A COVID-19 human viral challenge model. Learning from experience

Abstract

The controlled human infection model and specifically the human viral challenge model are not dissimilar to standard clinical trials while adding another layer of complexity and safety considerations. The models deliberately infect volunteers, with an infectious challenge agent to determine the effect of the infection and the potential benefits of the experimental interventions. The human viral challenge model studies can shorten the time to assess the efficacy of a new vaccine or treatment by combining this with the assessment of safety. The newly emerging SARS-CoV-2 virus is highly contagious, and an urgent race is on to develop a new vaccine against this virus in a timeframe never attempted before. The use of the human viral challenge model has been proposed to accelerate the development of the vaccine. In the early 2000s, the authors successfully developed a pathogenic human viral challenge model for another virus for which there was no effective treatment and established it to evaluate potential therapies and vaccines against respiratory syncytial virus. Experience gained in the development of that model can help with the development of a COVID-19 HVCM and the authors describe it here.

Keywords: COVID-19; RSV; SARS-CoV-19; controlled human infection model; human viral challenge model.

Figure 1

An outline of a HVCM study, specifically the Human viral challenge model. The study typically consists of inputs, such as the volunteers, their selection criteria, isolation in quarantine and exposure to a GMP virus. There are two treatment options; a vaccination/prophylaxis with an antiviral or b treatment with an antiviral. Outputs from the study summarised on the right, such as virus symptoms and virus shedding. X is the number of days before virus exposure vaccination may occur. Y is the number of days post‐virus exposure that a volunteer may be followed for ¹²

Figure 2

The role of the HVC model in the clinical development pathway. Short duration proof‐of‐concept studies, which incorporate the HVC model, typically include small numbers of subjects. The resulting safety and, particularly, efficacy data can more accurately guide decisions on whether to expose a larger number of subjects to promising candidate therapeutics in community‐based 14 field studies than conventional phase 1 safety data alone might otherwise ¹²

Figure 3

Viral load and disease over time in human volunteers. Timing of mean viral load and symptomatic disease. Mean data from all infected volunteers from each collection time point starting from Day 1 post‐inoculation are shown. The timing of peak viral load correlates with the occurrence of peak symptom severity. log PFUe/mL = log plaque‐forming unit equivalents per millilitre ⁴⁰

Figure 4

Relationships between IL‐6 concentration, disease severity, and quantity of respiratory syncytial virus (RSV). Concentrations of IL‐6 were measured in respiratory secretions of volunteers and were compared with disease measures and viral quantities. A, The cumulative sum of the IL‐6 concentrations vs disease severity as measured by individual volunteer cumulative symptom scores. B, The cumulative sum of IL‐6 concentrations vs disease severity as measured by individual volunteer cumulative nasal mucus weight. C, Comparison of the cumulative sum of IL‐6 concentrations vs area under the curve (AUC) viral load (quantitative real‐time reverse transcriptase‐polymerase chain reaction, qPCR). P values represent the probability that the slopes of the regression lines do not include a slope of zero. The dashed curved lines indicate the 95% confidence interval of the slopes of the regression line (solid line). Similar statistically significant direct relationships were observed when viral AUC was measured by quantitative culture ⁴⁰