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Respiratory syncytial virus is a major cause of illness in infants. In this randomized, double-blind, placebo-controlled trial, the safety and immunogenicity of a bivalent RSV prefusion F protein–based vaccine was assessed in pregnant women and their infants. Anti-RSV antibodies were elicited with efficient transplacental transfer.

Abstract Background Respiratory syncytial virus (RSV) is the leading viral cause of severe pediatric respiratory illness, and vaccines are needed. Live RSV vaccine D46/NS2/N/ΔM2-2-HindIII, attenuated by deletion of the RSV RNA regulatory protein M2-2, is based on previous candidate LID/ΔM2-2 but incorporates prominent differences from MEDI/ΔM2-2, which was more restricted in replication in phase 1. Methods RSV-seronegative children aged 6–24 months received 1 intranasal dose (105 plaque-forming units [PFUs] of D46/NS2/N/ΔM2-2-HindIII [n = 21] or placebo [n = 11]) and were monitored for vaccine shedding, reactogenicity, RSV-antibody responses and RSV-associated medically attended acute respiratory illness (RSV-MAARI) and antibody responses during the following RSV season. Results All 21 vaccinees were infected with vaccine; 20 (95%) shed vaccine (median peak titer, 3.5 log10 PFUs/mL with immunoplaque assay and 6.1 log10 copies/mL with polymerase chain reaction). Serum RSV-neutralizing antibodies and anti-RSV fusion immunoglobulin G increased ≥4-fold in 95% and 100% of vaccines, respectively. Mild upper respiratory tract symptoms and/or fever occurred in vaccinees (76%) and placebo recipients (18%). Over the RSV season, RSV-MAARI occurred in 2 vaccinees and 4 placebo recipients. Three vaccinees had ≥4-fold increases in serum RSV-neutralizing antibody titers after the RSV season without RSV-MAARI. Conclusions D46/NS2/N/ΔM2-2-HindIII had excellent infectivity and immunogenicity and primed vaccine recipients for anamnestic responses, encouraging further evaluation of this attenuation strategy. Clinical Trials Registration NCT03102034 and NCT03099291. Live respiratory syncytial virus (RSV) vaccine D46/NS2/N/ΔM2-2-HindIII attenuated by deletion of the RSV RNA regulatory protein M2-2 had excellent infectivity and immunogenicity, and primed for anamnestic responses, encouraging further evaluation of this attenuation strategy.

Technologies that define the atomic-level structure of neutralization-sensitive epitopes on viral surface proteins are transforming vaccinology and guiding new vaccine development approaches. Previously, iterative rounds of protein engineering were performed to preserve the prefusion conformation of the respiratory syncytial virus (RSV) fusion (F) glycoprotein, resulting in a stabilized subunit vaccine candidate (DS-Cav1), which showed promising results in mice and macaques. Here, phase I human immunogenicity data reveal a more than 10-fold boost in neutralizing activity in serum from antibodies targeting prefusion-specific surfaces of RSV F. These findings represent a clinical proof of concept for structure-based vaccine design, suggest that development of a successful RSV vaccine will be feasible, and portend an era of precision vaccinology.

