Safety and Immunogenicity of Respiratory Syncytial Virus Prefusion Maternal Vaccine Coadministered With Diphtheria-Tetanus-Pertussis Vaccine: A Phase 2 Study.

BACKGROUND: Respiratory syncytial virus (RSV) fusion protein stabilized in the prefusion conformation (RSVPreF3) was under investigation as a maternal vaccine. METHODS: This phase 2, randomized, placebo-controlled, single-dose, multicenter study enrolled healthy, nonpregnant women, randomized 1:1:1:1:1 to 5 parallel groups studying RSVPreF3 (60 or 120 µg) coadministered with diphtheria, tetanus, and acellular pertussis vaccine (dTpa) or placebo, and dTpa coadministered with placebo. Safety and humoral immune responses were assessed. An extension phase also assessed a RSVPreF3 120 µg vaccination 12-18 months after first vaccination. RESULTS: The safety profile of RSVPreF3 was unaffected by dose or dTpa coadministration. Solicited and unsolicited adverse events (AEs) were evenly distributed across study groups. Injection-site pain was higher following the second vaccination versus the first vaccination. Medically attended AEs were rare (<5% overall). Both RSVPreF3 dose levels (alone and with dTpa) were immunogenic, increasing levels of RSV-A neutralizing antibody ≥8-fold and anti-RSVPreF3 IgG antibody ≥11-fold at 1 month postvaccination, which persisted at 12-18 months postvaccination; modest 2-fold increases were observed with a second RSVPreF3 vaccination. CONCLUSIONS: This study indicates RSVPreF3 coadministration with dTpa induces robust immune responses and is well tolerated, regardless of the RSVPreF3 dose level used. CLINICAL TRIALS REGISTRATION: NCT04138056.

Cost-effectiveness of pharmaceutical strategies to prevent respiratory syncytial virus disease in young children: a decision-support model for use in low-income and middle-income countries.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of respiratory disease in young children. A number of mathematical models have been used to assess the cost-effectiveness of RSV prevention strategies, but these have not been designed for ease of use by multidisciplinary teams working in low-income and middle-income countries (LMICs). METHODS: We describe the UNIVAC decision-support model (a proportionate outcomes static cohort model) and its approach to exploring the potential cost-effectiveness of two RSV prevention strategies: a single-dose maternal vaccine and a single-dose long-lasting monoclonal antibody (mAb) for infants. We identified model input parameters for 133 LMICs using evidence from the literature and selected national datasets. We calculated the potential cost-effectiveness of each RSV prevention strategy (compared to nothing and to each other) over the lifetimes of all children born in the year 2025 and compared our results to a separate model published by PATH. We ran sensitivity and scenario analyses to identify the inputs with the largest influence on the cost-effectiveness results. RESULTS: Our illustrative results assuming base case input assumptions for maternal vaccination ($3.50 per dose, 69% efficacy, 6 months protection) and infant mAb ($3.50 per dose, 77% efficacy, 5 months protection) showed that both interventions were cost-saving compared to status quo in around one-third of 133 LMICs, and had a cost per DALY averted below 0.5 times the national GDP per capita in the remaining LMICs. UNIVAC generated similar results to a separate model published by PATH. Cost-effectiveness results were most sensitive to changes in the price, efficacy and duration of protection of each strategy, and the rate (and cost) of RSV hospital admissions. CONCLUSIONS: Forthcoming RSV interventions (maternal vaccines and infant mAbs) are worth serious consideration in LMICs, but there is a good deal of uncertainty around several influential inputs, including intervention price, efficacy, and duration of protection. The UNIVAC decision-support model provides a framework for country teams to build consensus on data inputs, explore scenarios, and strengthen the local ownership and policy-relevance of results.

New respiratory syncytial virus immunization products in low- and middle-income countries: potential for cost-effective impact on a high burden of disease in young infants.

As new, efficacious respiratory syncytial virus (RSV) immunization products reach the market, affordable pricing as well as improved estimation of disease burden and the full potential and cost effectiveness of RSV prevention in the hardest hit geographies in low- and middle-income countries are critical to inform country adoption and enable maximum impact against infant disease and mortality globally. The data reported in the special issue underscore the enormous burden, and associated cost, of RSV disease in young infants in several LMICs, including Kenya and South Africa, as well as the potential for RSV maternal vaccines or long-acting monoclonal antibodies, to be cost-effective and possibly even cost-saving.

