60 years, with similarly robust responses across subgroups. These immune responses corresponded with high RSVpreF VE against RSV-associated LRTI. RSVpreF had a favorable safety profile over 2 seasons.

Clinical Trials Registration. NCT05035212; EudraCT, 2021-003693-31.

RSV, RSVpreF, vaccine, efficacy, immunogenicity

Respiratory syncytial virus (RSV) is an important cause of lower respiratory tract illness (LRTI) and is associated with severe infection in older adults, especially among those who are frail or have underlying chronic medical conditions [1, 2]. In a 2020 meta-analysis, RSV accounted for 1%−10% of influenza-like acute respiratory tract illness (ARI) among persons aged ≥50 years globally [3]. Annually in the United States, RSV is associated with approximately 60 000–160 000 hospitalizations and 6000–10 000 deaths among persons aged ≥65 years [4]. However, because of challenges associated with conducting RSV reverse-transcription polymerase chain reaction testing and inconsistent reporting, RSV adult diagnoses likely underestimate true disease burden [5–9].

The bivalent RSV prefusion F vaccine (RSVpreF; ABRYSVO) consists of stabilized prefusion F antigens from the 2 major circulating antigenic RSV subgroups (RSV-A, RSV-B) [10]. RSVpreF is approved for prevention of RSV-LRTI in persons aged ≥60 years, persons aged 18–59 years at increased risk for RSV-LRTI, and infants through maternal vaccination [11–14].

RSVpreF licensure in persons aged 60 years was supported by efficacy and safety results from the global phase 3 RENOIR (RSV Vaccine Efficacy Study in Older Adults Immunized against RSV Disease) study [15]. At the end of season 1 (EOS1), RSVpreF vaccine efficacy (VE) point estimates (95% confidence interval [CI]) were 88.9% (53.6–98.7) and 65.1% (35.9–82.0) against RSV-LRTI with ≥3 and ≥2 symptoms, respectively [16]. These results were maintained at the end of season 2 (EOS2), with corresponding VE of 77.8% (51.4–91.1) and 55.7% (34.7–70.4). To support and complement efficacy and safety findings from the primary analysis, overarching final RSVpreF efficacy results from RENOIR through EOS1, EOS2, and across both seasons and immunogenicity and final safety results are described.

METHODS

Study Design and Participants

The methods of the RENOIR trial, a phase 3, multicenter, randomized, double-blind, placebo-controlled study to evaluate RSVpreF in RSV-LRTI prevention in persons aged ≥60 years, have been published previously [15]. Briefly, healthy participants or those with stable medical conditions, including chronic cardiopulmonary disease, were randomized from 241 sites across the Northern (United States, Canada, Japan, Finland, Netherlands) and Southern Hemispheres (Argentina, South Africa). Participants were randomized 1:1 to receive an intramuscular 120-µg (60 µg RSV-A, 60 µg RSV-B) dose of RSVpreF or matching placebo. Participants were followed across 2 RSV seasons spanning both hemispheres (Supplementary Table 1, Supplementary Figure 1). See the Supplementary material for ethical study conduct.

Efficacy

The primary efficacy objective was assessment of RSVpreF VE in preventing a first RSV-LRTI episode with ≥3 symptoms (more severe symptom profile) and ≥2 symptoms (less severe symptom profile) in the first RSV season post-vaccination (Supplementary Table 2 provides symptoms and case definitions). Secondary efficacy objectives were assessment of VE in preventing a first RSV-LRTI episode with ≥3 and ≥2 symptoms and RSV-associated ARI (RSV-ARI) in each season and across 2 seasons. RSV-LRTI that prompted healthcare visits (ie, medically attended RSV-LRTI), including telephone/telehealth medical practitioner consultation; doctor visit; urgent care visit; emergency department visit; or hospitalization in season 1, season 2, and across both seasons, were exploratory analyses. These efficacy results were described in part previously and are briefly included here to provide context to immunogenicity findings [15, 16].

