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Infection and Immunity, November 1999, p. 5841-5847, Vol. 67, No. 11
0019-9567/99/$04.00+0

Native and Mutant Forms of Cholera Toxin and Heat-Labile Enterotoxin Effectively Enhance Protective Efficacy of Live Attenuated and Heat-Killed Shigella Vaccines

Antoinette B. Hartman,1,* Lillian L. Van De Verg,2,dagger and Malabi M. Venkatesan1

Department of Enteric Infections1 and Department of Bacterial Diseases,2 Walter Reed Army Institute of Research, Washington, D.C. 20307-5100

Received 22 April 1999/Returned for modification 1 July 1999/Accepted 20 August 1999

Both native and mutant forms of cholera toxin (CT) and heat-labile enterotoxin (LT) are effective adjuvants for antigens and killed whole-cell preparations. To determine whether these toxin molecules could also boost the immunogenicity and efficacy of live attenuated vaccines directed against shigellosis, the guinea pig keratoconjunctivitis model was used to evaluate the adjuvant effect of these toxin molecules on EcSf2a-3, a Delta virG Delta aroD Escherichia coli-Shigella flexneri 2a hybrid vaccine strain that was previously found to be less protective than its parent strain in the guinea pig model. Experiments using native and mutant toxin molecules showed that both CT and LT and mutant derivatives were effective as an adjuvant for EcSf2a-3 and that the mutant toxin molecules, which were developed to retain adjuvanticity without the toxicity associated with the native molecules, were as effective as the native toxin molecules as adjuvants. Protective efficacy was enhanced for both the oral and intranasal routes of immunization. Serum antibody response to the S. flexneri 2a O antigen, the primary antigen for protective immunity, was not dependent on the addition of an adjuvant. However, enumeration of the O-antigen-specific immunoglobulin G (IgG) and IgA antibody-secreting cells in the spleen and draining lymph nodes following intranasal immunization suggested that enhancement of the local immune response by the toxin molecules may contribute to the observed increase in protective efficacy. The efficacy of heat-killed S. flexneri 2a was enhanced only by mutant LT molecules. These results suggest that the best candidates for enhancing the efficacy of both live attenuated and heat-killed Shigella vaccines with minimal reactogenicity are the mutant toxin molecules.

* Corresponding author. Mailing address: Department of Enteric Infections, Walter Reed Army Institute of Research, Bldg. 503, Washington, DC 20307-5100. Phone: (301) 319-9518. Fax: (301) 319-9801. E-mail: Antoinette.Hartman{at}army.mil.

dagger Present address: Joint Vaccine Acquisition Program, Ft. Detrick, MD 21702-5041.

Infection and Immunity, November 1999, p. 5841-5847, Vol. 67, No. 11
0019-9567/99/$04.00+0


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