Immunization technologies: Time to consider new preventative solutions for respiratory syncytial virus infections.

New technologies for the prevention of infectious diseases are emerging to address unmet medical needs, in particular, the use of long-acting monoclonal antibodies (mAb) to prevent Respiratory Syncytial Virus (RSV) lower respiratory tract disease in infants during their first RSV season. The lack of precedent for mAbs for broad population protection creates challenges in the assessment of upcoming prophylactic long-acting mAbs for RSV, with associated consequences in legislative and registration categorization, as well as in recommendation, funding, and implementation pathways. We suggest that the legislative and regulatory categorization of preventative solutions should be decided by the effect of the product in terms of its impact on the population and health-care systems rather than by the technology used or its mechanism of action. Immunization can be passive and active, both having the same objective of prevention of infectious diseases. Long-acting prophylactic mAbs work as passive immunization, as such, their recommendations for use should fall under the remit of National Immunization Technical Advisory Groups or other relevant recommending bodies for inclusion into National Immunization Programs. Current regulations, policy, and legislative frameworks need to evolve to embrace such innovative preventative technologies and acknowledge them as one of key immunization and public health tools.

Surveillance towards preventing paediatric incidence of respiratory syncytial virus attributable respiratory tract infection in primary and secondary/tertiary healthcare settings in Merseyside, Cheshire and Bristol, UK.

INTRODUCTION: Respiratory syncytial virus (RSV) is a common respiratory virus, particularly affecting children, and can cause respiratory infections such as croup and bronchiolitis. The latter is a leading cause of paediatric hospitalisation within the UK. Children <3 years of age and/or with underlying health conditions are more vulnerable to severe RSV infection.There are currently limited data on the incidence of laboratory-confirmed RSV, particularly within primary care settings and outside the typical 'RSV season', which in the Northern hemisphere tends to coincide with winter months. There is also a lack of data on the health economic impact of RSV infection on families and healthcare systems.This observational surveillance study aims to collect data on the incidence of laboratory-confirmed RSV-attributable respiratory tract infection (RTI) in children aged <3 years presenting to primary, secondary or tertiary care; it also aims to estimate the health economic and quality of life impact of RSV-attributable infection in this cohort. Such data will contribute to informing public health strategies to prevent RSV-associated infection, including use of preventative medications. METHODS AND ANALYSIS: Parents/carers of children <3 years of age with RTI symptoms will consent for a respiratory sample (nasal swab) to be taken. Laboratory PCR testing will assess for the presence of RSV and/or other pathogens. Data will be obtained from medical records on demographics, comorbidities, severity of infection and hospitalisation outcomes. Parents will complete questionnaires on the impact of ongoing infection symptoms at day 14 and 28 following enrolment. The primary outcome is incidence of laboratory-confirmed RSV in children <3 years presenting to primary, secondary or tertiary care with RTI symptoms leading to health-seeking behaviours. Recruitment will be carried out from December 2021 to March 2023, encompassing two UK winter seasons and intervening months. ETHICS AND DISSEMINATION: Ethical approval has been granted (21/WS/0142), and study findings will be published as per International Committee of Medical Journal Editors' guidelines.

Recent Advances in Inhaled Nanoformulations of Vaccines and Therapeutics Targeting Respiratory Viral Infections.

With the rapid outbreak of respiratory viral infections, various biological (e.g. vaccines, peptides, recombinant proteins, antibodies and genes) and antiviral agents (e.g. ribavirin, palivizumab and valaciclovir) have been successfully developed for the treatment of respiratory virus infections such as influenza, respiratory syncytial virus and SARS-CoV-2 infections. These therapeutics are conventionally delivered via oral, intramuscular or injection route and are associated with several adverse events due to systemic toxicity. The inherent in vivo instability of biological therapeutics may hinder them from being administered without proper formulations. Therefore, we have witnessed a boom in nanotechnology coupled with a needle-free administration approach such as the inhalation route for the delivery of complex therapeutics to treat respiratory infections. This review discussed the recent advances in the inhalation strategies of nanoformulations that target virus respiratory infections.

Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants.

BACKGROUND: Whether vaccination during pregnancy could reduce the burden of respiratory syncytial virus (RSV)-associated lower respiratory tract illness in newborns and infants is uncertain. METHODS: In this phase 3, double-blind trial conducted in 18 countries, we randomly assigned, in a 1:1 ratio, pregnant women at 24 through 36 weeks' gestation to receive a single intramuscular injection of 120 µg of a bivalent RSV prefusion F protein-based (RSVpreF) vaccine or placebo. The two primary efficacy end points were medically attended severe RSV-associated lower respiratory tract illness and medically attended RSV-associated lower respiratory tract illness in infants within 90, 120, 150, and 180 days after birth. A lower boundary of the confidence interval for vaccine efficacy (99.5% confidence interval [CI] at 90 days; 97.58% CI at later intervals) greater than 20% was considered to meet the success criterion for vaccine efficacy with respect to the primary end points. RESULTS: At this prespecified interim analysis, the success criterion for vaccine efficacy was met with respect to one primary end point. Overall, 3682 maternal participants received vaccine and 3676 received placebo; 3570 and 3558 infants, respectively, were evaluated. Medically attended severe lower respiratory tract illness occurred within 90 days after birth in 6 infants of women in the vaccine group and 33 infants of women in the placebo group (vaccine efficacy, 81.8%; 99.5% CI, 40.6 to 96.3); 19 cases and 62 cases, respectively, occurred within 180 days after birth (vaccine efficacy, 69.4%; 97.58% CI, 44.3 to 84.1). Medically attended RSV-associated lower respiratory tract illness occurred within 90 days after birth in 24 infants of women in the vaccine group and 56 infants of women in the placebo group (vaccine efficacy, 57.1%; 99.5% CI, 14.7 to 79.8); these results did not meet the statistical success criterion. No safety signals were detected in maternal participants or in infants and toddlers up to 24 months of age. The incidences of adverse events reported within 1 month after injection or within 1 month after birth were similar in the vaccine group (13.8% of women and 37.1% of infants) and the placebo group (13.1% and 34.5%, respectively). CONCLUSIONS: RSVpreF vaccine administered during pregnancy was effective against medically attended severe RSV-associated lower respiratory tract illness in infants, and no safety concerns were identified. (Funded by Pfizer; MATISSE ClinicalTrials.gov number, NCT04424316.).

Efficacy and Safety of a Bivalent RSV Prefusion F Vaccine in Older Adults.

BACKGROUND: Respiratory syncytial virus (RSV) infection causes considerable illness in older adults. The efficacy and safety of an investigational bivalent RSV prefusion F protein-based (RSVpreF) vaccine in this population are unknown. METHODS: In this ongoing, phase 3 trial, we randomly assigned, in a 1:1 ratio, adults (≥60 years of age) to receive a single intramuscular injection of RSVpreF vaccine at a dose of 120 µg (RSV subgroups A and B, 60 µg each) or placebo. The two primary end points were vaccine efficacy against seasonal RSV-associated lower respiratory tract illness with at least two or at least three signs or symptoms. The secondary end point was vaccine efficacy against RSV-associated acute respiratory illness. RESULTS: At the interim analysis (data-cutoff date, July 14, 2022), 34,284 participants had received RSVpreF vaccine (17,215 participants) or placebo (17,069 participants). RSV-associated lower respiratory tract illness with at least two signs or symptoms occurred in 11 participants in the vaccine group (1.19 cases per 1000 person-years of observation) and 33 participants in the placebo group (3.58 cases per 1000 person-years of observation) (vaccine efficacy, 66.7%; 96.66% confidence interval [CI], 28.8 to 85.8); 2 cases (0.22 cases per 1000 person-years of observation) and 14 cases (1.52 cases per 1000 person-years of observation), respectively, occurred with at least three signs or symptoms (vaccine efficacy, 85.7%; 96.66% CI, 32.0 to 98.7). RSV-associated acute respiratory illness occurred in 22 participants in the vaccine group (2.38 cases per 1000 person-years of observation) and 58 participants in the placebo group (6.30 cases per 1000 person-years of observation) (vaccine efficacy, 62.1%; 95% CI, 37.1 to 77.9). The incidence of local reactions was higher with vaccine (12%) than with placebo (7%); the incidences of systemic events were similar (27% and 26%, respectively). Similar rates of adverse events through 1 month after injection were reported (vaccine, 9.0%; placebo, 8.5%), with 1.4% and 1.0%, respectively, considered by the investigators to be injection-related. Severe or life-threatening adverse events were reported in 0.5% of vaccine recipients and 0.4% of placebo recipients. Serious adverse events were reported in 2.3% of participants in each group through the data-cutoff date. CONCLUSIONS: RSVpreF vaccine prevented RSV-associated lower respiratory tract illness and RSV-associated acute respiratory illness in adults (≥60 years of age), without evident safety concerns. (Funded by Pfizer; RENOIR ClinicalTrials.gov number, NCT05035212; EudraCT number, 2021-003693-31.).

