Mucosal immunization strategies are actively being pursued in the hopes of improving the efficacy of vaccines against the influenza virus. Our group investigated the oral immunization of mice via intragastric gavage with influenza hemagglutinin (HA) combined with mutant Escherichia coli heat-labile enterotoxins K63 (LT-K63) and R72 (LT-R72). These oral immunizations resulted in potent serum antibody and HA inhibition titers, in some cases stronger than those obtained with traditional intramuscular administration, in addition to HA-specific immunoglobulin A in the saliva and nasal secretions. This study demonstrates that it may be possible to develop effective oral influenza vaccines.Influenza is a serious human disease exhibiting high mortality in vulnerable populations such as the very young and the very old, as well as causing significant morbidity in the general population (17). The social and economic costs associated with yearly influenza outbreaks are high (7). Formalin-inactivated whole-virus and split-virus vaccines administered intramuscularly (i.m.) are commercially available to control the spread and severity of influenza (15,38). These prophylactic vaccines, although important agents in controlling influenza, suffer from a number of shortcomings that limit their efficacy and acceptability. Notably, inactivated whole-virus and split-virus vaccines are known to activate CD8 ϩ cytotoxic T-lymphocyte responses only sporadically, have poor cross-reactivity to antigenic variants, and produce poor secretory immunoglobulin A (IgA) responses (4,7,17,24,34,36). In addition, injection site reactogenicity and weak immune responses can be a problem in very young children (18,19). Significant efforts are currently being pursued to improve the vaccines' efficacy and tolerability primarily through the development of mucosally active influenza vaccines (2,7,10,33,40). Oral immunization is considered by many to be a highly desirable form of vaccination, although numerous obstacles make oral immunization using subunit antigens a significant challenge (3, 6, 11). Many approaches have been investigated to develop viable orally active influenza vaccines (3,21,29,30). Mucosal adjuvants, primarily Escherichia coli heat-labile enterotoxin (LT) and cholera toxin (CT), are the most commonly employed vaccine enhancers (11,12). Although potent mucosal adjuvants, LT and CT are toxic in humans at doses useful for adjuvanticity due to their ADPribosyltransferase activity (28). The nontoxic B subunit of CT (CTB) has also been investigated; however, studies have indicated that small amounts of the whole CT are required for sufficient adjuvant potency, inhibiting the potential of CTB in humans (44,45,46). Our group has investigated the mutant LT toxins LT-K63 and LT-R72, which demonstrate extremely low (LT-R72) to undetectable (LT-K63) levels of ADP-ribosyltransferase activity yet maintain potent mucosal adjuvant activity, demonstrating that ADP-ribosyltransferase activity may not be linked to the adjuvant activity (2, 13, 16). In thi...

Immunization of mice by the intranasal route with influenza virus hemagglutinin in combination with the mutant Escherichia coli heat-labile enterotoxin R72 (LT-R72) induced significantly enhanced serum and mucosal antibodies, surpassing, in most cases, responses achieved by traditional intramuscular immunization using inactivated split influenza vaccine. Furthermore, intranasal immunization with LT-R72 induced a potent serum immunoglobulin G2a response, indicating that this adjuvant has Th1 character.

No abstract

No abstract