Respiratory syncytial virus (RSV) is a leading cause of respiratory illness and there is no universally accepted serological correlate of protection (CoP). We evaluated serum pre-fusion immunoglobulin G binding (preF-IgG) and RSV-A2 neutralizing antibodies (RSV-nAb) in adults aged >60 years following vaccination with investigational Ad26.RSV.preF–RSV preF vaccine. PreF-IgG and RSV-nAb measured pre-vaccination (Day 1) and Day 15 post-vaccination were assessed as CoPs against RSV-mediated acute respiratory infection (ARI) and lower respiratory tract disease (LRTD). An increase in both preF-IgG and RSV-nAb at Day 15 was significantly associated with reduced occurrence of RSV-mediated ARI and LRTD during follow-up. Based on controlled vaccine-efficacy curves and Prentice criteria, both markers were identified as CoPs for RSV-mediated ARI and LRTD. These results were validated using samples from a second randomized, phase 3 efficacy trial. Comprehensive profiling of preF-specific antibody responses showed that preF IgG3 and IgG2 may also contribute to protection from RSV.

IntroductionRespiratory syncytial virus (RSV) causes significant lower-respiratory-tract disease in high-risk groups. A phase IIb trial showed that a combination vaccine of Ad26-vectored prefusion RSV F (Ad26.preF) plus soluble prefusion F protein (SpreF) was 80 % protective, yet the longevity and functionality of these humoral responses are unknown.MethodsSera from vaccinated adults were analyzed 12 months after the primary dose and 28 days after a homologous booster at 1 year. IgG subclasses, isotypes, Fc-γ receptor (FcγR) binding, and Fc-dependent effector functions including opsinophagocytosis against RSV-F subtypes A and B were quantified via Systems Serology.ResultsA single dose generated durable immunity: IgG3-driven opsonophagocytic activity and broad FcγR engagement (via IgG1, IgG2, and IgG3) persisted through 12 months without appreciable decay. The booster did not increase antibody titres, FcγR binding, or functional activity, indicating that the primary response had already plateaued.DiscussionOne dose of Ad26.preF + SpreF elicits a long-lasting, functionally potent humoral response that is not further enhanced by a booster at 12 months, suggesting limited benefit from early re-vaccination. Continued follow-up will clarify the duration of protection and inform booster timing in vulnerable populations.

Importance Uptake of recommended seasonal influenza and COVID-19 vaccines remains suboptimal. Objective To assess the immunogenicity and safety of an investigational mRNA-1083 vaccine against seasonal influenza and SARS-CoV-2 in adults 50 years and older. Design, Setting, and Participants This phase 3, randomized, observer-blinded trial was conducted across 146 US sites in adults 50 years and older enrolled between October 19, 2023, and November 21, 2023. Data extraction was complete on April 9, 2024. Interventions Participants in 2 age cohorts (>= 65 years and 50-64 years) were randomly assigned (1:1) to receive mRNA-1083 plus placebo or coadministered licensed quadrivalent seasonal influenza (>= 65 years: high-dose quadrivalent inactivated influenza vaccine [HD-IIV4]; 50-64 years: standard-dose IIV4 [SD-IIV4]) and COVID-19 (all ages: mRNA-1273) vaccines. Main Outcomes and Measures The primary objectives were to demonstrate the noninferiority of humoral immune responses following mRNA-1083 vs comparators against vaccine-matched strains at day 29 and to evaluate the reactogenicity and safety of mRNA-1083. Secondary objectives included demonstration of superiority of humoral immune responses elicited by mRNA-1083 relative to comparators at day 29. Results Overall, 8015 participants were enrolled and vaccinated (4017 aged >= 65 y and 3998 aged 50-64 y). Among adults 65 years and older and 50 to 64 years, the median age was 70 and 58 years, 54.2% and 58.8% were female, 18.4% and 26.7% were Black or African American, and 13.9% and 19.3% were Hispanic or Latino, respectively. Noninferior immunogenicity of mRNA-1083 was demonstrated against all vaccine-matched influenza and SARS-CoV-2 strains based on lower bound of the 97.5% CI of the geometric mean ratio greater than 0.667 and lower bound of the 97.5% CI of the seroconversion/seroresponse rate difference greater than -10%. mRNA-1083 elicited higher immune responses than SD-IIV4 (50-64 years) for all 4 influenza strains and HD-IIV4 (>= 65 years) for 3 influenza strains (A/H1N1, A/H3N2, B/Victoria) and against SARS-CoV-2 (all ages). Solicited adverse reactions were numerically higher in frequency and severity after mRNA-1083 vaccination than comparators in both age cohorts (>= 65 y: 83.5% and 78.1%; 50-64 y: 85.2% and 81.8%); most were grade 1 or 2 in severity and of short duration. No safety concerns were identified. Conclusions and Relevance In this study, mRNA-1083 met noninferiority criteria and induced higher immune responses than recommended standard care influenza (standard and high dose) and COVID-19 vaccines against all 4 influenza strains (among those ages 50-64 y), the 3 clinically relevant influenza strains (among those aged >= 65 y), and SARS-CoV-2 (all ages), with an acceptable tolerability and safety profile.