Immunogenicity

The immunogenicity objective (secondary objective) was to describe RSVpreF-elicited immune responses post-vaccination. Blood specimens were collected from a study participant subset from selected US and Japanese sites at 3 visits: pre-vaccination, 1 month post-vaccination, and before season 2. Sera was assayed for RSV-A− and RSV-B−neutralizing antibody titers. Geometric mean RSV 50% serum neutralizing titers were calculated for each time point. The percentages of participants with seroresponses (≥4-fold rise from baseline or ≥4× lower limit of quantitation [LLOQ] if baseline measurements were < LLOQ) 1 month post-vaccination and at the preseason 2 visit (occurring 8–20 months post-vaccination) are also reported.

Safety

Safety was a primary objective. An external safety data monitoring committee monitored safety data throughout the study. Reactogenicity event data collected from US and Japanese sites for 7 days post-vaccination were reported previously [15]. Described here are final safety findings, including unsolicited adverse events (AEs) collected from enrollment through 1 month post-vaccination and serious AEs (SAEs) and newly diagnosed chronic medical conditions collected throughout the study. Clinically important events included atrial fibrillation (AF; through 1 month post-vaccination), Guillain-Barré syndrome (GBS), and polyneuropathy without an underlying etiology (from vaccination to day 43).

Statistics

Sample size calculations and statistical analyses for efficacy have been described previously [15, 16]. Briefly, efficacy end points were primarily assessed in the evaluable efficacy population (eligible participants who received RSVpreF or placebo as randomly assigned, had no major protocol violations before the symptom onset date, and had a minimum follow-up through day 15 post-vaccination). VE was computed as (1 − RR) × 100%, where RR is the ratio of the number of confirmed first-episode RSV-LRTI cases in the RSVpreF group to the corresponding number of confirmed cases in the placebo group. The 95% CIs for VE were obtained using the conditional exact test based on the binomial distribution of number of RSVpreF cases divided by total number of cases.

For immunogenicity analyses, geometric mean titers (GMTs) were calculated by exponentiating the mean logarithm of RSV neutralizing titers, with associated 95% CIs based on Student t distributions. Geometric mean fold rises (GMFRs) from before to 1 month post-vaccination and from pre-vaccination to the preseason 2 visit were calculated by exponentiating the mean of the difference of logarithmically transformed assay results (later time point minus earlier time point), with associated 2-sided 95% CIs based on Student t distributions. Immunogenicity data are presented by group and stratified by RSV subgroup (RSV-A, RSV-B, RSV-A/B combined [geometric mean of RSV-A and RSV-B]), age group (60–69, 70–79, ≥80 years), and prespecified high-risk condition (none, ≥1 high-risk condition, ≥1 chronic cardiopulmonary condition). Immunogenicity end points were assessed in the evaluable immunogenicity population (eligible participants who received RSVpreF or placebo, had the 1-month post-vaccination blood collection within a prespecified time window [27–42 days], had ≥1 valid and determinate neutralizing titer result 1 month post-vaccination, and had no major protocol violations through the 1-month follow-up visit). Safety data are presented descriptively in the safety population (all randomized participants who received RSVpreF or placebo).

RESULTS

Participants

This study was conducted from 31 August 2021 through 18 December 2023. Overall, 36 862 participants received RSVpreF (n = 18 574) or placebo (n = 18 288; Figure 1). Demographic characteristics were similar across groups and generally similar to those reported previously (Supplementary Table 3) [15]. Median (range) age of participants was 67 years (59–97), 62.6% were aged 60–69 years, and 5.5% were aged ≥80 years; 51% were men, 80% were White, 12% were Black, and 41% were Hispanic/Latino. The majority had ≥1 prespecified high-risk condition (52.3%). Overall, 77.8% of participants completed the study.

Figure 1.

Enrollment, randomization, and RSVpreF vaccine or placebo administration. ^aNot all participants received the vaccine as randomized; 18 574 received RSVpreF, and 18 288 received placebo. ^bIncludes participants who discontinued because of early closure of selected sites and because of relocation or travel. Abbreviation: RSVpreF, respiratory syncytial virus prefusion F.

