Letter to the Editor：大阪大学 上田豊、木村正 神経治療34: 471, 2017
大阪大学産婦人科の上田豊先生が鹿児島大学の髙嶋博先生あてにLetter to the Editorを投稿した。HPVワクチンについて興味を持つ全ての方に必読の内容です。特に次に紹介する髙嶋先生のReply内容が素晴らしい。
Letter to the Editor: Reply 鹿児島大学 髙嶋博
Japanese doctor wins global prize for standing up to anti-vaccine activists
I list the key references about the adverse events of HPV vaccination from Japan. Dr Riko Muranaka is avoiding or hiding these new findings from her writings and speech. It is not a scientific attitude, indeed.
The Clinical observational study begins at first, gathering the similar patients as many as possible to find the common features and analyze the pattern of progression , making the tentative diagnostic criteria. Furthermore, trying to make the working hypothesis of the pathogenesis of the new disease. To extend and prove the hypothesis, to establish the animal model is necessary. The study of HANS has been done in the right track as shown in the articles below.
- Hirai T et al. Adverse effects of human papilloma virus vaccination on central nervous system: Neuro-endocrinological disorders of hypothalamo-pituitary axis. The Autonomic Nervous System 53: 49 -64, 2016
- Matsudaira T, et al. Cognitive dysfunction and regional cerebral blood flow changes in Japanese females after human papillomavirus vaccination. Neurology and Clinical Neuroscience. 4: 220–227, 2016,
- Takahashi Y, et al. Immunological studies of cerebrospinal fluid from patients with CNS symptoms after human papillomavirus vaccination. Journal of Neuroimmunology. 298: 71-78, 2016
- Aratani S, et al. Murine hypothalamic destruction with vascular cell apoptosis subsequent to combined administration of human papilloma virus vaccine and pertussis toxin. Scientific Reports 6: Article number: 36943 (2016) doi:10.1038/srep36943 (Muranaka criticized this article in her facebook, that this journal is one of open access journal which everybody can publish the paper if you pay the money. She downgraded the journal of Nature publishing company. She also criticized that using the pertussis toxin was flaw to make the experimental model. This statement is clearly false, and fake, because to make EAE (experimental allergic encephalomyelitis) in mice, the use of the pertussis toxin is usual method. She lacks in the fundamental knowledge of immunology and brain science. In her commercial article which is not a peer review journal, there were many flaws, such as the description of blood-brain barrier (BBB). In detecting the antibody of undetermined origin from the serum of immunized animal, to use the normal brain of mice without considering BBB is the usual way as a first step of research. She criticized this method erroneously. )
- Beppu H et al. Lessons learnt in Japan from adverse reactions to the HPV vaccine: a medical ethics perspective. Indian J Med Ethics. 2: 82-88, 2017.
- Ozawa, K., Hineno, A., Kinoshita, T. et al. Suspected adverse effects after human papillomavirus vaccination: A temporal relationship between vaccine administration and the appearance of symptoms in Japan. Drug Saf 40: 1219, 2017. https://doi.org/10.1007/s40264-017-0574-6
- 高橋幸利、ほか：脳と自律神経の症状を呈する新病態 ヒトパピローマウイルス(子宮頸がん)ワクチン接種後にみられる中枢神経系関連症状 (特集 内科診療に潜む脳炎・脳症). 日本内科学会雑誌 106:1591-1597, 2017 （In Japanese）
A new pathological state with symptoms of the brain and autonomic nerves
- 荒田 仁:子宮頸がんワクチン接種後の神経障害【本疾患の主病態は自己免疫性の脳炎・脳症と考えられ，適切な治療が必要】No.4856 (2017年05月20日発行) P.52 (In Japanese)
- 髙嶋修、ほか：子宮頸がんワクチンに関連した自己免疫脳症。神経治療34: S1 36, 2017 (Abstract, in Japanese)
- Maki Y et al. Differential Diagnosis of Immune-Mediated Encephalopathies: “Neurological Symptoms of Diffuse Brain Damage”: A New Concept. Brain Nerve 69: 1131-1141 (In Japanese)
- Kuroiwa Y et al. Pathophysiological hypothesis for neurological disorders occurring after human papillomavirus vaccination. Neurol Med (Tokyo) 85: 567-5821, 2016 (In Japanse)
- Arata H et al. Clinical analysis of neurological symptoms in the patients with HPV vaccination. Abstract Antibody: The anti-ganglioside antibody was positive in 38 %(13/34), and movement disorders were noted in 85 %(11/13) of positive patients. The anti-gAchR antibody was positive in 26% (9/35), and autonomic nervous system disorders were observed in 89%(8/9) of positive patients. The anti-GluR antibody in the CSF was positive in 78 %(7/9). Epidermal nerve fiber density analysis: 17 out of 32 patients showed reduction of the intraepidermal nerve fiber.Treatment: IAPP (TR350) was effective in 15 of 23 patients with movement disorders (mRS score>2). Azathioprine was used to suppress recurrence and often effective. Incidence rate was 1/1500. From World Congress of Neurology held in Kyoto, 2017 Muranaka: “I realized the HPV vaccine issue was the atomic bomb threatening thousands and millions of lives. But I tell you, I have never written recommending this vaccine.”