Uptake of recommended seasonal influenza and COVID-19 vaccines remains suboptimal. To assess the immunogenicity and safety of an investigational mRNA-1083 vaccine against seasonal influenza and SARS-CoV-2 in adults 50 years and older. This phase 3, randomized, observer-blinded trial was conducted across 146 US sites in adults 50 years and older enrolled between October 19, 2023, and November 21, 2023. Data extraction was complete on April 9, 2024. Participants in 2 age cohorts (≥65 years and 50-64 years) were randomly assigned (1:1) to receive mRNA-1083 plus placebo or coadministered licensed quadrivalent seasonal influenza (≥65 years: high-dose quadrivalent inactivated influenza vaccine [HD-IIV4]; 50-64 years: standard-dose IIV4 [SD-IIV4]) and COVID-19 (all ages: mRNA-1273) vaccines. The primary objectives were to demonstrate the noninferiority of humoral immune responses following mRNA-1083 vs comparators against vaccine-matched strains at day 29 and to evaluate the reactogenicity and safety of mRNA-1083. Secondary objectives included demonstration of superiority of humoral immune responses elicited by mRNA-1083 relative to comparators at day 29. Overall, 8015 participants were enrolled and vaccinated (4017 aged ≥65 y and 3998 aged 50-64 y). Among adults 65 years and older and 50 to 64 years, the median age was 70 and 58 years, 54.2% and 58.8% were female, 18.4% and 26.7% were Black or African American, and 13.9% and 19.3% were Hispanic or Latino, respectively. Noninferior immunogenicity of mRNA-1083 was demonstrated against all vaccine-matched influenza and SARS-CoV-2 strains based on lower bound of the 97.5% CI of the geometric mean ratio greater than 0.667 and lower bound of the 97.5% CI of the seroconversion/seroresponse rate difference greater than −10%. mRNA-1083 elicited higher immune responses than SD-IIV4 (50-64 years) for all 4 influenza strains and HD-IIV4 (≥65 years) for 3 influenza strains (A/H1N1, A/H3N2, B/Victoria) and against SARS-CoV-2 (all ages). Solicited adverse reactions were numerically higher in frequency and severity after mRNA-1083 vaccination than comparators in both age cohorts (≥65 y: 83.5% and 78.1%; 50-64 y: 85.2% and 81.8%); most were grade 1 or 2 in severity and of short duration. No safety concerns were identified. In this study, mRNA-1083 met noninferiority criteria and induced higher immune responses than recommended standard care influenza (standard and high dose) and COVID-19 vaccines against all 4 influenza strains (among those ages 50-64 y), the 3 clinically relevant influenza strains (among those aged ≥65 y), and SARS-CoV-2 (all ages), with an acceptable tolerability and safety profile. ClinicalTrials.gov Identifier: NCT06097273

Background: Respiratory syncytial virus (RSV) causes a significant disease burden in adults with chronic comorbidities. Rates of severe RSV disease and death are as high, or higher in younger adults with risk factors than in healthy older adults in whom RSV vaccination is recommended. We conducted an immunobridging study using the Ad26/protein RSV preF vaccine, which previously demonstrated efficacy in adults aged >65 years to support extrapolation of efficacy demonstrated in an older population to younger adult populations at high risk of severe RSV disease. Methods: This Phase 3 randomized, double-blind, placebo-controlled trial assessed the safety/tolerability and immunogenicity of Ad26/protein preF RSV in adults aged 18-59 years without (Cohort 1) and with (Cohort 2) chronic cardiac or pulmonary comorbidities, compared to adults aged >65 years (Cohort 3) in whom efficacy against RSV disease was demonstrated. Humoral and cellular immune responses were assessed at baseline, Days 15 and 183. Reactogenicity and safety were assessed in all participants. Results: 1118 participants were enrolled (Cohort 1: 387; Cohort 2: 388; Cohort 3: 343). Compared to adults aged >65 years RSV neutralizing antibody titers were non-inferior in adults aged 18-59 years, including those at highrisk. Levels of pre-F A IgG antibodies and frequencies of RSV-F specific interferon-gamma T-cells increased Day 15 post-vaccination, and remained above baseline for at least 6 months in all cohorts. Reactogenicity safety were clinically acceptable but age-dependent, with higher rates of Grade 3 systemic adverse events adults aged 18-59-years than adults >65 years. Conclusion: Ad26/protein preF RSV vaccine induced robust humoral and cellular immune responses in adults aged 18-59 years with or without chronic cardiac or pulmonary comorbidities, of similar magnitude to responses in older adults, allowing inference of efficacy and protection against RSV-associated respiratory disease in population.

