Using the Human Viral Challenge Model to design subsequent field based studies

September 12, 2014 2:54 pm

Robert Lambkin-Williams, Alex Mann, Andrew Catchpole and Anthony Gilbert, Retroscreen Virology Limited

The Human Viral Challenge Model of infection provides a unique experimental opportunity whereby healthy human volunteers are inoculated at a defined time point with a wild type, attenuated virus under controlled conditions (1,2,3). This has enhanced our understanding of how respiratory viruses like influenza behave under such conditions. The model allows us to examine a number of other parameters related to experimental infection and disease severity using subjective [self-reported symptom diary card scores(SDC)], and objective (spirometry, vital signs) measures and their temporal relationship to viral shedding (2, 3).

As part of a programme to develop the Human Viral Challenge Model we have conducted a retrospective analysis of data from our own and other groups’ studies to understand how results from such studies can be used to better design subsequent field based studies.

The Human Viral Challenge Model is unique in that the exact time of exposure to virus is known and sampling can be timed as required along with recording of volunteer self-reported symptoms and physician directed physical examination, this allows for a detailed analysis of viral replication and its relationship to the signs and symptoms of illness over time and thus gives the opportunity to evaluate the efficacy of novel antivirals and vaccines. The FDA has described the model as useful to assist the design of subsequent field studies and specifically possible doses of the vaccine or antiviral and the dosing regimen.

As a group we have inoculated over 1200 volunteers with several different influenza viruses, Respiratory Syncytial Virus and Human Rhinovirus, previously other groups have conducted similar research.

We found that the Human Viral Challenge Model has demonstrated utility in guiding the design of subsequent field trials conducted by other groups. In addition the model has been useful in better understanding the immune response to influenza at a humoral and cellular level, correlates of protection and the possible mechanisms of action of novel antiviral compounds or vaccines.

In conclusion;

  • The Human Viral Challenge Model can provide useful guidance for the subsequent design of larger field based studies.
  • By its nature the model allows for the detailed examination of the mode of action of novel antivirals or vaccines with the ability of to take multiple samples from volunteers under controlled conditions.
  • The Human Viral Challenge Model has been shown to be predictive of the results of subsequent field based studies in several case studies.

 

NOTE: This study was part of a programme of work to develop the various outcomes used to evaluate both infection and illness in the Human Viral Challenge Model.  The results of other studies investigating subjective and objective measures have also been submitted as abstracts to this conference.

 

 

REFERENCES

1:A host transcriptional signature for presymptomatic detection of infection in humans exposed to influenza H1N1 or H3N2.

Woods CW, McClain MT, Chen M, Zaas AK, Nicholson BP, Varkey J, Veldman T, Kingsmore SF, Huang Y, Lambkin-Williams R, Gilbert AG, Hero AO 3rd, Ramsburg E, Glickman S, Lucas JE, Carin L, Ginsburg GS. PLoS One. 2013;8(1):e52198. doi: 10.1371/journal.pone.0052198. Epub 2013 Jan 9.

2: Preexisting influenza-specific CD4+ T cells correlate with disease protection against influenza challenge in humans.

Wilkinson TM, Li CK, Chui CS, Huang AK, Perkins M, Liebner JC, Lambkin-Williams R, Gilbert A, Oxford J, Nicholas B, Staples KJ, Dong T, Douek DC, McMichael AJ, Xu XN. Nat Med. 2012 Jan 29;18(2):274-80. doi: 10.1038/nm.2612.

3: Viral load drives disease in humans experimentally infected with respiratory syncytial virus.DeVincenzo JP, Wilkinson T, Vaishnaw A, Cehelsky J, Meyers R, Nochur S, Harrison L, Meeking P, Mann A, Moane E, Oxford J, Pareek R, Moore R, Walsh E, Studholme R, Dorsett P, Alvarez R, Lambkin-Williams R.Am J Respir Crit Care Med. 2010 Nov 15;182(10):1305-14. doi: 10.1164/rccm.201002-0221OC. Epub 2010 Jul 9.

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