Respiratory syncytial virus (RSV) causes a significant disease burden in older adults. The live recombinant vaccine based on a nonreplicating modified vaccinia Ankara (MVA-BN) poxvirus, MVA-BN-RSV, encoding for multiple proteins of RSV subtypes A and B, was assessed for efficacy against respiratory disease caused by RSV. Adults aged ≥60 years, with or without underlying chronic conditions, were enrolled and randomized in a 1:1 ratio to receive a single dose of vaccine or placebo and were followed for disease caused by RSV infection during the 2022–2023 season. The 2 primary endpoints were RSV-associated lower respiratory tract disease (LRTD) with ≥3 and ≥ 2 symptoms; acute respiratory disease (ARD) was a key secondary endpoint. The humoral RSV-specific immune response was assessed at baseline and 14 days post-vaccination. Safety was evaluated by collection of solicited adverse events (AEs) and unsolicited AEs for 7 and 28 days post-vaccination respectively, and SAEs for the entire study period. In total, 18,348 participants were included in the final efficacy and safety analyses. Vaccine efficacy was 42.9 % (95 % CI: −16.1; 71.9) against RSV-associated LRTD with ≥3 symptoms, 59.0 % (95 % CI: 34.7; 74.3) against LRTD with ≥2 symptoms, and 48.8 % (95 % CI: 25.8; 64.7) against ARD. The primary objective was not met for LRTD with ≥3 symptoms since the lower bound of the 95 % CI was below 20 %, the prespecified success criterion. The vaccine-elicited immune response showed mean fold-increases of 1.7 for RSV A and B neutralizing antibodies and 2.9 and 4.3 for RSV-specific IgG and IgA, respectively. The vaccine displayed mild to moderate reactogenicity, and no safety concerns were identified. MVA-BN-RSV induced suboptimal protection against RSV-associated LRTD, likely due to suboptimal neutralizing antibody response. The vaccine had an acceptable safety profile and confirmed immunogenicity, overall showing promise for MVA-BN-vectored constructs targeting other diseases. Trial Registration:Clinicaltrials.gov Identifier NCT05238025 (Registered February 14, 2022).

Abstract Background Respiratory syncytial virus (RSV) is the leading global cause of severe pediatric acute respiratory tract illness, and a vaccine is needed. RSV/ΔNS2/Δ1313/I1314L contains 2 attenuating elements: (1) deletion of the interferon antagonist NS2 gene and (2) deletion of codon 1313 of the RSV polymerase gene and the stabilizing missense mutation I1314L. This live vaccine candidate was temperature-sensitive, genetically stable, replication restricted, and immunogenic in nonhuman primates. Methods A single intranasal dose of RSV/ΔNS2/Δ1313/I1314L was evaluated in a double-blind, placebo-controlled trial (vaccine-placebo ratio, 2:1) at 106 plaque-forming units (PFU) in 15 RSV-seropositive children and at 105 and 106 PFU in 21 and 30 RSV-seronegative children, respectively. Results In RSV-seronegative children, the 105 PFU dose was overattenuated, but the 106 PFU dose was well tolerated, infectious (RSV/ΔNS2/Δ1313/I1314L replication detected in 90% of vaccinees), and immunogenic (geometric mean serum RSV plaque-reduction neutralizing antibody titer, 1:64). After the RSV season, 9 of 20 vaccinees had increases in the RSV titer that were significantly greater than those in 8 of 10 placebo recipients (1:955 vs 1:69, respectively), indicating that the vaccine primed for anamnestic responses after natural RSV exposure. Conclusion Rational design yielded a genetically stable candidate RSV vaccine that is attenuated yet immunogenic in RSV-seronegative children, warranting further evaluation. Clinical Trials Registration NCT01893554. A live attenuated respiratory syncytial virus (RSV) vaccine containing a deletion of the interferon antagonist NS2 gene and mutations in the polymerase gene was well tolerated and infectious, inducing primary neutralizing antibody responses and potent memory antibody responses in RSV-seronegative children.

