Modulation of Disease, T Cell Responses, and Measles Virus Clearance in Monkeys Vaccinated with H-Encoding Alphavirus Replicon Particles

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...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 102; no. 33; pp. 11581 - 11588
Main Authors Pan, Chien-Hsiung, Valsamakis, Alexandra, Colella, Teresa, Nair, Nitya, Adams, Robert J., Polack, Fernando P., Greer, Catherine E., Perri, Silvia, Polo, John M., Griffin, Diane E.
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 16.08.2005
National Acad Sciences
SeriesInaugural Article
Subjects
Aging - physiology
Alphavirus
Alphavirus - genetics
Alphavirus - physiology
Animals
Antibodies
Antibodies, Viral - immunology
Biological Sciences
Dosage
Female
Hemagglutinins, Viral - genetics
Hemagglutinins, Viral - immunology
Infections
Interferon-gamma - biosynthesis
Interferon-gamma - immunology
Macaca
Macaca - immunology
Macaca - virology
Measles
Measles - immunology
Measles - virology
Measles Vaccine - chemistry
Measles Vaccine - genetics
Measles Vaccine - immunology
Measles virus
Measles virus - immunology
Measles virus - physiology
Mice
Mice, Inbred BALB C
Neutralizing antibodies
Replicon
RNA
RNA, Viral - genetics
Sindbis virus
T lymphocytes
T-Lymphocytes - immunology
Vaccination
Virion - genetics
Virion - immunology
Virus Replication
Viruses
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Summary: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 106or 108SIN-H particles and infant macaques with two doses of 108particles. A dose of 108particles induced sustained levels of high-titered, MV-neutralizing antibody and IFN-γ-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-γ-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.
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Present address: Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287.
Contributed by Diane E. Griffin, June 2, 2005
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.
This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected on April 20, 2004.
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@jhsph.edu.
Author contributions: C.-H.P. and D.E.G. designed research; C.-H.P., A.V., T.C., N.N., and F.P.P. performed research; C.-H.P., A.V., T.C., N.N., and D.E.G. analyzed data; C.E.G., S.P., and J.M.P. contributed new reagents/analytic tools; R.J.A. was the primate veterinarian who did all the monkey studies; and D.E.G. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0504592102