BACKGROUND:Safety and efficacy of Ad26.RSV.preF/RSV preF-based vaccine in preventing lower respiratory tract disease (LRTD) was assessed in controlled clinical trials globally. This phase 3 study evaluated efficacy, immunogenicity, and safety of Ad26.RSV.preF/RSV preF-based vaccine for respiratory syncytial virus (RSV)-mediated LRTD prevention in Japanese older adults (Cohort 1: ≥60 years), and immunogenicity and safety in Japanese younger adults (Cohort 2: 20-59 years). METHODS:The primary objective in Cohort 1 (≥60 years) was to assess the efficacy of vaccine against reverse transcriptase polymerase chain reaction (RT-PCR)-confirmed RSV-mediated LRTD over one RSV season versus placebo; in Cohort 2 the primary objective was to demonstrate non-inferiority of humoral response to RSV vaccine in younger adults versus older adults (20-59 years). RESULTS:In Cohort 1, 2003 participants were randomized (1:1) to vaccine (n = 996) or placebo (n = 1007). None had RSV-mediated LRTD during the first RSV season in vaccine group (study terminated prematurely). In Cohort 2, 180 participants were randomized (3:1) to vaccine (n = 135) or placebo (n = 45). Post-vaccination humoral response in younger adults was found non-inferior to that of older adults. Substantial rise in RSV binding and neutralizing antibody titers from baseline to Day 15 was observed in both Cohorts. Solicited and unsolicited adverse events were more frequent in vaccine group versus placebo group (Cohort 1: 119/149 [79.9 %] and 18/149 [12.1 %] versus 39/150 [26.0 %] and 10/150 [6.7 %]; Cohort 2: 134/138 [97.1 %] and 12/138 [8.7 %] versus 15/46 [32.6 %] and 0/46 [0 %]). CONCLUSIONS:Although vaccine efficacy could not be concluded, it was immunogenic with acceptable safety profile in both Japanese younger and older adult population. CLINICAL TRIAL REGISTRATION NUMBER:NCT05242432.

The Ad26.RSV.preF/RSV preF protein vaccine has previously demonstrated efficacyin protecting older adults against respiratory syncytial virus (RSV)-related lower respiratory tract disease in a phase 2b study. This study compared the immunogenicity of vaccine clinical trial material (CTM) representative of phase 2b clinical studies with CTM used in phase 3 clinical studies. A total of 248 adults aged 60-75 years, randomized in a 1:1 ratio, received one dose of either phase 3 CTM or phase 2b CTM. Solicited adverse events (AEs), unsolicited AEs, and serious AEs (SAEs) were assessed for 7-d, 28-d, and 6-month periods post-vaccination, respectively. RSV preF-ELISA antibody titers and RSV neutralizing titers were measured before and 14 d after vaccination. The phase 3 CTM-induced preF-ELISA response at Day 15, in terms of geometric mean titer, was shown to be non-inferior to that induced by phase 2b CTM. The RSV neutralizing antibody titers were also similar in the two groups at Day 15. The safety profile in terms of solicited AEs, unsolicited AEs, or SAEs was in general similar between the phase 3 CTM and phase 2b CTM groups, and solicited AEs were mostly mild to moderate in intensity. No related SAEs were reported, and no safety concerns were identified.

