Respiratory syncytial virus (RSV) is the main cause of low respiratory tract infections in infants under one year of age. In the 2023/2024 season, the monoclonal antibody nirsevimab was available to protect children from RSV, and Spain has become one of the first countries worldwide to implement this strategy. It is essential to evaluate the results of this first campaign and different characteristics of the immunized population in order to plan next campaigns, especially for countries that are going to include this immunization. Our coverage was high (91.5% for those born during the season and 88.3% globally). For those born during the season, only 4.9% preferred not to immunize at the maternity hospital, which meant an average delay of 27.45 days. We observed a lower coverage in the population of immigrant origin. There was a rapid pace of immunization, since for those born before the beginning of the campaign the mean to be immunized was 15.63 days, without differences between healthy and at-risk children. This allows immunization before the RSV season (90% of the catch-up children had been immunized on November 3). The average age at which all the immunized children have received nirsevimab was lower in healthy children compared to those with risk conditions (49.65 versus 232.85 days). For those born during the campaign, the average age was also lower in healthy children (3.14 versus 14.58 days). In conclusion, we consider that the implementation of the immunization strategy with nirsevimab in the Region of Murcia, Spain, has been a success.

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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.

Numerous enveloped viruses, such as coronaviruses, influenza, and respiratory syncytial virus (RSV), utilize class I fusion proteins for cell entry. During this process, the proteins transition from a prefusion to a postfusion state, undergoing substantial and irreversible conformational changes. The prefusion conformation has repeatedly shown significant potential in vaccine development. However, the instability of this state poses challenges for its practical application in vaccines. While non-native disulfides have been effective in maintaining the prefusion structure, identifying stabilizing disulfide bonds remains an intricate task. Here, we present a general computational approach to systematically identify prefusion-stabilizing disulfides. Our method assesses the geometric constraints of disulfide bonds and introduces a ranking system to estimate their potential in stabilizing the prefusion conformation. We hypothesized that disulfides restricting the initial stages of the conformational switch could offer higher stability to the prefusion state than those preventing unfolding at a later stage. The implementation of our algorithm on the RSV F protein led to the discovery of prefusion-stabilizing disulfides that supported our hypothesis. Furthermore, the evaluation of our top design as a vaccine candidate in a cotton rat model demonstrated robust protection against RSV infection, highlighting the potential of our approach for vaccine development.

BACKGROUND: The recently approved AS01E-adjuvanted respiratory syncytial virus (RSV) prefusion F protein-based vaccine for older adults (RSVPreF3 OA) demonstrated high efficacy against RSV-related disease in ≥60-year-olds.
METHODS: This ongoing phase 3 study in ≥60-year-olds evaluates immune persistence until 3 years after RSVPreF3 OA vaccination. Here, we describe interim results on humoral and cell-mediated immunogenicity, reactogenicity, and safety until 1 year post-dose 1.
RESULTS: In total, 1653 participants were vaccinated. One month post-dose 1, neutralization titers increased 10.5-fold (RSV-A) and 7.8-fold (RSV-B) vs pre-dose 1. Titers then declined to levels 4.4-fold (RSV-A) and 3.5-fold (RSV-B) above pre-dose 1 at month 6 and remained 3.1-fold (RSV-A) and 2.3-fold (RSV-B) above pre-dose 1 levels after 1 year. RSVPreF3-binding immunoglobulin G levels and CD4+ T-cell frequencies showed similar kinetics. Solicited administration-site and systemic adverse events (mostly mild to moderate and transient) were reported by 62.2% and 49.5% of participants. Serious adverse events were reported by 3.9% of participants within 6 months post-dose 1; 1 case was considered vaccine related.
CONCLUSIONS: One RSVPreF3 OA dose elicited cell-mediated and RSV-A- and RSV-B-specific humoral immune responses that declined over time but remained above pre-dose 1 levels for at least 1 year. The vaccine was well tolerated with an acceptable safety profile. Clinical Trials Registration. NCT04732871 (ClinicalTrials.gov).
Respiratory syncytial virus (RSV) is a major cause of illness and hospitalization in older adults. An RSV vaccine for older adults developed by GSK was recently approved. The vaccine was well tolerated and provided protection against RSV disease in adults aged ≥60 years during at least 1 RSV season. In this ongoing study, we are evaluating the magnitude and durability of the immune response, as well as vaccine safety, until 3 years after vaccination of adults aged ≥60 years from 5 countries. Here, we report the results of an interim analysis until 1 year after vaccination with 1 dose. In total, 1653 participants were vaccinated. We found that the vaccine induced a strong immune response that was evident 1 month after vaccination, after which it declined but persisted for at least 1 year. Study participants most often reported pain at the injection site, muscle pain, tiredness, and headache as adverse reactions, which were mostly mild to moderate and of short duration. One serious adverse reaction was considered related to the vaccine. The long-term immune response that was observed in this study is consistent with the vaccine providing protection during at least 1 RSV season.

