In context of the RSV GOLD Project, multiple articles have been published.

Nosocomial RSV-related In-hospital Mortality in Children <5 Years: A Global Case Series

According to the World Health Organization, the global burden of nosocomial infections is poorly characterized as surveillance systems are lacking. Nosocomial infections occur at higher rates in low- and lower-middle-income countries (LMICs) than in high-income countries (HICs). Current global RSV burden estimates are largely based on community-acquired infection. In this case series, there was aimed to characterize children with nosocomial RSV-related mortality and to understand the potential impact of RSV immunization strategies.

In total, 231 nosocomial and 931 community-acquired RSV-related in-hospital from deaths from 65 countries were studied. The results show that the proportion of nosocomial deaths among all RSV deaths was lower in LMICs than in upper-middle-income countries (UMICs) and HICs. Future infant-targeted immunization strategies could prevent the majority of nosocomial RSV-related deaths.

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Citation: Löwensteyn YN, Willemsen JE, Mazur NI, Scheltema NM, van Haastregt NCJ, Buuren AAAT, van Roessel I, Scheepmaker D, Nair H, van de Ven PM, Bont LJ; RSV GOLD Study Group. Nosocomial RSV-related In-hospital Mortality in Children <5 Years: A Global Case Series. Pediatr Infect Dis J. 2023 Jan 1;42(1):1-7. doi: 10.1097/INF.0000000000003747. Epub 2022 Nov 8. PMID: 36476518.

Global Respiratory Syncytial Virus–Related Infant Community Deaths

RSV GOLD, a global registry of under-5 children who have died with RSV-related illness, describes clinical characteristics of children dying of RSV through global data sharing. RSV GOLD acts as a collaborative platform for global deaths, including community mortality studies described in this supplement. There was aimed to compare the age distribution of infant deaths <6 months occurring in the community with in-hospital.

In total, 829 RSV-related deaths <1 year of age from 38 developing countries, including 166 community deaths from 12 countries, were studied. The results show that children in the community die at a younger age.

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Citation: Mazur NI, Löwensteyn YN, Willemsen JE, Gill CJ, Forman L, Mwananyanda LM, Blau DM, Breiman RF, Madhi SA, Mahtab S, Gurley ES, El Arifeen S, Assefa N, Scott JAG, Onyango D, Tippet Barr BA, Kotloff KL, Sow SO, Mandomando I, Ogbuanu I, Jambai A, Bassat Q; CHAMPS Network the RSV GOLD Study Group; Caballero MT, Polack FP, Omer S, Kazi AM, Simões EAF, Satav A, Bont LJ. Global Respiratory Syncytial Virus-Related Infant Community Deaths. Clin Infect Dis. 2021 Sep 2;73(Suppl_3):S229-S237. doi: 10.1093/cid/ciab528. PMID: 34472576; PMCID: PMC8411255.

ICU Network study protocol

To obtain access to RSV interventions, low- and lower-middle-income countries depend on support from Gavi, the Vaccine Alliance. To identify future vaccine target populations, information on children with severe RSV infection is required. The RSV GOLD III—ICU Network study aims to describe clinical, demographic and socioeconomic characteristics of children with life-threatening RSV infection in Gavi-eligible countries.

This international, prospective, observational multicenter study will be conducted in 10 Gavi-eligible countries at pediatric intensive care units and high-dependency units during local viral respiratory seasons for 2 years. Children younger than 2 years of age will be tested for RSV using a molecular point-of-care (POC) diagnostic device. Patient characteristics will be collected through a questionnaire. The study will provide a better understanding of the characteristics and mortality rates of children younger than 2 years with RSV infection admitted to the PICU/HDU in LMICs. The results will contribute to knowledge on global disease burden and awareness of RSV and will directly guide decision makers in their efforts to implement future RSV prevention.

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Citation: Löwensteyn YN, Mazur NI, Nair H, Willemsen JE, van Thiel G, Bont L, RSV GOLD III—ICU Network study group. Describing global pediatric RSV disease at intensive care units in GAVI-eligible countries using molecular point-of-care diagnostics: the RSV GOLD-III study protocol. BMC Infect Dis. 2021 Aug 23;21(1):857.

Influenza-related mortality and maternal vaccination

Influenza virus infection is an important cause of under-five mortality. While maternal vaccination protects children younger than 3 months of age from influenza infection, the extent of influenza-related mortality prevented by a maternal vaccine is still largely unknown. The FLU GOLD team researched this by collecting clinical and demographic characteristics of children younger than 5 years who died with influenza infection. The study was published in EClinicalMedicine in 2021. 