Cost-Effectiveness of Respiratory Syncytial Virus Preventive Interventions in Children: A Model Comparison Study.

OBJECTIVES: Model-based cost-effectiveness analyses on maternal vaccine (MV) and monoclonal antibody (mAb) interventions against respiratory syncytial virus (RSV) use context-specific data and produce varied results. Through model comparison, we aim to characterize RSV cost-effectiveness models and examine drivers for their outputs. METHODS: We compared 3 static and 2 dynamic models using a common input parameter set for a hypothetical birth cohort of 100 000 infants. Year-round and seasonal programs were evaluated for MV and mAb interventions, using available evidence during the study period (eg, phase III MV and phase IIb mAb efficacy). RESULTS: Three static models estimated comparable medically attended (MA) cases averted versus no intervention (MV, 1019-1073; mAb, 5075-5487), with the year-round MV directly saving ∼€1 million medical and €0.3 million nonmedical costs, while gaining 4 to 5 discounted quality-adjusted life years (QALYs) annually in <1-year-olds, and mAb resulting in €4 million medical and €1.5 million nonmedical cost savings, and 21 to 25 discounted QALYs gained. In contrast, both dynamic models estimated fewer MA cases averted (MV, 402-752; mAb, 3362-4622); one showed an age shift of RSV cases, whereas the other one reported many non-MA symptomatic cases averted, especially by MV (2014). These differences can be explained by model types, assumptions on non-MA burden, and interventions' effectiveness over time. CONCLUSIONS: Our static and dynamic models produced overall similar hospitalization and death estimates, but also important differences, especially in non-MA cases averted. Despite the small QALY decrement per non-MA case, their larger number makes them influential for the costs per QALY gained of RSV interventions.

Three Dose Levels of a Maternal Respiratory Syncytial Virus Vaccine Candidate Are Well Tolerated and Immunogenic in a Randomized Trial in Nonpregnant Women.

BACKGROUND: Respiratory syncytial virus (RSV) causes respiratory tract infections, which may require hospitalization especially in early infancy. Transplacental transfer of RSV antibodies could confer protection to infants in their first months of life. METHODS: In this first-in-human, placebo-controlled study, 502 healthy nonpregnant women were randomized 1:1:1:1 to receive a single dose of unadjuvanted vaccine containing 30/60/120 µg of RSV fusion (F) protein stabilized in the prefusion conformation (RSVPreF3) or placebo. RESULTS: Solicited local adverse events (AEs) were more frequently reported in the RSVPreF3 groups (4%-53.2%) versus placebo (0%-15.9%); most were mild/moderate. Unsolicited AEs were comparably reported among groups. Three serious AEs were reported; none was vaccination-related. Compared with prevaccination values, anti-RSV A neutralizing antibody geometric mean titers and anti-RSVPreF3 immunoglobulin G geometric mean concentrations increased 8- to 14-fold and 12- to 21-fold at day 8 and persisted 5- to 6-fold and 6- to 8-fold higher until day 91 in the RSVPreF3 groups versus 1-fold in placebo. Comparisons at day 8 and day 31 showed that the higher dose levels were significantly more immunogenic than the lowest one. CONCLUSIONS: The RSVPreF3 vaccine was well tolerated and immunogenic. The 60 and 120 µg dose levels were selected for further investigation in pregnant women. CLINICAL TRIALS REGISTRATION: NCT03674177.

Respiratory Syncytial Virus-Associated Mortality Among Young Infants in Karachi, Pakistan: A Prospective Postmortem Surveillance Study.

