Respiratory syncytial virus (RSV) causes a spectrum of respiratory illnesses in infants and young children that may lead to hospitalizations and a substantial number of outpatient visits, which result in a huge economic and healthcare burden. Most hospitalizations happen in otherwise healthy infants, highlighting the need to protect all infants against RSV. Moreover, there is evidence on the association between early-life RSV respiratory illness and recurrent wheezing/asthma-like symptoms As such, RSV is considered a global health priority. However, despite this, the only prevention strategy currently available is palivizumab, a monoclonal antibody (mAb) indicated in a subset of preterm infants or those with comorbidities, hence leaving the majority of the infant population unprotected against this virus. Therefore, development of prevention strategies against RSV for all infants entering their first RSV season constitutes a large unmet medical need. The aim of this review is to explore different immunization approaches to protect all infants against RSV. Prevention strategies include maternal immunization, immunization of infants with vaccines, immunization of infants with licensed mAbs (palivizumab), and immunization of infants with long-acting mAbs (e.g., nirsevimab, MK-1654). Of these, palivizumab use is restricted to a small population of infants and does not offer a solution for all-infant protection, whereas vaccine development in infants has encountered various challenges, including the immaturity of the infant immune system, highlighting that future pediatric vaccines will most likely be used in older infants (>6 months of age) and children. Consequently, maternal immunization and immunization of infants with long-acting mAbs represent the two feasible strategies for protection of all infants against RSV. Here, we present considerations regarding these two strategies covering key areas which include mechanism of action, “consistency” of protection, RSV variability, duration of protection, flexibility and optimal timing of immunization, benefit for the mother, programmatic implementation, and acceptance of each strategy by key stakeholders. We conclude that, based on current data, immunization of infants with long-acting mAbs might represent the most effective approach for protecting all infants entering their first RSV season.

RSV Prevention in All Infants: Which Is the Most Preferable Strategy?

The non-pharmaceutical interventions implemented to slow the spread of SARS-CoV-2 have had consequences on the transmission of other respiratory viruses, most notably paediatric respiratory syncytial virus (RSV) and influenza. At the beginning of 2020, lockdown measures in the southern hemisphere led to a winter season with a marked reduction in both infections. Intermittent lockdowns in the northern hemisphere also appeared to interrupt transmission during winter 2020/21. However, a number of southern and northern hemisphere countries have now seen delayed RSV peaks. We examine the implications of these unpredictable disease dynamics for health service delivery in Europe, such as paediatric hospital and intensive care bed space planning, or palivizumab prophylaxis. We discuss the challenges for RSV vaccine trials and influenza immunisation campaigns, and highlight the considerable research opportunities that have arisen with the SARS-CoV-2 pandemic. We argue that the rapid advances in viral whole genome sequencing, phylogenetic analysis, and open data sharing during the pandemic are applicable to the ongoing surveillance of RSV and influenza. Lastly, we outline actions to prepare for forthcoming influenza seasons and for future implementation of RSV vaccines.

Transmission of paediatric respiratory syncytial virus and influenza in the wake of the COVID-19 pandemic.

Over the past few years, the number and volume of data sources in healthcare databases has grown exponentially. Analyzing these voluminous medical data is both opportunity and challenge for knowledge discovery in health informatics. In the last decade, social network analysis techniques and community detection algorithms are being used more and more in scientific fields, including healthcare and medicine. While community detection algorithms have been widely used for social network analysis, a comprehensive review of its applications for healthcare in a way to benefit both health practitioners and the health informatics community is still overwhelmingly missing. This paper contributes to fill in this gap and provide a comprehensive and up-to-date literature research. Especially, categorizations of existing community detection algorithms are presented and discussed. Moreover, most applications of social network analysis and community detection algorithms in healthcare are reviewed and categorized. Finally, publicly available healthcare datasets, key challenges, and knowledge gaps in the field are studied and reviewed. 

