A comparison of four respiratory vaccine programmes shows how controlled infection studies and field trials can inform development decisions together.

Human challenge studies answer a deliberately narrow question: under a defined exposure, in a carefully selected population, does an intervention produce a measurable biological or clinical effect?

For respiratory vaccines, that effect might be a reduction in nasal viral load, viral shedding, infection or short-term symptoms. Human challenge studies provide early biological proof-of-concept and rich mechanistic evidence, while field trials assess clinical protection under natural exposure. Together, these approaches can refine the questions addressed at successive stages of development.

The distinction becomes clearer when the challenge and field studies are examined side by side. For a poster presented at World Vaccine Congress Europe 2026, I compared four selected respiratory vaccine programmes using eight primary clinical reports: three RSV vaccine trajectories and one influenza vaccine trajectory. The purpose was not to calculate how accurately CHIM results predict field efficacy. It was to identify what changed between the studies, and what can reasonably be inferred from each result.

Four programmes, four lessons

1. RSVpreF: a positive challenge result, a different clinical question

In a controlled RSV-A challenge study of Pfizer's bivalent RSVpreF vaccine, healthy adults aged 18–50 received vaccine or placebo before intranasal exposure. Among 62 challenged participants, efficacy against the study's defined symptomatic RSV infection endpoint was 86.7% (95% CI 53.8–96.5). Viral-load and symptom measures were also prespecified endpoints [1].

The subsequent RENOIR field trial studied adults aged 60 years or older during natural RSV circulation. For the same named bivalent RSVpreF vaccine, efficacy against RSV-associated lower respiratory tract illness was 66.7% when at least two signs or symptoms were required, and 85.7% when at least three were required. Those estimates had distinct case definitions and 96.66% confidence intervals [2].

These are encouraging findings across two settings, but the percentages are not interchangeable. The population shifted from younger healthy adults to older adults; exposure moved from scheduled inoculation to community circulation; and the primary clinical question moved from symptomatic infection after challenge to lower respiratory tract illness over an RSV season.

Development lesson: Evidence from the same vaccine can be complementary without measuring the same outcome.

Human challenge and field trials generate complementary evidence: early virological and immunological signals alongside clinical outcomes under natural exposure.

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2. MVA-BN-RSV: biological activity does not settle a field success criterion

In the MVA-BN-RSV challenge trial, 63 healthy adults received vaccine or placebo before RSV-A exposure. The median nasal viral-load area under the curve was 0.00 in vaccinees versus 49.05 with placebo (P=.017). Median total symptom scores were 2.50 versus 27.00 (P=.004) [3]. These were meaningful signals of activity in the controlled model.

In VANIR, the vaccine was assessed in adults aged 60 years or older during the 2022–23 RSV season. Efficacy against RSV-associated lower respiratory tract disease with at least three symptoms was 42.9% (95% CI −16.1 to 71.9), and the prespecified success criterion for that endpoint was not met. For disease defined by at least two symptoms, efficacy was 59.0% (95% CI 34.7–74.3) [4].

It would be inaccurate to describe the field result simply as either success or failure. The trial reported protection under one case definition, but it did not meet the required criterion under the more stringent primary definition. The challenge study established activity against viral replication and symptoms under controlled exposure; it did not establish the probability of satisfying a later field-trial success threshold.

Development lesson: Distinguish a biological signal, an endpoint-specific efficacy estimate and a prespecified decision threshold.

3. Ad26.RSV.preF: the formulation changed

The Janssen challenge study tested Ad26.RSV.preF vector alone in healthy adults aged 18–50. Following RSV-A challenge, the prespecified primary RT-qPCR viral-load AUC had a median of 0 in vaccinees versus 236 in controls (P=.012) [5].

The CYPRESS field trial subsequently assessed a combination of Ad26.RSV.preF and RSV prefusion F protein, not the vector-alone formulation tested in challenge. In adults aged 65 years or older, reported vaccine efficacy against the trial's first lower respiratory tract disease case definition was 80.0% (94.2% CI 52.2–92.9) [6].

The field result supports the efficacy of the combination vaccine in the studied setting. It is not a direct validation of the vector-alone CHIM formulation. This distinction matters when the challenge evidence is used to support product or portfolio decisions.

Development lesson: Before linking results across phases, verify formulation, dose and regimen identity—not merely the programme name.

4. MVA-NP+M1: a small challenge signal, no demonstrated incremental field benefit

The early influenza A challenge study of the T-cell-focused MVA-NP+M1 vaccine was a small, open-label, non-randomised comparison: 11 vaccinees and 11 controls. Laboratory-confirmed influenza occurred in 2/11 and 5/11, respectively. Among participants who became infected, mean virus-shedding duration was 0.45 versus 1.09 days (P=.036). These findings were preliminary, not an established efficacy estimate [7].

