Andrew Catchpole, Chief Scientific Officer at hVIVO
Respiratory syncytial virus (RSV) continues to impose a heavy burden on global health, particularly among infants, older adults, and individuals with underlying conditions. The recent approval of the first RSV vaccines marks a major milestone, yet the scientific and clinical challenges associated with developing next‑generation vaccines and antivirals remain substantial. Seasonal variability, unpredictable transmission patterns, and the need for large, lengthy field trials all contribute to slow progress.
Human challenge trials offer a powerful complement to traditional development pathways. By enabling controlled, deliberate exposure to a well‑characterised virus in healthy adult volunteers, these studies provide a level of precision that is difficult to achieve in the community. They allow researchers to observe infection dynamics in real time, measure immune responses with granularity, and generate early efficacy signals that can guide programme decisions long before a field trial is feasible.
Over the past two decades, hVIVO has built one of the world’s most extensive portfolios of respiratory challenge models. The RSV‑A Memphis model, in particular, has played a central role in the development of several vaccines that have now reached the market. Building on that foundation, the team has recently developed the world’s first RSV‑B human challenge model — a significant step forward as the field moves toward broader, combination‑based respiratory vaccines.
RSV A and RSV B co-circulate in the community, typically with one of them dominating in any given season but it is impossible to predict which will be most prevalent. They cause similar disease burden. RSV A human challenge studies were used to generate the first proof of concept efficacy data conclusively demonstrating the efficacy of the current class of RSV vaccines based on pre-F antigen presentation. . However, the research landscape is shifting. Developers are now pursuing bivalent and trivalent formulations that combine RSV‑A, RSV‑B, and often human metapneumovirus (hMPV) and sometimes also Parainfluenza virus (PIV). To support this evolution, a robust RSV‑B model is essential.
Furthermore, vaccine producers need to have efficacy data against both RSV A and B strains to support broad spectrum RSV protection label claims. Given the unpredictability of the circulation of these two major subtypes, field trials can often result in insufficient data obtained from the subdominant circulating subtype to determine efficacy. Hence it is essential that both RSV A and RSV B challenge models exist so that they can be used not only for early proof of concept studies but also as supporting efficacy data to late-stage studies to fill in gaps from field trial data due to low circulation.
The development of the RSV‑B model began with the collection of clinical isolates from individuals with naturally acquired infections. These samples were screened against a broad pathogen panel, and promising candidates were evaluated for their ability to grow on GMP‑compliant cell lines. Minimal passage was a critical requirement: the goal was to preserve the characteristics of the circulating virus and avoid adaptation to cell culture. Once a suitable isolate was identified, it underwent extensive safety testing, including targeted PCR panels and next‑generation sequencing, to ensure that only the intended pathogen was present.
The result is a well‑characterised, GMP‑manufactured challenge virus that reflects contemporary RSV‑B strains circulating in the community.
The first clinical study using the RSV‑B model demonstrated strong performance across key endpoints. Infection rates reached approximately 90% by PCR criteria, and volunteers developed clear, measurable symptoms. Importantly, the model produced high levels of moderate‑to‑severe symptomatic disease — the category most relevant for translational value because it mirrors the types of cases that typically present in field trials.
When compared to the established RSV‑A Memphis model, the RSV‑B strain produced equal or higher levels of disease severity across multiple measures. This provides confidence that the model will be highly effective for evaluating both vaccines and antivirals.
The symptom profile was also notable. Volunteers exhibited a broad range of upper respiratory symptoms, including nasal discharge, sneezing, malaise, and headache. A smaller proportion experienced mild lower respiratory involvement, consistent with expectations for healthy adults. The model’s ability to generate robust, reproducible symptoms makes it particularly valuable for assessing clinical endpoints and understanding the relationship between viral load and disease expression.
Human challenge trials have already demonstrated their value in RSV vaccine development. Several vaccines that recently reached the market received expedited regulatory designations based partly on challenge study data. These studies provided early efficacy signals, helped refine dose selection, and supported the design of later‑phase trials.
The RSV‑B model extends these capabilities. It allows developers to test the RSV‑B component of combination vaccines and to evaluate cross‑strain protection. It also enables detailed exploration of immune responses, including mucosal immunity and correlates of protection — areas that are difficult to study in field trials.
For antiviral development, challenge trials offer a unique opportunity to evaluate treatment timing. Traditional designs trigger dosing based on PCR positivity, but this does not reflect real‑world behaviour. Many individuals seek treatment only when they begin to feel unwell. To address this, hVIVO has incorporated patient‑perception triggers into its challenge designs, allowing dosing to begin when volunteers report that they “feel a cold coming on.” This approach aligns more closely with community practice and improves the predictive value of challenge data for field performance.
Alongside the RSV‑B model, hVIVO has developed a new human metapneumovirus (hMPV) challenge model. hMPV is a close relative of RSV and is increasingly recognised as a significant respiratory pathogen. As developers move toward combination respiratory vaccines, validated challenge models for each component become essential. The hMPV model has shown strong infection rates and robust symptoms, making it a valuable addition to the respiratory challenge platform. Development of a PIV model has now also begun.
Together, the RSV‑A, RSV‑B, and hMPV models provide a comprehensive suite of tools for evaluating next‑generation vaccines and therapeutics. They enable precise, early‑phase assessment of each component in a controlled environment, reducing uncertainty and accelerating development.
The future of respiratory virus research will rely increasingly on tools that can generate high‑quality data early in development. Human challenge trials are uniquely positioned to meet this need. They offer a controlled setting for understanding infection dynamics, identifying correlates of protection, and evaluating the performance of vaccines and antivirals long before large field trials are possible.
As respiratory vaccine development becomes more complex — particularly with the rise of combination products — the ability to test each component individually will be invaluable. The introduction of the RSV‑B and hMPV models represents a major step forward, providing developers with the precision and flexibility needed to advance the next generation of respiratory therapeutics.
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