Comparative Cytokine and Histology Studies on HPV and Other Viral Vaccinations: No Pathogenicity of HPV Vaccine Adjuvants.

In Japan, neuropsychological symptoms after human papillomavirus (HPV) vaccinations were publicized as "adverse effects," leading to vaccine hesitancy. Anti-vaccine activists claimed that adjuvants in HPV vaccines could cause an immune-mediated neurological disease. Adjuvants in the bivalent HPV vaccine (2vHPV) and quadrivalent HPV vaccine (4vHPV) are AS04 [composed of aluminum (Al) hydroxide (AH) and monophosphoryl lipid A (MPL)] and Al hydroxyphosphate sulfate (AHS), respectively. We determined whether HPV vaccinations in mice could reproduce alleged immunopathology. We injected mice intramuscularly with 2vHPV, 4vHPV, two hepatitis B virus vaccines containing AH or AHS, or a varicella-zoster virus vaccine (vVZV) containing an adjuvant AS01 (comprising MPL and QS-21). Histologically, 12 weeks after vaccinations, all four Al-containing vaccine groups had Al-laden macrophage accumulation at the injected muscle; no groups had abnormalities in any other organs, including the brain, heart, liver, and kidney. Immunologically, although the four Al-containing vaccine groups had continuously increased levels of several cytokines, including interferon (IFN)-β, cytokine profiles were not associated with muscle pathology. No groups exhibited any clinical signs, except for the vVZV group, which lost body weight temporarily following each injection. Weight loss in the vVZV group was associated with increased levels of cytokines, including interleukin (IL)-18. Experiments using IL-18 receptor-deficient mice and AS01 injection alone demonstrated that IL-18 and AS01 contributed to weight loss. Since 2vHPV containing AS04 (AH and MPL) did not induce weight loss, QS-21, but not MPL, in AS01 seemed responsible for weight loss, demonstrating the safety of MPL.