Critical evaluation on roles of macrophagic myofasciitis and aluminum adjuvants in HPV vaccine-induced adverse events

Abstract

Cervical cancer is caused by human papillomavirus (HPV) infection, which is preventable by HPV vaccines. In Japan, the HPV vaccination rate has remained extremely low due to the concerns for alleged neuropsychological symptoms or "diverse symptoms" following injections of two HPV vaccines, Cervarix and Gardasil, in HPV vaccine lawsuits. In the lawsuits, the attorneys' group has used several manuscripts proposing that aluminum (Al) adjuvant contained in HPV vaccines causes an immune-mediated disease, called macrophagic myofasciitis (MMF), as well as pathology in the central nervous system (CNS). We scientifically evaluated these manuscripts describing the "Al adjuvant-induced pathologies," particularly MMF. Although MMF patients have been reported to develop clinical symptoms/signs in various organs, including the CNS, muscle biopsy of the patients and animal experiments demonstrated that MMF pathology was localized only at the injected muscle. No muscle pathology which characterizes MMF was observed in any other muscles; thus, the systemic and neurological signs of MMF cases were irrelevant to localized MMF pathology. We evaluated that MMF-like pathology was induced as a local inflammatory response following vaccinations; MMF pathology was not the cause of systemic inflammation or "diverse symptoms." Lastly, MMF cases have been reported after vaccinations with Al-hydroxide-containing vaccines exclusively. As Al-hydroxide is a component of Cervarix, but not Gardasil, "diverse symptoms" following two HPV vaccinations in Japan cannot be explained by MMF. Our evaluation would help readers understand the validity of the manuscripts on the role of Al adjuvants or MMF for the alleged "diverse symptoms."

Keywords: family Papillomaviridae; uterine cervical neoplasms; vaccination hesitancy; vaccine adjuvants; vaccine-preventable diseases.

FIGURE 1

Scientific evaluation of macrophagic myofasciitis (MFF). Some vaccines contain aluminum (Al) hydroxide as an adjuvant, enhancing immune responses to antigens. Following intramuscular vaccination in the deltoid muscle, macrophages phagocytose Al‐adsorbed antigens and present antigens to lymphocytes. (Top) Subsequently, the local inflammation induced by the vaccination is subsided, and macrophages and a few lymphocytes could be seen as scar or a “vaccination tattoo” in the deltoid muscle. (Middle) When autoimmune diseases or microbial infections occur, pro‐inflammatory cytokine levels in sera can be increased, activating pre‐existing infiltrated macrophages in the deltoid muscle in a bystander fashion (“bystander activation”); Al‐containing activated macrophages can be observed as MMF pathology. Here, MMF is the result of systemic inflammation. (Bottom) Authier's group proposed that the vaccination with an Al‐containing vaccine causes pathological inflammation composed of macrophages with Al in the cytoplasm in the deltoid muscle by, as yet, an unknown mechanism. Although MMF pathology is localized at the deltoid, this leads to diffuse myalgia at the upper and lower extremities, and sometimes can cause autoimmune diseases, such as multiple sclerosis by, as yet, an unknown mechanism. Here, MMF is the cause of autoimmune diseases.