Background Respiratory syncytial virus (RSV) causes serious illness in children. The Ad26.RSV.preF vaccine candidate was immunogenic with acceptable safety in a phase 1/2a study of RSV-seropositive children. Here, we assessed its safety and immunogenicity in RSV-seronegative children.Methods In this randomized, observer-blinded, placebo-controlled, phase 1/2a study (NCT03606512; https://www.clinicaltrials.gov/ct2/show/NCT03606512), RSV-seronegative toddlers aged 12-24 months received Ad26.RSV.preF (2.5 x 1010 viral particles) or placebo on days 1, 29, and 57 (a meningococcal vaccine [Nimenrix] could substitute for day 57 placebo). Primary endpoints were solicited local and systemic adverse events (AEs; 7 days after each vaccination), unsolicited AEs (28 days postvaccination), and serious AEs (first vaccination until study end). Participants were monitored for RSV-respiratory tract infection to assess infection rates and for severe RSV-lower respiratory tract infection as an indication of enhanced disease. RSV-A2 neutralizing, RSV (A and B) preF binding, and RSV postF immunoglobulin G-binding antibodies were evaluated on days 1 (predose), 8, and 85, and after RSV season 1.Results Thirty-eight participants were enrolled and vaccinated (Ad26.RSV.preF, n = 20; placebo, placebo/Nimenrix, n = 18). Solicited AEs were more common following Ad26.RSV.preF than placebo; most were mild/moderate. No vaccine-related serious AEs were reported. Five of 19 participants receiving Ad26.RSV.preF and 2/18 receiving placebo or placebo/Nimenrix had confirmed RSV-respiratory tract infection or RSV-associated otitis media; none were considered severe. At the final season 1 study visit, most Ad26.RSV.preF recipients had >= 2-fold increases from baseline in RSV-A2 neutralizing, RSV A and B preF binding, and RSV postF antibodies.Conclusions Ad26.RSV.preF was well tolerated and immunogenic in RSV-seronegative toddlers. In this phase 1/2a study, 3 doses of the Ad26.RSV.preF vaccine (2.5 x 1010 vp) was well tolerated and elicited an immunogenic response in RSV-seronegative toddlers aged 12-14 months through 2 RSV seasons.

BACKGROUND:Respiratory syncytial virus (RSV) is increasingly recognized as a significant cause of lower respiratory tract disease (LRTD) in older adults. The Ad26.RSV.preF/RSV preF protein vaccine demonstrated protective efficacy against RSV related LRTD in a Phase 2b study in the United States. Hence, Ad26.RSV.preF/RSV preF protein vaccine candidate was evaluated in the Japanese older adult population. METHODS:This Phase 1 study evaluated safety, reactogenicity, and immunogenicity of Ad26.RSV.preF/RSV preF protein vaccine at dose level of 1 × 1011 vp/150 μg in Japanese healthy adult aged ≥60 years. The study included a screening Phase, vaccination, 28-day follow up Phase, a 182-day follow-up period, and final visit on Day 183. A total of 36 participants were randomized in a 2:1 ratio to receive Ad26.RSV.preF/RSV preF protein vaccine (n = 24) or placebo (n = 12). After study intervention administration, the safety and immunogenicity analysis were performed as per planned schedule. Immune responses including virus-neutralizing and preF-specific binding antibodies were measured on Days 1, 15, 29, and 183. RESULTS:There were no deaths, SAEs, or AEs leading to discontinuation reported during the study. The Ad26.RSV.preF/RSV preF protein vaccine had acceptable safety and tolerability profile with no safety concern in Japanese older adults. The Ad26.RSV.preF/RSV preF protein vaccine induced RSV-specific humoral immunity, with increase in antibody titers on Days 15 and 29 compared with baseline which was well maintained until Day 183. CONCLUSIONS:A single dose of Ad26.RSV.preF/RSV preF protein vaccine had an acceptable safety and tolerability profile and induced RSV-specific humoral immunity in Japanese healthy adults. TRIAL REGISTRATION:NCT number: NCT04354480; Clinical Registry number: CR108768.

