Assessment of effectiveness and impact of universal prophylaxis with nirsevimab for prevention of hospitalizations due to respiratory syncytial virus in infants. The NIRSE-GAL study protocol.

Nirsevimab has been recently licensed for universal RSV prophylaxis in infants. NIRSE-GAL is a three-year population-based study initiated in Galicia in September 2023. It aims to evaluate nirsevimab effectiveness against RSV-related hospitalizations lower respiratory tract infections (LRTI), severe RSV, all-cause LRTI, and all-cause hospitalization. NIRSE-GAL also aims to estimate nirsevimab impact on primary healthcare use in the short and mid-term, children's wheezing and asthma, and medical prescriptions for RSV. The immunization campaigns will be scheduled based on the expected start week for the RSV season and will last the whole season. Immunization will be offered to: i) infants born during the campaign (seasonal), ii) infants < 6 months at the start of the campaign (catch-up), and iii) infants with high-risk factors, aged 6-24 months at the start of the campaign (high-risk). The follow-up period will start: i) the immunization date for all immunized infants, ii) the start of the campaign, for the non-immunized catch-up or high-risk groups, or iii) the birthdate for the non-immunized seasonal group. Infants will be followed up until outcome occurrence, death, or end of study. Nirsevimab effectiveness will be estimated using Poisson and Cox regression models. Sensitivity and stratified analyses will be undertaken. The number of averted cases and the number needed to immunize will be estimated. Immunization failure and nirsevimab safety will be monitored. NIRSE-GAL was approved by the ethics committee of Galicia (CEIC 2023-377) and registered in ClinicalTrials.gov (ID: NCT06180993). Findings will be mainly shared via peer-reviewed publications and scientific conferences.

Vaccination against Respiratory Syncytial Virus.

Respiratory syncytial virus (RSV) causes infection throughout life, with infants, adults who are severely immunocompromised, and the elderly at special risk of developing lower respiratory tract disease, hospitalisation, and death. The burden of severe disease in the elderly is comparable to seasonal influenza, and there remains no effective anti-viral drugs or vaccine for any target population. The development of a vaccine to confer immunity against severe disease is a major global health priority. A multitude of safe and immunogenic vaccine candidates have failed to induce the protective immunity needed for licensure, and in recent years this has included the largest clinical trials of RSV vaccines in history. The obstacles to vaccine development in elderly populations include an incomplete understanding of the immune responses needed for protection, the effect of aging on induction and maintenance of immunity (natural and vaccine induced immunity), and the high rate of co-morbid disease in older adults. Recent advances in structural biology, new biological platforms for antigen delivery, and insights from experimental challenge models mark the latest developments in over 50 years of research. This continues to be an active and evolving field of scientific discovery with renewed hope for a vaccine in the future.

In vitro model for the assessment of human immune responses to subunit RSV vaccines.

Respiratory syncytial virus (RSV) is the single most important cause of serious lower respiratory tract disease in infants and young children worldwide and a high priority for vaccine development. Despite over 50 years of research, however, no vaccine is yet available. One block to vaccine development is an incomplete understanding of the aberrant memory response to the formalin-inactivated RSV vaccine (FI-RSV) given to children in the 1960s. This vaccine caused enhanced respiratory disease (ERD) with later natural RSV infection. Concern that any non-live virus vaccine may also cause ERD has blocked development of subunit vaccines for young children. A number of animal FI-RSV studies suggest various immune mechanisms behind ERD. However, other than limited data from the original FI-RSV trial, there is no information on the human ERD-associated responses. An in vitro model with human blood specimens may shed light on the immune memory responses likely responsible for ERD. Memory T cell responses to an antigen are guided by the innate responses, particularly dendritic cells that present an antigen in conjunction with co-stimulatory molecules and cytokine signaling. Our in vitro model involves human monocyte derived dendritic cells (moDC) and allogenic T cell cultures to assess innate responses that direct T cell responses. Using this model, we evaluated human responses to live RSV, FI-RSV, and subunit RSV G vaccines (G-containing virus-like particles, G-VLP). Similar to findings in animal studies, FI-RSV induced prominent Th2/Th17-biased responses with deficient type-1 responses compared to live virus. Responses to G-VLPs were similar to live virus, i.e. biased towards a Th1 and not a Th2/Th17. Also mutating CX3C motif in G gave a more pronounced moDC responses associated with type-1 T cell responses. This in vitro model identifies human immune responses likely associated with ERD and provides another pre-clinical tool to assess the safety of RSV vaccines.