Efficacy

VE for season 1, season 2, and through 2 seasons has been described previously [15]. Briefly, average ARI surveillance periods were 7.1 and 7.6 months for seasons 1 and 2, respectively, with average time since vaccination through end of surveillance of 17.6 months among those followed for 2 seasons (Supplementary Table 4). RSVpreF effectively prevented the first RSV-LRTI episode with ≥3 symptoms throughout 2 seasons (Figure 2A), with VE (95% CI) of 88.9% (53.6–98.7) and 77.8% (51.4–91.1) at EOS1 and EOS2, respectively (Figure 2B). Consistent efficacy against first RSV-LRTI episode with ≥3 symptoms for each season was observed by RSV subgroup (RSV-A, RSV-B), age group (60–69, 70–79, ≥80 years), and risk group (with and without ≥1 prespecified high-risk condition; Figures 2B–D).

Figure 2.

A, Cumulative distribution curve of lower respiratory tract illness associated with respiratory syncytial virus (RSV-LRTI) cases with ≥3 symptoms through 2 RSV seasons and vaccine efficacy for first episode of RSV-LRTI with ≥3 symptoms in the first and second RSV season overall and stratified by RSV subgroup (B), by age group (C), and by presence of high-risk condition (D). Data are for the evaluable efficacy population. Vaccine efficacy is based on the case count ratio, which was calculated as 1 – (P/[1 – P]), where P is the number of RSVpreF cases divided by the total number of cases. The 95% CI was obtained using the conditional exact test based on the binomial distribution of P. Prespecified high-risk conditions included current tobacco use; diabetes; and lung, heart, liver, or renal disease. These data have been previously tabulated [16]. Abbreviations: CI, confidence interval; RSVpreF, respiratory syncytial virus prefusion F.

Consistent efficacy of RSVpreF against RSV-LRTI with ≥2 symptoms at EOS1, EOS2, and across both seasons overall was observed by stratified group (RSV subgroup, age group, risk group; Supplementary Figure 2). RSVpreF efficacy against RSV-ARI was also similar at EOS1, EOS2, and across both seasons (Supplementary Figure 3). Across 2 seasons, VE (95% CI) against medically attended RSV with ≥3 symptoms, medically attended RSV with ≥2 symptoms, and medically attended RSV-ARI was 76.3% (50.2–89.9), 60.0% (37.2–75.2), and 53.2% (35.7–66.2), respectively.

Immunogenicity

The immunogenicity subset consisted of 1151 participants, and the evaluable immunogenicity population included 1067 participants (RSVpreF, n = 537; placebo, n = 530). Demographic characteristics for the immunogenicity-evaluable population are shown in Table 1. Compared with the overall population, the immunogenicity-evaluable population had a higher percentage of men and Asian participants and a lower percentage with ≥1 prespecified high-risk condition.

Table 1.