Background Since influenza and respiratory syncytial virus (RSV) carry significant burden in older adults with overlapping seasonality, vaccines for both pathogens would ideally be coadministered in this population. Here we evaluate the immunogenicity and safety of concomitant administration of Ad26.RSV.preF/RSV preF protein and high-dose seasonal influenza vaccine (Fluzone-HD) in adults >= 65 years old.Methods Participants were randomized 1:1 to the Coadministration or Control group. The Coadministration group received concomitant Ad26.RSV.preF/RSV preF protein and Fluzone-HD on day 1 and placebo on day 29, while the Control group received Fluzone-HD and placebo on day 1 and Ad26.RSV.preF/RSV preF protein on day 29. Influenza hemagglutination-inhibiting and RSV preF-binding antibody titers were measured postvaccination and tested for noninferiority between both groups. Safety data were collected throughout the study and analyzed descriptively.Results Coadministered Ad26.RSV.preF/RSV preF protein and Fluzone-HD vaccines induced noninferior immune responses compared to each vaccine administered alone. Seroconversion and seroprotection rates against influenza were similar between groups. Both vaccines remained well tolerated upon concomitant administration.Conclusions Coadministration of Ad26.RSV.preF/RSV preF protein and Fluzone-HD showed an acceptable safety profile and did not hamper the immunogenicity of either vaccine, thus supporting that both vaccines can be concomitantly administered in adults >= 65 years old. Respiratory syncytial virus (RSV) and influenza vaccines would ideally be coadministered in adults >= 65 years. Coadministration of an RSV vaccine candidate (Ad26.RSV.preF/RSV preF protein) and Fluzone-HD had an acceptable safety profile and did not hamper the immunogenicity of either vaccine.

Background. Ad26.RSV.preF is an adenovirus serotype 26 vector-based respiratory syncytial virus (RSV) vaccine encoding a prefusion conformation-stabilized RSV fusion protein (preF) that demonstrated robust humoral and cellular immunogenicity and showed promising efficacy in a human challenge study in younger adults. Addition of recombinant RSV preF protein might enhance RSV-specific humoral immune responses, especially in older populations. Methods. This randomized, double-blind, placebo-controlled, phase 1/2a study compared the safety and immunogenicity of Ad26.RSV.preF alone and varying doses of Ad26.RSV.preF-RSV preF protein combinations in adults aged >= 60 years. This report includes data from cohort 1 (initial safety, n = 64) and cohort 2 (regimen selection, n = 288). Primary immunogenicity and safety analyses were performed 28 days postvaccination (cohort 2) for regimen selection. Results. All vaccine regimens were well tolerated, with similar reactogenicity profiles among them. Combination regimens induced greater humoral immune responses (virus-neutralizing and preF-specific binding antibodies) and similar cellular ones (RSV-F-specific T cells) as compared with Ad26.RSV.preF alone. Vaccine-induced immune responses remained above baseline up to 1.5 years postvaccination. Conclusions. All Ad26.RSV.preF-based regimens were well tolerated. A combination regimen comprising Ad26.RSV.preF, which elicits strong humoral and cellular responses, and RSV preF protein, which increases humoral responses, was selected for further development.

Vaccination with Ad26.RSV.preF, an Adenoviral serotype 26 vector encoding RSV F protein stabilized in its prefusion conformation, has previously shown to be immunogenic and protective in RSV seropositive adults and immunogenic in seropositive infants. Human and bovine RSV (bRSV) are genetically highly related and share many aspects of pathogenesis, epidemiology and clinical manifestations at young age. As such, infection of calves with bRSV represents a clinically relevant model with high translational value, enabling preclinical evaluation of Ad26.RSV.preF vaccine efficacy in seronegative young animals. Immunization of young calves with Ad26.RSV.preF induced antibodies neutralizing both human and bovine RSV as well as RSV-specific cellular responses. After bRSV challenge, placebo immunized calves showed viral replication in the respiratory tract, and developed fever and lethargy accompanied with severe respiratory distress, resulting in pre-termination of 7/8 calves. In contrast, all Ad26.RSV.preF immunized calves completed the study with only mild clinical symptoms, strongly and significantly diminished viral loads in nasopharynx and lungs, and only minimal lung pathology. Thus, Ad26.RSV.preF is immunogenic in young calves and efficacious in a stringent heterologous bRSV challenge model, demonstrating induction of broadly protective immunity against severe disease.