BACKGROUND: Respiratory syncytial virus (RSV) is an important cause of infant morbidity and mortality and a potential target for maternal immunization strategies. However, data on the role of RSV in young infant deaths in developing countries are limited. METHODS: We conducted a community-based mortality surveillance from August 2018-March 2020 for infants ≤6 months in Karachi, Pakistan. We tested (reverse transcription-polymerase chain reaction) nasopharyngeal swabs from deceased infants for presence of RSV. We performed verbal autopsies and calculated odds of RSV-associated mortality with 95% CIs and used multivariable logistic regression to evaluate associations. RESULTS: We collected 490 nasopharyngeal specimens from 1280 eligible infant deaths. There were 377/490 (76.9%) live births and 14/377 (3.7%; 95% CI: 1.8-5.6) were RSV positive. Most deaths occurred in neonates (254/377; 67.4%), males (226/377; 59.9%), and respiratory illnesses (206/377; 54.6%). Postneonatal age (10/14, 71.4%; OR: 5.5; 95% CI: 1.7-18.0), respiratory symptoms (12/14, 85.7%; OR: 5.2; 1.2-23.7), and high RSV season (9/14, 64.3%; OR: 4.4; 1.4-13.3) were associated with RSV mortality. In multivariable logistic regression analysis, respiratory symptoms (OR: 6.6; 95% CI: 1.3-32.5), RSV seasonality (6.1; 1.8-20.4), and age (9.2; 2.6-33.1) were significant predictors of RSV-associated mortality. CONCLUSIONS: RSV has a significant mortality burden in early infancy in Karachi, Pakistan. Age, RSV seasonality, and respiratory symptoms were significant predictors of RSV-associated mortality. Our findings have implications for clinical management of young infants with cold-like symptoms, policy development, and research regarding maternal immunization against RSV during pregnancy, in resource-constrained, low-income, and vaccine-hesitant populations.

Modelling the household-level impact of a maternal respiratory syncytial virus (RSV) vaccine in a high-income setting.

BACKGROUND: Respiratory syncytial virus (RSV) infects almost all children by the age of 2 years, with the risk of hospitalisation highest in the first 6 months of life. Development and licensure of a vaccine to prevent severe RSV illness in infants is a public health priority. A recent phase 3 clinical trial estimated the efficacy of maternal vaccination at 39% over the first 90 days of life. Households play a key role in RSV transmission; however, few estimates of population-level RSV vaccine impact account for household structure. METHODS: We simulated RSV transmission within a stochastic, individual-based model framework, using an existing demographic model, structured by age and household and parameterised with Australian data, as an exemplar of a high-income country. We modelled vaccination by immunising pregnant women and explicitly linked the immune status of each mother-infant pair. We quantified the impact on children for a range of vaccine properties and uptake levels. RESULTS: We found that a maternal immunisation strategy would have the most substantial impact in infants younger than 3 months, reducing RSV infection incidence in this age group by 16.6% at 70% vaccination coverage. In children aged 3-6 months, RSV infection was reduced by 5.3%. Over the first 6 months of life, the incidence rate for infants born to unvaccinated mothers was 1.26 times that of infants born to vaccinated mothers. The impact in older age groups was more modest, with evidence of infections being delayed to the second year of life. CONCLUSIONS: Our findings show that while individual benefit from maternal RSV vaccination could be substantial, population-level reductions may be more modest. Vaccination impact was sensitive to the extent that vaccination prevented infection, highlighting the need for more vaccine trial data.

A Novel Hexavalent Capsular Polysaccharide Conjugate Vaccine (GBS6) for the Prevention of Neonatal Group B Streptococcal Infections by Maternal Immunization.

BACKGROUND: Group B streptococcus (GBS) causes serious diseases in newborn infants, often resulting in lifelong neurologic impairments or death. Prophylactic vaccination of pregnant women prior to delivery could provide comprehensive protection, as early onset and late-onset disease and maternal complications potentially could be addressed. METHODS: Capsular polysaccharide conjugate vaccine GBS6 was designed using surveillance data yielded by whole-genome sequencing of a global collection of recently recovered GBS isolates responsible for invasive neonatal GBS disease. Capsular polysaccharides were isolated, oxidized using sodium periodate, and conjugated to CRM197 by reductive amination in dimethyl sulfoxide. Immune responses in mice and rhesus macaques were measured in a multiplex Luminex immunoglobulin G (IgG) assay and opsonophagocytic activity assays. RESULTS: The optimized conjugates were immunogenic, alone and in combination, in mice and rhesus macaques, inducing IgG antibodies that mediated opsonophagocytic killing. Active immunization of murine dams with GBS6 prior to mating resulted in serotype-specific protection of pups from a lethal challenge with GBS. Protection following passive administration of serotype-specific IgG monoclonal antibodies to dams demonstrated conclusively that anticapsular polysaccharide IgG alone is sufficient for protection. CONCLUSIONS: The findings support the ongoing clinical evaluation of maternal GBS6 vaccination as a potential alternative method to prevent GBS disease in infants.

Epidemiology of Pertussis Among Young Pakistani Infants: A Community-Based Prospective Surveillance Study.

