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Clinical and Vaccine Immunology, July 2008, p. 1042-1053, Vol. 15, No. 7
1071-412X/08/$08.00+0     doi:10.1128/CVI.00397-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Correlation of Cellular Immune Responses with Protection against Culture-Confirmed Influenza Virus in Young Children

Bruce D. Forrest,^1* Michael W. Pride,¹ Andrew J. Dunning,^1, Maria Rosario Z. Capeding,² Tawee Chotpitayasunondh,³ John S. Tam,^4, Ruth Rappaport,¹ John H. Eldridge,¹ and William C. Gruber¹

Wyeth Vaccines Research, 401 N. Middletown Road, Pearl River, New York 10960,¹ Research Institute for Tropical Medicine, Muntinlupa City, Philippines,² Queen Sirikit National Institute of Child Health, Bangkok, 10400, Thailand,³ Chinese University of Hong Kong, Hong Kong SAR, China⁴

Received 1 October 2007/ Returned for modification 2 November 2007/ Accepted 10 January 2008

The highly sensitive gamma interferon (IFN-) enzyme-linked immunosorbent spot (ELISPOT) assay permits the investigation of the role of cell-mediated immunity (CMI) in the protection of young children against influenza. Preliminary studies of young children confirmed that the IFN- ELISPOT assay was a more sensitive measure of influenza memory immune responses than serum antibody and that among seronegative children aged 6 to <36 months, an intranasal dose of 10⁷ fluorescent focus units (FFU) of a live attenuated influenza virus vaccine (CAIV-T) elicited substantial CMI responses. A commercial inactivated influenza virus vaccine elicited CMI responses only in children with some previous exposure to related influenza viruses as determined by detectable antibody levels prevaccination. The role of CMI in actual protection against community-acquired, culture-confirmed clinical influenza by CAIV-T was investigated in a large randomized, double-blind, placebo-controlled dose-ranging efficacy trial with 2,172 children aged 6 to <36 months in the Philippines and Thailand. The estimated protection curve indicated that the majority of infants and young children with 100 spot-forming cells/10⁶ peripheral blood mononuclear cells were protected against clinical influenza, establishing a possible target level of CMI for future influenza vaccine development. The ELISPOT assay for IFN- is a sensitive and reproducible measure of CMI and memory immune responses and contributes to establishing requirements for the future development of vaccines against influenza, especially those used for children.

Published ahead of print on 30 April 2008.

Present address: Sanofi Pasteur, Discovery Drive, Swiftwater, PA 18370.

Present address: Wyeth Vaccines Research, 401 N. Middletown Road, Pearl River, NY 10960.