Demographic Characteristics of the Evaluable Immunogenicity Population

	United States			Japan			Total
Characteristic	RSVpreF (n = 307)a	Placebo (n = 303)a	Total (N = 610)a	RSVpreF (n = 230)a	Placebo (n = 227)a	Total (N = 457)a	RSVpreF (n = 537)a	Placebo (n = 530)a	Total (N = 1067)a
Sex, n (%)
Male	184 (59.9)	163 (53.8)	347 (56.9)	160 (69.6)	161 (70.9)	321 (70.2)	344 (64.1)	324 (61.1)	668 (62.6)
Female	123 (40.1)	140 (46.2)	263 (43.1)	70 (30.4)	66 (29.1)	136 (29.8)	193 (35.9)	206 (38.9)	399 (37.4)
Race, n (%)
Asian	8 (2.6)	7 (2.3)	15 (2.5)	230 (100.0)	227 (100.0)	457 (100.0)	238 (44.3)	234 (44.2)	472 (44.2)
White	188 (61.2)	191 (63.0)	379 (62.1)	0	0	0	188 (35.0)	191 (36.0)	379 (35.5)
Black or African American	101 (32.9)	94 (31.0)	195 (32.0)	0	0	0	101 (18.8)	94 (17.7)	195 (18.3)
Not reported	6 (2.0)	2 (0.7)	8 (1.3)	0	0	0	6 (1.1)	2 (0.4)	8 (0.7)
Unknown	1 (0.3)	6 (2.0)	7 (1.1)	0	0	0	1 (0.2)	6 (1.1)	7 (0.7)
Otherb	3 (1.0)	3 (1.0)	6 (1.0)	0	0	0	3 (0.6)	3 (0.6)	6 (0.6)
Ethnicity, n (%)
Non-Hispanic/Non-Latino	254 (82.7)	245 (80.9)	499 (81.8)	230 (100.0)	227 (100.0)	457 (100.0)	484 (90.1)	472 (89.1)	956 (89.6)
Hispanic/Latino	40 (13.0)	49 (16.2)	89 (14.6)	0	0	0	40 (7.4)	49 (9.2)	89 (8.3)
Not reported	13 (4.2)	9 (3.0)	22 (3.6)	0	0	0	13 (2.4)	9 (1.7)	22 (2.1)
Age at vaccination, n (%), y
60−69	220 (71.7)	218 (71.9)	438 (71.8)	147 (63.9)	149 (65.6)	296 (64.8)	367 (68.3)	367 (69.2)	734 (68.8)
70−79	82 (26.7)	74 (24.4)	156 (25.6)	75 (32.6)	71 (31.3)	146 (31.9)	157 (29.2)	145 (27.4)	302 (28.3)
≥80	5 (1.6)	11 (3.6)	16 (2.6)	8 (3.5)	7 (3.1)	15 (3.3)	13 (2.4)	18 (3.4)	31 (2.9)
Median (range)	66.0 (60–86)	66.0 (60–87)	66.0 (60–87)	66.0 (60–87)	66.0 (60–85)	66.0 (60–87)	66.0 (60–87)	66.0 (60–87)	66.0 (60–87)
Prespecified significant conditions, n (%)
With ≥1 prespecified significant condition	150 (48.9)	140 (46.2)	290 (47.5)	86 (37.4)	78 (34.4)	164 (35.9)	236 (43.9)	218 (41.1)	454 (42.5)
Current tobacco use	53 (17.3)	41 (13.5)	94 (15.4)	28 (12.2)	27 (11.9)	55 (12.0)	81 (15.1)	68 (12.8)	149 (14.0)
Diabetes	63 (20.5)	58 (19.1)	121 (19.8)	31 (13.5)	20 (8.8)	51 (11.2)	94 (17.5)	78 (14.7)	172 (16.1)
Lung diseasec	19 (6.2)	23 (7.6)	42 (6.9)	14 (6.1)	14 (6.2)	28 (6.1)	33 (6.1)	37 (7.0)	70 (6.6)
Heart diseased	21 (6.8)	27 (8.9)	48 (7.9)	19 (8.3)	20 (8.8)	39 (8.5)	40 (7.4)	47 (8.9)	87 (8.2)
Liver disease	1 (0.3)	2 (0.7)	3 (0.5)	16 (7.0)	11 (4.8)	27 (5.9)	17 (3.2)	13 (2.5)	30 (2.8)
Renal disease	7 (2.3)	8 (2.6)	15 (2.5)	11 (4.8)	10 (4.4)	21 (4.6)	18 (3.4)	18 (3.4)	36 (3.4)
≥1 chronic cardiopulmonary condition	39 (12.7)	41 (13.5)	80 (13.1)	24 (10.4)	17 (7.5)	41 (9.0)	63 (11.7)	58 (10.9)	121 (11.3)
Asthma	32 (10.4)	31 (10.2)	63 (10.3)	10 (4.3)	6 (2.6)	16 (3.5)	42 (7.8)	37 (7.0)	79 (7.4)
Chronic obstructive pulmonary disease	10 (3.3)	8 (2.6)	18 (3.0)	6 (2.6)	5 (2.2)	11 (2.4)	16 (3.0)	13 (2.5)	29 (2.7)
Chronic heart failure	3 (1.0)	6 (2.0)	9 (1.5)	8 (3.5)	8 (3.5)	16 (3.5)	11 (2.0)	14 (2.6)	25 (2.3)
No prespecified significant conditions	157 (51.1)	163 (53.8)	320 (52.5)	144 (62.6)	149 (65.6)	293 (64.1)	301 (56.1)	312 (58.9)	613 (57.5)

Abbreviation: RSVpreF, respiratory syncytial virus prefusion F.

^aNumber of participants in the specified group or the total sample; this is the denominator for the percentage calculations.

^bIncludes American Indian or Alaska Native, multiracial, and native Hawaiian or other Pacific Islander.

^cIncludes chronic obstructive pulmonary disease and other lung disease.