In-Depth Analysis of the Re-Emergence of Respiratory Syncytial Virus at a Tertiary Care Hospital in Germany in the Summer of 2021 after the Alleviation of Non-Pharmaceutical Interventions Due to the SARS-CoV-2 Pandemic.

Following the extensive non-pharmaceutical interventions (NPIs) and behavioral changes in the wake of the SARS-CoV-2 pandemic, an interseasonal rise in respiratory syncytial virus (RSV) cases was observed in Germany in 2021. The aim of this study was to characterize the local molecular epidemiology of RSV infections in comparison to the three pre-pandemic seasons. Additionally, clinical data were retrieved from patient charts to determine the clinical significance of RSV infections. RSV detections peaked in calendar week 40 of 2021, 18 weeks earlier than the usual peak observed in the three pre-pandemic seasons. Sequence analysis revealed a close phylogenetic relatedness regardless of the season of origin. A significantly higher amount of pediatric cases (88.9% of all cases, p < 0.001) was observed for season 2021/2022. For the pediatric cases, significant differences were observed for an increased number of siblings in the household (p = 0.004), a lower rate of fever (p = 0.007), and a reduced amount of co-infections (p = 0.001). Although the mean age of the adult patients was significantly younger (47.1 vs. 64.7, p < 0.001), high rates of comorbidities, lower respiratory tract infections and intensive care unit admissions prevailed. The NPIs in the wake of the SARS-CoV-2 pandemic had a tremendous impact on the epidemiologic characteristics and seasonality of RSV and warrant further epidemiologic studies of this important pathogen.

Next-generation RSV vaccines avoid flipping out.

In clinical trials, RSV prefusion F protein induced higher neutralizing antibodies and more activated memory B cells than postfusion F protein (Chang et al.).

Respiratory Syncytial Virus Prefusion F Protein Vaccine in Older Adults.