Antibody Epitopes of Pneumovirus Fusion Proteins.

The pneumoviruses respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) are two widespread human pathogens that can cause severe disease in the young, the elderly, and the immunocompromised. Despite the discovery of RSV over 60 years ago, and hMPV nearly 20 years ago, there are no approved vaccines for either virus. Antibody-mediated immunity is critical for protection from RSV and hMPV, and, until recently, knowledge of the antibody epitopes on the surface glycoproteins of RSV and hMPV was very limited. However, recent breakthroughs in the recombinant expression and stabilization of pneumovirus fusion proteins have facilitated in-depth characterization of antibody responses and structural epitopes, and have provided an enormous diversity of new monoclonal antibody candidates for therapeutic development. These new data have primarily focused on the RSV F protein, and have led to a wealth of new vaccine candidates in preclinical and clinical trials. In contrast, the major structural antibody epitopes remain unclear for the hMPV F protein. Overall, this review will cover recent advances in characterizing the antigenic sites on the RSV and hMPV F proteins.

Burden of Respiratory Syncytial Virus Disease and Mortality Risk Factors in Argentina: 18 Years of Active Surveillance in a Children's Hospital.

BACKGROUND: Respiratory syncytial virus is the leading cause of acute lower respiratory infection in children. We aimed to describe the clinical-epidemiologic pattern and risk factors for mortality associated with RSV infection. METHODS: This is a prospective, cross-sectional study of acute lower respiratory infection in children admitted to the Children's Hospital during 2000 to 2017. Viral diagnosis was made by fluorescent antibody techniques or real-time-polymerase chain reaction. We compared clinical-epidemiologic characteristics of RSV infection in nonfatal versus fatal cases. Multiple logistic regression was used to identify independent predictors of mortality. RESULTS: Of 15,451 patients with acute lower respiratory infection, 13,033 were tested for respiratory viruses and 5831 (45%) were positive: RSV 81.3% (4738), influenza 7.6% (440), parainfluenza 6.9% (402) and adenovirus 4.3% (251). RSV had a seasonal epidemic pattern coinciding with months of lowest average temperature. RSV cases show a case fatality rate of 1.7% (82/4687). Fatal cases had a higher proportion of prematurity (P < 0.01), perinatal respiratory history (P < 0.01), malnourishment (P < 0.01), congenital heart disease (P < 0.01), chronic neurologic disease (P < 0.01) and pneumonia at clinical presentation (P = 0.014). No significant difference between genders was observed. Most deaths occurred among children who had complications: respiratory distress (80.5%), nosocomial infections (45.7%), sepsis (31.7%) and atelectasis (13.4%). Independent predictors of RSV mortality were moderate-to-severe malnourishment, odds ratio (OR): 3.69 [95% confidence interval (CI): 1.98-6.87; P < 0.0001]; chronic neurologic disease, OR: 4.14 (95% CI: 2.12-8.08; P < 0.0001); congenital heart disease, OR: 4.18 (95% CI: 2.39-7.32; P< 0.0001); and the age less than 6 months, OR: 1.99 (95% CI: 1.24-3.18; P = 0.004). CONCLUSIONS: RSV showed an epidemic pattern affecting mostly young children. Malnourishment, chronic neurologic disease, congenital heart disease and the age less than 6 months were the independent risk factors for RSV mortality.

Respiratory syncytial virus seasonality and its implications on prevention strategies.