^dIncludes chronic heart failure and other heart disease.

Neutralizing GMTs for the RSVpreF group were substantially increased from before to 1 month post-vaccination for RSV-A and RSV-B and for RSV-A and RSV-B combined (Figure 3A). RSV-A GMFRs from before to 1 month post-vaccination were 11.6 in the RSVpreF group and 1.1 in the placebo group. Corresponding GMFRs for RSV-B were 12.7 for RSVpreF and 1.1 for placebo. At the preseason 2 visit (occurring from 8–20 months post-vaccination), neutralizing GMTs decreased but remained substantially higher than baseline. Combined RSV-A/RSV-B GMFRs from before vaccination to preseason 2 were 4.7 in the RSVpreF group and 1.3 in the placebo group. For subgroup analyses by age group and prespecified significant conditions, neutralizing GMTs and GMFRs for RSV-A and RSV-B were generally similar to those observed in the main analyses, although with wider 95% CIs in some subgroups, reflecting low participant numbers in some subgroups (Figures 3B–C). Preseason 2 GMTs remained relatively constant regardless of time interval from vaccination across 8–20 months (Figure 4).

Figure 3.

GMTs and GMFRs (95% CIs) for RSV 50% neutralizing titers by RSV subgroup and overall (A), by age group (B), and by high-risk status (C). Data are for the evaluable immunogenicity population. GMT values for placebo were ≤2302 at any time point. Prespecified high-risk conditions included current tobacco use; diabetes; and lung, heart, liver, or renal disease. Chronic cardiopulmonary conditions included asthma, chronic obstructive pulmonary disease, and congestive heart failure. The LLOQ for each neutralization titer was RSV-A 50% = 242, RSV-B 50% = 99. Assay results < LLOQ were set to 0.5 × LLOQ. Abbreviations: CI, confidence interval; GMFR, geometric mean fold rise; GMT, geometric mean titer; LLOQ, lower limit of quantitation; RSV, respiratory syncytial virus.

Figure 4.

Combined RSV-A/RSV-B neutralizing titer GMTs by time interval post-vaccination with RSVpreF and by country. Data are for the evaluable immunogenicity population. The LLOQ for each neutralization titer was RSV-A 50% = 242, RSV-B 50% = 99. Assay results < LLOQ were set to 0.5 × LLOQ. Abbreviations: GMT, geometric mean titer; LLOQ, lower limit of quantitation; RSV, respiratory syncytial virus.

In the RSVpreF group, percentages of participants with seroresponses were higher 1 month post-vaccination (RSV-A, 84.3%; RSV-B, 85.6%) compared with preseason 2 values (59.4% and 57.5%, respectively) and substantially higher than placebo values (≤3.0% and ≤7.7%, respectively, at any time point; Supplementary Figure 4).

Safety

In this final safety analysis, 10.8% and 10.5% of participants in the RSVpreF and placebo groups, respectively, reported AEs through 1 month post-vaccination (Table 2). Most AEs were mild/moderate in severity, with severe or life-threatening events reported in 0.6% and 0.5% of RSVpreF and placebo recipients, respectively. Overall, 1.4% and 1.0% of RSVpreF and placebo recipients reported AEs through 1 month post-vaccination, assessed as being related to study intervention by the investigator. Eleven (<0.1%) participants in the RSVpreF group and 3 (<0.1%) in the placebo group reported AEs of AF through 1 month post-vaccination, with 6 and 2 participants in the RSVpreF and placebo groups, respectively, having a medical history of AF. None of these events were assessed by the investigator as related to study intervention, and the majority of participants who reported AFs had histories of other cardiac conditions or risk factors for cardiac disease.

Table 2.

Summary of Adverse Events Through the End of Season 2 in the Safety Population

Adverse Event	RSVpreF (Na = 18 574) nb (%)	Placebo (Na = 18 288) nb (%)
Any AE (through 1 month post-vaccination)	2012 (10.8)	1917 (10.5)
Relatedc	264 (1.4)	179 (1.0)
Severe or life-threatening	106 (0.6)	97 (0.5)
Immediate (within 30 min of vaccination)	39 (0.2)	35 (0.2)
Any serious AE (throughout study)	1149 (6.2)	1107 (6.1)
Relatedc	3 (<0.1)	0
Any AE that led to discontinuation (throughout study)	20 (0.1)	17 (<0.1)
Relatedc	0	0
Any AE that led to death (throughout study)	160 (0.9)	157 (0.9)
Relatedc	0	0
Newly diagnosed chronic medical condition (throughout study)	1267 (6.8)	1208 (6.6)
Relatedc	1 (<0.1)	1 (<0.1)

Abbreviations: AE, adverse event; RSVpreF, respiratory syncytial virus prefusion F.

