new future anthrax vaccine candidates

[Guest guest]

This is the way to properly develop an anthrax vaccine, by actually

studying immunogenicy and duration of immunity in animal models before

trying random vaccine candidates in expensive, dangerous, and time-

consuming human trials.--Nass

Vaccine. 2007 Dec 26 [Epub ahead of print]

Selection and evaluation of the immunogenicity of protective

antigen mutants as anthrax vaccine candidates.

Yan M, Roehrl MH, Basar E, Wang JY.

Channing Laboratory, Department of Medicine, Brigham and Women's

Hospital, Harvard Medical School, 181 Longwood Avenue, Boston, MA

02115, United States.

Protective antigen (PA) is a central component of anthrax toxin

and a major antigen in anthrax vaccines. However, the use of native PA

as a vaccine is not optimal. If administered to people who have been

freshly exposed to anthrax, PA may actually aid in anthrax toxin

formation and thus may pose a serious safety concern for postexposure

vaccination applications. A non-functional PA mutant may be a much

safer alternative. To identify an improved anthrax vaccine antigen, we

examined four non-functional mutants of PA, each being impaired in a

critical step of the cellular intoxication pathway of PA. These

mutants were Rec(-) (unable to bind PA-receptors), SSSR (resistant to

activation by furin), Oligo(-) (unable to form oligomers), and DNI

(Dominant Negative Inhibitory, unable to form endosomal transmembrane

pores). When tested in mice and after three doses of immunization, all

four mutants were highly potent in eliciting PA-specific, toxin-

neutralizing antibodies, with immunogenicity increasing in the order

of PA<Rec(-)<SSSR<Oligo(-)<DNI. While the differences between Rec(-)

or SSSR and PA were small and not statistically significant, DNI and

Oligo(-) were significantly more immunogenic than wild-type PA. One

year after immunization and compared with PA-immunized mice, DNI-

immunized mice maintained significantly higher levels of anti-PA IgG

with correspondingly higher titers of toxin-neutralizing activity. In

contrast, Oligo(-)-immunized mice had high levels of anti-PA IgG but

lower titers of toxin-neutralizing activity, suggesting that Oligo(-)

mutation sites may overlap with critical protective epitopes of PA.

Our study demonstrates that PA-based vaccines could be improved both

in terms of safety and efficacy by strategic mutations that not only

render PA non-functional but also simultaneously enhance its

immunogenic potency. Recombinant PA mutants, particularly DNI, hold

great promise as better and safer antigens than wild-type PA for use

in postexposure vaccination.

PMID: 18192092

Meryl Nass, MD

Mount Desert Island Hospital

Bar Harbor, Maine 04609

207 288-5081 ext. 220

http://anthraxvaccine.blogspot.com

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