BackgroundAd26.RSV.preF–RSV preF protein showed 80·0% vaccine efficacy against respiratory syncytial virus (RSV) lower respiratory tract disease (LRTD) in older adults during one RSV season. No RSV vaccines have shown three-season efficacy. We aimed to evaluate efficacy of Ad26.RSV.preF–RSV preF protein over three RSV seasons.MethodsCYPRESS was a randomised, double-blind, placebo-controlled, phase 2b study done at 40 US clinical research centres wherein adults aged 65 years or older were centrally randomly assigned 1:1 by computer algorithm to receive Ad26.RSV.preF–RSV preF protein or placebo (one intramuscular injection) on day 1. Investigators, participants, site personnel, and the sponsor were masked to vaccine allocation, except for individuals involved in preparation of study vaccinations. The primary endpoint (first occurrence of RSV-mediated LRTD meeting one of three case definitions) was previously reported. Here, the predefined exploratory endpoint of vaccine efficacy against RSV-positive LRTD was assessed in the per-protocol efficacy set (all participants randomly assigned and vaccinated without protocol deviations affecting efficacy) through season 1 and from day 365 until the end of season 3. Humoral and cellular immunogenicity was assessed in a subset of randomly assigned and vaccinated participants. The secondary endpoint of safety through the first RSV season was previously reported; follow-up for selected safety outcomes (fatal adverse events, adverse events leading to study discontinuation, serious adverse events, and vaccine-related serious adverse events) until study completion is reported here in all randomly assigned and vaccinated participants. This trial is registered with ClinicalTrials.gov, NCT03982199 and is complete.FindingsOf 6672 adults screened, 5782 participants (2891 each receiving vaccine or placebo) were enrolled and vaccinated between Aug 5 and Nov 13, 2019. The season 2 per-protocol efficacy set included 2124 vaccine recipients and 2126 placebo recipients (season 3: 864 and 881; across three seasons: 2795 and 2803, respectively). Vaccine efficacy against RSV LRTD was 76·1% (95% CI 26·9–94·2) over seasons 2 and 3 and 78·7% (57·3–90·4) across three seasons. For those in the immunogenicity subset (vaccine n=97; placebo n=98), immune responses remained above baseline for at least 1 year. Serious adverse events occurred in 47 (2·1%) and 12 (1·3%) vaccine recipients and 45 (2·1%) and 10 (1·1%) placebo recipients during seasons 2 and 3, respectively. No treatment-related serious or fatal adverse events were reported.InterpretationAd26.RSV.preF–RSV preF protein maintained high efficacy against RSV LRTD in older adults across three RSV seasons.FundingJanssen Vaccines & Prevention.

Background: Respiratory syncytial virus (RSV) can cause severe illness in older adults. A combination vaccine containing Ad26.RSV.preF and purified recombinant RSV preF protein has previously demonstrated efficacy and tolerability in older adults. We report results of a dose-ranging study to determine immunogenicity and safety of different doses of the Ad26.RSV.preF component in the combined Ad26.RSV.preF/RSV preF protein vaccine to support Ad26.RSV.preF drug product release and stability specifications. Methods: In this randomized, double-blind, placebo-controlled, phase 2a study, adults aged >= 60 years in good or stable health were randomly assigned within 1 of 3 cohorts to receive either placebo or Ad26.RSV.preF/RSV preF protein, composed of different doses of Ad26.RSV.preF with a fixed dose of RSV preF protein (150 mu g). Ad26.RSV.preF doses in Cohort 1 (4 dose-down groups) ranged from 3.7 x 10(9) to 1.0 x 10(11) viral particles (vp). Doses in Cohorts 2 and 3 (2 dose-up groups, each) ranged from 1.0 to 1.6 x 10(11) vp. Primary endpoints were immunogenicity (RSV preF protein antibody titers) for Cohort 1 and safety (solicited local and systemic adverse events [AEs] and unsolicited AEs) for Cohorts 2 and 3. Immunogenicity analyses (RSV preF protein antibody titers, RSV A2 neutralizing antibodies, and RSV-F-specific interferon-gamma enzyme-linked immunosorbent spot) were performed on the day of vaccination and 14 days, 3 months, and 6 months postvaccination. Safety was monitored from vaccination until study end. Results: Overall, 454 participants were enrolled and received 1 dose of study vaccine or placebo (Cohort 1, n = 226; Cohort 2, n = 124; Cohort 3, n = 104). No substantial differences in measured immune responses were observed between lower or higher Ad26.RSV.preF doses compared with Ad26.RSV.preF 1.0 x 10(11) vp across all postvaccination time points. All Ad26.RSV.preF doses between 3.7 x 10(9) vp and 1.6 x 10(11) vp were well tolerated, with no safety issues identified. Conclusions: Results of this dose-ranging study may be used to inform the refinement of Ad26.RSV.preF drug product release and stability specifications. Clinical trial registration: ClinicalTrials.gov Identifier: NCT04453202.

