A landscape review of the published research output relating to respiratory syncytial virus (RSV) in North & Central America and Europe between 2011-2015

Background The high disease burden of respiratory syncytial virus (RSV) infection and renewed focus on developing a vaccine has led to sustained interest in published RSV-related research. The majority of this research comes from Europe and North/Central America and this landscape review aimed to identify and characterize RSV-related research published during 2011-2015 in these geographical areas. Methods We conducted a literature review on electronic databases Scopus and Web of Science to identify published studies investigating RSV throughout Europe and North/Central America. We stratified RSV-related publications between 2011-2015 by study type, country, research institution and funding body. Results The annual published output of RSV-related research has increased by 29% over the period 2011-2015. Eighty seven percent (13/15) of the most highly cited papers on RSV during this period were from North America. US universities with the highest number of RSV-related publications included Emory (n = 23), Vanderbilt (n = 23), University of Michigan (n = 21) and Ohio State (n = 20). The UK (n = 125), Netherlands (n = 97) and Spain (n = 76) were major European contributors to RSV-related publications. University Medical Centre Utrecht (n = 40) and Imperial College London (n = 28) were the European universities with the largest number of RSV-related publications. The National Institutes of Health provided funding for one quarter of all RSV-related publications. However, few countries in Eastern Europe, Central America and the Caribbean published RSV-related research. Few epidemiological studies focused on adult populations over 18 years old (n = 28, 7%) with only five publications specifically investigating elderly populations over 65. Conclusions This review identifies key regions and research institutions which contributed to RSV-related research during 2011-2015 as well as the donor agencies which supported this research. Further research investment is required in a number of countries. More research in the elderly and in high-risk adults is required given the lack of studies pertaining to these populations. Researchers and those commissioning research can use the data from this review to identify productive research institutions and geographical gaps in RSV research.

A landscape review of the published research output relating to respiratory syncytial virus (RSV) in North & Central America and Europe between [2011][2012][2013][2014][2015] Background The high disease burden of respiratory syncytial virus (RSV) infection and renewed focus on developing a vaccine has led to sustained interest in published RSV-related research. The majority of this research comes from Europe and North/Central America and this landscape review aimed to identify and characterize RSV-related research published during 2011-2015 in these geographical areas.

Methods
We conducted a literature review on electronic databases Scopus and Web of Science to identify published studies investigating RSV throughout Europe and North/Central America. We stratified RSV-related publications between 2011-2015 by study type, country, research institution and funding body.

Results
The annual published output of RSV-related research has increased by 29% over the period 2011-2015. Eighty seven percent (13/15) of the most highly cited papers on RSV during this period were from North America. US universities with the highest number of RSV-related publications included Emory (n = 23), Vanderbilt (n = 23), University of Michigan (n = 21) and Ohio State (n = 20). The UK (n = 125), Netherlands (n = 97) and Spain (n = 76) were major European contributors to RSV-related publications. University Medical Centre Utrecht (n = 40) and Imperial College London (n = 28) were the European universities with the largest number of RSV-related publications. The National Institutes of Health provided funding for one quarter of all RSV-related publications. However, few countries in Eastern Europe, Central America and the Caribbean published RSV-related research. Few epidemiological studies focused on adult populations over 18 years old (n = 28, 7%) with only five publications specifically investigating elderly populations over 65.
Conclusions This review identifies key regions and research institutions which contributed to RSV-related research during 2011-2015 as well as the donor agencies which supported this research. Further research investment is required in a number of countries. More research in the elderly and in high-risk adults is required given the lack of studies pertaining to these populations. Researchers and those commissioning research can use the data from this review to identify productive research institutions and geographical gaps in RSV research.

Electronic supplementary material:
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journal of health global VIEWPOINTS PAPERS Respiratory syncytial virus (RSV) is a major global cause of morbidity, particularly in infants and young children [1]. It is one of the leading causes of acute lower respiratory tract infections in children worldwide, causing over 3.4 million severe infections annually [2]. It is also associated with significant mortality in children in low and lower-middle income countries [1,2], and is increasingly acknowledged as an important pathogen in adults with comorbidities and the elderly [3][4][5]. As a result, the World Health Organization (WHO) Product Development and Vaccine Advisory Committee (PDVAC) has recognized RSV as the most important future new vaccine target [6]. The increased recognition of the high disease burden from RSV has resulted in an increasing volume of RSV-related research over recent decades [7]. An analysis of RSV-related research output between 1990 and 2013 found that the majority of this research came from high-income countries, particularly Europe and North America [7]. However, no previous review has identified and provided summaries of the current output of RSV-related research by study type, research institution and funding body in these areas. This landscape review provides an overview of RSV-related publications throughout Europe and North/Central America between 2011-2015 to inform the planning of future research in this topic area. This study therefore aimed to determine the types of study and geographical spread of RSV-related publications from Europe and North/Central America. This study also aimed to identify productive research institutions and funding bodies, who contributed to RSV research throughout this time.

Literature search
Systematic literature searches were conducted on Scopus and Web of Science Core Collection, identified as comprehensive medical databases likely to provide an accurate reflection of RSV-related research output. The main search heading used was Respiratory Syncytial Virus (RSV). Literature searches were limited to European, North American, Central American and Caribbean countries as defined by UN region [8]. Searches were limited to articles published between 1 January 2011 and 31 December 2015. Searches for European countries were undertaken in January 2016 and subsequently for North/Central America in May 2016. The full search strategy is detailed in Appendix S1 of Online Supplementary Document. Duplicate articles were identified and removed from the final search result using Endnote (Clarivate Analytics, Philadelphia, PA, USA)initially and subsequently via manual selection by reviewers.

