The human viral challenge model: accelerating the evaluation of respiratory antivirals, vaccines and novel diagnostics

Abstract

The Human Viral Challenge (HVC) model has, for many decades, helped in the understanding of respiratory viruses and their role in disease pathogenesis. In a controlled setting using small numbers of volunteers removed from community exposure to other infections, this experimental model enables proof of concept work to be undertaken on novel therapeutics, including vaccines, immunomodulators and antivirals, as well as new diagnostics.Crucially, unlike conventional phase 1 studies, challenge studies include evaluable efficacy endpoints that then guide decisions on how to optimise subsequent field studies, as recommended by the FDA and thus licensing studies that follow. Such a strategy optimises the benefit of the studies and identifies possible threats early on, minimising the risk to subsequent volunteers but also maximising the benefit of scarce resources available to the research group investing in the research. Inspired by the principles of the 3Rs (Replacement, Reduction and Refinement) now commonly applied in the preclinical phase, HVC studies allow refinement and reduction of the subsequent development phase, accelerating progress towards further statistically powered phase 2b studies. The breadth of data generated from challenge studies allows for exploration of a wide range of variables and endpoints that can then be taken through to pivotal phase 3 studies.We describe the disease burden for acute respiratory viral infections for which current conventional development strategies have failed to produce therapeutics that meet clinical need. The Authors describe the HVC model’s utility in increasing scientific understanding and in progressing promising therapeutics through development.The contribution of the model to the elucidation of the virus-host interaction, both regarding viral pathogenicity and the body’s immunological response is discussed, along with its utility to assist in the development of novel diagnostics.Future applications of the model are also explored.Electronic supplementary materialThe online version of this article (10.1186/s12931-018-0784-1) contains supplementary material, which is available to authorized users.

Structural Insight into Paramyxovirus and Pneumovirus Entry Inhibition

“…Of the small molecule RSV entry inhibitors that have entered the clinical testing phase so far, five have advanced to efficacy testing ( Table 1). The majority of these phase II trials employed an established human challenge model of RSV infection that is based on experimental infection of adult healthy volunteers and thus provides a framework to assess treatment under controlled, predefined conditions [93]. Primary efficacy end point of the model was typically shed virus load in nasal swab samples, secondary end points included total mucus weight produced during the acute infection period and symptom scores.…”

Multicenter evaluation of the QIAstat Respiratory Panel—A new rapid highly multiplexed PCR based assay for diagnosis of acute respiratory tract infections

“…Most pathogens have predilection for either the upper or lower respiratory tract but may move into the other compartment. The etiology is diverse, led by a high viral heterogeneity and also comprises bacteria [2,3]. The health-related burden of acute respiratory tract infections is significant in defined populations like the very young, the elderly, the chronically ill with underlying comorbidities (e.g., heart or lung disease, diabetes), the malnourished and the immunocompromised (e.g., transplant recipients, HIV-infected individuals) [4][5][6][7][8][9].…”

Extraordinary diseases require extraordinary solutions

“…Multiple candidates have been proposed and many are in clinical trials, but the question remains as to whether emergency use of a SARS-2 vaccine should await collection of controlled data from large populations that are experiencing epidemic SARS-2 disease or whether to expedite vaccination by moving quickly through animal studies and doing human challenge studies in volunteers [4]. Human volunteer challenge studies have been done previously with several agents, yielding important information [5,6]. Of course, such studies put volunteers at risk of disease and death and deaths have occurred in drug studies.…”