This study assessed three Ad26.RSV.preF/RSV preF protein combinations, combining different Ad26.RSV.preF doses and naturally aged preF protein, representing the expected critical vaccine quality attributes close to release, around intermediate shelf-life (ISL) and near-presumed end-of-shelf-life (EoSL), as a way to evaluate the vaccine immunogenicity and safety throughout its shelf-life. A single dose of Ad26.RSV.preF/RSV preF protein vaccine was administered to adults 60-75 years of age. Solicited adverse events (AEs), unsolicited AEs, and serious AEs (SAEs) were assessed for 7-day, 28-day, and 6-month periods after vaccination, respectively. RSV preF-binding antibody concentrations and RSV neutralizing titers were measured 14 days post-vaccination as primary and secondary endpoints, respectively; binding antibodies were also measured 6 months post-vaccination. The RSV preF-binding antibody responses induced by Ad26.RSV.preF/RSV preF protein vaccine lots representing the critical quality attributes around ISL and near presumed EoSL were noninferior to the responses induced by the vaccine lot representing the critical quality attributes near release. The RSV preF-binding and RSV neutralizing antibody levels measured 14 days post-vaccination were similar across the 3 groups. RSV preF-binding antibody concentrations were also similar 6 months post-vaccination. Solicited AEs were mostly mild to moderate in intensity, and a decreased reactogenicity was observed from the Release group to the ISL and EoSL group. None of the reported SAEs were considered related to study vaccination. The study provided evidence of sustained immunogenicity and safety over the intended shelf-life of the Ad26.RSV.pref/RSV preF protein vaccine. The three vaccine lots had acceptable safety profiles.

Background The Respiratory Infection Intensity and Impact Questionnaire (RiiQ™) is a patient-reported outcome measure designed to assess symptoms and impacts of respiratory syncytial virus (RSV) infection. This study evaluated the construct validity, reliability, and responsiveness of the RiiQ™ Respiratory and Systemic Symptoms Scale scores. Methods Prospective data were analyzed from a total of 1795 participants, including from non-hospitalized patients with acute respiratory infection (ARI) and no coinfections enrolled in a Phase 2b RSV vaccine study (RSV-positive: n = 60; RSV-negative: n = 1615), and two observational studies of patients hospitalized with RSV (n = 20; n = 100). Descriptive statistics, confirmatory factor analysis (CFA), test–retest intraclass correlation coefficients (ICCs), construct validity correlations (between a clinician-assessed clinical questionnaire and the RiiQ™ symptoms scale), known-groups validity, and responsiveness (correlations of change scores) were evaluated. Results Mean patient age ranged from 66.5 to 71.5 years and the majority of patients were female. Initial assessments in the vaccine trial (ARI Day 1) were suggestive of less severe illness than in the observational studies with hospitalized patients. CFA loadings (> 0.40) supported summary scores. ICCs exceeding the recommended threshold of 0.70 supported test–retest reliability for Respiratory and Systemic Symptoms, except in the small observational study. At the scale level, correlations were moderate to strong (| r | ≥ 0.3) and positive between the Respiratory Symptoms Scale and the related clinical questionnaire scores, reflecting measurement of similar symptoms in support of convergent validity. Correlations with change in Patient Global Impression of Severity > 0.30 supported responsiveness. Conclusions Psychometric tests applied to the RiiQ™ Symptoms scales provide evidence of its reliability, construct validity, discriminating ability, and responsiveness for use in clinical studies to assess the onset and severity of RSV symptoms.

RSV is divided into two antigenic subtypes, RSV A and RSV B, which is largely based on the variation in the G protein, while the fusion protein F is more conserved and a target for antibody-mediated neutralization. Here we evaluate the breadth of the protective immune responses across RSV A and RSV B subtypes, induced by vaccines based on the RSV A-based fusion protein, stabilized in the prefusion conformation (preF) in preclinical models. Immunization of naïve cotton rats with preF subunit or preF encoded by a replication incompetent Adenoviral 26, induced antibodies capable of neutralizing recent RSV A and RSV B clinical isolates, as well as protective efficacy against a challenge with RSV A and RSV B strains. Similarly, induction of cross-neutralizing antibodies was observed after immunization with Ad26-encoded preF, preF protein or a mix of both (Ad26/preF protein) in RSV pre-exposed mice and African Green Monkeys. Transfer of serum of human subjects immunized with Ad26/preF protein into cotton rats provide protection against challenges with both RSV A and RSV B, with complete protection against both strains observed in the lower respiratory tract. In contrast, almost no protection against RSV A and B infection was observed after the transfer of a human serum pool isolated pre-vaccination. These results collectively show that the RSV A-based monovalent Ad26/preF protein vaccine induced neutralizing antibodies, as well as protection against both RSV A and RSV B subtypes in animals, including by passive transfer of human antibodies alone, suggesting that clinical efficacy against both subtypes can be achieved.

