Attenuated Salmonella enterica Serovar Typhi and Shigella
flexneri 2a Strains Mucosally Deliver DNA Vaccines Encoding Measles Virus
Hemagglutinin, Inducing Specific Immune Responses and Protection in Cotton Rats.
Pasetti MF, Barry EM, Losonsky G, Singh M, Medina-Moreno SM, Polo JM, Ulmer
J, Robinson H, Sztein MB, Levine MM.
Center for Vaccine Development. Departments of Pediatrics. Medicine, University
of Maryland School of Medicine, Baltimore, Maryland. Chiron Vaccines,
Emeryville, California. Vaccine Center, Emory University, Atlanta, Georgia.
Measles remains a leading cause of child mortality in developing countries.
Residual maternal measles antibodies and immunologic immaturity dampen
immunogenicity of the current vaccine in young infants. Because cotton rat
respiratory tract is susceptible to measles virus (MV) replication after
intranasal (i.n.) challenge, this model can be used to assess the efficacy of MV
vaccines. Pursuing a new measles vaccine strategy that might be effective in
young infants, we used attenuated Salmonella enterica serovar Typhi CVD 908-htrA
and Shigella flexneri 2a CVD 1208 vaccines to deliver mucosally to cotton rats
eukaryotic expression plasmid pGA3-mH and Sindbis virus-based DNA replicon
pMSIN-H encoding MV hemagglutinin (H). The initial i.n. dose-response with
bacterial vectors alone identified a well-tolerated dosage (1 x 10(9) to 7 x
10(9) CFU) and a volume (20 micro l) that elicited strong antivector immune
responses. Animals immunized i.n. on days 0, 28, and 76 with bacterial vectors
carrying DNA plasmids encoding MV H or immunized parenterally with these naked
DNA vaccine plasmids developed MV plaque reduction neutralizing antibodies and
proliferative responses against MV antigens. In a subsequent experiment of
identical design, cotton rats were challenged with wild-type MV 1 month after
the third dose of vaccine or placebo. MV titers were significantly reduced in
lung tissue of animals immunized with MV DNA vaccines delivered either via
bacterial live vectors or parenterally. Since attenuated serovar Typhi and S.
flexneri can deliver measles DNA vaccines mucosally in cotton rats, inducing
measles immune responses (including neutralizing antibodies) and protection,
boosting strategies can now be evaluated in animals primed with MV DNA vaccines.
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