^aNumber of participants in the specified group; this is the denominator for the percentage calculations.

^bNumber of participants reporting ≥1 occurrence of the specified event category. The number for “any event” is the number of participants reporting ≥1 occurrence of any event.

^cThe investigator assessed the event as related to the investigational product.

Throughout the study, 6.2% of RSVpreF and 6.1% of placebo recipients reported an SAE. The most commonly reported SAEs according to system organ class were categorized as cardiac disorders (RSVpreF, 1.4%; placebo, 1.4%) and infections and infestations (RSVpreF, 1.2%; placebo, 1.1%; Supplementary Table 5). Three SAEs were assessed as being related to RSVpreF; these SAEs were described in the primary analysis and included 2 participants with variants of GBS (the remaining event was delayed allergic reaction) [15]. One participant received a diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) 8 days after receipt of the study intervention, while a second participant was diagnosed with Miller Fisher syndrome (MFS) 9 days post-vaccination. The participant with CIDP had a potentially confounding factor because symptoms started 1 day after acute myocardial infarction. The participant with MFS also had a potential alternative etiology because the event was preceded by upper respiratory infection symptoms. No additional related SAEs were reported through EOS2.

AEs that led to death were reported in 0.9% of participants in each of the RSVpreF and placebo groups, and AEs that led to withdrawal were reported in 0.1% of RSVpreF and <0.1% of placebo recipients. No deaths or AEs that led to withdrawal were assessed by investigators as related to RSVpreF or placebo.

DISCUSSION

In this analysis of the global phase 3 RENOIR efficacy study, a single dose of the bivalent RSVpreF vaccine administered to persons aged ≥60 years maintained high efficacy against RSV-LRTI with a consistent favorable safety profile through 2 complete RSV seasons in the Northern and Southern Hemispheres. RSVpreF also elicited robust neutralizing responses post-vaccination that remained well above baseline pre-vaccination neutralizing titers before the start of the second RSV season through 8–20 months post-vaccination. RSVpreF-elicited immune responses were generally consistent when stratified by RSV subgroup, age group, and presence of prespecified high-risk conditions.

In the placebo group, RSV case accrual in season 2 was higher than during season 1 [16], possibly reflecting increased RSV circulation after reduction in coronavirus disease 2019 (COVID-19) pandemic mitigation strategies as suggested previously [17–20], as well as timely surveillance from the beginning of the season, which required site start-up and vaccination before the start of season 1 surveillance. Despite this, RSVpreF maintained efficacy through EOS2, during which time the dominant subgroup changed from RSV-B in season 1 to RSV-A in season 2 [16]. The durable efficacy of RSVpreF against both RSV subgroups across 2 seasons is important because although strains of RSV-A and RSV-B cocirculate, 1 subgroup is usually predominant [21]; therefore, protection against both subgroups is required.

The first season of the RENOIR trial was epidemiologically atypical because of the COVID-19 pandemic. Despite this, efficacy was preserved over 2 years, suggesting vaccination does not specifically need to be tied to seasonality. In seasons in which RSV starts to circulate in the summer, early vaccinations could be considered knowing that efficacy and immunogenicity remain strong into season 2. Additionally, RSVpreF can be conveniently coadministered with seasonal influenza vaccine. Coadministration of RSVpreF with influenza and COVID-19 vaccines is suggested by the US Centers for Disease Control and Prevention, particularly to optimize protection for the fall/winter seasons by vaccinating against all recommended respiratory viruses for an individual patient [22]. When coadministered, immune responses to RSVpreF, the COVID-19 vaccine BNT162b2, and influenza vaccines are noninferior to immune responses when the vaccines are administered separately and with no safety or tolerability concerns [23]. Consistent with pediatric vaccine schedules, coadministration of RSVpreF, influenza, and COVID-19 vaccines in a single healthcare visit may increase uptake in individuals for whom these vaccines are recommended [24].

