RESCEU and PROMISE: The Success of 8 Years of European Public-Private Partnership to Prevent RSV

THE LEGACY OF RESCEU: PARTNERING AGAINST RSV

Health promotion through population-based interventions for infectious disease prevention and control requires broad stakeholder collaboration from public health and regulatory bodies, small and medium-sized enterprises, and large industry, academia, and research organizations, funders, policy makers, and civil society organizations. For example, surveillance programs guide the prioritization of research and development investments, constitute a critical source of clinical isolates, which are the starting point of development of prophylactic and therapeutic solutions, and are instrumental in postmarketing safety and effectiveness monitoring of interventions. Uniform case definitions, sensitive and specific diagnostic tests, sustainable surveillance and laboratory networks, and well-defined reporting practices all require cross-disciplinary collaboration.

The respiratory syncytial virus (RSV), first discovered in 1955 [1], has long been the focus of intense study with the aim of developing an effective vaccine or treatment. However, following the failure of the initial formalin-inactivated vaccine in 1965–1966, there was substantial setback to research and development investment in RSV. With the discovery of the structure of the F protein in 2013, and the demonstration that it can be stabilized in its prefusion form, interest in RSV peaked once more, not only among scientists but also international agencies like the World Health Organization (WHO) [2], funders like Bill and Melinda Gates Foundation, and the pharmaceutical industry.

In response to this need and to the willingness to generate more comprehensive data on RSV in Europe, the RESCEU initiative was launched in 2017. This collaborative effort, funded by the Innovative Medicines Initiative (IMI), a European Commission and European Federation of Pharmaceutical Industries and Associations partnership, brought together researchers and scientists from both the public and private sectors across Europe, all united by a common, strong objective: to deepen our understanding of RSV. The initiative's strength was the expertise of the individuals involved, including an external scientific board composed of the most renowned experts in the field of RSV research.

Despite the coronavirus disease 2019 (COVID-19) pandemic, which impacted the entire world, and particularly the researchers involved in RESCEU, some of whom were mobilized as part of national and global response, the work continued unabated. The team managed to produce high-quality research published in top-tier peer-reviewed journals, including 2 supplements of The Journal of Infectious Diseases [3, 4]. These results have informed policy on RSV surveillance and recommendations for implementation of RSV vaccines and monoclonal antibodies in national immunization programs across Europe. Another notable highlight of the project was the launch of the RSV awareness week, spearheaded by the consortium's Patient Advisory Board, to raise public awareness and understanding of the virus.

PROMISE CARRIES ON THE MISSION

With the anticipated licensure and subsequent market availability of RSV immunizations by 2025, PROMISE was funded by IMI in 2021 to build on RESCEU's achievements and address remaining key questions, including RSV impact on specific populations such as pregnant individuals or adults with comorbidities, as well as the impact of COVID-19 pandemic on RSV. This PROMISE supplement includes articles that span a broad range of areas—from epidemiology to public health to basic sciences—an illustration of the wide scope and impact of the project.

There is limited understanding of the impact of RSV A and B subgroups on RSV seasonality, as studies report conflicting results. Deng and colleagues conducted a systematic review of studies reporting multiyear data from various regions and found that RSV subgroup distribution has negligible impact on the year-on-year variations in RSV seasonality [5]. This is important (and reassuring) as some of the prophylactic products do not include RSV B, although there is a substantial degree of cross-protection.

A multitude of severity scores for bronchiolitis and RSV disease have been developed over the last 2 decades. Sheikh and colleagues conducted a systematic review and found that none of the 31 scores further assessed were sufficiently validated [6]. They reported that the ReSViNET score was positively associated with hospitalization, pediatric intensive care unit admission, mechanical ventilation, and respiratory support requirement. In a separate paper, they used RESCEU and secondary data from tertiary hospitals in Rwanda and Colombia for validation [7]. They observed that fever could be excluded from the original ReSViNET score without compromising on its discriminative validity, which is a critical output to better characterize the disease and to harmonize RSV severity criteria.

RSV during pregnancy poses substantial health risks both to the fetus and the birthing parent. There is limited knowledge regarding RSV disease burden in pregnant individuals [8]. Kenmoe and colleagues conducted a systematic review and meta-analysis of all available data (published and unpublished) in this population risk group and report that although RSV-associated hospitalizations were uncommon in pregnant individuals, and no RSV-associated deaths were observed, the incidence of RSV in pregnant individuals was comparable to the incidence of RSV in adults ≥ 18 years with underlying medical conditions [9].

Electronic health records from hospitals are now being routinely used to estimate RSV disease burden but this approach can lead to an underestimation of disease burden, particularly in adults. Egeskov-Cavling and colleagues have used Danish National Patient Registry data linked to Danish Microbiology Database (2015–2018), and report that the overall sensitivity of RSV-coded hospitalizations was 42.4% (95% confidence interval, 39.3%–45.6%) [10]. Osei-Yeboah and colleagues have used data from Scotland and Denmark to estimate RSV-associated hospitalizations in adults with comorbidities [11]. They report that the risk for RSV hospitalization is 1.5- to 3-fold higher in adults ≥ 45 years with asthma; 2- to 4-fold higher in those with chronic obstructive pulmonary disease, ischemic heart disease, stroke and diabetes; and 3- to 7-fold for those with chronic kidney disease. These estimates are comparable to those for seasonal human influenza for a similar age group in Scotland and highlight the need for including adults ≥ 45 years with comorbidities in RSV immunization programs. In another paper, they demonstrated that there is a 2-fold difference between the least and the most deprived socioeconomic groups in RSV-associated hospitalizations across all age groups in Scotland, the difference being more pronounced in infants and young children [12].

