Clinical studies have indicated that subvirion
inactivated vaccines against
avian influenza viruses, particularly H5N1, are poorly immunogenic in humans. As a consequence, the use of adjuvants has been championed for the efficient vaccination of a naïve population against
avian influenza.
Aluminum salts (
alum) and the oil-in-water
emulsion MF59 are safe and effective adjuvants that are being used with
influenza vaccines, but the mechanism underlying their stimulation of the immune system remains poorly understood. It was shown recently that activation of a cytosolic innate immune-sensing complex known as "NLR-Pyrin domain containing 3" (NLRP3)
inflammasome, also known as "cryopyrin," "cold-induced autoinflammatory syndrome 1" (CIAS1), or nacht domain-,
leucine-rich repeat-, and PYD-containing
protein 3 (Nalp3), is essential for the adjuvant effect of
alum. Here we show that the
inflammasome component apoptosis-associated speck-like
protein containing a caspase recruitment domain (ASC), an adapter
protein within the NLRP3
inflammasome, is a crucial
element in the adjuvant effect of
MF59 when combined with H5N1
subunit vaccines. In the absence of ASC, H5-specific
IgG antibody responses are significantly reduced, whereas the responses are intact in NLRP3(-/-) and
caspase-1(-/-) mice. This defect is caused mainly by the failure of
antigen-specific B cells to switch from
IgM to
IgG production. We conclude that ASC plays an
inflammasome-independent role in the induction of
antigen-specific humoral immunity after vaccination with MF59-adjuvanted
influenza vaccines. These findings have important implications for the rational design of next-generation adjuvants.