BACKGROUND: Respiratory syncytial virus (RSV) is an important cause of acute respiratory infection, lower respiratory tract disease, clinical complications, and death in older adults. There is currently no licensed vaccine against RSV infection. METHODS: In an ongoing, international, placebo-controlled, phase 3 trial, we randomly assigned, in a 1:1 ratio, adults 60 years of age or older to receive a single dose of an AS01E-adjuvanted RSV prefusion F protein-based candidate vaccine (RSVPreF3 OA) or placebo before the RSV season. The primary objective was to show vaccine efficacy of one dose of the RSVPreF3 OA vaccine against RSV-related lower respiratory tract disease, confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR), during one RSV season. The criterion for meeting the primary objective was a lower limit of the confidence interval around the efficacy estimate of more than 20%. Efficacy against severe RSV-related lower respiratory tract disease and RSV-related acute respiratory infection was assessed, and analyses according to RSV subtype (A and B) were performed. Safety was evaluated. RESULTS: A total of 24,966 participants received one dose of the RSVPreF3 OA vaccine (12,467 participants) or placebo (12,499). Over a median follow-up of 6.7 months, vaccine efficacy against RT-PCR-confirmed RSV-related lower respiratory tract disease was 82.6% (96.95% confidence interval [CI], 57.9 to 94.1), with 7 cases (1.0 per 1000 participant-years) in the vaccine group and 40 cases (5.8 per 1000 participant-years) in the placebo group. Vaccine efficacy was 94.1% (95% CI, 62.4 to 99.9) against severe RSV-related lower respiratory tract disease (assessed on the basis of clinical signs or by the investigator) and 71.7% (95% CI, 56.2 to 82.3) against RSV-related acute respiratory infection. Vaccine efficacy was similar against the RSV A and B subtypes (for RSV-related lower respiratory tract disease: 84.6% and 80.9%, respectively; for RSV-related acute respiratory infection: 71.9% and 70.6%, respectively). High vaccine efficacy was observed in various age groups and in participants with coexisting conditions. The RSVPreF3 OA vaccine was more reactogenic than placebo, but most adverse events for which reports were solicited were transient, with mild-to-moderate severity. The incidences of serious adverse events and potential immune-mediated diseases were similar in the two groups. CONCLUSIONS: A single dose of the RSVPreF3 OA vaccine had an acceptable safety profile and prevented RSV-related acute respiratory infection and lower respiratory tract disease and severe RSV-related lower respiratory tract disease in adults 60 years of age or older, regardless of RSV subtype and the presence of underlying coexisting conditions. (Funded by GlaxoSmithKline Biologicals; AReSVi-006 ClinicalTrials.gov number, NCT04886596.).

Efficacy and Safety of an Ad26.RSV.preF-RSV preF Protein Vaccine in Older Adults.

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.).

Prophylactic intranasal administration of lipid nanoparticle formulated siRNAs reduce SARS-CoV-2 and RSV lung infection.

RNA interference (RNAi) is an emerging and promising therapy for a wide range of respiratory viral infections. This highly specific suppression can be achieved by the introduction of short-interfering RNA (siRNA) into mammalian systems, resulting in the effective reduction of viral load. Unfortunately, this has been hindered by the lack of a good delivery system, especially via the intranasal (IN) route. Here, we have developed an IN siRNA encapsulated lipid nanoparticle (LNP) in vivo delivery system that is highly efficient at targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and respiratory syncytial virus (RSV) lung infection in vivo. Importantly, IN siRNA delivery without the aid of LNPs abolishes anti-SARS-CoV-2 activity in vivo. Our approach using LNPs as the delivery vehicle overcomes the significant barriers seen with IN delivery of siRNA therapeutics and is a significant advancement in our ability to delivery siRNAs. The study presented here demonstrates an attractive alternate delivery strategy for the prophylactic treatment of both future and emerging respiratory viral diseases.

RSV through the COVID-19 pandemic: Burden, shifting epidemiology, and implications for the future.

Respiratory syncytial virus (RSV) represents a major global healthcare burden, particularly in those under 5 years of age. There is no available vaccine, with treatment limited to supportive care or palivizumab for high-risk children. Additionally, although a causal relationship has not been established, RSV has been associated with the development of asthma or wheezing in some children. The COVID-19 pandemic and the introduction of nonpharmaceutical interventions (NPIs) have caused substantial changes to RSV seasonality and epidemiology. Many countries have experienced an absence of RSV during the time of a typical season, followed by an out-of-season surge upon relaxation of NPI use. These dynamics have disrupted traditional RSV disease patterns and assumptions, but also provide a unique opportunity to learn more about the transmission of RSV and other respiratory viruses, as well as inform future approaches to RSV preventive strategies. Here, we review the RSV burden and epidemiology through the COVID-19 pandemic and discuss how new data may affect future decisions regarding RSV prevention.

Impact of breastfeeding on the incidence and severity of respiratory syncytial virus bronchiolitis in infants: systematic review.

