Risk analysis for outpatient experimental infection as a pathway for affordable RSV vaccine development

Abstract

Controlled human infection models (CHIMs) are an important tool for accelerating clinical development of vaccines. CHIM costs are driven by quarantine facilities but may be reduced by performing CHIM in the outpatient setting. Furthermore, outpatient CHIMs offer benefits beyond costs, such as a participant-friendly approach and increased real-world aspect. We analyze safety, logistic and ethical risks of respiratory syncytial virus (RSV) CHIM in the outpatient setting. A review of the literature identified outpatient CHIMs involving respiratory pathogens. RSV transmission risk was assessed using data from our inpatient and outpatient RSV CHIMs (EudraCT 020-004137-21). Fifty-nine outpatient CHIMs using RSV, Streptococcus pneumoniae, rhinovirus, and an ongoing Bordetella Pertussis outpatient CHIM were included. One transmission event was recorded. In an inpatient RSV CHIM, standard droplet and isolation measures were sufficient to limit RSV transmission and no symptomatic third-party transmission was measured in the first outpatient RSV CHIM. Logistic and ethical advantages support outpatient CHIM adoption. We propose a framework for outpatient RSV CHIM with risk mitigation strategies to enhance affordable vaccine development.

Fig. 1. Flowchart study selection and data collection.

Preferred reporting items for systematic reviews and meta-analyses (PRISM) flow diagram. The search yielded 2390 records, of which 621 duplicates were removed. Based on title- and abstract screening 1396 records were excluded. In total, 58 reports were not retrieved (14 with no full text available and 44 conference abstracts). Authors of conference abstracts were contacted to identify eligibility and availability of full text articles after which no additional reports were included. In total, 254 reports were excluded for various reasons, the majority due to an inpatient trial setting. For 20 records the study setting remained unknown after contacting authors, and records were excluded. Fourteen studies were included through snowballing via a list provided by the authors of included studies, detailing their published CHIM studies. In total, 52 corresponding authors were contacted and for 41 of the included studies, six interviews, and three questionnaires were completed.

Fig. 2. Outpatient and partially outpatient respiratory CHIM studies per pathogen.

Pie chart of included studies per pathogen showing number of challenged participants, the percentage of participants out of the total number of participants who participated in outpatient respiratory CHIMs and the range of inoculation doses used. Two studies were partially outpatient: (1) an RSV CHIM in which participants resided at home for the first three days and stayed at a quarantine unit for the remainder of the study on the basis of expected viral shedding43 and (2) a Streptococcus pneumoniae pilot trial conducted in Malawi in which inoculated participants remained at the clinic for the first three days, as this period posed the greatest risk of disease manifestation.44 Two ongoing unpublished outpatient CHIMs using B. Pertussis were not included in this figure. Created in BioRender. Delemarre, E. (2025) https://BioRender.com/i14r556.

Fig. 3. RSV transmission via high-risk fomites before and after cleaning with alcohol in quarantine rooms of RSV-positive participants.

Respiratory syncytial virus (RSV) recovered from high-risk fomites was measured via viral titration (RSV viral titer). Viral titration (Y-axis) was measured in Log10 TCID50, with a limit of detection of 0.5 Log10 TCID50 and a previously established minimal dose needed for infection of 3.2 Log10TCID50. Samples were taken from high-risk fomites including faucet, light switch, toilet flush and doorhandle (shown from left to right on the X-axis). Samples were collected from the rooms of all RSV+ participants, above shows the median and interquartile range of all the samples per fomite. Dark colors indicate the samples taken before fomite cleaning with 70% ethanol, while light colors represent samples taken after fomite cleaning. Created in BioRender. Delemarre, E. (2025) https://BioRender.com/b08z113.

Fig. 4. Key safety, logistic, and ethical risks of outpatient respiratory CHIMs and proposed risk mitigation strategies for RSV outpatient CHIM.

Key risks regarding safety (third-party transmission and the ability to provide emergency care), logistics (study costs, quality of symptom monitoring and transportation and timing of sample collection) and ethics (obtaining ethical approval and participant burden) are shown in the top row. For each risk a corresponding risk mitigation strategy for an outpatient RSV CHIM is proposed. Created in BioRender. Delemarre, E. (2025) https://BioRender.com/n07n656.