As RSV immunization products are being introduced in national immunization programs across Europe, there is an urgent need for robust RSV surveillance, which includes harmonization of laboratory techniques and reporting practices across Europe. Presser and colleagues summarized the diverse practices of European Respiratory Syncytial Virus Laboratory Network members from 26 member states surveyed in 2022 [13]. These findings could inform WHO and the European Centre for Disease Prevention and Control (ECDC) currently considering integrated surveillance for respiratory pathogens [14, 15]. PROMISE investigators also developed generic protocols to support National Public Health agencies conducting effectiveness studies for licensed vaccines and monoclonal antibodies using register-based cohort design or tests-negative case-control approaches [16, 17].

A substantial proportion of RSV episodes in young children are not medically attended. Among those, Hak and colleagues reported that 93% of RSV episodes had a median duration of illness of 6 days with respiratory symptoms scored by parents as moderate-severe, inducing substantial parental anxiety and workplace absenteeism of at least 1 day [18]. These findings are particularly important to inform RSV immunization policies as non-medically attended children are not currently included as part of disease burden estimates.

Finally, there is currently poor understanding of the role of monocytes in severe RSV disease. Chappin and colleagues used transcriptomics profiling of peripheral blood and airway monocytes and found that monocytes in RSV patients upregulate pathways associated with interferon and antiviral responses, suggesting that blood monocytes are activated to become inflammatory/antiviral prior to being actively recruited to the airways in response to an RSV infection [19].

WHAT REMAINS TO BE DONE TO ENSURE RSV PREVENTION IN EUROPE

Since 2016, two European Union-funded public-private partnerships have worked to prepare the European Union for the introduction of RSV vaccines for pregnant women, children, and older adults. These collaborative research efforts always included the voice of patients and public health bodies, including ECDC and WHO, to ensure societal relevance of the work. Literature reviews as well as prospective studies were undertaken to maximize understanding of the health and health-economic consequences of RSV for all ages. These partnerships have substantially contributed to the set-up of RSV surveillance at a European level. The implications of the COVID-19 pandemic on RSV epidemiology were absorbed. Epidemiology studies were continuously aligned with translational research questions. Major progress was made in understanding pathophysiology, molecular epidemiology, and vaccine immunology of RSV, including a better understanding of mucosal immune mechanisms of RSV infection and correlates of protection relevant for vaccine development. A data repository and biobank have been set up to ensure the sustainability of knowledge, research infrastructure, and biological materials, with the hope that these results can be leveraged for future RSV studies.

Although both these consortia have made a major contribution to RSV understanding and awareness, several gaps in knowledge remain. First, the consequence of the COVID-19 pandemic on RSV burden remains incompletely understood. Seasonality has been disrupted during the pandemic and resulted in a delayed summer outbreak. Although RSV has started to peak in the winter again, seasonality has not returned to pre–COVID-19 patterns.

Second, previous studies have focused on general populations. Incidence of severe RSV disease in specific, vulnerable populations, such as children with asthma, neuromuscular disease, immunocompromised children, or children with cancer remains largely unknown. This is particularly relevant for children older than 1 year as development of pediatric vaccines is approaching late-stage clinical development. For older adults, RSV burden in long-term care facilities with irregular RSV outbreaks associated with mortality is largely unknown.

Third, we are currently in an era in which various RSV immunization strategies are deployed in Europe. We do not yet know the duration of protection or the impact of vaccination on RSV upper respiratory infection, including viral shedding pattern. Direct impact of RSV immunization products on hospitalization admission and duration of stay, disease severity, antimicrobial use, and coinfections is unknown. Indirect broader impact is also understudied, including quality of life of carers, and RSV transmission in households/childcare settings or elderly facilities.

Fourth, a next step required for successful prevention of RSV infection is increasing RSV awareness at all levels of society. Anecdotally, we observed that the general public has heard of RSV more often today than one decade ago. Nevertheless, it is obvious that very few people know about the burden of RSV infection, for example that all babies are at risk of severe disease. Policy makers are currently learning about RSV infection as all countries are in the process of formulating policies on RSV immunization in various target populations. Health care practitioners have variable knowledge of RSV infection. While most pediatricians know the disease quite well, others such as general practitioners, geriatricians, and adult intensivists do not have first-hand experience as RSV is rarely diagnosed in their patient populations. A multistakeholder approach, building upon the foundations of patient involvement developed by RESCEU and PROMISE, is required to reach broad RSV awareness necessary for successful disease prevention.

In conclusion, RESCEU and PROMISE are examples of successful public-private partnerships in the precompetitive space where multiple stakeholders joined forces to get Europe ready for RSV prevention. With the first-ever approval of RSV immunizations in the European Union in 2022, we are confident that the projects’ results will live for many more years and facilitate the prevention of one of the most important acute infections at all ages. We call for continued collaboration in the field of infectious diseases prevention and control to accelerate the development of life-saving public health interventions, guarantee health emergency preparedness, and ensure equity of access.

Notes

Disclaimer. The funders had no role in the design of the study; the collection, analysis, or interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication.

Financial support. The PROMISE project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement 101034339. This Joint Undertaking receives support from the European Union's Horizon 2020 Research and Innovation Programme and the European Federation of Pharmaceutical Industries and Associations.

Supplement sponsorship. This article appears as part of the supplement “Preparing Europe for Introduction of Immunization Against RSV: Bridging the Evidence and Policy Gap.”

References

Author notes