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and plasticity inherent in
E. coli
genomes (
Rasko et al., 2008
) combined
within complete protection afforded by LT and poor inherent immunogenicity
of ST peptides have hampered progress toward a broadly protective vaccine
.
This strategy has been further confounded by lack of identifiable CF antigens
in a significant proportion of strains (
Peruski et al., 1999
), and both geo-
graphic and temporal variation in prevalent CF antigens (
Isidean et al., 2011
).
In addition, epidemiologic studies which affirm a significant protective effect
following natural ETEC infections, suggest that LT and other unexplored
antigens rather than CFs (
Steinsland et al., 2003
) may stimulate protective
immune responses. An oral vaccine consisting of recombinant cholera toxin
B subunit combined with a mixture of killed ETEC expressing a variety of
CF antigens induced immune responses to CFs, afforded protection against
severe diarrheal illness from ETEC in travelers (
Sack et al., 2007
), but failed
to protect children in endemic areas (
Walker et al., 2007
), despite immunoge-
nicity (
Savarino et al., 2002
). Similarly, a compilation of three live-attenuated
strains expressing six different CF antigens (
Turner et al., 2011
) and LTB
elicited substantial immune responses to target antigens in volunteers (
Harro
et al., 2011b
), but offered only modest protection in clinical challenge studies
(NCT01060748). Remarkably, transcutaneous immunization (TCI) with
heat-labile toxin has been shown to elicit significant immune responses to
LT in volunteer studies (
Frech et al., 2008
), and to co-immunogens in experi-
mental animal studies (
Yu et al., 2002
). Although the protective efficacy of LT
patch-based TCI in subsequent clinical trials was disappointing (
McKenzie
et al., 2007
;
Svennerholm and Lundgren, 2012
), this strategy could prove
useful in subsequent iterations of ETEC vaccines that incorporate additional
antigens. Collectively, these studies indicate that anti-CF and/or anti-LT
immunity may not offer sufficiently robust protection, and that additional
antigens coupled with technology to generate safe and effective ST toxoids
(
Taxt et al., 2010
) may need to be incorporated in future ETEC vaccine devel-
opment strategies.
CONCLUSIONS
Although ETEC were discovered now more than 40 years ago (
Sack, 2011
), our
current understanding of the pathogenesis of these important pathogens remains
insufficient, and ideal approaches to vaccine development are still not completely
defined. Despite the inherent plasticity of these pathogens recent discoveries of
relatively conserved novel virulence factors should afford additional avenues for
investigation and approaches to development of an effective vaccine.
REFERENCES
Escherichia coli
diarrhea in a pediatric cohort in a periurban area of lower Egypt. J. Infect. Dis.
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