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Inaugural Article
MICROBIOLOGY
Modulation of disease, T cell responses, and measles virus clearance in monkeys vaccinated with H-encoding alphavirus replicon particles

Chien-Hsiung Pan ^*, Alexandra Valsamakis ^* , Teresa Colella ^* , Nitya Nair ^*, Robert J. Adams , Fernando P. Polack ^*, ¶, Catherine E. Greer ^||, Silvia Perri ^||, John M. Polo ^||, and Diane E. Griffin ^*, **

^*W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205; Departments of Comparative Medicine and ^¶Pediatrics, The Johns Hopkins University School of Medicine, Baltimore, MD 21218; and ^||Chiron Corporation, Emeryville, CA 94608

Contributed by Diane E. Griffin, June 2, 2005

Measles remains a major worldwide problem partly because of difficulties with vaccination of young infants. New vaccine strategies need to be safe and to provide sustained protective immunity. We have developed Sindbis virus replicon particles that express the measles virus (MV) hemagglutinin (SIN-H) or fusion (SIN-F) proteins. In mice, SIN-H induced high-titered, dose-dependent, MV-neutralizing antibody after a single vaccination. SIN-F, or SIN-H and SIN-F combined, induced somewhat lower responses. To assess protective efficacy, juvenile macaques were vaccinated with a single dose of 10⁶ or 10⁸ SIN-H particles and infant macaques with two doses of 10⁸ particles. A dose of 10⁸ particles induced sustained levels of high-titered, MV-neutralizing antibody and IFN--producing memory T cells, and most monkeys were protected from rash when challenged with wild-type MV 18 months later. After challenge, there was a biphasic appearance of H- and F-specific IFN--secreting CD4⁺ and CD8⁺ T cells in vaccinated monkeys, with peaks 1 and 3–4 months after challenge. Viremia was cleared within 14 days, but MV RNA was detectable for 4–5 months. These studies suggest that complete clearance of MV after infection is a prolonged, phased, and complex process influenced by prior vaccination.

cellular immunity | interferon- | vaccine | protective immunity

This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected on April 20, 2004.

Abbreviations: EIA, enzyme immunoassay; F, fusion; H, hemagglutinin; i.d., intradermal; MV, measles virus; PBMC, peripheral blood mononuclear cell; SFC, spot-forming cells; SINV, Sindbis virus; SIN-H, SINV replicon to express MV protein H; SIN-F, SINV replicon to express MV protein F; ELISPOT, enzyme-linked immunospot; GMT, geometric mean titer; N, nucleoprotein.

See accompanying Profile on page 11578.

Present address: Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287.

Present address: Sterne Kessler Goldstein and Fox, 1100 New York Avenue NW, Washington, DC 20005.

^** To whom correspondence should be addressed at: The Johns Hopkins Bloomberg School of Public Health, 615 North Wolfe Street, Room E5132, Baltimore, MD 21205. E-mail: dgriffin{at}jhsph.edu.

© 2005 by The National Academy of Sciences of the USA

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Profile of Diane E. Griffin

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PNAS 2005 102: 11578-11580. [Extract] [Full Text]  

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				C.-H. Pan, N. Nair, R. J. Adams, M. C. Zink, E.-Y. Lee, F. P. Polack, M. Singh, D. T. O'Hagan, and D. E. Griffin Dose-Dependent Protection against or Exacerbation of Disease by a Polylactide Glycolide Microparticle-Adsorbed, Alphavirus-Based Measles Virus DNA Vaccine in Rhesus Macaques Clin. Vaccine Immunol., April 1, 2008; 15(4): 697 - 706. [Abstract] [Full Text] [PDF]

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				A. V. E. Capozzo, K. Ramirez, J. M. Polo, J. Ulmer, E. M. Barry, M. M. Levine, and M. F. Pasetti Neonatal Immunization with a Sindbis Virus-DNA Measles Vaccine Induces Adult-Like Neutralizing Antibodies and Cell-Mediated Immunity in the Presence of Maternal Antibodies J. Immunol., May 1, 2006; 176(9): 5671 - 5681. [Abstract] [Full Text] [PDF]

				N. Zagorski Profile of Diane E. Griffin PNAS, August 16, 2005; 102(33): 11578 - 11580. [Full Text] [PDF]

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