The later FLU009 field trial asked a different question: did MVA-NP+M1 add protection after seasonal quadrivalent influenza vaccination? Among 2,152 participants in the intention-to-treat population, laboratory-confirmed influenza occurred in 35/1,077 MVA-NP+M1 recipients and 23/1,075 placebo recipients (P=.14). The trial did not demonstrate an incremental benefit under that regimen [8].

The change in background vaccination, alongside the very small and non-randomised challenge comparison, limits any direct programme-level extrapolation. A signal following challenge in one context does not establish added clinical value when a new intervention is layered onto existing standard vaccination.

Development lesson: Define the comparator and background standard of care before interpreting whether a new vaccine adds value.

What should a development team carry forward?

CHIMs have several strengths that are difficult to reproduce in conventional field trials. Exposure timing is known, sampling can be frequent, and virological and symptom trajectories can be followed closely. These features may clarify mechanism, select endpoints, challenge assumptions about dose or immune response, and support an evidence-based decision about the next study.

The boundary of inference must be just as explicit. A programme review should document at least five differences before using challenge results to support a field claim:

1. Product and regimen. Was the same formulation, dose, schedule and combination used?

2. Population. How do age, baseline immunity and comorbidities differ from the intended recipients?

3. Exposure. How does a characterised inoculum compare with natural circulation, repeated exposure and strain diversity?

4. Endpoint. Is the result based on viral kinetics, infection, symptoms, lower respiratory tract disease or a more clinically consequential outcome?

5. Observation period. Does a short post-inoculation follow-up address the protection and durability needed across a season or longer?

Once these differences are visible, the right question is not, “What field efficacy does the challenge percentage predict?” It is, “Which uncertainty did the challenge study reduce, and what uncertainty remains before the next development decision?”

For example, a strong effect on nasal viral-load AUC may justify further investigation, but it does not by itself define protection against lower respiratory tract disease. Likewise, moving from a small healthy-adult model to older adults introduces clinical and immunological uncertainties that cannot be resolved by comparing percentages alone.

Value beyond a single efficacy estimate

Challenge studies can contribute to programmes even when a subsequent field trial reports modest, endpoint-dependent or no demonstrated benefit. Their value can lie in characterising the infection model, clarifying viral and symptom kinetics, identifying assay performance, or exposing a weak biological hypothesis earlier. However, the four comparisons reviewed here do not measure whether the CHIM itself accelerated development, changed a go/no-go decision or reduced programme cost. Those would require different evidence.

This analysis is also deliberately limited. The four programmes were selected for a structured comparison; they are not a representative or systematic sample of respiratory vaccine development. Two comparisons involved changes in formulation or regimen. No pooled efficacy, correlation between challenge and field results, or estimate of predictive accuracy was calculated.

The practical conclusion

Human challenge models and field efficacy trials address different, complementary stages of vaccine evidence generation. The most useful contribution of a CHIM may be the quality and granularity of the early evidence it produces—not a single percentage carried forward as an expected field result.

For vaccine developers, disciplined translation starts by specifying the decision to be made, the target clinical claim and the differences between the controlled model and the intended population. That makes it easier to use a positive challenge result appropriately, to interpret a discordant field outcome honestly, and to design the additional evidence that still needs to be generated.

References (eight primary reports)

1. Schmoele-Thoma B, et al. Vaccine Efficacy in Adults in a Respiratory Syncytial Virus Challenge Study. N Engl J Med. 2022. PMID 35731653.

2. Walsh EE, et al. Efficacy and Safety of a Bivalent RSV Prefusion F Vaccine in Older Adults. N Engl J Med. 2023. PMID 37018468.

3. Jordan E, et al. Reduced Respiratory Syncytial Virus Load, Symptoms, and Infections: A Human Challenge Trial of MVA-BN-RSV Vaccine. J Infect Dis. 2023. PMID 37079393.

4. Jordan E, et al. A multivalent RSV vaccine based on the modified vaccinia Ankara vector shows moderate protection against disease caused by RSV in older adults in a phase 3 clinical study. Vaccine. 2024. PMID 39461302.

5. Sadoff J, et al. Prevention of Respiratory Syncytial Virus Infection in Healthy Adults by a Single Immunization of Ad26.RSV.preF in a Human Challenge Study. J Infect Dis. 2021. PMID 33400792.

6. Falsey AR, et al. Efficacy and Safety of an Ad26.RSV.preF-RSV preF Protein Vaccine in Older Adults. N Engl J Med. 2023. PMID 36791161.

7. Lillie PJ, et al. Preliminary assessment of the efficacy of a T-cell-based influenza vaccine, MVA-NP+M1, in humans. Clin Infect Dis. 2012. PMID 22441650.

8. Evans TG, et al. Efficacy and safety of a universal influenza A vaccine (MVA-NP+M1) in adults when given after seasonal quadrivalent influenza vaccine immunisation (FLU009): a phase 2b, randomised, double-blind trial. Lancet Infect Dis. 2022. PMID 35305317.