With maternal and infant vaccines against respiratory syncytial virus (RSV) in development, it is timely to consider how the deployment of these vaccines might vary according to local RSV disease seasonality. In temperate regions RSV infection is predictably limited to a period of 3 to 5 months, while in tropical regions disease seasonality is often both more variable and more prolonged. Accordingly, in tropical regions a year-round immunisation schedule for both maternal and infant immunisation might be appropriate. In contrast, in temperate regions the benefit of year-round maternal immunisation would be heavily dependent on the duration of protection this provided, potentially necessitating a strategy directed at children due to be born in the months immediately prior to the RSV season. This review will consider the impact of seasonality on maternal and infant immunisation strategies against RSV, and the potential of an alternative approach of passive immunisation for all infants immediately prior to the RSV season.

Respiratory syncytial virus immunization program for the United States: impact of performance determinants of a theoretical vaccine.

OBJECTIVES: To inform strategic decisions on respiratory syncytial virus (RSV) vaccine development and identify critical endpoints likely to drive the vaccine's medical and economic impact. DESIGN: A decision-analysis model populated using healthcare utilization data and costs from the literature; vaccine efficacy and duration based on assumptions. SETTING: Vaccination in the physician office setting in the USA. PARTICIPANTS: A hypothetical cohort of newborn infants. INTERVENTION: Vaccination of children at low and high risk of respiratory sequelae with a theoretical RSV vaccine vs palivizumab prophylaxis for children at high risk. OUTCOME MEASURES: Medical and economic value of RSV vaccination, including cost per quality adjusted life-year (QALY) gained. RESULTS: Using base-case assumptions (efficacy 50% at birth; half-life 12 months), RSV vaccination would prevent 23,069 hospitalizations and 66 deaths per vaccinated birth cohort in the USA. Excluding vaccination costs, direct medical costs for RSV would reduce by $236 million, and income and productivity losses by $134 million. Assuming a vaccine cost per course similar to Rotarix® in the USA ($232 including administration fees), the cost per QALY gained would be $93,401 (95% CI: $65,815-$126,060) from the healthcare system perspective and $65,115 (95% CI: $41,003-$93,679) from the societal perspective. The net cost (healthcare system perspective) per life-year saved would be $216,120 (95% CI: $161,184-$263,981); the cost per hospitalization averted would be $19,172 (95% CI: $14,679-$22,093). Aside from efficacy, the vaccine's impact is sensitive to the start of protective immunity and the duration of protection. CONCLUSIONS: Development of an RSV vaccine would substantially reduce inpatient hospitalizations and outpatient visits. It would also have an impact on infant mortality. To demonstrate the full medical and economic value of the vaccine, appropriate endpoints or endpoint surrogates for hospitalization, mortality, and total case reductions should be collected during vaccine development.

A neutralization assay for respiratory syncytial virus using a quantitative PCR-based endpoint assessment.

BACKGROUND: Few studies have used quantitative polymerase chain reaction (qPCR) as an approach to measure virus neutralization assay endpoints. Its lack of use may not be surprising considering that sample nucleic acid extraction and purification can be expensive, labor-intensive, and rate-limiting. METHODS: Virus/antibody mixtures were incubated for one hour at 37°C and then transferred to Vero cell monolayers in a 96-well plate format. At 24 (or 48) hours post-infection, we used a commercially available reagent to prepare cell lysates amenable to direct analysis by one-step SYBR Green quantitative reverse transcription PCR using primers specific for the RSV-N gene, thereby obviating the need for cumbersome RNA extraction and purification. The neutralization titer was defined as the reciprocal of the highest dilution needed to inhibit the PCR signal by 90% when compared with the mean value observed in virus control wells in the absence of neutralizing antibodies. RESULTS: We have developed a qPCR-based neutralization assay for human respiratory syncytial virus. Due to the sensitivity of qPCR in detecting virus replication, endpoints may be assessed as early as 24 hours post-infection. In addition, the dynamic range of qPCR provides a basis for the assay to be relatively robust to perturbations in input virus dose (i.e., the assay is in compliance with the Percentage Law). CONCLUSIONS: This qPCR-based neutralization assay is suitable for automated high-throughput applications. In addition, our experimental approach may be generalizable for the rapid development of neutralization assays for other virus families.

Prophylactic and therapeutic testing of Nicotiana-derived RSV-neutralizing human monoclonal antibodies in the cotton rat model.