Study selection
Studies were selected according to the following criteria. Exclusion criteria: -Editorial material/ letter/ conference paper/ meeting abstract/ expert commentary/ review; -Study or publication relating to non-respiratory disease; -Study or publication where RSV is mentioned in the abstract but the study does not contain research related to RSV; -Study or publication relating to bovine RSV; -Both first and last authors not from European, North American, Central American or Caribbean country or research institute.

Data extraction
One study reviewer extracted details of publications into standard templates on Microsoft Excel. These included the publication year, country of the first and last author, affiliated institution of the first and last author, funding source and study population. Where first and last authors were from different countries VIEWPOINTS PAPERS or institutions, these were both noted. Publications were mapped by geographical location using the online program MapChart (url: https://mapchart.net/).
Publications were categorized as either epidemiological, clinical or laboratory studies. Epidemiological publications included research on the incidence, prevalence and burden of disease of RSV, vaccine research and other public health interventions. Clinical publications included research on risk factors, disease presentation, investigation, treatment and complications. Laboratory publications included research on viral genetics, life cycle and pathogenesis of the disease. Decisions on categorization followed the broad areas listed in Table 1 and were assigned by reviewers. Where publications covered more than one aspect of RSV research across categories, the main focus of the article (as judged by reviewers) was used to assign publications to a single category.

RESULTS
Publications were identified and screened systematically, as shown in Figure 1. After applying the selection criteria, 1233 publications were identified and included in this review. Of publications identified, there were 443 publications relating to clinical studies, 420 publications relating to epidemiological studies and 370 publications relating to laboratory studies.
Geographical spread of RSV-related publications The countries with the most epidemiological publications were the USA (n = 162), Spain (n = 37) and the Netherlands (n = 30). The countries with the most clinical publications were the USA (n = 129), the UK (n = 47) and the Netherlands (n = 40). The countries where the highest number of laboratory studies were published were the USA (n = 207), the UK (n = 50) and the Netherlands (n = 27) ( Table 2). Over half of RSV-related publications from North/Central America came from five US states; Maryland (n = 94), Georgia (n = 66), Tennessee (n = 41), Texas (n = 39) and Massachusetts (n = 37). Maryland had the largest number of epidemiological publications (n = 52) and laboratory publications (n = 27). New York (n = 19) had

RSV-related publications by research institution
The number of RSV-related publications from different research institutions and the type of study they published is displayed in Figure 3 with

RSV-related publications by funding body
The funding bodies who provided funding for RSV-related publications in Europe and North/Central America are displayed in Figure 4 with full tables of results in Appendix S5 of Online Supplementary Document. The National Institutes of Health was the agency that provided funding for the largest number of publications (n = 305), as well as within each category (76 epidemiological, 64 clinical and 161 laboratory studies). This is in comparison to other government agencies within Europe such as the European Commission (n = 45) and the UK National Institute for Health Research (UK NIHR) (n = 18). AstraZeneca/Medimmune provided funding for the second highest number of RSV-related publications (n = 68), and funded the second highest number of epidemiological studies (n = 44).

Epidemiological publications by study population
The majority of epidemiological studies focused on paediatric populations aged <18 years (n = 231, 55%) of which 67 publications focused solely on children aged <1 year. Few epidemiological publications focused on adult populations >18 years (n = 28, 7%). Specifically, of these publications studying adult populations, only five publications studied populations aged over 65. The remaining publications covered   The great majority of research was conducted in Western European countries, the USA and Canada. The USA was the country with the largest number of RSV-related publications in each category (clinical n = 129, epidemiological n = 162 and laboratory n = 207) and was associated with the majority of highly cited RSV-related publications (12/15). Within Europe, the UK was the most productive contributor with 125 publications. These major contributions to RSV research from the UK and USA in recent years continue a trend since 1990 where the UK and USA both dominated in terms of RSV-related research output [7].

RSV-related publications by year in Europe and North/Central America
Consistent with previous work, this review found a significant lack of research in low-and lower-middle income countries [7]. Seven low and lower-middle income countries (Guatemala, Honduras, Nicaragua, Haiti, El Salvador, Georgia and Belize according to 2011 World Bank classifications) were included in this search, and only one of these, Guatemala, published any RSV research (two RSV-related publications) within the study period [9]. No RSV-related research was identified from forty three countries/territories included in the search. There was a noticeable lack of research in several countries in Central America, the Caribbean and Eastern Europe. Greater funding should be invested and academic support should be promoted for clinical and epidemiological RSV research in these countries.
Despite increased vulnerability to RSV infection in the elderly, there was a lack of epidemiological studies which specifically studied elderly populations. The preponderance of studies in infants and children is understandable, given the large burden of disease of RSV in this population and because the majority of vaccine research is focusing on maternal or neonatal vaccination [2]. However, the lack of studies in populations such as the elderly or high-risk adults is surprising given the associated burden of disease and the potential for these populations to benefit from implementation of an RSV vaccine [10].
The National Institutes of Health provided funding for nearly a quarter of all the RSV related publications (n = 301) identified in this review. This is in comparison to other governmental bodies such as the European Commission (n = 45) and UK NIHR (n = 18) and the funder of the second highest number of