Coadministration of a respiratory syncytial virus (RSV) vaccine with seasonal influenza or SARS-CoV-2 vaccines could reduce health-care visits and increase vaccination uptake in older adults who are at high risk for severe respiratory disease. The RSV mRNA-1345 vaccine demonstrated efficacy against RSV disease with acceptable safety in the ConquerRSV trial in adults aged 60 years and older. We aimed to evaluate the safety and immunogenicity of mRNA-1345 coadministered with a seasonal influenza vaccine or SARS-CoV-2 mRNA vaccine. We conducted a two-part, phase 3, observer-blinded, placebo-controlled, randomised trial in medically stable adults aged 50 years or older in the USA. In part A, participants were randomly assigned in a 7:10:10 ratio to receive 50 μg mRNA-1345 plus placebo (0·9% sodium chloride) or coadministered with 60 μg of a standard-dose quadrivalent inactivated influenza vaccine (SIIV4), or SIIV4 plus placebo. In part B, participants were randomly assigned in a 1:1:1 ratio to receive 50 μg mRNA-1345 plus placebo or coadministered with 50 μg SARS-CoV-2 mRNA-1273.214 (bivalent [Wuhan-Hu-1 plus omicron BA.1]), or mRNA-1273.214 plus placebo. Random allocation in both parts was stratified by age group (50–59 years, 60–74 years, and ≥75 years) and used interactive response technology. The coprimary objectives in each part were safety in the safety set throughout the study and non-inferiority for six immunogenicity endpoints in the per-protocol set comparing coadministered versus individual vaccines on day 29. Immunogenicity endpoints were geometric mean titre (GMT) ratios (GMRs) of RSV-A neutralising antibodies (nAbs; in parts A and B), GMRs of haemagglutination inhibition (HAI) titres to each of the four influenza strains in SIIV4 (A/Victoria/2570/2019 [H1N1]pdm09-like virus [A/H1N1], A/Cambodia/e0826360/2020 [H3N2]-like virus [A/H3N2], B/Washington/02/2019-like virus [B/Victoria], and B/Phuket/3073/2013-like virus [B/Yamagata]; in part A), GMRs of nAbs against SARS-CoV-2 (ancestral [D614G] and omicron BA.1; part B), and differences in seroresponse rates for nAbs against RSV-A (parts A and B) and SARS-CoV-2 (ancestral [D614G] and omicron BA.1; part B). Non-inferiority was declared when the lower bound of the 95% CI for GMRs was greater than 0·667 and for seroresponse rate differences was greater than −10%. This trial is registered with ClinicalTrials.gov (NCT05330975) and is ongoing. Between April 1 and June 9, 2022, 1631 participants were randomly allocated in part A and 1623 received vaccinations on day 1 (685 [42%] received mRNA-1345 plus SIIV4, 249 [15%] mRNA-1345 plus placebo, and 689 [42%] SIIV4 plus placebo). Due to an interactive response technology error, the mRNA-1345 plus placebo group was smaller than planned (249 vs 420 participants). Of the 1623 participants in the safety set, 877 (54%) were female and 746 (46%) were male. Between July 27 and Sept 28, 2022, 1691 participants were randomly allocated in part B and 1681 received vaccinations on day 1 (564 [34%] received mRNA-1345 plus mRNA-1273.214, 558 [33%] mRNA-1345 plus placebo, and 559 [33%] mRNA-1273.214 plus placebo). Among the 1681 participants in the safety set, 924 (55%) were female and 757 (45%) were male. The reactogenicity profiles of the coadministered regimens were generally similar to the profiles when the vaccines were administered alone. As of the 6-month and 7-month follow-up times for parts A and B, respectively, no serious adverse events, adverse events of special interest, discontinuations due to adverse events, or fatal events considered related to study vaccination were reported. In part A, the GMR of nAbs against RSV-A in the mRNA-1345 plus SIIV4 group versus the mRNA-1345 alone group was 0·81 (95% CI 0·67 to 0·97), and the seroresponse rate difference in nAbs against RSV-A between the groups was −11·2% (95% CI −17·9 to −4·1). GMRs of anti-HAI titres in the mRNA-1345 plus SIIV4 versus SIIV4 alone groups were 0·89 (0·77 to 1·03) for A/H1N1, 0·97 (0·86 to 1·09) for A/H3N2, 0·93 (0·82 to 1·05) for B/Victoria, and 0·91 (0·81 to 1·02) for B/Yamagata. In part B, the GMR of nAbs against RSV-A in the mRNA-1345 plus mRNA-1273.214 versus the mRNA-1345 alone groups was 0·80 (95% CI 0·70 to 0·90), and the seroresponse rate difference was –4·4% (95% CI –9·9 to 1·0). Comparing the mRNA-1345 plus mRNA-1273.214 group with the mRNA-1273.214 alone group, the GMR of nAbs was 0·96 (0·87 to 1·06) for the ancestral (D614G) virus and 1·00 (0·89 to 1·14) for omicron BA.1; seroresponse rate differences were 0·2% (95% CI –6·0 to 6·3) for SARS-CoV-2 ancestral and –0·9% (–6·6 to 4·7) for omicron BA.1. Coadministered mRNA-1345 plus SIIV4 or mRNA-1273.214 vaccines had acceptable safety profiles and elicited mostly non-inferior immune responses compared to individual vaccines in adults aged 50 years or older; only the seroresponse rate difference in nAbs against RSV-A in part A did not meet the non-inferiority criterion. Overall, these data support coadministration of mRNA-1345 with these vaccines in this population; longer-term evaluation continues in this study. Moderna.

