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.
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.
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.
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.