title: Dose-dependent protection against or exacerbation of disease by a polylactide glycolide microparticle-adsorbed, alphavirus-based measles virus DNA vaccine in rhesus macaques.
abstract: Measles remains an important cause of vaccine-preventable child mortality. Development of a low-cost, heat-stable vaccine for infants under the age of 6 months could improve measles control by facilitating delivery at the time of other vaccines and by closing a window of susceptibility prior to immunization at 9 months of age. DNA vaccines hold promise for development, but achieving protective levels of antibody has been difficult and there is an incomplete understanding of protective immunity. In the current study, we evaluated the use of a layered alphavirus DNA/RNA vector encoding measles virus H (SINCP-H) adsorbed onto polylactide glycolide (PLG) microparticles. In mice, antibody and T-cell responses to PLG-formulated DNA were substantially improved compared to those to naked DNA. Rhesus macaques received two doses of PLG/SINCP-H delivered either intramuscularly (0.5 mg) or intradermally (0.5 or 0.1 mg). Antibody and T-cell responses were induced but not sustained. On challenge, the intramuscularly vaccinated monkeys did not develop rashes and had lower viremias than vector-treated control monkeys. Monkeys vaccinated with the same dose intradermally developed rashes and viremia. Monkeys vaccinated intradermally with the low dose developed more severe rashes, with histopathologic evidence of syncytia and intense dermal and epidermal inflammation, eosinophilia, and higher viremia compared to vector-treated control monkeys. Protection after challenge correlated with gamma interferon-producing T cells and with early production of high-avidity antibody that bound wild-type H protein. We conclude that PLG/SINCP-H is most efficacious when delivered intramuscularly but does not provide an advantage over standard DNA vaccines for protection against measles.
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, 615 N. Wolfe St., Baltimore, MD 21205, USA.
authors.forename: Chien-Hsiung
authors.initials: CH
authors.lastname: Pan
authors.forename: Nitya
authors.initials: N
authors.lastname: Nair
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Adams
authors.forename: M Christine
authors.initials: MC
authors.lastname: Zink
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Lee
authors.forename: Fernando P
authors.initials: FP
authors.lastname: Polack
authors.forename: Manmohan
authors.initials: M
authors.lastname: Singh
authors.forename: Derek T
authors.initials: DT
authors.lastname: O'Hagan
authors.forename: Diane E
authors.initials: DE
authors.lastname: Griffin
mesh_terms: D000818:Animals; D000917:Antibody Formation; D002522:Chlorocebus aethiops; D004306:Dose-Response Relationship, Immunologic; D004333:Drug Administration Routes; D005260:Female; D005822:Genetic Vectors / Q000235:genetics; D007111:Immunity, Cellular; D019344:Lactic Acid / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D008253:Macaca mulatta; D008457:Measles / Q000276:immunology / Q000517:prevention & control; D008458:Measles Vaccine / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D008459:Measles virus / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D011091:Polyesters / Q000737:chemistry / Q000494:pharmacology*; D011100:Polyglycolic Acid / Q000737:chemistry / Q000494:pharmacology*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D012845:Sindbis Virus / Q000235:genetics*; D019444:Vaccines, DNA / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology*; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D008458:Measles Vaccine; D011091:Polyesters; D019444:Vaccines, DNA; D014764:Viral Proteins; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C033616:poly(lactide)