Review: included studies

Altogether, 59 outpatient CHIM studies with a total of 2789 participants were included (Fig. 1) in the systematic review. Six interviews and three questionnaires were completed with corresponding authors for 41/59 of the included studies. Data from 59 studies were extracted (Fig. 2 and Supplementary Table 3) and three different respiratory pathogens were identified (44 rhinovirus studies with 1774 participants, 14 Streptococcus pneumoniae studies with 966 participants and one RSV study with 49 participants). Additionally, data regarding safety were collected from two ongoing outpatient trials for Bordetella Pertussis (B. Pertussis) identified through the interviews. 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 shedding¹² 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 manifestation¹³.

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.

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.

Review: safety

We examined safety risks of outpatient CHIM studies by collecting data on third-party transmission, PPE usage, inoculation, participant transportation, and emergency care provision. No studies (0/59) implemented home quarantine measures. Various strategies, such as the exclusion of volunteers who reside with at-risk individuals, were implemented to limit third-party transmission risk (Table 1). One rhinovirus study incorporated assessment of third-party transmission into the study protocol¹⁴. In this study, one transmission event occurred (1/42, 2.4%) to a household member, which resulted in mild upper respiratory tract symptoms. No other studies reported incidents of third-party pathogen transmission. The potential risk of third-party transmission was explained to participants before enrollment and most authors attributed the prevention of third-party transmission to participants’ responsibility. One Streptococcus pneumoniae study requested signatures from the roommates of participants to indicate their consent to the potential risk of third-party transmission. Two outpatient trials¹⁵ for Bordetella Pertussis are currently ongoing. One of these trials requires pre-consent in order to confirm that participants understand the risks of participation in the trial. In both trials, a phased approach is used to transition from inpatient to outpatient trials including (1) collecting data on environmental shedding in an inpatient trial¹⁶ (2) involving the national public health authority (3) enrolling bedroom-sharers in the outpatient setting to study transmission. It will be assumed that if there is no transmission to bedroom sharers then community dissemination is unlikely in a population with a high vaccination rate, broad circulation of Bordetella Pertussis and no contact with high-risk individuals. [Personal communications Robert Read & Dimitri Diavaopoulos].

Measures to ensure the provision of emergency care, PPE usage, and instructions for participants on commuting to the study site, varied across studies (Table 1). General PPE measures have increased since the COVID-19 pandemic, either due to increased awareness of infection risk or to prevent co-infection with SARS-CoV-2, regardless of the inoculum. In all outpatient studies the inoculation procedure was identical to inpatient CHIMs and was conducted at the study site. After inoculation participants returned to their natural living environment. Several incidents (i.e., participant became unwell or fainted ultimately attributed to a mild-viral co-infection) occurred during Streptococcus pneumoniae CHIMs for which emergency care was needed and care was provided through an emergency home visit or a telephone call to the study doctor. For these incidents, emergency care could be provided sufficiently and the outpatient setting did not prove to be a barrier. However, difficulties were experienced in the potential ability to provide emergency care due to either participants traveling, which was against study protocol, or unreachability of participants. In the event of unreachability, the next of kin were contacted or study personnel visited the participants’ homes to assess the situation.

In summary, key safety risks identified include third-party transmission and the ability to provide emergency care. Risk mitigation strategies using PPE and contact information are successful in limiting transmission and allowing for the timely provision of emergency care (Table 1, Fig. 4).

Primary data: safety—RSV transmission in an inpatient RSV CHIM

In our inpatient RSV CHIM, there were no instances of direct or indirect transmission of RSV. No infectious virus was detected on the most frequently contaminated fomites¹⁷ in rooms of infected participants although genetic material was recovered [Supplementary Fig. 1]. The TCID₅₀ was below the limit of detection for all fomite samples before and after cleaning with alcohol (Fig. 3). Therefore, the pre-determined acceptance criterion of viral titer at least ten times lower than the titer needed for potential infection (2.2 Log₁₀ 50% tissue culture infectious dose (TCID50))¹⁸ was met. Genetic RSV material was measured using q-PCR on fomites, which was reduced through cleaning with alcohol (Supplementary Fig. 1) (for full results see supplementary materials). Furthermore, personnel in close contact with infected participants (performing inoculation and sample collection) tested negative (n = 4) for RSV indicating lack of direct RSV transmission when adhering to WHO droplet and isolation procedures. It should be noted that these results are based on transmission of the Memphis-37 strain, which is currently the most widely used RSV inoculum. Between 2010 and 2024, the Memphis37 challenge strain has been used 21 times, accounting for 100% of the conducted RSV CHIMs during this period. When using a different strain additional measures may be considered as third-party transmission risk should be reevaluated although in general pathogen-specific precautions are not strain-specific

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 established¹⁸ 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.

Primary data: safety—RSV transmission in an outpatient RSV CHIM

In the first RSV outpatient CHIM, study participants reported 13 housemates with symptoms of respiratory tract infection during daily home visits. When household members of participants became symptomatic a single point-of-care (POC) test was performed from study day 6 onward. Five of these reports met the criteria for a potential transmission event and were tested for RSV; all (5/5) tested negative for RSV [Supplementary Fig. 3]. Eight housemates with respiratory symptoms were not tested as their symptoms did not correspond to a potential transmission event (symptoms started before day six (n = 6), study participant was RSV-negative (n = 1) or no contact between study participant and housemate (n = 1). In summary, there was no symptomatic RSV transmission to household members in the first global RSV outpatient CHIM.

