Novel targets and compositions for use in decontamination, immunoprophylaxis, and post-exposure therapy against anthrax

Abstract

The present invention relates to the decontamination of anthrax spores, prophylaxis and treatment of anthrax infections and, more particularly, to compounds that act as specific inhibitors of B. anthracis germination / outgrowth-associated proteins, methods and means for making such inhibitors and their use as pharmaceuticals and / or vaccines. The invention also relates to the prophylaxis and treatment of anthrax infections and, more particularly, to vaccines and compositions that comprise B. anthracis antigens, epitopes, proteins, or nucleic acid molecules, including anthrax protective antigen, anthrax lethal factor, anthrax edema factor and anthrax proteins associated with spore germination and outgrowth, as well as methods and means for making such compositions and their use pharmaceuticals and / or vaccines.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application 60 / 486,369 filed Jul. 11, 2003. Reference is also made to the following jointly-owned applications and patents: U.S. patent application Ser. No. 10 / 346,021 filed Jan. 16, 2003, which is a continuation-in-part of U.S. patent application Ser. No. 10 / 116,963, filed Apr. 5, 2002, which is a continuation-in-part of U.S. patent application Ser. No. 10 / 052,323, filed Jan. 18, 2002, which is a continuation-in-part of U.S. patent application Ser. No. 09 / 563,826, filed May 3, 2000 (issued Feb. 19, 2002 as U.S. Pat. No. 6,348,450), which claims priority from U.S. Provisional Application No. 60 / 132,216, filed May 3, 1999, and is also a continuation-in-part of U.S. patent application Ser. No. 09 / 533,149, filed Mar. 23, 2000, which in turn is a continuation of U.S. patent application Ser. No. 09 / 402,527, filed on Aug. 13, 2000. Each of these above-referenced applications and each of the...

AI Technical Summary

Benefits of technology

[0047] Accordingly, it is an object of the invention described herein to provide compositions that are capable of precisely targeting B. anthracis spore proteins without producing significant undesirable side effects.

[0050] Both non-invasive vaccination onto the skin (NIVS) and intranasal application can improve vaccination schemes because skin and nasal mucosa are immunocompetent tissues and this non-invasive procedure requires no specially trained personnel. Skin-targeted non-invasive gene delivery can achieve localized transgene expression in the skin and the elicitation of immune responses (Tang 1997). These results indicate that vector-based NUVS is a novel and efficient method for the delivery of vaccines. The simple, effective, economical and painless immunization protocol of the present invention should make vaccination less dependent upon medical resources and, therefore, achieve vaccination of large numbers of individuals against anthrax in a timely manner by non-medical personnel.

Problems solved by technology

Naturally occurring human cases of anthrax are invariably zoonotic in origin, with no convincing data to suggest that human-to-human transmission has ever taken place.

Due to the rapidly fatal hemorrhagic mediastinitis caused by inhalation of anthrax spores, the dissemination of airborne spores in a populated area could be devastating.

Germination is thought to take place in macrophages, and toxin release results in edema and tissue necrosis but little or no purulence, probably because of inhibitory effects of the toxins on leukocytes.

Transport to mesenteric or other regional lymph nodes and replication occur, resulting in dissemination, bacteremia, and a high mortality rate.

Bacteremia occurs, and death soon follows.

Penicillin resistance remains extremely rare in naturally occurring strains; however, the possibility of resistance should be suspected in a biological warfare attack.

The more severe forms require intensive supportive care and have a high mortality rate despite optimal therapy.

However, one significant limitation on the use of vaccines is that existing vaccines provide no protection against a number of strains of B. anthracis.

This vaccine also has several undesirable side effects and unknown efficacy (Demicheli 1998).

Dispersal experiments with the simulant Bacillus globigii in the New York subway system in the 1960s suggested that release of a similar amount of B. anthracis during rush hour would result in 10,000 deaths.

The dissemination of an odorless and invisible aerosol containing PA-free anthrax spores encoding exogenous toxins would be devastating, as all PA-targeted anthrax vaccines (Price 2001; Welkos 2001; Joellenbeck 2002; Rhie 2003; Tan 2003) and remedies (Sellman 2001) are ineffective in protection against anthrax strains without PA.

Furthermore, although targeting PA has proven effective to varying degrees of success in counteracting anthrax, it is unknown at this time whether any of the PA-targeted methods can protect humans against inhalational anthrax (Inglesby 2002) during a massive onslaught with airborne anthrax spores used as a bioweapon.

Both approaches required the disruption of E. coli cells prior to inoculation into animals, in conjunction with subsequent extraction and purification of recombinant protein and DNA, respectively; it is hazardous to inject undisrupted E. coli cells into humans as a vaccine due to the presence of endotoxin.

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