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 (CA) 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 the cause pandemic disease COVID-19. An urgent race in 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 2000’s 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. The authors feel that the experience gained in the development of that model can help with the development of a COVID-19 HVCM and describe it here. Word count: 197
Point-of-care tests (POCTs) offer considerable potential for improving clinical and public health management of COVID-19 by providing timely information to guide decision-making, but data on real-world performance are in short supply. Besides SARS-CoV2-specific tests, there is growing interest in the role of surrogate (non-specific) tests such as FebriDx, a biochemical POCT which can be used to distinguish viral from bacterial infection in patients with influenza-like illnesses. This short communication assesses what is currently known about FebriDx performance across settings and populations by comparison with some of the more intensively evaluated SARS-CoV2-specific POCTs. While FebriDx shows some potential in supporting triage for early-stage infection in acute care settings, this is dependent on SARS-CoV2 being the most likely cause for influenza-like illnesses, with reduction in discriminatory power when COVID-19 case numbers are low, and when co-circulating viral respiratory infections become more prevalent during the autumn and winter. Too little is currently known about its performance in primary care and the community to support use in these contexts and further evaluation is needed. Reliable SARS CoV2-specific POCTs – when they become available – are likely to rapidly overtake surrogates as the preferred option given the greater specificity they provide.
Background: It has long been known that nasal inoculation with influenza A virus produces asymptomatic to febrile infections. Uncertainty persists about whether these infections are sufficiently similar to natural infections for studying human-to-human transmission. Methods: We compared influenza A viral aerosol shedding from volunteers nasally inoculated with A/Wisconsin/2005 (H3N2) and college community adults naturally infected with influenza A/H3N2 (2012-2013), selected for influenza-like illness with objectively measured fever or a positive Quidel QuickVue A&B test. Propensity scores were used to control for differences in symptom presentation observed between experimentally and naturally infected groups. Results: Eleven (28%) experimental and 71 (86%) natural cases shed into fine particle aerosols (p<0.001). The geometric mean (geometric standard deviation) for viral positive fine aerosol samples from experimental and natural cases was 5.1E+3 (4.72) and 3.9E+4 (15.12) RNA copies/half hour, respectively. The 95th percentile shedding rate was 2.4 log10 greater for naturally infected cases (1.4E+07 versus 7.4E+04). Certain influenza-like illness related symptoms were associated with viral aerosol shedding. The almost complete lack of symptom severity distributional overlap between groups did not support propensity score adjusted shedding comparisons. Conclusions: Due to selection bias, the natural and experimental infections had limited symptom severity distributional overlap precluding valid, propensity score adjusted comparison. Relative to the symptomatic naturally infected cases, where high aerosol shedders were found, experimental cases did not produce high aerosol shedders. Studying the frequency of aerosol shedding at the highest observed levels in natural infections without selection on symptoms or fever would support helpful comparisons.