BACKGROUND: Pertussis remains a cause of morbidity and mortality among young infants. There are limited data on the pertussis disease burden in this age group from low- and lower-middle-income countries, including in South Asia. METHODS: We conducted an active community-based surveillance study from February 2015 to April 2016 among 2 cohorts of young infants in 4 low-income settlements in Karachi, Pakistan. Infants were enrolled either at birth (closed cohort) or at ages up to 10 weeks (open cohort) and followed until 18 weeks of age. Nasopharyngeal swab specimens were obtained from infants who met a standardized syndromic case definition and tested for Bordetella pertussis using real-time polymerase chain reaction. We determined the incidence of pertussis using a protocol-defined case definition, as well as the US Centers for Disease Control and Prevention (CDC) definitions for confirmed and probable pertussis. RESULTS: Of 2021 infants enrolled into the study, 8 infants met the protocol-defined pertussis case definition, for an incidence of 3.96 (95% confidence interval [CI], 1.84-7.50) cases per 1000 infants. Seven of the pertussis cases met the CDC pertussis case definition (5 confirmed, 2 probable), for incidences of CDC-defined confirmed pertussis of 2.47 (95% CI, .90-5.48) cases per 1000 infants, and probable pertussis of 0.99 (95% CI, .17-3.27) cases per 1000 infants. Three of the pertussis cases were severe according to the Modified Preziosi Scale score. CONCLUSIONS: In one of the first prospective surveillance studies of infant pertussis in a developing country, we identified a moderate burden of pertussis disease in early infancy in Pakistan.

Respiratory syncytial virus transplacental antibody transfer and kinetics in mother-infant pairs in Bangladesh.

BACKGROUND: Pneumonia is the leading cause of childhood mortality globally. Respiratory syncytial virus (RSV) is the most important viral cause of pneumonia. Maternal serum antibody protects infants from RSV disease. The objective of our study was to characterize RSV antibody levels in mother-infant pairs. METHODS: Serial serum samples were collected from mother-infant pairs in Bangladesh from the third trimester of pregnancy to 72 weeks postpartum and tested using an RSV antibody microneutralization assay. Serologic infection was defined as a 4-fold increase in antibody titer. Maternal antibody half-life was calculated using infant antibody titers from birth to 20 weeks. RESULTS: The ratio of infant cord blood to maternal serum RSV antibody titers in 149 mother-infant pairs was 1.01 (95% confidence interval [CI], .99-1.03). Maternal RSV antibody titers in the third trimester and at birth were strongly correlated (R = 0.68). Antibody half-life was 38 days (95% CI, 36-42 days). Higher cord blood RSV antibody titers were associated with a lower risk of serologic infection (P = .01) and maintenance of antibody titer above a potentially protective threshold (P < .001). CONCLUSIONS: Efficient transplacental transfer of RSV-specific antibody from mother to the fetus was documented in mother-infant pairs in Asia. Higher cord blood antibody titers were associated with protection from serologic infection.

Attitudes of pregnant women in the Dominican Republic towards a future maternal Group B Streptococcus vaccine.

INTRODUCTION: Current protocols aim to prevent some infant GBS infection through screening and peripartum antibiotics, however such strategies cannot be widely implemented in resource-limited settings. On the other hand, maternal vaccines in development against Group B Streptococcus (GBS) can provide a feasible universal approach. The success of any vaccine will depend on uptake in the population. Rates of maternal GBS colonization in the Dominican Republic (DR) and Caribbean region are among the highest in the world, but little is known about attitudes towards maternal vaccines in this region. METHODS: A cross-sectional, multicenter, mixed-methodology survey evaluated facilitators and barriers to maternal immunization and acceptability of a hypothetical Group B Streptococcus vaccine among pregnant women in three hospitals in the DR. RESULTS: Six-hundred and fifty women completed the survey of whom 85 % had never heard of GBS. Following receipt of information about GBS and a vaccine, 94 % of women stated that they would be likely or very likely to receive a vaccine. Being 18 years or younger was associated with a lower likelihood of GBS vaccine receipt (AOR 0.32, 95 % CI 0.14-0.69). Being born in the DR was associated with a higher likelihood of GBS vaccine receipt (AOR 2.73, 95 % CI 1.25-5.97). Among women who were unlikely to receive the vaccine, uncertainty about potential harm from a novel vaccine was the prominent theme elicited from free text responses. CONCLUSION: There was a high level of acceptance of a future GBS vaccine among this sample of pregnant women in the DR. However, knowledge of vaccines and vaccine-preventable diseases was low, and most women had concerns about the safety of new vaccines. Interventions that strengthen existing maternal immunisation infrastructures, including increasing education of pregnant women about vaccines, will aid the successful implementation of a future GBS vaccine.