/pdf/community-detection-algorithms-in-healthcare-applications-a-1x31pefh.pdf

Community Detection Algorithms in Healthcare Applications: A Systematic Review

Seasonal epidemics of respiratory syncytial virus (RSV) is one of the leading causes of hospitalization and mortality among children. Preventive measures implemented to reduce the spread of SARS-CoV-2, including facemasks, stay-at-home orders, closure of schools and local-national borders, and hand hygiene, may have also prevented the transmission of RSV and influenza. However, with the easing of COVID-19 imposed restrictions, many regions are noticing a delayed RSV outbreak. Some of these regions have also noted an increase in severity of these delayed RSV outbreaks partly due to a lack of protective immunity in the community following a lack of exposure from the previous season. Lessons learned from the COVID-19 pandemic can be implemented for controlling RSV outbreaks, including: (1) measures to reduce the spread, (2) effective vaccine development, and (3) genomic surveillance tools and computational modeling to predict the timing and severity of RSV outbreaks. These measures can help reduce the severity and prepare the health care system to deal with future RSV outbreaks by appropriate and timely allocation of health care resources.

https://www.mdpi.com/2036-7449/14/4/59/pdf?version=1659067344

Impact of COVID-19 on the Changing Patterns of Respiratory Syncytial Virus Infections

Background Nirsevimab is an extended half-life monoclonal antibody to the respiratory syncytial virus (RSV) fusion protein that has been developed to protect infants for an entire RSV season. Previous studies have shown that the nirsevimab binding site is highly conserved. However, investigations of the geotemporal evolution of potential escape variants in recent (ie, 2015–2021) RSV seasons have been minimal. Here, we examine prospective RSV surveillance data to assess the geotemporal prevalence of RSV A and B, and functionally characterise the effect of the nirsevimab binding-site substitutions identified between 2015 and 2021. Methods We assessed the geotemporal prevalence of RSV A and B and nirsevimab binding-site conservation between 2015 and 2021 from three prospective RSV molecular surveillance studies (the US-based OUTSMART-RSV, the global INFORM-RSV, and a pilot study in South Africa). Nirsevimab binding-site substitutions were assessed in an RSV microneutralisation susceptibility assay. We contextualised our findings by assessing fusion-protein sequence diversity from 1956 to 2021 relative to other respiratory-virus envelope glycoproteins using RSV fusion protein sequences published in NCBI GenBank. Findings We identified 5675 RSV A and RSV B fusion protein sequences (2875 RSV A and 2800 RSV B) from the three surveillance studies (2015–2021). Nearly all (25 [100%] of 25 positions of RSV A fusion proteins and 22 [88%] of 25 positions of RSV B fusion proteins) amino acids within the nirsevimab binding site remained highly conserved between 2015 and 2021. A highly prevalent (ie, >40·0% of all sequences) nirsevimab binding-site Ile206Met:Gln209Arg RSV B polymorphism arose between 2016 and 2021. Nirsevimab neutralised a diverse set of recombinant RSV viruses, including new variants containing binding-site substitutions. RSV B variants with reduced susceptibility to nirsevimab neutralisation were detected at low frequencies (ie, prevalence <1·0%) between 2015 and 2021. We used 3626 RSV fusion-protein sequences published in NCBI GenBank between 1956 and 2021 (2024 RSV and 1602 RSV B) to show that the RSV fusion protein had lower genetic diversity than influenza haemagglutinin and SARS-CoV-2 spike proteins. Interpretation The nirsevimab binding site was highly conserved between 1956 and 2021. Nirsevimab escape variants were rare and have not increased over time. Funding AstraZeneca and Sanofi. Nirsevimab is an extended half-life monoclonal antibody to the respiratory syncytial virus (RSV) fusion protein that has been developed to protect infants for an entire RSV season. Previous studies have shown that the nirsevimab binding site is highly conserved. However, investigations of the geotemporal evolution of potential escape variants in recent (ie, 2015–2021) RSV seasons have been minimal. Here, we examine prospective RSV surveillance data to assess the geotemporal prevalence of RSV A and B, and functionally characterise the effect of the nirsevimab binding-site substitutions identified between 2015 and 2021. We assessed the geotemporal prevalence of RSV A and B and nirsevimab binding-site conservation between 2015 and 2021 from three prospective RSV molecular surveillance studies (the US-based OUTSMART-RSV, the global INFORM-RSV, and a pilot study in South Africa). Nirsevimab binding-site substitutions were assessed in an RSV microneutralisation susceptibility assay. We contextualised our findings by assessing fusion-protein sequence diversity from 1956 to 2021 relative to other respiratory-virus envelope glycoproteins using RSV fusion protein sequences published in NCBI GenBank. We identified 5675 RSV A and RSV B fusion protein sequences (2875 RSV A and 2800 RSV B) from the three surveillance studies (2015–2021). Nearly all (25 [100%] of 25 positions of RSV A fusion proteins and 22 [88%] of 25 positions of RSV B fusion proteins) amino acids within the nirsevimab binding site remained highly conserved between 2015 and 2021. A highly prevalent (ie, >40·0% of all sequences) nirsevimab binding-site Ile206Met:Gln209Arg RSV B polymorphism arose between 2016 and 2021. Nirsevimab neutralised a diverse set of recombinant RSV viruses, including new variants containing binding-site substitutions. RSV B variants with reduced susceptibility to nirsevimab neutralisation were detected at low frequencies (ie, prevalence <1·0%) between 2015 and 2021. We used 3626 RSV fusion-protein sequences published in NCBI GenBank between 1956 and 2021 (2024 RSV and 1602 RSV B) to show that the RSV fusion protein had lower genetic diversity than influenza haemagglutinin and SARS-CoV-2 spike proteins. The nirsevimab binding site was highly conserved between 1956 and 2021. Nirsevimab escape variants were rare and have not increased over time. 

