Heterologous Prime-Boost strategies using live-attenuated and viral vector vaccines to combat pneumonic plague

Mice immunized with a 2-dose strategy utilizing either 2-doses of an adenovirus vector (Ad5-YFV) or a heterologous strategy utilizing Ad5-YFV and a live-attenuated (LMA) vaccine were evaluated for protective efficacy against pneumonic plague. A single immunization event giving both Ad5-YFV and LMA at once was also tested as a potential strategy for use during an outbreak when quick protective immunity is desired. While the Ad5-YFV vaccine harbors a fusion cassette of three genes encoding YscF, F1, and LcrV, LMA represents a mutant of parental Yersinia pestis CO92 deleted for genes encoding Lpp, MsbB, and Ail. Ad5-YFV and LMA were either administered simultaneously (1-dose regimen) or 21 days apart in various order and route of administration combinations (2-dose regimen). The 2-dose regimen induced robust immune responses to provide full protection to animals against parental CO92 and its isogenic F1 (CAF-)-deletion mutant challenges during both short- and long-term studies. While all of these approaches were completely protective, differences in the immune phenotype of these mice were observed based on which vaccine was given first. Mice intranasally (i.n.) immunized with Ad5-YFV first followed by LMA (i.n. or intramuscularly [i.m.]) had higher T- and B- cell proliferative responses and LcrV antibody titers than those in mice vaccinated with LMA (i.n. or i.m.) first ahead of Ad5-YFV (i.n.) during the long-term study. Mice immunized with Ad5-YFV first had the highest levels of T and B-cell replication. Mice immunized first with LMA had the strongest Th17 phenotypes. In addition, when Ad5-YFV was given as the first dose, mice had a Th1 favored response while when LMA was given first, a more balanced phenotype of Th1, Th2, and Th17 responses were seen. There are different advantages in vaccine administration based on the different combinations as well. The 2-dose vaccination strategy would be ideal for regions where plague is endemic and yearly outbreaks occur like in Madagascar. An intranasal only administration strategy eliminates the use of needles. The simultaneous administration strategy would be ideal for use in an outbreak response scenario where high levels of protection generated in the shortest time would be ideal.