Exploring parental perspectives: Maternal RSV vaccination versus infant RSV monoclonal antibody.

Respiratory Syncytial Virus poses a significant global public health threat, particularly affecting infants aged less than one year of age. Recently, two forms of passive immunization against infant RSV have been developed and brought to market; nirsevimab a long-acting monoclonal antibody (mAb) and RSV-PreF, a maternal RSV vaccine. The acceptability and uptake of these products will play a pivotal role in determining the success of any national immunization strategy aimed at safeguarding infants from RSV. It is crucial at this time to reflect on the factors that influence parental decisions surrounding immunization to facilitate more informed discussions, enhance healthcare communication, and contribute to the design of effective RSV prevention strategies that resonate with the concerns and aspirations of parents worldwide.

mSphere of Influence: Pertussis Vaccination and Antibodies in Mothers and Infants.

Susana Portillo works in the field of mother-infant immunity with an emphasis on vaccination and prevention of respiratory diseases. In this mSphere of Influence, she reflects here on how two pertussis vaccine articles made an impact on her research. She discusses how much more remains to be understood about the role of maternal antibodies in preventing or reducing infant illnesses, their capacity to engage other immune components to deliver an efficient antimicrobial response, and their influence on the infant's own response to vaccination. She emphasizes the need for safe and effective interventions that strengthen maternal and infant immunity before and after birth.

Vaccine safety surveillance in Kenya using GAIA standards: A feasibility assessment of existing national and subnational research and program systems.

BACKGROUND: Active surveillance systems for monitoring vaccine safety among pregnant women address some of the limitations of a current passive surveillance approach utilized in low- and middle-income countries (LMIC). However, few active surveillance systems in LMIC exist. Our study assessed the feasibility of utilizing three existing data collection systems in Kenya for active surveillance of maternal immunization and to assess the applicability of Global Alignment of Immunization Safety Assessment in pregnancy (GAIA) case definitions that were initially developed for clinical trials within these systems. METHODS: We assessed applicability of GAIA case definition for maternal Tetanus Toxoid exposure, stillbirth, low birth weight, small for gestational age, Neonatal Invasive Blood Stream Infection (NIBSI), prematurity and neonatal death in two routine web-based health information systems (Kenya EMR and DHIS-2), and a web-based population-based pregnancy research platform (ANCOV1) in Kenya. RESULTS: All three HIS were capable of reporting selected outcomes to varying degrees of GAIA certainty. The ANCOV platform was the most robust in collecting and collating clinical data for effective maternal pharmacovigilance. The utilization of facility- and district-aggregated data limits the usefulness of DHIS-2 in pharmacovigilance as currently operationalized. While the Kenya EMR contained individual level data and meets the key considerations for effective pharmacovigilance, it was used primarily for HIV care and treatment records in a small proportion of health facilities and would require additional resources to expand to all antenatal care facilities and to link maternal and infant records. DISCUSSION: Population-based research studies may offer a responsive short-term option for implementing maternal vaccine pharmacovigilance in LMICs. However, the foundation exists for long-term capacity building within the national health electronic data systems to provide this critical service as well as ensure participation of the country in international studies on maternal vaccine safety.

Preparing for Group B Streptococcus vaccine. Attitudes of pregnant women in two countries.

Group B Streptococcus (GBS) vaccines, designed to be given to pregnant women, are in clinical trials. There is an opportunity to conduct preparatory research now to understand the drivers of and barriers to GBS vaccine acceptance. This will enable targeted interventions so that delays in vaccine uptake might be avoided. A multicenter, mixed-methodology, cross-sectional study evaluated the acceptability of a hypothetical GBS vaccine among pregnant women in two countries with differing health systems. Pregnant women in Philadelphia, US, and Dublin, Ireland, completed an electronic survey and a Discrete Choice Experiment. Five hundred and two women were included in the final analysis. Fifty-three percent of US and 30% of Irish participants reported both awareness and understanding of GBS. The median likelihood score for vaccine receipt (measured on a 10-point scale) was 9 (US: 9 (IQR 7-10), IRL: 9 (IQR 6-10)). Among the US participants, identifying as Black or African American was associated with a lower likelihood of vaccine receipt. Possession of a college degree was associated with increased likelihood of vaccine receipt. Perceived infant benefit was the most important driver of GBS vaccine acceptance. Safety concerns about a novel vaccine was the most prominent barrier identified. Good GBS vaccine uptake is achievable through strong messaging that highlights vaccine safety and the potential infant benefits. Preparation for vaccine implementation should include efforts to increase awareness among pregnant women about GBS infection and a continued focus on improving acceptability of currently recommended maternal vaccines, particularly in population subgroups with low uptake of maternal immunizations.