UNASSIGNED: A nonadjuvanted bivalent respiratory syncytial virus (RSV) prefusion F (RSVpreF [Pfizer]) protein subunit vaccine was newly approved and recommended for pregnant individuals at 32 0/7 to 36 6/7 weeks\' gestation during the 2023 to 2024 RSV season; however, clinical vaccine data are lacking.
UNASSIGNED: To evaluate the association between prenatal RSV vaccination status and perinatal outcomes among patients who delivered during the vaccination season.
UNASSIGNED: This retrospective observational cohort study was conducted at 2 New York City hospitals within 1 health care system among patients who gave birth to singleton gestations at 32 weeks\' gestation or later from September 22, 2023, to January 31, 2024.
UNASSIGNED: Prenatal RSV vaccination with the RSVpreF vaccine captured from the health system\'s electronic health records.
UNASSIGNED: The primary outcome is preterm birth (PTB), defined as less than 37 weeks\' gestation. Secondary outcomes included hypertensive disorders of pregnancy (HDP), stillbirth, small-for-gestational age birth weight, neonatal intensive care unit (NICU) admission, neonatal respiratory distress with NICU admission, neonatal jaundice or hyperbilirubinemia, neonatal hypoglycemia, and neonatal sepsis. Logistic regression models were used to estimate odds ratios (ORs), and multivariable logistic regression models and time-dependent covariate Cox regression models were performed.
UNASSIGNED: Of 2973 pregnant individuals (median [IQR] age, 34.9 [32.4-37.7] years), 1026 (34.5%) received prenatal RSVpreF vaccination. Fifteen patients inappropriately received the vaccine at 37 weeks\' gestation or later and were included in the nonvaccinated group. During the study period, 60 patients who had evidence of prenatal vaccination (5.9%) experienced PTB vs 131 of those who did not (6.7%). Prenatal vaccination was not associated with an increased risk for PTB after adjusting for potential confounders (adjusted OR, 0.87; 95% CI, 0.62-1.20) and addressing immortal time bias (hazard ratio [HR], 0.93; 95% CI, 0.64-1.34). There were no significant differences in pregnancy and neonatal outcomes based on vaccination status in the logistic regression models, but an increased risk of HDP in the time-dependent model was seen (HR, 1.43; 95% CI, 1.16-1.77).
UNASSIGNED: In this cohort study of pregnant individuals who delivered at 32 weeks\' gestation or later, the RSVpreF vaccine was not associated with an increased risk of PTB and perinatal outcomes. These data support the safety of prenatal RSVpreF vaccination, but further investigation into the risk of HDP is warranted.

Influenza A Virus (IAV) and Respiratory Syncytial Virus (RSV) are both responsible for millions of severe respiratory tract infections every year worldwide. Effective vaccines able to prevent transmission and severe disease, are important measures to reduce the burden for the global health system. Despite the strong systemic immune responses induced upon current parental immunizations, this vaccination strategy fails to promote a robust mucosal immune response. Here, we investigated the immunogenicity and efficacy of a mucosal adenoviral vector vaccine to tackle both pathogens simultaneously at their entry site. For this purpose, BALB/c mice were immunized intranasally with adenoviral vectors (Ad) encoding the influenza-derived proteins, hemagglutinin (HA) and nucleoprotein (NP), in combination with an Ad encoding for the RSV fusion (F) protein. The mucosal combinatory vaccine induced neutralizing antibodies as well as local IgA responses against both viruses. Moreover, the vaccine elicited pulmonary CD8+ and CD4+ tissue resident memory T cells (TRM) against the immunodominant epitopes of RSV-F and IAV-NP. Furthermore, the addition of Ad-TGFβ or Ad-CCL17 as mucosal adjuvant enhanced the formation of functional CD8+ TRM responses against the conserved IAV-NP. Consequently, the combinatory vaccine not only provided protection against subsequent infections with RSV, but also against heterosubtypic challenges with pH1N1 or H3N2 strains. In conclusion, we present here a potent combinatory vaccine for mucosal applications, which provides protection against two of the most relevant respiratory viruses.