BACKGROUND AND AIMS: Breastfeeding practices have demonstrated a protective effect against severe respiratory syncytial virus (RSV) disease outcomes. RSV is the principal cause of lower respiratory tract infections in infants worldwide, and an important cause of morbidity, hospitalization, and mortality. The primary aim is to determine the impact of breastfeeding on the incidence and severity of RSV bronchiolitis in infants. Secondly, the study aims to determine if breastfeeding contributes to reduction of hospitalization rates, length of stay and oxygen use in confirmed cases. METHODS: A preliminary database search was conducted using agreed keywords and MeSH headings in MEDLINE, PubMed, Google Scholar, EMBASE, MedRχiv and Cochrane Reviews. Articles were screened based on inclusion/exclusion criteria for infants aged 0-12 months. Full text, abstract and conference articles published in English were included from 2000 to 2021. Covidence® software was used for evidence extraction using paired investigator agreement and PRISMA guidelines were followed. RESULTS: 1368 studies were screened and 217 were eligible for full text review. 188 were excluded. Twenty-nine articles were selected for data extraction: RSV-bronchiolitis (18) and viral bronchiolitis (13), with two articles discussing both. Results showed that non-breastfeeding practices are a significant risk factor for hospitalization. Exclusive breastfeeding for >4-6 months significantly lowered admission rates, length of stay and supplemental oxygen use, reducing unscheduled GP visits and emergency department presentation. DISCUSSION: Exclusive and partial breastfeeding reduce severity of RSV bronchiolitis, length of hospital stay and supplemental oxygen requirement. Breastfeeding practices should be supported and encouraged as a cost-effective method to prevent infant hospitalization and severe bronchiolitis infection.

Respiratory syncytial virus infection in the modern era.

PURPOSE OF REVIEW: Respiratory syncytial virus (RSV) continues to be a major cause of severe lower respiratory tract infection in infants, young children, and older adults. In this review, changes in the epidemiology of RSV during the coronavirus disease 2019 (COVID-19) pandemic are highlighted together with the role which increased molecular surveillance efforts will have in future in assessing the efficacy of vaccines and therapeutics. RECENT FINDINGS: The introduction of nonpharmaceutical intervention (NPIs) strategies during the COVID-19 pandemic between 2020 and 2022 resulted in worldwide disruption to the epidemiology of RSV infections, especially with respect to the timing and peak case rate of annual epidemics. Increased use of whole genome sequencing along with efforts to better standardize the nomenclature of RSV strains and discrimination of RSV genotypes will support increased monitoring of relevant antigenic sites in the viral glycoproteins. Several RSV vaccine candidates based on subunit, viral vectors, nucleic acid, or live attenuated virus strategies have shown efficacy in Phase 2 or 3 clinical trials with vaccines using RSVpreF protein currently the closest to approval and use in high-risk populations. Finally, the recent approval and future use of the extended half-life human monoclonal antibody Nirsevimab will also help to alleviate the morbidity and mortality burden caused by annual epidemics of RSV infections. SUMMARY: The ongoing expansion and wider coordination of RSV molecular surveillance efforts via whole genome sequencing will be crucial for future monitoring of the efficacy of a new generation of vaccines and therapeutics.

Application of a forecasting model to mitigate the consequences of unexpected RSV surge: Experience from the post-COVID-19 2021/22 winter season in a major metropolitan centre, Lyon, France.

Background: The emergence of COVID-19 triggered the massive implementation of non-pharmaceutical interventions (NPI) which impacted the circulation of respiratory syncytial virus (RSV) during the 2020/2021 season. Methods: A time-series susceptible-infected-recovered (TSIR) model was used early September 2021 to forecast the implications of this disruption on the future 2021/2022 RSV epidemic in Lyon urban population. Results: When compared to observed hospital-confirmed cases, the model successfully captured the early start, peak timing, and end of the 2021/2022 RSV epidemic. These simulations, added to other streams of surveillance data, shared and discussed among the local field experts were of great value to mitigate the consequences of this atypical RSV outbreak on our hospital paediatric department. Conclusions: TSIR model, fitted to local hospital data covering large urban areas, can produce plausible post-COVID-19 RSV simulations. Collaborations between modellers and hospital management (who are both model users and data providers) should be encouraged in order to validate the use of dynamical models to timely allocate hospital resources to the future RSV epidemics.