Assessment of gestational age at antenatal care visits among Kenyan women to inform delivery of a maternal respiratory syncytial virus (RSV) vaccine in low- and middle-income countries.

Background: Maternal respiratory syncytial virus (RSV) vaccines that are likely to be implementable in low- and middle-income countries (LMICs) are in final stages of clinical trials. Data on the number of women presenting for antenatal care (ANC) per day and proportion attending within the proposed gestational window for vaccine delivery, is a prerequisite to guide development of vaccine vial size and inform vaccine uptake in this setting. Methods: We undertook administrative review and abstraction of ANC attendance records from 2019 registers of 24 selected health facilities, stratified by the level of care, from Kilifi, Siaya and Nairobi counties in Kenya. Additional data were obtained from Mother and Child Health (MCH) booklets of women in each of the Health and Demographic Surveillance System (HDSS) areas of Kilifi, Nairobi and Siaya. Data analysis involved descriptive summaries of the number (mean, median) and proportion of women attending ANC within the gestational window period of 28-32 weeks and 24-36 weeks. Results: A total of 62,153 ANC records were abstracted, 33,872 from Kilifi, 19,438 from Siaya and 8,943 from Nairobi Counties. The median (Interquartile range, IQR) number of women attending ANC per day at a gestational age window of 28-32 and 24-36 weeks, respectively, were: 4 (2-6) and 7 (4-12) in dispensaries, 5 (2-9) and 10 (4-19) in health centres and 6 (4-11) and 16 (10-26) in county referral hospitals. In the HDSS areas of Kilifi, Siaya and Nairobi, pregnant women attending at least one ANC visit, within a window of 28-32 weeks, were: 77% (360/470), 75% (590/791) and 67% (547/821), respectively. Conclusions: About 70% of pregnant women across three distinct geographical regions in Kenya, attend ANC within 28-32 weeks of gestation. A multidose vial size with about five doses per vial, approximates daily ANC attendance and would not incur possible wastage in similar settings.

Impact and cost-effectiveness of strategies to prevent respiratory syncytial virus (RSV) disease in Vietnam: A modelling study.

BACKGROUND: New prevention strategies for respiratory syncytial virus (RSV) are emerging, but it is unclear if they will be cost-effective in low- and middle-income countries. We evaluated the potential impact and cost-effectiveness of two strategies to prevent RSV disease in young children in Vietnam. METHODS: We used a static cohort model with a finely disaggregated age structure (weeks of age <5 years) to calculate the RSV disease burden in Vietnam, with and without a single dose of maternal vaccine (RSVpreF, Pfizer) or of monoclonal antibody (Nirsevimab, Sanofi, Astra Zeneca). Each strategy was compared to no pharmaceutical intervention, and to each other. We assumed both strategies would be administered year round over a ten-year period. The primary outcome measure was the cost per disability-adjusted life year (DALY) averted, from a societal perspective. We ran probabilistic and deterministic uncertainty analyses. RESULTS: With central input assumptions for RSVpreF vaccine ($25/dose, 69 % efficacy, 6 months protection) and Nirsevimab ($25/dose, 77 % efficacy, 5 months protection), both options had similar cost-effectiveness ($3442 versus $3367 per DALY averted) when compared separately to no pharmaceutical intervention. RSVpreF vaccine had a lower net cost than Nirsevimab (net discounted cost of $213 m versus $264 m) but prevented fewer RSV deaths (24 % versus 31 %). Our results were very sensitive to assumptions about the dose price, efficacy, and duration of protection. At $5/dose and a willingness-to-pay threshold of 0.5 times the national GDP per capita, both prevention strategies are cost-effective. CONCLUSIONS: RSVpreF vaccine and Nirsevimab may be cost-effective in Vietnam if appropriately priced.

Cost-effectiveness of monoclonal antibody and maternal immunization against respiratory syncytial virus (RSV) in infants: Evaluation for six European countries.