Identifying an immunologic marker as a correlate of protection (CoP) for RSV vaccination is important. In the pivotal phase 3 trial, the mRNA-1345 vaccine demonstrated efficacy against RSV in older adults (NCT05127434). Here, we evaluate neutralizing antibodies (nAb) against RSV-A and -B, and IgG binding antibodies (bAb) to RSV fusion antigens as correlates of risk (CoR) and CoP against the pivotal trial’s efficacy endpoints of RSV lower respiratory tract disease with ≥2 or ≥3 signs/symptoms (RSV-LRTD-2+ and −3 + ) and acute respiratory disease (RSV-ARD). Day 29 RSV nAb and prefusion (preF) IgG demonstrate consistent inverse correlates with RSV endpoint occurrence. Day 29 point estimates (95% CIs) of the hazard ratio of each endpoint (RSV-LRTD-2 + , RSV-LRTD-3 + , RSV-ARD) per 10-fold increase in RSV-A nAb are 0.44 (0.30-0.65), 0.41 (0.20-0.84), and 0.45 (0.28-0.71), respectively, similar to RSV-B nAb and preF IgG. These results demonstrate Day 29 RSV nAb and preF IgG are CoRs and support their role as CoPs against RSV endpoints. Identifying an immunologic marker as a correlate of protection (CoP) for RSV vaccination is important. Here, the authors demonstrate RSV neutralizing antibodies and RSV prefusion IgG binding antibodies as CoP for mRNA vaccination against RSV disease.

Abstract Background Respiratory syncytial virus (RSV) is the leading cause of infant lower respiratory tract disease and hospitalization worldwide. Methods Safety and immunogenicity of RSV fusion (F) protein nanoparticle vaccine or placebo were evaluated in 50 healthy third-trimester pregnant women. Assessments included vaccine tolerability and safety in women and infants, and RSV-specific antibody measures in women before and after vaccination, at delivery and post partum. Results The vaccine was well tolerated; no meaningful differences in pregnancy or infant outcomes were observed between study groups. RSV-specific antibody levels increased significantly among vaccine recipients, including responses competitive with well-described monoclonal antibodies specific for multiple RSV neutralizing epitopes. No significant antibody increase was seen among placebo recipients, although a shallow upward trend across the RSV season was noted. Transplacental antibody transfer was 90%–120% across assays for infants of vaccinated women. Women with an interval of ≥30 days between vaccination and delivery demonstrated higher placental antibody transfer rates than women with an interval <30 days. Half-lives of RSV-specific antibodies in infants approximated 40 days. There was no evidence of severe RSV disease in infants of vaccinated mothers. Conclusions Data from this phase 2 study support a maternal immunization strategy to protect infants from RSV disease. Clinical Trials Registration NCT02247726. Immunization of pregnant women with an RSV F protein nanoparticle vaccine was well-tolerated by the women and their infants, and produced antibody responses that were transferred via the placenta and exhibited a half-life of approximately 40 days in infants.

