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Review of a published report of cerebral vasculitis after vaccination with the Human Papillomavirus (HPV) Vaccine

November 9, 2012

Recently there was discussion on a federally-sponsored vaccine safety listserv of a report in the literature of cerebral vasculitis after vaccination with the Human Papillomavirus Vaccine (HPV) (Tomljenovic L, Shaw CA. Death after Quadrivalent Human Papillomavirus (HPV) Vaccination: Causal or Coincidental?  Pharmaceutical Regulatory Affairs: Open Access 2012,S12:001).  To address questions about the findings and conclusions reported in this manuscript, CDC convened a CDC-Clinical Immunization Safety Assessment (CISA) working group. Researchers from Vanderbilt Medical Center, Johns Hopkins University, Columbia University, Duke Clinical Research Institute (Duke University), CDC and FDA participated in the call.  Participants have expertise in vaccine safety, infectious diseases, clinical medicine, pathology, and laboratory science.

In the Tomljenovic manuscript, the authors present two cases of young women who died in presumed association with the human papillomavirus (HPV) vaccine. The first case was a 19-year-old woman who died in her sleep 6 months after receiving the 3rd dose of quadrivalent human papillomavirus vaccine (HPV4) vaccine.  Autopsy revealed no abnormalities.  The second case was a 14-year-old girl who developed migraines, weakness, and confusion two weeks following the 1st dose of HPV4 vaccine.  She recovered, but was found unconscious 15 days after the 2nd dose of HPV4 vaccine, having suffered a cardiac arrest.  An autopsy was performed that demonstrated hypoxic-ischemic encephalopathy secondary to cardiac arrest.

The authors report immunohistochemical (IHC) results on formalin-fixed, paraffin-embedded, autopsy brain tissue from these two cases.  They interpret the results as demonstrating an autoimmune cerebral vasculitis with HPV-16L1 vaccine particles within the cerebral vasculature.   Based on this interpretation, the authors conclude that these cases represent HPV-16L1 vaccine particle-induced cerebral vasculitis.  They further suggest that many adverse events reported through the Vaccine Adverse Event Reporting System (VAERS) may actually be a result of previously undiagnosed cerebral vasculitis.

On review, the CDC-CISA working group identified scientific concerns with the article, primarily, interpretation of histopathology and immunopathology methods. These concerns negate the authors’ conclusions and significantly limit any interpretation of the results shown in the paper.  Below we describe key limitations in this publication:

  1. Lack of validity for the diagnosis of vasculitis: The histologic diagnosis of vasculitis requires demonstration of an inflammatory infiltrate within the vessel wall that is associated with destructive changes (Ref: Practical Neurology 2002, 2, 80-93). These changes would be visible with standard hematoxylin and eosin (H&E) stain. None of the illustrated H&E or immunohistochemical images demonstrate an inflammatory infiltrate or vascular damage. The only finding illustrated is the presence of hemorrhage, commonly seen in autopsy specimens. Hence, there is insufficient evidence presented in this publication to support the diagnosis of vasculitis in the two fatal case reports.
  2. Questionable immunohistochemical methods: Many details of the immunohistochemical staining are not provided, including the characterization of the antibody clones, the isotypes of the antibody, and the specific details of the blocking procedures. Appropriate negative controls were lacking from the IHC methodology; these should include a negative antibody control (omission of primary antibody or non-immune serum) and use of negative tissue samples. Specificity of the primary antibodies in formalin-fixed, paraffin-embedded tissues is not demonstrated and cannot be assumed. The specificity of the staining methods the authors used has not been established, and there are many examples of cross-reactive immunostaining methods that result in false positive tests. Having a clear measurement of the specificity of the IHC tests noted in the article is critical to interpretation of results.
  3. Flawed interpretation of immunohistochemical results: The publication describes the presence of HPV-16L1 particles within the cerebral vasculature with some HPV-16L1 particles within the blood vessel walls. Viral particles, including HPV particles, are so small that they cannot be visualized by light microscopy; rather, electron microscopy (EM) would be required to identify viral particles. The authors do not report methods or data suggesting that EM was performed on any of the specimens. The authors only describe findings from IHC staining for the two case-patient autopsy specimens. No IHC staining results are described for control specimens. Without appropriate controls the clinical importance of finding positive IHC results cannot be determined.
  4. Lack of information about potential alternative causes of death: There are insufficient clinical and autopsy data provided in the article to assess potential alternative causes of death in each case.

The working group also reviewed information from the Vaccine Adverse Event Reporting System (VAERS) database, available medical records, and the medical literature.  A single VAERS death report of cerebral vasculitis was found in a 37-year-old female with immunodeficiency and multiple medical problems who had received HPV4 vaccine 45 days earlier.

A review of published medical literature revealed a single report of two cases of vasculitis after HPV vaccine; however, both were associated with Henoch-Schonlein Purpura and neither had cerebral vasculitis (Rheumatology (Oxford). 2012 Aug 9. “Vasculitis following HPV immunization”.  Melo Gomes S, Glover M, Malone M, Brogan P).  Review of post-licensure VAERS surveillance data, as reported by Slade et al, revealed no concerning signals for HPV vaccine-associated vasculitis (Slade BA, Leidel L, Vellozzi C et al. Postlicensure safety surveillance for the quadrivalent human papillomavirus recombinant vaccine. JAMA 2009;302:750).

Assessment: After thorough review and discussion of the Tomljenovic article, the CDC-CISA working group identified substantial methodological concerns and lack of evidence to support the authors’ conclusions that the two patients had vasculitis, that HPV4 vaccine particles were in the brain tissue, or that HPV vaccine was causally associated with death from cerebral vasculitis.

Disclaimer: The information and conclusions in this report are those of the work group participants addressing this issue and do not necessarily represent the official position of CDC.

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