Value profile for respiratory syncytial virus vaccines and monoclonal antibodies.

Respiratory syncytial virus (RSV) is the predominant cause of acute lower respiratory infection (ALRI) in young children worldwide, yet no licensed RSV vaccine exists to help prevent the millions of illnesses and hospitalizations and tens of thousands of young lives taken each year. Monoclonal antibody (mAb) prophylaxis exists for prevention of RSV in a small subset of very high-risk infants and young children, but the only currently licensed product is impractical, requiring multiple doses and expensive for the low-income settings where the RSV disease burden is greatest. A robust candidate pipeline exists to one day prevent RSV disease in infant and pediatric populations, and it focuses on two promising passive immunization approaches appropriate for low-income contexts: maternal RSV vaccines and long-acting infant mAbs. Licensure of one or more candidates is feasible over the next one to three years and, depending on final product characteristics, current economic models suggest both approaches are likely to be cost-effective. Strong coordination between maternal and child health programs and the Expanded Program on Immunization will be needed for effective, efficient, and equitable delivery of either intervention. This 'Vaccine Value Profile' (VVP) for RSV is intended to provide a high-level, holistic assessment of the information and data that are currently available to inform the potential public health, economic and societal value of pipeline vaccines and vaccine-like products. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, public private partnerships and multi-lateral organizations, and in collaboration with stakeholders from the WHO headquarters. All contributors have extensive expertise on various elements of the RSV VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information.

RSV neutralization assays - Use in immune response assessment.

Respiratory syncytial virus (RSV) is a leading cause of respiratory illness among children and infants worldwide, yet no licensed vaccine exists to reduce the risk of disease. At least 16 RSV vaccine candidates are currently in clinical development and many are designed to induce robust virus neutralizing immune responses. RSV neutralizing antibody (nAb)-mediated interventions such as intravenous immunoglobulin (IVIG) and palivizumab provide passive protection against serious lower respiratory tract disease due to RSV, validating nAbs as a correlate of protection. To identify correlates of protection for vaccine candidates that have demonstrated their protective efficacy, an investigator can use assays designed to measure nAb responses. However, there is no standard method of measurement; individual laboratories have developed their own methods to measure the ability of nAbs to reduce the infectivity of a defined virus dose in a variety of cell lines, leading to establishment of the broad variety of RSV neutralization assay formats currently in use. Standardizing the RSV neutralization assay is an essential step toward better assessment of nAb responses to vaccine candidates. Use of a common reference standard by all makes comparing the immunogenicity of different vaccine candidates feasible. In the context of vaccine development, the WHO 1st International Standard for Antiserum to RSV (RSV IS) has been shown to be suitable for harmonizing results across laboratories and assay formats used to measure nAb titers to RSV/A and RSV/B in human sera. This review describes the broad variety of RSV virus neutralization assay formats currently in use and the importance of the RSV IS for harmonization of results across formats and across laboratories. It also outlines good practices for key assay components and data analysis to promote the quality and consistency of measuring RSV nAb titers in serum specimens.

Impact and cost-effectiveness of potential interventions against infant respiratory syncytial virus (RSV) in 131 low-income and middle-income countries using a static cohort model.

OBJECTIVES: Interventions to prevent childhood respiratory syncytial virus (RSV) disease are limited and costly. New interventions are in advanced stages of development and could be available soon. This study aims to evaluate the potential impact and cost-effectiveness of two interventions to prevent childhood RSV-a maternal vaccine and a monoclonal antibody (mAb). DESIGN: Using a static population-based cohort model, we evaluate impact and cost-effectiveness of RSV interventions, from a health systems perspective. The assumed baseline efficacy and duration of protection were higher for the mAb (60%-70% efficacy, protection 6 months) compared with the maternal vaccine (40%-60% efficacy, protection 3 months). Both interventions were evaluated at US$3 and US$5 per dose for Gavi and non-Gavi countries, respectively. A range of input values were considered to explore uncertainty. SETTINGS: 131 low-income and middle-income countries. PARTICIPANTS: Pregnant women and live birth cohorts. INTERVENTIONS: Maternal vaccine given to pregnant women and mAb given to young infants. PRIMARY AND SECONDARY OUTCOME MEASURES: Disability-adjusted life years averted, severe case averted, deaths averted, incremental cost effectiveness ratios. RESULTS: Under baseline assumptions, maternal vaccine and mAbs were projected to avert 25% and 55% of RSV-related deaths among infants younger than 6 months of age, respectively. The average incremental cost-effectiveness ratio per disability-adjusted life year averted was US$1342 (range US$800-US$1866) for maternal RSV vaccine and US$431 (range US$167-US$692) for mAbs. At a 50% gross domestic product per capita threshold, maternal vaccine and mAbs were cost-effective in 60 and 118 countries, respectively. CONCLUSIONS: Both interventions are projected to be impactful and cost-effective in many countries, a finding that would be enhanced if country-specific Gavi cofinancing to eligible countries were included. mAbs, with assumed higher efficacy and duration of protection, are expected to be more cost-effective than RSV maternal vaccines at similar prices. Final product characteristics will influence this finding.

Inferring antenatal care visit timing in low- and middle-income countries: Methods to inform potential maternal vaccine coverage.

BACKGROUND: The timing of antenatal care (ANC) visits directly affect health intervention coverage and impact, especially for those interventions requiring strict gestational age windows for administration, such as maternal respiratory syncytial virus (RSV) vaccine. Existing nationally representative population-based surveys do not record the timing of ANC visits beyond the first, limiting the availability of reliable data around timing of subsequent ANC visits in most low- and middle-income countries (LMICs). Here, we describe a model that estimates the timing of ANC visits by gestational age using publicly available multi-country survey data. METHODS AND FINDINGS: We used the Demographic and Health Surveys (DHS) data from 69 LMICs. We used several factors to estimate the timing of subsequent ANC visits by gestation age: the timing of the first ANC visit (ANC1) in a given pregnancy, derived from the DHS; the country's reported average ANC coverage at each ANC visit (ANC1 through the fourth ANC visit [ANC4]); and the World Health Organization's guidance on recommended ANC visit. We then used the timing of ANC visit by gestation age to predict the coverage of a potential maternal RSV vaccine administered at 24-36 weeks of gestation. We calculated the maternal immunization coverage by summing the number of eligible women vaccinated at any ANC visit divided by the total number of pregnant women. We find, in general, countries with higher ANC1 coverage were predicted to have higher vaccination coverage. In 82% of countries, the modeled vaccine coverage is less than ANC4 coverage. CONCLUSIONS: The methods illustrated in this paper have implications on the precision of estimating impact and programmatic feasibility of time-critical interventions, especially for pregnant women. The methods can be easily adapted to vaccine demand forecasts models, vaccine impact assessments, and cost-effectiveness analyses and can be adapted to other maternal interventions that have administration timing restrictions.