Background. Innate immunity, including Toll-like receptor (TLR)–mediated expression of the B7 costimulatory molecules CD80 and CD86, is critical for vaccine immunity. We examined whether CD80 and CD86 expression vary with aging and predict response to the trivalent inactivated influenza vaccine.

Methods. One hundred sixty-two subjects between 21 and 30 years of age (the young group) or⩾65 years of age (the older group) enrolled before vaccination. We determined TLR-induced monocyte CD80/CD86 expression by flow cytometry and vaccine antibody responses by hemagglutination inhibition.

Results. The mean increase in TLR-induced CD80⁺ monocytes was reduced in older, compared with young, adults by 68% (P = .0002), and each decile increase of CD80⁺ cells was associated with an 8.5% increase in mean number of vaccine strains with a⩾4-fold titer increase (P = .01 ) and a 3.8% increase in mean number of strains with a postvaccine titer⩾1:64 (P = .037 ). Each decile decrease of CD86⁺ cells was associated with an 11% increase in the mean number of strains with a 4-fold increase (P = .002) and a 3.9% increase in the mean number of strains with a postvaccine titer⩾1:64 (P = .07).

Conclusions. CD80 and CD86 expression on activated monocytes is highly associated with influenza vaccine response. This approach prospectively identifies adults unlikely to respond to immunization who may benefit from alternative vaccines or antiviral prophylaxis during influenza outbreaks.