Supporting Pediatric RSV Clinical Trials Through Close Epidemiological Surveillance During the SARS‐CoV‐2 Pandemic

Abstract

ABSTRACT

Clesrovimab, an extended half‐life monoclonal antibody, aims to protect infants for an entire RSV season. The pandemic impacted RSV epidemiology and strategies were implemented to support clesrovimab trials. Near real‐time monitoring of data showed minimal RSV activity in 2020. In 2021, RSV resurged early in some countries and was delayed in others, resulting in a change in trial enrollment strategy.

Respiratory Syncytial Virus (RSV) is a common respiratory virus that can cause severe disease, especially among the elderly, immunocompromised, young children, and infants. RSV is the most common cause of lower respiratory infections and hospitalizations among infants [1, 2]. Thirty-three million episodes of RSV are estimated to occur annually in children under 5 years of age globally, resulting in 3.6 million hospitalizations [3]. RSV is highly seasonal and circulates during winter in temperate climates and rainy season in tropical climates [4]. Phase 3 trials for a long-acting RSV monoclonal antibody, clesrovimab, in more than 300 sites across 34 countries globally ended recently. Clesrovimab is designed to be injected once at the beginning of the RSV season to protect against RSV disease in infants during the entire season.

The enrollment windows for the clesrovimab phase 3 trials were established before the SARS-CoV-2 pandemic using public RSV surveillance, existing literature, and feedback from local sites. The objective was to ensure that infants in the trials were immunized just before or as early as possible during RSV circulation. The beginning of the season was typically determined by a threshold of around 3% positivity rate of specimens tested using polymerase chain reaction tests. Where data were available, this process was completed for the participating sites across the globe and required reviewing RSV data from all the countries and specific sites to determine their seasonality. The process of determining enrollment windows was more challenging in countries with limited or unreliable RSV surveillance or literature. In these cases, the team relied heavily on local clinical teams, health information systems, and clinical investigators to inform the understanding of RSV seasonality. Understanding the epidemiology of RSV also required consideration of sub-national patterns where seasonality varied due to climatic and other factors.

The SARS-CoV-2 pandemic in the Spring of 2020 had a significant impact on RSV seasonality [5]. The disruption posed challenges for the enrollment process in the clesrovimab clinical trials. This paper aims to describe the effects of the SARS-CoV-2 pandemic on RSV seasonality and the epidemiologic strategies that were implemented to support clesrovimab trials. Several measures were implemented to determine appropriate enrollment windows for the clinical trials amidst the disrupted RSV seasonality: (1) identification of publicly available national and regional surveillance sources for RSV, SARS-CoV-2, and other respiratory viruses and weekly monitoring in all enrolling countries of the trial where surveillance was available, giving sites enough time to get ready to administer clesrovimab at the beginning of the RSV season, defined by a sustained rise in RSV-positivity (~3%), threshold used by the CDC [6].(2) insights gathering from local Merck & Co. Inc., Rahway, NJ, USA teams and clinicians from the trial sites regarding non-pharmaceutical interventions and the level of circulation of RSV and other respiratory diseases. In general, when an increase in RSV cases for three consecutive weeks was observed, enrollment was opened; (3) establishment of optimal enrollment windows for each site to ensure that infants were immunized just before or as early as possible during RSV season onset.

RSV In 2020 and 2021

The 2020 RSV season was absent or delayed in most countries due to non-pharmaceutical interventions such as lockdowns, masking, and school closures to control the spread of SARS-CoV-2 [7]. In 2021, RSV circulated earlier than usual in some countries while it was delayed in others. In the US, the typical pre-pandemic RSV season begins in October with the peak in December [8]. The 2021–2022 RSV season began in May 2021, about 5 months earlier than the expected onset, peaked in July 2021, and lasted until January 2022 [9]. Another example is from Denmark, where the regular RSV season typically begins in late November. Based on the regular seasonality, a planned enrollment window of 17 weeks from October to January was established in Denmark. Due to the pandemic, RSV activity was observed 4 months early during the summer of 2021, around July 2021 (Week 26) [2]. A similar situation was observed in the UK where RSV started increasing in May 2021 [9, 10]. This type of early RSV activity was difficult to predict, and most sites were unprepared and unable to start enrolling before late October 2021. On the other hand, countries like South Korea experienced a delayed 2021 season that started in December 2021, instead of the typical season start from September/October [11].

RSV In 2022 and 2023

In 2022, RSV and SARS-CoV-2 activity were continued to be monitored closely to foresee RSV activity as accurately as possible. To inform the start and end of the enrollment period, RSV activity was monitored weekly in all enrolling countries of the trial where surveillance was available. This gave the sites enough time to get ready to administer clesrovimab at the beginning of the RSV season, defined by a sustained rise in the RSV-positivity (~3%). In countries like the US and Denmark with anticipated early seasons based on information from 2021 to 2022, data from the national surveillance systems were regularly monitored for RSV, SARS-CoV-2, and other respiratory viruses, and relevant non-pharmaceutical interventions were gathered [2, 12]. As anticipated, the 2022–2023 RSV season was early. Foreseeing and monitoring this allowed for the recommendation of a more appropriate enrollment window in all countries throughout the country-specific enrollment period.

Conclusion

This brief report aimed to describe the strategies that were developed to address the disruptions of SARS-CoV-2 on RSV seasonality, in order to support the clinical development of clesrovimab phase 3 trials during the pandemic. Because of the seasonal nature of RSV, enrollment into clinical trials required careful consideration of RSV seasons and was challenged by disruptions to regular seasonality during the SARS-CoV-2 pandemic. The 2020 RSV season was delayed and missing in most countries compared to prior years, and the following seasons in 2021 and 2022 were also significantly disrupted by the pandemic. To maintain and support the clinical trials for clesrovimab, RSV and other respiratory virus data from various surveillance systems were monitored. While some countries had excellent pathogen surveillance data, many countries did not have consistent national surveillance systems for RSV. Monitoring RSV activity and determining appropriate enrollment windows for clinical trials in these areas were challenging even prior to SARS-CoV-2. This challenge was heightened during the pandemic and underscored the need for regular communication with local teams to gather near real-time data and information on RSV and SARS-CoV-2 to support clinical trial enrollment. SARS-CoV-2 demonstrated the possibility of including multiple respiratory viruses in national or local surveillance systems for pandemic preparedness, which may support drug and vaccine development.

Author Contributions

All authors were involved in the following: conception, design of work/acquisition or interpretation of data and drafting or revising manuscript. All authors provided final approval of the version to be published. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All authors provided final approval of the version to be published. All authors agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Ethics Statement

Our paper used publicly available surveillance data. All data sources are referenced in this paper.

Conflicts of Interest

P.S. was an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. Inc., Rahway, NJ, USA, at the time of writing. All other authors are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co. Inc., Rahway, NJ, USA, who may own stock and/or hold stock options in Merck & Co. Inc., Rahway, NJ, USA.

Data Availability Statement

Our paper used publicly available surveillance data. All data sources are referenced in this paper.

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