Severe lower respiratory tract infection in infants and small children is commonly caused by respiratory syncytial virus (RSV). Palivizumab (Synagis(®)), a humanized IgG1 monoclonal antibody (mAb) approved for RSV immunoprophylaxis in at-risk neonates, is highly effective, but pharmacoeconomic analyses suggest its use may not be cost-effective. Previously described potent RSV neutralizers (human Fab R19 and F2-5; human IgG RF-1 and RF-2) were produced in IgG format in a rapid and inexpensive Nicotiana-based manufacturing system for comparison with palivizumab. Both plant-derived (palivizumab-N) and commercial palivizumab, which is produced in a mouse myeloma cell line, showed protection in prophylactic (p < 0.001 for both mAbs) and therapeutic protocols (p < 0.001 and p < 0.05 respectively). The additional plant-derived human mAbs directed against alternative epitopes displayed neutralizing activity, but conferred less protection in vivo than palivizumab-N or palivizumab. Palivizumab remains one of the most efficacious RSV mAbs described to date. Production in plants may reduce manufacturing costs and improve the pharmacoeconomics of RSV immunoprophylaxis and therapy.

Whole genome sequencing and evolutionary analysis of human respiratory syncytial virus A and B from Milwaukee, WI 1998-2010.

BACKGROUND: Respiratory Syncytial Virus (RSV) is the leading cause of lower respiratory-tract infections in infants and young children worldwide. Despite this, only six complete genome sequences of original strains have been previously published, the most recent of which dates back 35 and 26 years for RSV group A and group B respectively. METHODOLOGY/PRINCIPAL FINDINGS: We present a semi-automated sequencing method allowing for the sequencing of four RSV whole genomes simultaneously. We were able to sequence the complete coding sequences of 13 RSV A and 4 RSV B strains from Milwaukee collected from 1998-2010. Another 12 RSV A and 5 RSV B strains sequenced in this study cover the majority of the genome. All RSV A and RSV B sequences were analyzed by neighbor-joining, maximum parsimony and Bayesian phylogeny methods. Genetic diversity was high among RSV A viruses in Milwaukee including the circulation of multiple genotypes (GA1, GA2, GA5, GA7) with GA2 persisting throughout the 13 years of the study. However, RSV B genomes showed little variation with all belonging to the BA genotype. For RSV A, the same evolutionary patterns and clades were seen consistently across the whole genome including all intergenic, coding, and non-coding regions sequences. CONCLUSIONS/SIGNIFICANCE: The sequencing strategy presented in this work allows for RSV A and B genomes to be sequenced simultaneously in two working days and with a low cost. We have significantly increased the amount of genomic data that is available for both RSV A and B, providing the basic molecular characteristics of RSV strains circulating in Milwaukee over the last 13 years. This information can be used for comparative analysis with strains circulating in other communities around the world which should also help with the development of new strategies for control of RSV, specifically vaccine development and improvement of RSV diagnostics.

Pneumonia case-finding in the RESPIRE Guatemala indoor air pollution trial: standardizing methods for resource-poor settings.

OBJECTIVE: Trials of environmental risk factors and acute lower respiratory infections (ALRI) face a double challenge: implementing sufficiently sensitive and specific outcome assessments, and blinding. We evaluate methods used in the first randomized exposure study of pollution indoors and respiratory effects (RESPIRE): a controlled trial testing the impact of reduced indoor air pollution on ALRI, conducted among children 90% of children meeting ALRI criteria, of whom about 70% attended a physician. Referrals for cough without respiratory signs and self-referrals contributed 19.0% and 17.9% of physician-diagnosed ALRI cases respectively. Intervention group attendance following ALRI referral was 7% higher than controls, a trend also seen in compliance with RSV tests and CXR. There was no evidence of bias by intervention status in fieldworker classification or physician diagnosis. Incidence of fieldworker ALRI (1.12 episodes/child/year) is consistent with high sensitivity and low specificity; incidence of physician-diagnosed ALRI (0.44 episodes/child/year) is consistent with comparable studies. CONCLUSION: The combination of case-finding methods achieved good sensitivity and specificity, but intervention cases had greater likelihood of reaching the physician and being investigated. There was no evidence of bias in fieldworkers classifications despite lack of concealment at home visits. Pulse oximetry offers practical, objective severity assessment for field studies of ALRI.

