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Respiratory syncytial virus (RSV) causes a spectrum of respiratory illnesses in infants and young children that may lead to hospitalizations and a substantial number of outpatient visits, which result in a huge economic and healthcare burden. Most hospitalizations happen in otherwise healthy infants, highlighting the need to protect all infants against RSV. Moreover, there is evidence on the association between early-life RSV respiratory illness and recurrent wheezing/asthma-like symptoms As such, RSV is considered a global health priority. However, despite this, the only prevention strategy currently available is palivizumab, a monoclonal antibody (mAb) indicated in a subset of preterm infants or those with comorbidities, hence leaving the majority of the infant population unprotected against this virus. Therefore, development of prevention strategies against RSV for all infants entering their first RSV season constitutes a large unmet medical need. The aim of this review is to explore different immunization approaches to protect all infants against RSV. Prevention strategies include maternal immunization, immunization of infants with vaccines, immunization of infants with licensed mAbs (palivizumab), and immunization of infants with long-acting mAbs (e.g., nirsevimab, MK-1654). Of these, palivizumab use is restricted to a small population of infants and does not offer a solution for all-infant protection, whereas vaccine development in infants has encountered various challenges, including the immaturity of the infant immune system, highlighting that future pediatric vaccines will most likely be used in older infants (>6 months of age) and children. Consequently, maternal immunization and immunization of infants with long-acting mAbs represent the two feasible strategies for protection of all infants against RSV. Here, we present considerations regarding these two strategies covering key areas which include mechanism of action, “consistency” of protection, RSV variability, duration of protection, flexibility and optimal timing of immunization, benefit for the mother, programmatic implementation, and acceptance of each strategy by key stakeholders. We conclude that, based on current data, immunization of infants with long-acting mAbs might represent the most effective approach for protecting all infants entering their first RSV season.

Respiratory syncytial virus (RSV) infection is a frequent cause of hospitalisation in the first few months of life; however, this risk rapidly decreases with age. Nirsevimab immunoprophylaxis was approved in the European Union for the prevention of RSV-associated lower respiratory tract disease in infants during their first RSV season. We evaluated the effectiveness of nirsevimab in preventing hospitalisations for confirmed RSV infection and the impact of a strategy of immunisation at birth. A population-based cohort study was performed in Navarre, Spain, where nirsevimab was offered at birth to all children born from October to December 2023. Cox regression was used to estimate the hazard ratio of hospitalisation for PCR-confirmed RSV infection between infants who received and did not receive nirsevimab. Of 1177 infants studied, 1083 (92.0%) received nirsevimab. The risk of hospitalisation for RSV was 8.5% (8/94) among non-immunised infants versus 0.7% (8/1083) in those that were immunised. The estimated effectiveness of nirsevimab was 88.7% (95% confidence interval, 69.6–95.8). Immunisation at birth of infants born between October and December 2023 prevented one hospitalisation for every 15.3 immunised infants. Immunisation of children born from September to January might prevent 77.5% of preventable hospitalisations for RSV in infants born in 2023–2024. These results support the recommendation of nirsevimab immunisation at birth to children born during the RSV epidemic or in the months immediately before to prevent severe RSV infections and alleviate the overload of paediatric hospital resources.

In September 2023, France was one of the first countries that started a national immunisation campaign with nirsevimab, a new monoclonal antibody against respiratory syncytial virus (RSV). Using data from a network of paediatric intensive care units (PICUs), we aimed to estimate nirsevimab effectiveness against severe cases of RSV bronchiolitis in France. We conducted a case–control study based on the test‐negative design and included 288 infants reported by 20 PICUs. We estimated nirsevimab effectiveness at 75.9% (48.5–88.7) in the main analysis and 80.6% (61.6–90.3) and 80.4% (61.7–89.9) in two sensitivity analyses. These real‐world estimates confirmed the efficacy observed in clinical studies.

Health Canada recently authorized the RSVpreF pregnancy vaccine and nirsevimab to protect infants against respiratory syncytial virus (RSV) disease. Assess the cost-effectiveness of RSVpreF and nirsevimab programs in preventing RSV disease in infants, compared to a palivizumab program. We used a static cohort model of a Canadian birth cohort during their first RSV season to estimate sequential incremental cost-effectiveness ratios (ICERs) in 2023 Canadian dollars per quality-adjusted life year (QALY) for nine strategies implemented over a one-year time period, from the health system and societal perspectives. Sensitivity and scenario analyses were conducted to explore the impact of uncertainties on the results. All-infants nirsevimab programs averted more RSV-related outcomes than year-round RSVpreF programs, with the most RSV cases averted in a seasonal nirsevimab program with catch-up. Assuming list prices for these immunizing agents, all-infants nirsevimab and year-round RSVpreF programs were never cost-effective, with ICERs far exceeding commonly used cost-effectiveness thresholds. Seasonal nirsevimab with catch-up for infants born outside the RSV season was a cost-effective program if prioritized for infants at moderate/high-risk (ICER <$28,000 per QALY) or those living in settings with higher RSV burden and healthcare costs, such as remote communities where transport would be complex (ICER of $5700 per QALY). Using a $50,000 per QALY threshold, an all-infants nirsevimab program could be optimal if nirsevimab is priced at <$110–190 per dose. A year-round RSVpreF for all pregnant women and pregnant people plus nirsevimab for infants at high-risk was optimal if nirsevimab is priced at >$110–190 per dose and RSVpreF priced at <$60–125 per dose. Prophylactic interventions can substantially reduce RSV disease in infants, and more focused nirsevimab programs are the most cost-effective option at current product prices.