This study included 314 children from 31 countries, consisting of low- and lower-middle-income countries (LMICs), upper-middle-income countries (UMICs), and high-income countries (HICs). The results showed that less than 20% of children is younger than 3 months at time of influenza-related death. 

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Citation: Löwensteyn YN, Nair H, Nunes MC, van Roessel I, Vernooij FS, Willemsen J et al. Estimated impact of maternal vaccination on global paediatric influenza-related in-hospital mortality: A retrospective case series. EClinicalMedicine. 2021 June 9. 

C.RSV-related mortality and Down syndrome

Down syndrome is an important risk factor of severe RSV infection, but global data on RSV-related mortality in children with Down syndrome is lacking. The RSV GOLD team collected cases of children younger than 5 years with Down syndrome who died with RSV infection and described demographic and clinical characteristics. The study was published in the Pediatric Infectious Disease Journal in 2020.

A total of 53 children from 20 different countries were included. One-fourth of children did not have risk factors for severe RSV disease. The majority of children was older than 3 months, indicating that maternal vaccination is not sufficient to protect this high-risk group against RSV-related mortality.  

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Citation: Löwensteyn YN, Phijffer EWEM, Simons JVL, Scheltema NM, Mazur NI, Nair H et al. Respiratory syncytial virus-related death in children with Down syndrome: The RSV GOLD study. Pediatr Infect Dis J. 2020 Apr 23.

Potential impact of vaccination

After having gathered data on characteristics of young children who died with RSV-infection and information regarding vaccine candidates, the RSV GOLD team aimed to estimate the potential impact of maternal vaccination against RSV. For this study, which was published in Vaccine in 2018, a mathematical model was developed.

The model predicted that maternal vaccination at 30 weeks gestational age could have prevented a substantial portion of global RSV-related in-hospital mortality. Preterm children and children with comorbidities were predicted to benefit less than (healthy) term children.

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Citation: Scheltema NM, Kavelaars XM, Thorburn K, Hennus MP, van Woensel JB, van der Ent CK et al. Potential impact of maternal vaccination on life-threatening respiratory syncytial virus infection during infancy. Vaccine. 2018; 36(31): 4693-4700.

RSV Vaccine Landscape

The RSV GOLD team has written a review on vaccine development that was published in The Lancet Infectious diseases in 2018. As RSV vaccine development has gained momentum over recent years, we aimed to provide a comprehensive overview of RSV vaccine candidates and monoclonal antibodies in clinical development.

The RSV vaccine landscape includes 19 vaccine candidates and monoclonal antibodies in clinical trials using four approaches: (1) particle-based, (2) live-attenuated or chimeric, (3) subunit, (4) vector-based.

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Citation: Mazur NI, Higgins D, Nunes MC, Melero JA, Langedijk AC, Horsley N et al. The respiratory syncytial virus vaccine landscape: lessons from the graveyard and promising candidates. Lancet Infect Dis. 2018; 18(10): e295-e311.

Breast milk and maternal vaccines

Protection by maternal vaccination is mainly based on transplacental antibody transfer. Antibody transfer via breast milk might offer additional protection. In 2018, this study on the potential role of breast milk as a route of administration for RSV vaccines was published in The Journal of Infectious Diseases.

The study involved 174 infants under the age of 6 months. Infants were stratified by risk factors into a group with and a group without RSV. A slightly lower IgG antibody count was found in the group with RSV. This suggests that addition of IgG to breast milk will probably transfer protection to infants against RSV disease, additional to transplacental antibody transfer.

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Citation: Mazur NI, Horsley NM, Englund JA, Nederend M, Magaret A, Kumar A et al. Breast Milk Prefusion F Immunoglobulin G as a Correlate of Protection Against Respiratory Syncytial Virus Acute Respiratory Illness. J Infect Dis. 2019; 219(1): 59-67.

Retrospective case series

In 2017, the RSV GOLD pilot case series of children who died with RSV infection was published in The Lancet Global Health. Through performing this study, the RSV GOLD team aimed to identify clinical and socioeconomic characteristics of children aged younger than 5 years with RSV-related in-hospital mortality.

A total of 358 children from 23 countries across the world were included in the analysis, which showed that a substantial proportion of children with RSV-related death had comorbidities. These children died at a younger age than children without comorbidity and may therefore need additional preventive interventions.

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Citation: Scheltema NM, Gentile A, Lucion F, Nokes DJ, Munywoki PK, Madhi SA et al. Global respiratory syncytial virus-associated mortality in young children (RSV GOLD): a retrospective case series. Lancet Glob Health. 2017; 5(10): e984-e991.