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.

Generation of a More Immunogenic Measles Vaccine by Increasing Its Hemagglutinin Expression

“…The variable presence of maternal antibodies is the hurdle to overcome to reduce measles mortality among the very young. The use of DNA vaccines (38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50); non-MV vectors expressing H, F, and/or N (51-57); immune-stimulating complexes incorporating the H and F proteins (57); or a combination of these strategies (58) has been proposed. Vaccination by these methods presumably avoids inhibition by maternal antibodies, and some of these vaccines have indeed proven protective when administered to infant macaques with circulating maternal antibodies.…”

Antibody-Mediated Protection against Mucosal Simian-Human Immunodeficiency Virus Challenge of Macaques Immunized with Alphavirus Replicon Particles and Boosted with Trimeric Envelope Glycoprotein in MF59 Adjuvant

“…Most importantly, recombinant alphaviruses provide a platform that has been shown to elicit protec- tive Ab responses against many diverse pathogens in preclinical models (15,22,36,44,48). In one key example, protection of both juvenile and infant rhesus macaques against measles virus was achieved after a single intradermal dose of recombinant VEE/SIN VRP expressing measles virus hemagglutinin (35).…”

“…The chimeric (VEE/SIN) alpha-virus vector system used in this study was derived from Venezuelan equine encephalitis virus (VEE) and the Sindbis virus (SIN). The recombinant VEE, SIN, and Semliki viruses expressing SIV or HIV antigens as well as antigens from a diverse and growing list of pathogens have been evaluated extensively in animals by several groups (6,15,16,17,22,32,34,35,36,38,42,44,57,58). The chimeric alphavirus replicon particles (VRP) used here were designed to combine the immune potency of the VEE replicon with the safety profile of the SIN structural proteins (38).…”

A Chimeric Alphavirus Replicon Particle Vaccine Expressing the Hemagglutinin and Fusion Proteins Protects Juvenile and Infant Rhesus Macaques from Measles

“…Tissues were embedded in paraffin, sectioned, and stained with hematoxylin and eosin. MV-infected cells were identified using a mouse monoclonal antibody to the MV N protein (Chemicon), horseradish peroxidase (HRP)-conjugated rabbit anti-mouse IgG (Dako) and diaminobenzidine (DAB) as previously described (43).…”