IntroductionNirsevimab is an extended half-life (M252Y/S254T/T256E [YTE]-modified) monoclonal antibody to the pre-fusion conformation of the respiratory syncytial virus (RSV) Fusion protein, with established efficacy in preventing RSV-associated lower respiratory tract infection in infants for the duration of a typical RSV season. Previous studies suggest that nirsevimab confers protection via direct virus neutralization. Here we use preclinical models to explore whether fragment crystallizable (Fc)-mediated effector functions contribute to nirsevimab-mediated protection.MethodsNirsevimab, MEDI8897* (i.e., nirsevimab without the YTE modification), and MEDI8897*-TM (i.e., MEDI8897* without Fc effector functions) binding to Fc γ receptors (FcγRs) was evaluated using surface plasmon resonance. Antibody-dependent neutrophil phagocytosis (ADNP), antibody-dependent cellular phagocytosis (ADCP), antibody-dependent complement deposition (ADCD), and antibody-dependent cellular cytotoxicity (ADCC) were assessed through in vitro and ex vivo serological analyses. A cotton rat challenge study was performed with MEDI8897* and MEDI8897*-TM to explore whether Fc effector functions contribute to protection from RSV.ResultsNirsevimab and MEDI8897* exhibited binding to a range of FcγRs, with expected reductions in FcγR binding affinities observed for MEDI8897*-TM. Nirsevimab exhibited in vitro ADNP, ADCP, ADCD, and ADCC activity above background levels, and similar ADNP, ADCP, and ADCD activity to palivizumab. Nirsevimab administration increased ex vivo ADNP, ADCP, and ADCD activity in participant serum from the MELODY study (NCT03979313). However, ADCC levels remained similar between nirsevimab and placebo. MEDI8897* and MEDI8897*-TM exhibited similar dose-dependent reduction in lung and nasal turbinate RSV titers in the cotton rat model.ConclusionNirsevimab possesses Fc effector activity comparable with the current standard of care, palivizumab. However, despite possessing the capacity for Fc effector activity, data from RSV challenge experiments illustrate that nirsevimab-mediated protection is primarily dependent on direct virus neutralization.

Respiratory syncytial virus (RSV) represents a high burden of disease in children and the primary cause of hospitalization, especially in children under 1 year old. In the Valencian Community (Spain), nirsevimab, a long-acting monoclonal antibody, was introduced for the RSV 2023–2024 season as a universal pre-exposure prophylaxis for high-risk children and those under 6 months old. This study examines its impact, coverage, and effectiveness. The campaign achieved 88.5 % coverage and 73.7 % of effectiveness. Analysis of over 27,000 susceptible children (over 24,000 immunized), showed that those immunized exhibited a threefold reduction in RSV incidence compared to non-immunized ones. To prevent one case, the number needed to immunize (NNI) was 63. Hospitalizations due to acute respiratory infections were almost two times lower in immunized children compared to non-immunized ones (0.9 % vs 1.6 %, respectively). These first results showcase the preliminary positive impact of this public health intervention.

