Virus Shedding from the nasal mucosa is closely correlated with illness severity in the Human Viral Challenge Model

September 12, 2014 2:44 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, in this study we analysed the placebo data from several previously conducted clinical trials which occurred over multiple quarantines in a purpose built facility designed for the conduct of such trials. Importantly the volunteers are isolated from each other in individual en suite negative pressure rooms, rather than on open wards common to phase I units. Strict infection control procedures were followed  during the trials to prevent cross infection with the challenge virus between volunteers and importantly the accidental introduction of another virus into the unit from a staff member or volunteer.

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 thus allowing a detailed analysis of viral replication and its relationship to the signs and symptoms of illness over time.

Here we present data from healthy volunteers inoculated with a wild type strain of influenza (A/Wiscconsin/67/2005, H3N2) that was manufactured under GMP conditions and had previously been assessed extensively by ourselves for safety, pathogenicity and virulence.

We found that there was a strong temporal correlation between virus replication in the nasal mucosa and the severity of symptoms when plotted over time. Primarily we observed upper respiratory tract symptoms as expected with this model. Physician directed examination were not particularly revealing.

Importantly we observed these very similar results over multiple studies and for different influenza viruses.

In conclusion;

  • The severity of infection as determined by virus shedding is directly related to the severity of illness as determined by the self-reported symptoms of volunteers in the Human Viral Challenge Model.
  • Upper respiratory tract symptoms are primarily observed in the Human Viral Challenge Model, however mild lower respiratory tract symptoms are also observed.

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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