Nirsevimab binding-site conservation in respiratory syncytial virus fusion glycoprotein worldwide between 1956 and 2021: an analysis of observational study sequencing data.

Respiratory syncytial virus (RSV) is a major health problem. A better understanding of the geographical and temporal dynamics of RSV circulation will assist in tracking resistance against therapeutics currently under development. Since 2015, the field of RSV molecular epidemiology has evolved rapidly with around 20-30 published articles per year. The objective of this systematic review is to identify knowledge gaps in recent RSV genetic literature to guide global molecular epidemiology research. We included 78 studies published between 2015 and 2020 describing 12,998 RSV sequences of which 8,233 (63%) have been uploaded to GenBank. Seventeen (22%) studies were performed in low- and middle-income countries (LMICs), and seven (9%) studies sequenced whole-genomes. Although most reported polymorphisms for monoclonal antibodies in clinical development (nirsevimab, MK-1654) have not been tested for resistance in neutralisation essays, known resistance was detected at low levels for the nirsevimab and palivizumab binding site. High resistance was found for the suptavumab binding site. We present the first literature review of an enormous amount of RSV genetic data. The need for global monitoring of RSV molecular epidemiology becomes increasingly important in evaluating the effectiveness of monoclonal antibody candidates as they reach their final stages of clinical development. We have identified the following three knowledge gaps: whole-genome data to study global RSV evolution, data from LMICs and data from global surveillance programs.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/rmv.2284

A systematic review on global RSV genetic data: Identification of knowledge gaps

Respiratory syncytial virus (RSV) is a global cause of severe respiratory morbidity and mortality in infants While preventive and therapeutic interventions are being developed, including antivirals, vaccines and monoclonal antibodies, little is known about the global molecular epidemiology of RSV INFORM is a prospective, multicenter, global clinical study performed by ReSViNET to investigate the worldwide molecular diversity of RSV isolates collected from children less than 5 years of age The INFORM study is performed in 17 countries spanning all inhabited continents and will provide insight into the molecular epidemiology of circulating RSV strains worldwide Sequencing of > 4000 RSV-positive respiratory samples is planned to detect temporal and geographical molecular patterns on a molecular level over five consecutive years Additionally, RSV will be cultured from a subset of samples to study the functional implications of specific mutations in the viral genome including viral fitness and susceptibility to different monoclonal antibodies The sequencing and functional results will be used to investigate susceptibility and resistance to novel RSV preventive or therapeutic interventions Finally, a repository of globally collected RSV strains and a database of RSV sequences will be created

/pdf/global-molecular-diversity-of-rsv-the-inform-rsv-study-rzowkrkexf.pdf

Global molecular diversity of RSV – the “INFORM RSV” study

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A systematic review on global RSV genetic data: Identification of knowledge gaps

Global molecular diversity of RSV – the “INFORM RSV” study