The use of health economics to guide drug development decisions: Determining optimal values for an RSV-vaccine in a model-based scenario-analytic approach.

Health-economic modelling is useful for assessing the clinical requirements and impact of new vaccines. In this study, we estimate the impact of potential vaccination for respiratory syncytial virus (RSV) of infants in the Netherlands. A decision analysis model was employed using seasonal data from a cohort of children (1996-1997 through 1999-2000) to assess hospitalisation, costs and impact of vaccination. Yearly, an estimated 3670 infants are hospitalised with RSV-infection in the Netherlands, vaccination protecting infants from 3 months of life onwards could prevent approximately 1000-3000 hospitalisations, depending on the effectiveness of the potential vaccine. Additionally, vaccination could prevent a major share of RSV-related costs. Comparison of the calculated break-even prices with the average price of recently introduced vaccines indicates that pricing for a potential RSV-vaccine most likely allows for only a single dose vaccination or several doses at a relatively low price per dose in order to achieve cost savings. However, if evidence on relevant RSV-related mortality would become available, higher pricing would be justified, while still remaining below accepted thresholds for cost-effectiveness.

Bronchiolitis.

Bronchiolitis is a distressing, potentially life-threatening respiratory condition that affects young babies. Around 2-3% of all infants younger than 1 year are admitted to hospital with bronchiolitis, usually during the seasonal epidemic. The majority of these infants are infected with respiratory syncytial virus and all have an intense inflammatory response in their airways. Although most infants recover, they have an increased risk of recurrent wheezing. Although bronchiolitis is common, little is known about what causes infants to be susceptible. Diagnostic interventions have little effect on clinical outcome, and apart from supportive measures, there is no specific treatment. Bronchiolitis therefore presents an intriguing clinical conundrum and a major challenge to researchers. High quality clinical studies are needed to clarify assessment of disease severity and criteria for hospital admission, particularly the use of pulse oximetry and chest radiography. Careful mapping of the inflammatory pathways in the pathogenesis of bronchiolitis should lead to development of new therapies to alleviate symptoms.

Passive immunisation of preterm infants with palivizumab against RSV infection.

Palivizumab is a monocloncal antibody used for prevention of respiratory syncytial virus infection. This study reviews the literature regarding evidence of efficacy, safety and cost-effectiveness. The only randomised controlled trial into efficacy of palivizumab in preterm infants demonstrates clinical benefit and suggests a favourable safety profile. Further studies, however, do not provide evidence that costs saved by the reduction in hospitalisation would outweigh actual costs of the immunization for the recommended indications. There is considerable controversy over which groups of patients to include in immunization programs and analyses of cost-effectiveness are complicated by the fact that incidence of RSV infection, rates of hospitalisation and ventilation, health care costs and economic resources are variable among different health care systems and settings. Studies of cost-analysis, despite their implicit weaknesses, do not currently support the widespread use of palivizumab. In the absence of high quality cost-benefit analysis, we currently only recommend the use of palivizumab in infants at high risk of severe bronchiolitis, such as those with active chronic lung disease of prematurity. To illustrate current practice we also present data from an audit of the use of palivizumab in a regional centre in the North-East of England.

[Prevention of respiratory syncytial virus infection by SYNAGIS (palivizumab)]. / Prévention de l'infection à virus respiratoire syncytial (VRS) par le SYNAGIS (palivizumab).

