Genetically detoxified mutants of heat‐labile enterotoxin from Escherichia coli are effective adjuvants for induction of cytotoxic T‐cell responses against HIV‐1 gag‐p55

Abstract

There is an urgent need for prophylactic and therapeutic vaccines against human immunodeficiency virus (HIV). Mucosal immunization strategies have great potential to elicit both mucosal and systemic cellular immunity required to protect against HIV-induced acquired immune deficiency syndrome (AIDS). However, mucosal immunizations with soluble protein antigens generally require adjuvants. In this study, we tested two mutants of the heat-labile enterotoxin (LT) from Escherichia coli, LTK63: with no measurable ADP-ribosyltransferase activity, and LTR72: with residual ADP-ribosyltransferase activity, as mucosal adjuvants for induction of cytotoxic T lymphocyte (CTL) responses to coadministered HIV gag p55 protein. We found that intranasal (i.n.) immunizations with HIV gag p55 protein coadministered with LTK63 or LTR72 induced systemic CTL responses comparable to that obtained following intramuscular (i. m.) immunizations with the same adjuvants. Moreover, oral coadministration of LTR72, but not LTK63, resulted in local as well as systemic p55-specific CTL responses in mesenteric lymph nodes (MLN) and spleens (SP) of the immunized mice. These data have important implications for current efforts to develop a safe vaccine against HIV.

Delivery strategies to enhance oral vaccination against enteric infections

“…In preclinical intranasal studies, whole cell mucosal vaccines adjuvanted with LT mutants led to protection against challenge with the mucosal pathogens Bordetella pertussis [124] and Streptococcus pneumoniae [125]. Additionally, oral and intranasal administration of a human immunodeficiency virus (HIV)-1 p55 gag subunit vaccine adjuvanted with LT mutants elicited strong cytotoxic T cell responses [126]. However, when tested in clinical trials, despite lacking all enzymatic activity [123], Bell's Palsy was documented in a small number of patients receiving an LTK63 adjuvanted intranasal vaccine [36].…”

Approach to discover T- and B-cell antigens of intracellular pathogens applied to the design of Chlamydia trachomatis vaccines

“…BALB/c mice were immunized i.m. with randomly selected two-antigen combinations in the presence of the Th1 adjuvant LTK63+CpG (29,30). Two weeks after the last immunization, mice were given 10 3 EBs, and IFUs were counted in lung homogenates 10 d after challenge.…”

Mucosal Administration of Ag85B-ESAT-6 Protects against Infection withMycobacterium tuberculosisand Boosts Prior Bacillus Calmette-Guérin Immunity

“…LTK63 has been shown to behave as a strong mucosal adjuvant in a number of animal models, when coadministered with recombinant proteins or synthetic peptides, and has been shown to prime both Ag-specific CD4 and CD8 T cells (11)(12)(13). In various studies, coadministration with candidate vaccines enhanced the cytotoxic T cell response to HIV gag-p55 (14) and respiratory syncytial virus matrix proteins (12), increased the protective efficacy of the VacA protein of Helicobacter pylori lysate (15), and induced Abs to tetanus toxin when delivered transcutaneously (16). Delivery via the respiratory tract improves the efficacy of the group C meningococcal conjugate vaccine (17), enhances immunity to the SAG1 Ag of Toxoplasma gondii (18), and induces Th1 immunity to Bordetella pertussis (19).…”