Determination of the virulence of the pigmentation-deficient and pigmentation-/plasminogen activator-deficient strains of Yersinia pestis in non-human primate and mouse models of pneumonic plague
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Abstract
The current human plague vaccine, a killed Yersinia pestis whole-cell preparation,
does not protect against aerosol challenge and is reactogenic and antigenically undefined.
Live attenuated Y. pestis, such as pigmentation-deficient (Pgm-) strains, have been
used frequently as vaccines and are efficacious. They are used widely in plague research
and assumed to be safe. However, they can cause serious adverse reactions, and their
aerosol infectivity is not known. We tested the virulence of a defined Pgm- variant
of the C092 strain of Y. pestis in mouse and non-human primate models of pneumonic
plague. The ten-fold lower median lethal dose by the aerosol compared to the subcutaneous
(s.c.) routes of the Pgm- strain in mice suggested that the Pgm- strain might be less
attenuated by the former than by the latter route. After exposure of 16 African green
monkeys to inhaled doses ranging from 1.1 x 10(4) to 8.1 x 10(7)cfu, eight died and
eight survived. The terminal cultures collected from five of the non-survivors were
all positive for Y. pestis. Two of the remaining three non-survivors were culture-negative
but had pathologic and immunologic evidence of infection with Y. pestis, specimens
could not be obtained nor the cause of death determined for the third one. The deaths
were not dose-related, and there were some differences in the pathology associated
with infection by the Pgm- strain compared to the wild-type (wt) strain. However,
the Pgm- derivative was clearly virulent for monkeys by the aerosol route. A mutant
of the Pgm- strain, which has a deletion in the plasminogen activator (Pla) virulence
locus (pla), appeared to be more attenuated than was either the Pgm- single mutant
(in NHPs and mice) or the Pla- single mutant strain (in mice) and has potential as
a live vaccine.