BACKGROUND: Respiratory syncytial virus (RSV) imposes a substantial burden on pediatric hospital capacity in Europe. Promising prophylactic interventions against RSV including monoclonal antibodies (mAb) and maternal immunizations (MI) are close to licensure. Therefore, we aimed to evaluate the cost-effectiveness of potential mAb and MI interventions against RSV in infants, for six European countries. METHODS: We used a static cohort model to compare costs and health effects of four intervention programs to no program and to each other: year-round MI, year-round mAb, seasonal mAb (October to April), and seasonal mAb plus a catch-up program in October. Input parameters were obtained from national registries and literature. Influential input parameters were identified with the expected value of partial perfect information and extensive scenario analyses (including the impact of interventions on wheezing and asthma). RESULTS: From the health care payer perspective, and at a price of €50 per dose (mAb and MI), seasonal mAb plus catch-up was cost-saving in Scotland, and cost-effective for willingness-to-pay (WTP) values ≥€20,000 (England, Finland) or €30,000 (Denmark) per quality adjusted life-year (QALY) gained for all scenarios considered, except when using ICD-10 based hospitalization data. For the Netherlands, seasonal mAb was preferred (WTP value: €30,000-€90,000) for most scenarios. For Veneto region (Italy), either seasonal mAb with or without catch-up or MI was preferred, depending on the scenario and WTP value. From a full societal perspective (including leisure time lost), the seasonal mAb plus catch-up program was cost-saving for all countries except the Netherlands. CONCLUSION: The choice between a MI or mAb program depends on the level and duration of protection, price, availability, and feasibility of such programs, which should be based on the latest available evidence. Future research should focus on measuring accurately age-specific RSV-attributable hospitalizations in very young children.

Modelling the impact of maternal pneumococcal vaccination on infant pneumococcal disease in low-income settings.

Pneumococcal disease is a leading cause of mortality in young children. The largest burden of pneumococcal disease is in the first six months of life before protection from a complete schedule of direct immunisation is possible. Maternal pneumococcal vaccination has been proposed as a strategy for protection in this period of early childhood; however, limited clinical trial data exists. In this study, we developed an age-structured compartmental mathematical model to estimate the impact of maternal pneumococcal vaccination. Our model demonstrates how maternal pneumococcal vaccination could prevent 73% (range 49-88%) of cases in those aged <1 month and 55% (range 36-66%) in those 1-2 months old. This translates to an estimated 17% reduction in deaths due to invasive pneumococcal disease in children under five. Overall, this study demonstrates the potential for maternal pneumococcal vaccination to meaningfully reduce the burden of infant pneumococcal disease, supporting the case for appropriate field-based clinical studies.

The clinical impact of multiple prevention strategies for respiratory syncytial virus infections in infants and high-risk toddlers in the United States.

BACKGROUND: Respiratory syncytial virus (RSV) remains a leading cause of medically-attended acute respiratory infection in infants and children. With multiple preventative interventions under development, accurate estimates of health care resource utilization are essential for policy decision making. METHODS: We developed a literature-based decision-tree model that estimated annual medically-attended RSV (MA-RSV) lower respiratory tract infection (LRTI) and non-LRTI episodes in the US for all infants and for high-risk toddlers. The model accounted for the gestational age and birth-month of infants, and the seasonal variation in RSV incidence. The impact of no prophylaxis, palivizumab, maternal vaccine, and long-acting monoclonal antibody (mAb) interventions was estimated. RESULTS: We estimated 1.23 million (range: 0.96 million-1.40 million) annual MA-RSV LRTI/non-LRTI episodes comprised of 1.19 million (range: 0.93 million-1.36 million) emergency department (ED) and outpatient visits, and 39,040 (range: 32,726-45,851) hospitalizations. Outpatient and ED visits were comprised of 586,034 (range: 430,595-718,868) LRTIs and 608,733 (range: 495,705-644,658) non-LRTIs. The long-acting mAb intervention resulted in the greatest number of averted outpatient and ED episodes (310,997 [53%] LRTIs; 284,305 [47%] non-LRTIs) and hospitalizations (21,845 [56%]). Full-term infants constitute the highest proportion of episodes across all interventions. CONCLUSIONS: MA-RSV disease is substantial in infants and high-risk toddlers. Long-acting mAbs are most effective at reducing the number of MA-RSV LRTI/non-LRTI episodes, and the only intervention that prevents disease in older infants (≥6 months old).