Validation of a Wild-Type Influenza A Human Challenge Model: H1N1pdMIST, An A(H1N1)pdm09 Dose Finding IND Study

NIH Researchers Establish Human Model of H1N1 Flu Infection

In 2013, NIH researchers reported the initial results of a clinical study assessing H1N1 flu infection in healthy volunteers. The volunteers were infected with escalating doses of flu virus and monitored at the NIH Clinical Center.

The latest study reports how flu symptoms, virus levels, and immune responses correlate. The researchers established the optimal dose needed to induce mild-to-moderate illness and noted that symptoms appeared after viral shedding occurred, meaning that people may be infectious before flu symptoms develop.

The results of this study promises to improve the design of future flu research and clinical trials.

Validation of a Wild-Type Influenza A Human Challenge Model: H1N1pdMIST, An A(H1N1)pdm09 Dose Finding IND Study

1. Matthew J. Memoli1,*, 
2. Lindsay Czajkowski1, 
3. Susan Reed1, 
4. Rani Athota1, 
5. Tyler Bristol1,
6. Kathleen Proudfoot1, 
7. Sarah Fargis1, 
8. Matthew Stein1, 
9. Rebecca L. Dunfee1, 
10. Pamela A. Shaw2,
11. Richard T. Davey3, and 
12. Jeffery K. Taubenberger1

+Author Affiliations

1. ¹Viral pathogenesis and Evolution Section, Laboratory of Infectious Diseases National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 USA
2. ²Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 USA
3. ³Clinical Research Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892 USA

1. ↵*Corresponding Author: Matthew J. Memoli, M.D., M.S. Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MSC 3203 33 North Dr. Bethesda, MD 20892-3203, Phone: 301-443-5971, Email: memolim@niaid.nih.gov

1. Alternate Corresponding Author: Jeffery Taubenberger, MD, PhD, Section Chief, Viral Pathogenesis and Evolution Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, MSC 3203 33 North Dr. Bethesda, MD 20892-3203, Phone: 301-443-5960, Email: taubenbergerj@niaid.nih.gov

Abstract

Background. Healthy volunteer wild-type influenza challenge models offer a unique opportunity to evaluate multiple aspects of this important virus. Such studies have not been performed in the U.S. in over a decade, limiting our capability to investigate this virus and develop countermeasures. We have completed the first ever wild-type influenza A challenge study under an IND. This dose finding study will lead to further development of this model both for A(H1N1)pdm09 and other strains of influenza.

Methods. Volunteers were admitted to an isolation unit at the NIH Clinical Center for a minimum of 9 days. A reverse genetics, cell-based, GMP produced, wild-type A(H1N1)pdm09 virus was administered intranasally. Escalating doses were given until a dose was reached that produced disease in a minimum of 60% of volunteers.

Results. An optimal dose of 10⁷ TCID50 was reached which caused mild to moderate influenza disease in 69% of individuals with mean viral shedding for 4-5 days and significant rises in convalescent influenza antibody titers. Viral shedding preceded symptoms by 12-24 hours and terminated 2-3 days prior to symptom resolution, indicating that individuals may be infectious before symptom development. As expected nasal congestion and rhinorrhea were most common, but interestingly, fever was observed in only 10%.

Conclusion. This study represents the first healthy volunteer influenza challenge model using a GMP-produced wild-type virus under an IND. This unique clinical research program will facilitate future studies of influenza pathogenesis, animal model validation, and the rapid, efficient, and cost-effective evaluation of efficacy of novel vaccines and therapeutics.

• Received July 8, 2014.
• Accepted October 19, 2014.

• Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014. This work is written by (a) US Government employee(s) and is in the public domain in the US.