Recently, respiratory syncytial virus (RSV) vaccines based on the prefusion F (pre-F) antigen were approved in the United States. We aimed to develop an enzyme-linked immunosorbent assay (ELISA)-based protocol for the practical and large-scale evaluation of RSV vaccines. Two modified pre-F proteins (DS-Cav1 and SC-TM) were produced by genetic recombination and replication using an adenoviral vector. The protocol was established by optimizing the concentrations of the coating antigen (pre-F proteins), secondary antibodies, and blocking buffer. To validate the protocol, we examined its accuracy, precision, and specificity using serum samples from 150 participants across various age groups and the standard serum provided by the National Institute of Health. In the linear correlation analysis, coating concentrations of 5 and 2.5 μg/mL of DS-Cav1 and SC-TM showed high coefficients of determination (r > 0.90), respectively. Concentrations of secondary antibodies (alkaline phosphatase-conjugated anti-human immunoglobulin G, diluted 1:2000) and blocking reagents (5% skim milk/PBS-T) were optimized to minimize non-specific reactions. High accuracy was observed for DS-Cav1 (r = 0.90) and SC-TM (r = 0.86). Further, both antigens showed high precision (coefficient of variation < 15%). Inhibition ELISA revealed cross-reactivity of antibodies against DS-Cav1 and SC-TM, but not with the attachment (G) protein.

Respiratory syncytial virus (RSV) is a major cause of severe respiratory tract disease worldwide, and a pediatric vaccine is not available. We generated a filamentous RSV-based virus-like particle (VLP) that presents the central conserved region of the attachment protein G. This was achieved by co-expressing the matrix protein, phosphoprotein, nucleoprotein, and a hybrid fusion protein in which the F ectodomain was replaced with the G central region (GCR). The latter is relatively conserved and contains a receptor binding site and hence is a logical vaccine target. The immunogenicity and efficacy of the resulting VLP, termed VLP-GCR, were examined in mice using intranasal application without adjuvant. VLP-GCR induced substantial anti-N antibody levels but very low anti-G antibody levels, even after three vaccinations. In contrast, a VLP presenting prefusion-stabilized fusion (preF) protein instead of GCR induced both high anti-F and anti-nucleoprotein antibody levels, suggesting that our GCR antigen was poorly immunogenic. Challenge of VLP-GCR-vaccinated mice caused increased weight loss and lung pathology, and both VLPs induced mucus in the lungs. Thus, neither VLP is suitable as a vaccine for RSV-naive individuals. However, VLP-preF enhanced the proportion of preF antibodies and could serve as a multi-antigen mucosal booster vaccine in the RSV-experienced population.

When designing live-attenuated respiratory syncytial virus (RSV) vaccine candidates, attenuating mutations can be developed through biologic selection or reverse-genetic manipulation and may include point mutations, codon and gene deletions, and genome rearrangements. Attenuation typically involves the reduction in virus replication, due to direct effects on viral structural and replicative machinery or viral factors that antagonize host defense or cause disease. However, attenuation must balance reduced replication and immunogenic antigen expression. In the present study, we explored a new approach in order to discover attenuating mutations. Specifically, we used protein structure modeling and computational methods to identify amino acid substitutions in the RSV nonstructural protein 1 (NS1) predicted to cause various levels of structural perturbation. Twelve different mutations predicted to alter the NS1 protein structure were introduced into infectious virus and analyzed in cell culture for effects on viral mRNA and protein expression, interferon and cytokine expression, and caspase activation. We found the use of structure-based machine learning to predict amino acid substitutions that reduce the thermodynamic stability of NS1 resulted in various levels of loss of NS1 function, exemplified by effects including reduced multi-cycle viral replication in cells competent for type I interferon, reduced expression of viral mRNAs and proteins, and increased interferon and apoptosis responses.