Review: logistics

According to author interviews, study costs of outpatient CHIMs were considerably lower than those of inpatient CHIMs. Inpatient CHIM costs are driven by rental of the quarantine unit (estimated based on an average CHIM protocol at 35,000 euros per participant), round-the-clock study staff, participant facilities (e.g., food), and higher participant compensation in the inpatient setting. Costs specific to the outpatient setting may be associated with home visits and sample transport to the lab.

In most of the included studies (58/59), participants commuted to the study site for sample collection and in all studies participants were compensated for transportation costs (e.g., taxi or fuel costs). Home sampling was utilized for selected samples if self-sampling was feasible (i.e., nasosorption¹⁹ and nasal-swab) and if samples did not require immediate processing (i.e., nasal lavage)²⁰. Home samples were stored in the freezer until collected by research staff. No difficulties with home sampling were experienced and a high compliance rate was achieved (96.8%)²⁰. Risks of home sampling include non-synchronized sample collection times causing diurnal fluctuations of samples, increased time until sample processing, fluctuations in sample temperature during transport, suboptimal sample collection conditions in participants homes, and inadequate collection technique when not observed by study staff (in case of self-sampling). However, home collection offers the advantage of reducing participant burden and further minimizing the potential risk of third-party transmission. In the included studies, symptom monitoring was done by self-reported symptom diaries, telephone contact, and clinical evaluations during site visits. Clinical evaluations enhance the quality of symptom monitoring as symptoms are objectified by study staff.

Another advantage of outpatient CHIMs is that it may aid recruitment. Ease of recruitment may be further enhanced due to the COVID-19 pandemic, in which home quarantine and the use of PPE have become more familiar and acceptable to the general public.

In summary, key logistic risks identified were study costs, quality of symptom monitoring, and logistics of sample collection (Fig. 4). Implementing risk mitigation strategies effectively results in minimal logistic risks for outpatient RSV CHIMs.

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.

Primary data: logistics of first global RSV outpatient CHIM and inoculation stress test

In the first global outpatient RSV CHIM risk mitigation strategies were used to minimize logistic challenges. The majority of study participants resided within a ten-kilometer radius of the study site allowing for a minimal time from sample collection to sample processing. Inoculation was performed at the study site instead of the home setting as we observed that the viral titer of RSV-A Memphis 37b stored on wet ice drops ~1 log TCID50 every 30 min [Supplementary Fig. 2]. The stress test of the RSV-A Memphis 37b inoculum stored on wet ice showed a mean titer of 1 × 10⁴ TCID50/ml after 15 min and 3, 16 × 10³ TCID50/ml after 30 min compared to 4, 21 × 10⁴ TCID50/ml before storage at t = 0 [Supplementary Fig. 2]. Thus, the titer of the inoculum was sufficiently stable for a maximum of 15 min stored on wet ice, which prohibited inoculation during home visits and supported the choice to inoculate at the study site. Coordination of home visits and laboratory processing was logistically more challenging than in the inpatient setting or than outpatient CHIM where sample collection occurred at the study site. The majority of sample collection was performed during home visits to minimize the burden for study participants.

Review: ethics

In general, there were no insurmountable ethical challenges in obtaining ethical approval specific to outpatient based CHIM studies. However, some research groups initially experienced difficulties due to the possible risk of third-party transmission. To obtain ethical approval, it was argued that the pathogen used is a common circulating pathogen and therefore the added risk of circulation due to CHIMs is negligible. Furthermore, because of general circulation of the pathogen amongst the population there is considerable population immunity and therefore a significantly decreased risk of causing an outbreak. Respiratory CHIM in higher-risk participants, such as patients with asthma or chronic obstructive pulmonary disease, raised safety concerns for the institutional review board. Safety of a CHIM in these selected high-risk groups was first shown in the inpatient setting with HRV²¹. Later, researchers were able to demonstrate the safety of outpatient CHIM studies by either conducting pilot studies or by slowly building a track-record of conducting safe CHIMs²². For high risk RSV populations, safety of CHIM has been demonstrated in the inpatient setting in older adults²².

In medical research, there is an ethical imperative to minimize the research burden to participants wherever possible. We examined the acceptability of participant burden in the outpatient setting. All authors noted that compared to inpatient CHIMs, the study burden on participants in the outpatient setting is significantly reduced because there is no need for inpatient quarantine, which is disruptive to participants lives. By adhering to minimally required isolation measures in the outpatient setting, participant burden can be further reduced. One research group conducted an acceptability study and found that participants perceived the study burden to be low in the outpatient setting²³.

Another advantage of outpatient CHIM studies is increased generalizability of results because participants remain in their regular living conditions, exposed to the same environmental conditions, pathogens and environmental factors, such as air quality, allergen exposure, and behavioral routines as they would in their everyday lives. Furthermore, outpatient CHIMs are more participant friendly making recruitment easier and faster, and make more widespread possibility to conduct RSV CHIM as availability of an inpatient quarantine capacity is not a limiting factor²⁴. On the other hand, the outpatient setting is a less controlled setting making it more difficult to identify results in a smaller group due to potential increased variability. In addition to these benefits, a clear ethical advantage of outpatient CHIMs is that by further reducing costs it has the potential to contribute to global vaccine equity. Furthermore, there is an ethical imperative to avoid restricting participants’ freedoms via quarantine if there is no scientific or public health reason to do so. In summary, key ethical risks of outpatient CHIM include not obtaining ethical approval and acceptability of participant burden [Fig. 4]. Other potential ethical considerations that could be made are the possibility to treat or manage third-party transmission events, consequences of third-party transmission, pathogen survival outside the host and mode of transmission.

From an ethics perspective, a risk is comprised of the chance of the event happening and the consequences of the event (“impact”). For a framework to assess risks related to outpatient CHIMs see Supplementary Table 4. Primary data on ethics from our outpatient CHIM are listed in supplementary note 4.