A nontoxic derivative of lipopolysaccharide increases immune responses to Gardasil® HPV vaccine in mice

Human papillomavirus (HPV) is the causative agent of cervical cancer, the second most common cause of cancer death in women worldwide. The licensed HPV vaccine Gardasil® from Merck & Co. is a quadrivalent vaccine containing virus-like particles (VLPs) of the L1 proteins from HPV types 6, 11, 16, and 18 adsorbed on aluminum salts (alum). CIA07 is an immunostimulatory agent comprised of bacterial DNA fragments (CIA02) and a nontoxic derivative of lipopolysaccharide (CIA05) that has been shown to have antitumor activity and adjuvant activity for viral and bacterial vaccine antigens. We investigated whether these CIAs are capable of promoting the immune response to Gardasil®. Balb/c mice were immunized intramuscularly twice three weeks apart with 1/20 human dose of Gardasil® alone or in combination with CIA02, CIA05 or both, and immune responses were assessed. The serum anti-HPV16 L1 VLP IgG antibody titer was significantly higher in mice administered CIA05 or CIA05 plus CIA02, but not in those given CIA02, compared with mice given Gardasil® alone. A secreted alkaline phosphatase (SEAP)-based pseudovirus neutralization assay showed increased neutralizing antibody titers in both CIA05 and CIA05 plus CIA02 groups. Coadministration of CIA05 with Gardasil® led to a marked increase in serum IgG2a antibody titer and the percentage of interferon (IFN)-γ+ cells in the spleen, indicating that CIA05 effectively promotes Th1-type immune responses. These data indicate that CIA05, in synergy with alum, enhances the immune response to HPV L1 VLPs and suggest its potential as an adjuvant for the development of a potent prophylactic HPV vaccine.