ABSTRACT An Ad26.RSV.preF/RSV preF protein combination vaccine demonstrated 80.0% vaccine efficacy for the prevention of respiratory syncytial virus (RSV)-mediated lower respiratory tract disease in a phase 2b study. In addition to neutralizing antibodies, Fc-effector functions are associated with protective immunity against RSV. Here, vaccine-induced Fc-effector functions were evaluated for the Ad26.RSV.preF/RSV preF protein vaccine in a subset of participants enrolled in a phase 1/2a study. RSV preF-specific antibody subclasses, isotypes, Fcγ receptor binding, and Fc-effector functions were evaluated on days 1 (pre-vaccination), 15, 29, and 183. Compared with Ad26.RSV.preF or RSV preF protein alone, the combination vaccine induced greater Fc-effector functions, including antibody-dependent neutrophil phagocytosis and antibody-dependent natural killer cell activation. Despite RSV pre-exposure, antibody-dependent neutrophil phagocytosis and antibody-dependent natural killer cell activation were not observed at baseline but were induced de novo following vaccination. Compared with the individual vaccine components, the combination vaccine induced a more polyfunctional antibody response. IMPORTANCE Respiratory syncytial virus (RSV) can cause serious illness in older adults (i.e., those aged ≥60 years). Because options for RSV prophylaxis and treatment are limited, the prevention of RSV-mediated illness in older adults remains an important unmet medical need. Data from prior studies suggest that Fc-effector functions are important for protection against RSV infection. In this work, we show that the investigational Ad26.RSV.preF/RSV preF protein vaccine induced Fc-effector functional immune responses in adults aged ≥60 years who were enrolled in a phase 1/2a regimen selection study of Ad26.RSV.preF/RSV preF protein. These results demonstrate the breadth of the immune responses induced by the Ad26.RSV.preF/RSV preF protein vaccine.

BACKGROUND Respiratory syncytial virus (RSV) can cause serious lower respiratory tract disease in older adults, but no licensed RSV vaccine currently exists. An adenovirus serotype 26 RSV vector encoding a prefusion F (preF) protein (Ad26.RSV.preF) in combination with RSV preF protein was previously shown to elicit humoral and cellular immunogenicity. METHODS We conducted a randomized, double-blind, placebo-controlled, phase 2b, proof-of-concept trial to evaluate the efficacy, immunogenicity, and safety of an Ad26.RSV.preF-RSV preF protein vaccine. Adults who were 65 years of age or older were randomly assigned in a 1:1 ratio to receive vaccine or placebo. The primary end point was the first occurrence of RSV-mediated lower respiratory tract disease that met one of three case definitions: three or more symptoms of lower respiratory tract infection (definition 1), two or more symptoms of lower respiratory tract infection (definition 2), and either two or more symptoms of lower respiratory tract infection or one or more symptoms of lower respiratory tract infection plus at least one systemic symptom (definition 3). RESULTS Overall, 5782 participants were enrolled and received an injection. RSV-mediated lower respiratory tract disease meeting case definitions 1, 2, and 3 occurred in 6, 10, and 13 vaccine recipients and in 30, 40, and 43 placebo recipients, respectively. Vaccine efficacy was 80.0% (94.2% confidence interval [CI], 52.2 to 92.9), 75.0% (94.2% CI, 50.1 to 88.5), and 69.8% (94.2% CI, 43.7 to 84.7) for case definitions 1, 2, and 3, respectively. After vaccination, RSV A2 neutralizing antibody titers increased by a factor of 12.1 from baseline to day 15, a finding consistent with other immunogenicity measures. Percentages of participants with solicited local and systemic adverse events were higher in the vaccine group than in the placebo group (local, 37.9% vs. 8.4%; systemic, 41.4% vs. 16.4%); most adverse events were mild to moderate in severity. The frequency of serious adverse events was similar in the vaccine group and the placebo group (4.6% and 4.7%, respectively). CONCLUSIONS In adults 65 years of age or older, Ad26.RSV.preF-RSV preF protein vaccine was immunogenic and prevented RSV-mediated lower respiratory tract disease. (Funded by Janssen Vaccines and Prevention; CYPRESS ClinicalTrials.gov number, NCT03982199.).