Although no correlate of protection is established, available data associate higher serum RSV neutralization titers with less severe disease and low serum RSV neutralization titers with increased infection risk [25]. In RENOIR, persistent RSV neutralizing antibody titers observed in the immunogenicity subset through the preseason 2 visit align with efficacy results that showed durable protection over 2 full seasons. Notably, in some subgroups (eg, individuals with high-risk conditions), VE point estimates were lower at EOS2 versus EOS1, with wide CIs reflecting small event numbers; however, corresponding robust neutralizing antibody titers were observed 1 month post-vaccination and before season 2. The robust RSVpreF-elicited neutralizing responses in persons aged 18–59 years with risk factors for severe RSV illness from a recently reported phase 3 trial, which were immunobridged to the primary efficacy results from RENOIR, provide additional support for the protection afforded by RSVpreF in individuals at high risk for severe RSV-LRTI [26]. Additionally, in a phase 1/2 clinical trial, initial revaccination 12 months after initial vaccination with RSVpreF at the 240-µg dose level was well tolerated in persons aged 18–85 years and elicited RSV-A and RSV-B neutralizing responses; however, responses were less pronounced than following initial vaccination [27]. Interestingly, revaccination with GlaxoSmithKline's monovalent RSV vaccine (RSVPreF3) in older adults given 1 year after the initial dose in a phase 3 trial showed similar immunological trends and did not appear to provide further efficacy benefit compared with the efficacy benefit from initial vaccination in the overall study population. This might be related to persistence of RSV-specific antibodies up to 1 year after initial vaccination [28], as was observed in the pre-season 2 data in our study. It is encouraging that RSVpreF elicited robust immune responses in persons aged 70‒79 years and ≥80 years; the corresponding efficacy in these older adults will likely be confirmed in real-world studies and post-licensure surveillance.

Further investigation is required to ascertain duration of immunologic responses and protection provided by RSVpreF beyond 2 RSV seasons. Forthcoming substudies from RENOIR to assess revaccination and longer-term immunogenicity kinetics in this population of older adults, together with real-world effectiveness data, will help to determine if, when, and for whom revaccination is required, including with intervals of ≥2 years between vaccine doses.

Overall, RSVpreF was safe and well tolerated in participants aged ≥60 years. Safety results in all study participants through EOS2 were consistent with those from the EOS1 and primary analyses. AE frequencies were generally similar for the RSVpreF and placebo groups. No AEs of AF were assessed as related to RSVpreF by the investigator. The 2 participants with GBS variants were reported previously [15], and both cases had potentially confounding etiologies. Recent preliminary US Food and Drug Administration real-world analyses reported adjusted GBS rates after RSVpreF vaccination of 25.1 (95% CI, 6.7–43.4)/million doses and GBS risk following RSV vaccination in ≥65-year-olds of <10 cases/million doses [29, 30]. Stated limitations of these analyses included use of aggregate historical rates that increase the potential for confounding and bias, diagnosis codes within claims databases that are subject to misclassification, and verification of potential signals that is challenging because GBS is rare and the number of cases is small [29, 30]. These findings contributed to the Advisory Committee on Immunization Practices emphasizing that GBS risk with protein subunit RSV vaccines be considered in the context of public health benefits [31]. In published studies, background GBS incidence rates increase with age and vary by country, age group, and population (from 1.9/100 000 for persons aged 60–69 years to 12/100 000 for persons aged ≥85 years), and the reported odds ratio varies by vaccine (eg, from 1.03 for rotavirus diarrhea to 77.91 for influenza vaccines reported in a study using the World Health Organization global AE database from 1967–2023) [32–36]. GBS events should continue to be closely monitored in future studies and with post-marketing surveillance and real-world data.