Respiratory syncytial virus (RSV) causes most of the cases of bronchiolitis and thousands of deaths annually, particularly in infants less than 6 months old. In Catalonia (Spain), infants born between April 2023 and March 2024 aged 0–6 months during their first RSV season have been candidates to receive nirsevimab, the novel monoclonal antibody against RSV, since October 2023. We aimed to analyse the dynamics of all-causes bronchiolitis diagnoses and RSV community infections in the current season and compare them to pre-nirsevimab epidemics. We collected epidemiological data from the Information System for Surveillance of Infections in Catalonia (SIVIC) on daily all-causes bronchiolitis clinical diagnoses and RSV-confirmed cases provided by rapid antigen tests in primary care practices. We calculated the rate ratio (RR) for the incidence of all-causes bronchiolitis for children aged 0-11 m-old with respect to 12-35 m-old between September 2014 and January 2024. We analysed the RR of the incidence of RSV-confirmed infection for 0-11 m-old and 12-35 m-old with respect to the > 35 m-old, from January 2021 to January 2024. We then computed the relative difference of the RR, designated as percentage of reduction of risk, between season 2023/2024 and former epidemics. With a global coverage recorded rate for nirsevimab of 82.2% in January 2024, the age-specific 0-11 m-old RR (95% CI) of RSV infection incidence for > 35 m-old was 1.7 (1.5–2.0) in season 2023/2024. The RR (95% CI) had been 7.4 (5.6–9.9), 8.8 (6.9–11.3), and 7.1 (5.7–8.9) in 2020/2021, 2021/2022, and 2022/2023, respectively. Regarding the incidence of all-causes bronchiolitis for the 0-11 m-old group compared to the 12-35 m-old, the pre-pandemic (2014/2015–2019/2020) and 2022/2023 RR (95% CI) were 9.4 (9.2–9.6) and 6.0 (5.7–6.2), respectively, significantly higher than the RR of 3.6 (3.4–3.8) for the most recent season, 2023/2024. Conclusion : Concurring with the introduction of nirsevimab, the risk of RSV infection for infants aged 0-11 m-old compared to > 35 m-old has been reduced by 75.6% (73.4–77.5) in last season, and the risk for all-causes bronchiolitis for 12-35 m-old by 61.9% (60.9–62.9) from the pre-pandemic period and by 39.8% (39.3–40.2) from the 2022/2023 epidemic, despite high RSV community transmission, especially in older infants What is Known: • RSV is responsible for approximately 70% of bronchiolitis cases and causes severe disease, particularly in infants < 6 months of age. • Nirsevimab effectiveness against RSV-associated disease, particularly hospitalisations, was expected to be around 80%; other Spanish regions, such as Galicia and Valencia, and European countries including Luxembourg and Germany, have already reported good results in implementing nirsevimab to prevent RSV-associated hospitalisations and PICU stays. What is New: • We provide insight into the community incidence of RSV and all-causes bronchiolitis for season 2023/2024, when nirsevimab has been introduced to the Catalan population, using.   primary healthcare data, which enabled us to assess the burden of RSV infections and bronchiolitis in the commonly seasonally saturated primary healthcare practices. • Our study reveals that the risk of all-causes bronchiolitis for infants aged 0-11 m-old compared to older infants was reduced by 40% compared to the previous season and 62% compared to pre-pandemic standards, and for RSV infection it was reduced by 76%.

Respiratory syncytial virus (RSV) bronchiolitis remains a significant global health burden, particularly in newborns and infants during their first year of life. The quest for an effective preventive strategy against RSV has long been sought, and recent developments have shown promise in the form of nirsevimab, a monoclonal antibody specifically designed for RSV prophylaxis. Valle d’Aosta was the first Italian region to propose universal prophylaxis with nirsevimab for newborns and infants in their first epidemic season as early as 2023–2024. This study describes the effectiveness and safety of the universal prevention program of RSV bronchiolitis using the monoclonal antibody nirsevimab in children resident in Valle d’Aosta born during the 2023–2024 epidemic season. There were 556 neonates born from 1 May 2023 to 15 February 2024. The risk of hospitalization for RSV bronchiolitis in 2023–2024 was 3.2%, compared to 7% in the 2022–2023 epidemic season (p < 0.001). After the start of the prophylaxis campaign with nirsevimab, the risk of hospitalization was 8.3% in the sample of infants who did not adhere to the prophylaxis, while no child in the sample of those treated (p < 0.001) was hospitalized for bronchiolitis. Few mild transient side effects were reported. This study shows the efficacy and safety of universal prophylaxis with nirsevimab in neonates, making Valle d’Aosta the first Italian region to offer universal prophylaxis to newborns without risk factors for RSV complications. Future research could further explore its long-term impact and cost-effectiveness.

In 2023 and 2024, governments around the world, including France, Luxembourg, Spain, and some states in Australia, commenced infant RSV immunisation programs using nirsevimab. To support rollouts of nirsevimab and drive uptake, governments developed communication materials targeting parents and healthcare providers. As yet, little is known about how governments communicated with these audiences about this new immunisation and the extent to which messaging varied between jurisdictions. This study comparatively analysed government communications from France, Luxembourg, Spain, and Australia disseminated as part of nirsevimab program rollouts. It engaged in text analysis to identify key components within messaging, and a values expression analysis, drawing on the Schwartz theory of personal values, to provide a systematic understanding of how messaging was presented to parents and healthcare providers, and the specific motivations messaging sought to tap in to. We found three key components in messaging from all jurisdictions: educational, information, and activation messaging. However, while the types of messages were similar, we found country-based differences in how materials presented messages, including risk-framing, use of emotive language, and the extent to which parents were linked to trustworthy sources of information. We further identified that personal values expressions of security, benevolence, and universalism were prevalent across messaging from all jurisdictions, but observed greater prevalence of self-direction values expression in parent targeted materials from France and Australia, and greater conformity expressions in material aimed at healthcare providers. Our study reveals how different governments communicated with their population around the introduction of infant RSV immunisation, and how this messaging aimed to encourage uptake. Findings from this study provide insight as to how messaging approaches could be translated and tailored in developing government communications to support infant RSV immunisation implementation and uptake elsewhere in the world, as well as rollout of other prospective immunisation programs.