Infection with respiratory syncytial virus is frequent but most often benign. The serious forms of the illness, which make necessary hospitalisation or care in an intensive Care Unit, appear in infants of less than 6 weeks and especially in those with underlying pathologies, prematurity, congenital cardiopathies or chronic respiratory illnesses. Palivizumab (SYNAGIS) is mouse humanized monoclonal antibody which is used for prevention by monthly injections before and during the epidemic period. In a pivotal study performed on 1502 infants aged less than 6 months and former prematures of less than 36 weeks gestational age (GA) or aged less than 2 years and preventing a bronchopulmonary dysplasia, 1002 infants received 5 monthly injections, compared with 500 infants treated with placebo. There was a significant reduction of 55% risk of hospitalisation with VRS infections in the treated group, but no significant reduction in the number of stays in intensive care or deaths. The recommendation in France now is to use SYNAGIS in children aged less than 6 months, born with or GA of less then 32 weeks or aged less than 2 years and presenting a bronchopulmonary dysplasia. Questions remain on the cost-benefit ratio of this treatment and the favourable effects of this treatment in children who carry other chronic pulmonary or cardiac pathologies.

Costs and benefits of respiratory syncytial virus immunoglobulin to prevent hospitalization for lower respiratory tract illness in very low birth weight infants.

BACKGROUND: Respiratory syncytial virus immunoglobulin intravenous (RSV-IGIV) has been shown to reduce the risk of lower respiratory illness (LRI) hospitalization in preterm infants and infants with bronchopulmonary dysplasia (BPD). The purpose of this analysis was to estimate the economic costs and benefits of prophylaxis with RSV-IGIV in these groups. METHODS: The analysis was performed from a payer's perspective and therefore included only costs and cost savings that would be realized by an insurer. Estimates of the direct costs of prophylaxis and the risk and cost of LRI hospitalization were based on data about preterm very low birth weight infants cared for at our medical center. Estimates of the reduction in risk of LRI hospitalization associated with RSV-IGIV were based on data from a randomized trial (the PREVENT Study). RESULTS: The range of cost for a five-dose course of RSV-IGIV was estimated to be $3280 to $8800 for infants weighing 1.2 to 10.0 kg at the time of the initial dose. Risks of LRI hospitalization were estimated to be 12, 17 and 28%, respectively, for preterm infants without BPD, with mild BPD and with moderate to severe BPD. Estimates of duration and per diem cost of LRI hospitalizations were, respectively, 5 days and $971. The estimated net cost of prophylaxis per infant ranged between $5415 for a 6-kg infant without BPD to $1689 for an infant with BPD and age < or =3 months. CONCLUSIONS: The cost of RSV-IGIV typically exceeds the cost of hospitalizations prevented by several thousand dollars. Cost minus benefit is lower for infants with BPD and infants 3 months of age or younger.

A number-needed-to-treat analysis of the use of respiratory syncytial virus immune globulin to prevent hospitalization.

OBJECTIVES: To estimate how many infants in selected high-risk subgroups would require treatment with respiratory syncytial virus immune globulin (RSV-IG) to avoid 1 hospital admission and to determine whether this is economically justified. DESIGN: Cost-benefit analysis. Data from 3 randomized controlled trials of RSV-IG are used to estimate the number needed to treat to prevent 1 hospital admission for respiratory syncytial virus infection. The threshold number needed to treat is computed according to a formula incorporating costs and benefits of RSV-IG prophylaxis. Estimates of the willingness to pay were obtained from a sample of 39 health care providers (35 physicians and 4 nurses). MAIN OUTCOME MEASURES: The number needed to treat to prevent 1 hospital admission for respiratory syncytial virus infection. The threshold number needed to treat that would balance costs with benefits. RESULTS: More than 16 (95% confidence interval, 12.5-23.8) infants would need to be treated with RSV-IG to avoid 1 hospital admission for respiratory syncytial virus infection, ranging from 63 for premature infants without chronic lung disease to 12 (confidence interval, 6.3-100.0) for infants with bronchopulmonary dysplasia. A sensitivity analysis of the costs and values of hospital admission for respiratory syncytial virus infection and RSV-IG treatment resulted in a weak recommendation against the treatment of infants with bronchopulmonary dysplasia and strong recommendations that the costs and risks of RSV-IG treatment outweigh the benefits for the combined sample of infants and premature infants without lung disease. CONCLUSIONS: The number-needed-to-treat procedures offer a method to assess evidence of treatment effects and decision rules for whether to accept treatment recommendations. Under plausible assumptions, treatment with RSV-IG is not recommended for infants without lung disease. Institutions can examine cost and benefit assumptions that best fit their own practice setting.