Limitations of the final RENOIR analyses include the small numbers of participants in some stratified groups, including few participants who were aged >80 years. Immunogenicity analyses were conducted only in a subset of participants. Therefore, it is not possible to determine currently the RSV neutralizing antibody titer levels among participants who later developed RSV-associated disease, although this will be the focus of future investigations. This was a healthy population, and immunocompromised individuals and younger adults with high-risk medical conditions who are also at risk from adverse outcomes from RSV-associated disease were excluded, although immune responses and safety and tolerability findings in these populations were investigated in phase 3 trials and will be reported separately. Finally, the study was conducted at the height of the COVID-19 pandemic, and factors such as social distancing and masking may have affected case accrual, particularly in the first season.

In conclusion, these data from the RENOIR study continue to support vaccination of older adults with bivalent RSVpreF to prevent RSV illness from both RSV-A and RSV-B subgroups.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Author contributions. E. E. W., G. P. M., C. L., M. R., Y. F., N. H., and J. C. were involved in acquisition or generation of data. D. E., J. W., T. M., and I. M. were involved in acquisition or generation of data, data interpretation, data analysis, and data verification. Q. J. was involved in concept and study design, data interpretation, data analysis, and statistical analysis. M. P. was involved in concept and study design, acquisition or generation of data, data interpretation, data analysis, and data verification. A. Z. was involved in concept and study design and acquisition or generation of data. K. L. was involved in data interpretation. M. M. L. was involved in acquisition or generation of data and data interpretation. E. V. K. was involved in concept and study design, acquisition or generation of data, and data analysis. K. A. S. and A. G. were involved in concept and study design and data interpretation. All authors critically reviewed the manuscript and approved the final draft.

Acknowledgments. The authors thank all of the participants who volunteered for this study. They also thank all of the study site personnel for their contributions to this study. Medical writing support was provided by Sheena Hunt, PhD, Tricia Newell, PhD, and Erin O’Keefe, PhD, of ICON (Blue Bell, PA) and was funded by Pfizer, Inc. The authors especially acknowledge the following members of the Safety Data Monitoring Committee, who have been reviewing the trial safety data: Flor Muñoz (chair), Christy Chuang-Stein, Kim Fortner, Tina Hartert, R. Phillips Heine, and Jonathan Zenilman. They also acknowledge the following Pfizer, Inc, colleagues for their contributions to this work: James Baber, Wen Hao Bao, Michelle A. Bleile, Adriana M. Cahill, Raghava Chadive, Lesong Chen, David Cooper, Kimberly Ann Cristall, Tifani Dawson, Ekta Desai, Matthew Gawel, Jon E. Godshall, Megha Gupta, Kannan Iyyemperumal, Luciana de Jesus, Anisha Amol Karmalkar, Venkateswarlu Layam, Jennifer Maloney, Patricia Heath, Melissa Ann Marshall, John Omanoff, Ahmed Osman, Divyaja Padamati, Sneha Pandey, Dharti H. Patel, Allison B. Peffer, Deepali Purwar, Fuminori Sakai, Katherine Schneider, Yasuko Shoji, Joy E. Sieklucki, Melissa Simek-Lemos, Beate Schmoele-Thoma, Janet Timpano, Shaojun Xiao, and all of the Pfizer, Inc, colleagues not named here who contributed to the success of this study.

Disclaimer. Pfizer, Inc, was responsible for the study design and conduct; data collection, analysis, and interpretation; and writing of the manuscript.

Data sharing. Upon request, and subject to review, Pfizer, Inc, will provide the data that support the findings of this study. Subject to certain criteria, conditions, and exceptions, Pfizer, Inc, may also provide access to the related individual deidentified participant data. See https://www.pfizer.com/science/clinical-trials/trial-data-and-results for more information.

Financial support. This work was sponsored by Pfizer, Inc.

Author notes

Study Group team members are listed in the Supplementary material.

Potential conflicts of interest. E. E. W. is a grant recipient and unpaid consultant for Pfizer, Inc. G. P. M. is an investigator for Pfizer, Inc, Moderna, Merck, and Medicago. M. R. states that Finnish Vaccine Research, Ltd (formally Tampere University Vaccine Research Center) carries out clinical vaccine trials sponsored by all major vaccine manufacturers including Pfizer, Inc. D. E., J. W., Q. J., M. P., T. M., A. Z., K. I., M. M. L., E. V. K., K. A. S., A. G., and I. M. are Pfizer, Inc, employees and may hold stock or stock options. All other authors report no potential conflicts.

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.