Abstract Background The safety and immunogenicity of live respiratory syncytial virus (RSV) candidate vaccine, LID/ΔM2-2/1030s, with deletion of RSV ribonucleic acid synthesis regulatory protein M2-2 and genetically stabilized temperature-sensitivity mutation 1030s in the RSV polymerase protein was evaluated in RSV-seronegative children. Methods Respiratory syncytial virus-seronegative children ages 6–24 months received 1 intranasal dose of 105 plaque-forming units (PFU) of LID/ΔM2-2/1030s (n = 21) or placebo (n = 11). The RSV serum antibodies, vaccine shedding, and reactogenicity were assessed. During the following RSV season, medically attended acute respiratory illness (MAARI) and pre- and postsurveillance serum antibody titers were monitored. Results Eighty-five percent of vaccinees shed LID/ΔM2-2/1030s vaccine (median peak nasal wash titers: 3.1 log10 PFU/mL by immunoplaque assay; 5.1 log10 copies/mL by reverse-transcription quantitative polymerase chain reaction) and had ≥4-fold rise in serum-neutralizing antibodies. Respiratory symptoms and fever were common (60% vaccinees and 27% placebo recipients). One vaccinee had grade 2 wheezing with rhinovirus but without concurrent LID/ΔM2-2/1030s shedding. Five of 19 vaccinees had ≥4-fold increases in antibody titers postsurveillance without RSV-MAARI, indicating anamnestic responses without significant illness after infection with community-acquired RSV. Conclusions LID/ΔM2-2/1030s had excellent infectivity without evidence of genetic instability, induced durable immunity, and primed for anamnestic antibody responses, making it an attractive candidate for further evaluation. Live respiratory syncytial virus (RSV) vaccine LID/∆M2-2/1030s attenuated by deletion of the RNA regulatory protein M2-2 and temperature-sensitivity mutation 1030s had excellent immunogenicity and genetic stability in RSV-seronegative 6- to 24-month-old children, making it an attractive candidate for further evaluation.

In a randomized, placebo-controlled, phase 2b clinical trial, an adjuvanted vaccine containing the respiratory syncytial virus (RSV) fusion protein was immunogenic but did not protect older adults from disease caused by RSV. Abstract Background Respiratory syncytial virus (RSV) is an important cause of illness in older adults. This study assessed efficacy of a vaccine for prevention of RSV-associated acute respiratory illness (ARI), defined by specified symptoms with virologic confirmation. Methods This phase 2b study evaluated RSV postfusion F protein (120 µg) with glucopyranosyl lipid adjuvant (5 µg) in 2% stable emulsion. Subjects aged ≥60 years were randomly assigned at a ratio of 1:1 to receive vaccine or placebo (all received inactivated influenza vaccine). Ill subjects recorded symptoms and provided blood and nasal swab samples. Results In the per-protocol population (n = 1894), the incidence of RSV-associated ARI occurring ≥14 days after dosing was 1.7% and 1.6% in the vaccine and placebo groups, respectively, for a vaccine efficacy (VE) of –7.1% (90% confidence interval [CI], –106.9%–44.3%). Efficacy was not observed in secondary analyses that included seroresponse to nonvaccine RSV antigens (VE, 8.9%; 90% CI, –28.5%–35.4%) or symptoms combined with seroresponse (VE, 10.0%; 90% CI, –45.4%–44.4%). On day 29, 92.9% of vaccinees had an anti-F immunoglobulin G antibody seroresponse. Overall, 48.5% and 30.9% of RSV vaccine recipients reported local and systemic solicited symptoms, respectively. Conclusion The RSV vaccine was immunogenic but did not protect older adults from RSV illness. Clinical Trials Registration NCT02508194.