Safety and immunogenicity of an influenza vaccine A/H5N1 (A/Vietnam/1194/2004) when coadministered with a heat-labile enterotoxin (LT) adjuvant patch.

Background: The use of adjuvants to enhance the immune response to novel pandemic influenza vaccine candidates may overcome the poor immune responses seen in immunologically naïve populations. The confluence of a highly pathogenic H5N1 influenza virus and the widespread absence of pre-existing immunity has driven the search for effective strategies for immunization in the face of a lethal pandemic. The potent adjuvant, heat labile enterotoxin from E. coli (LT), placed over the immunization site in a patch, is a novel adjuvant strategy for immune enhancement, and was evaluated using an H5N1 injectable vaccine.

Methods: In this observer-blind, placebo-controlled clinical study, 500 healthy adults 18-49 years of age were randomized to receive two intramuscular doses of A/Vietnam/1194/2004 A/H5N1 vaccine (5microg, 15microg or 45microg) or placebo (saline) 21 days apart. For each of the influenza vaccine doses, a 50microg LT adjuvant patch was applied over the injection site at either the second or both immunizations and the HI responses (titers) were compared to H5N1 vaccine alone. The study's primary endpoint was safety, and secondary immunogenicity endpoints were evaluated using European (CHMP) licensure criteria.

Results: The vaccine was safe and well tolerated, and subjects generally lacked pre-existing H5N1 immunity. The single-dose injection 45microg HA/LT patch regimen met all CHMP licensure criteria, including a 73% seroprotection rate compared to 49% seroprotection without a patch. Significant adjuvant effects were seen at all HA doses on Day 21. By contrast, only modest adjuvant effects were observed with the boosting regimen in subjects first primed with H5N1 alone and given the adjuvant patch only on the second immunization. The two-injection/two-patch 45microg HA regimen achieved significantly higher titers and GMFR compared to injection alone (GMFR 33.1 vs. 16.9, HI 226 vs. 94, p<0.05) and a 94% seroprotection rate.

Conclusions: The LT adjuvant patch placed over the injection site was safe, significantly enhanced the immune response to an H5N1 candidate vaccine, and achieved a 73% seroprotection rate after a single dose. The LT adjuvant patch has more modest benefits in recently primed populations similar to other candidate vaccine adjuvants, but a two-dose patch plus injection regimen resulted in robust HI responses.