Her description of HPV vaccine issue was the atomic bomb is improper, because, there are benefits as well as risks from those suffering from adverse reactions. “I have never written recommending this vaccine” is a false statement. She made a HPV vaccine promotion in the invited lectures elsewhere in Japan. By writing there was no adverse reactions indirectly support the safety of the vaccine and recommend the vaccine.
She nominated the name to the mother whose daughter is suffering as monster mother, and also indicated her as Munchhausen syndrome by proxy. Muranaka got the personal information illegally from patient girl.
(Riko Muranaka: HPV vaccine and monster mother
Riko Muranaka: Radiation and HPV vaccine
Document of accusation from the attorney of the illegally contacted girl’s mother)
“However, while misleading images and stories of so-called the dangers of the HPV vaccine was spread through Japanese society by the media, Dr. Shuichi Ikeda, principal researcher of the group commissioned by the Ministry of Health Labour and Welfare to investigate adverse reactions of the HPV vaccine, and professor of neurology at Shinshu University, presented the shocking results of a mouse experiment at the meeting in the Ministry.
He showed a slide with only the brain section of a mouse marked “HPV” glowing in green florescence, emphasized with a white circle. Dr. Ikeda said: “Apparently, the brain is damaged. It shows the objective findings common to the girls complaining of brain damage.” According to Dr. Ikeda, when mice were given the flu vaccine, the Hepatitis B vaccine and the HPV vaccine, and the brain was observed 10 months later, only the brain section of the mouse vaccinated with the HPV vaccine showed “deposition” with abnormal auto-antibody. His presentation was broadcast on a popular TV news program.”
A: Her statement was wrong. At the meeting of the Ministry, the serum from immunized with HPV vaccine stained the hippocampus of normal mouse brain. This experiment was done by the researcher in the Department of Gynecology of Shinshu University. In closed research meeting, the professor of the Department of Gynecology reported the study. Dr Ikeda borrowed the one slide to make the presentation in public meeting. There was misunderstanding between him and TV media. TV media broadcasted the misinformation, the brain of mice immunized by the HPV vaccine showed the damage. Instead, there was the antibody in the immunized mice to bind to the hippocampus of normal mice, identified as anti-GM1 antibody.
Ref. The progress meeting of HPV vaccine injected mice. One slide was used in the public presentation, without fabrication.
“After months of investigation, I found the researcher who designed and performed the mouse experiment. He told me that the brain sections Dr. Ikeda showed were not from the injected mouse. They had injected vaccines into genetically modified mice that produce auto-antibody naturally just by aging. Then they sprayed the serum taken from these mice, full of auto-antibody, to the brain sections of the normal wild-type mouse and took a picture.”
As she did not attend the public presentation meeting, she misunderstood the procedure and results of the experiment. The use of genetically modified mice that are prone to produce autoantibody is reasonable way to get the autoantibody easily. The serum from control group did not bind to the hippocampus of normal brain.
“The number of mice used for each vaccine was only “one”, and the dose given was 100 times that normally given to humans. Of course, there were brain sections showing green florescence by serum from the mouse given other vaccines, too. “
“I called the result presented by Dr. Ikeda a “fabrication”.”
The experiment was preliminary study and only presented in the closed research group meeting. The study was of course not published in peer review journal, and further study was necessary to elucidate the pathomechanism. The dose of 100 times was usual way to make the experimental model. The last part that green florescence by serum from the mouse given other vaccines was a fake, because, the outside inquiry committee concluded that there was no fabrication.
Ref. There was no fabrication in the study of HPV vaccine
“Dr. Ikeda filed a libel lawsuit against me, claiming my allegation of fabrication was defamation because he had just cited a slide from the slide set that other researchers made. Dr. Ikeda’s attorney said this lawsuit is not about the science of the HPV vaccine, but my allegation of fabrication. This attorney is famous for leading many major drug injury lawsuits for the plaintiffs in Japan in the past.”
As I stated before, she fabricated the facts, not Dr Ikeda. And so, it is matter of course that she was filed a libel lawsuit for defamation.
“Meanwhile, the Global Advisory Committee on Vaccine Safety at the World Health Organization, where I used to work, has no doubt about the safety of this vaccine:
Their new evaluation statement issued this year ended like this.
“Despite the extensive safety data available for this vaccine, attention has continued to focus on spurious case reports and unsubstantiated allegations. The Committee continues to express concern that the ongoing unsubstantiated allegations have a demonstrable negative impact on vaccine coverage in a growing number of countries, and that this will result in real harm. While ongoing monitoring and collection of robust data are important to maintain confidence, one of the challenges associated with the continued generation of data is that artifacts will be observed, which could pose further challenges for communication when taken in haste, out of context, and in the absence of the overall body of evidence.””
- WHO adopted only the articles of clinical trials of RCT having high level of evidence. The observational case series studies were rejected, because low level of evidence. However, the frequency of adverse reaction was low and is approximately 0.09% in Japan, and serious adverse reactions were 0.05%. The discovery of the signal is difficult in clinical trials in small number of subjects from several hundreds to several thousands. Thus, post-marketing observational case series study becomes important (The frequency of adverse reactions of autoimmune encephalitis was 1/1500 in Kagoshima in Japan.)
- In the clinical trial of RCT, there were very few studies using the saline which is inactive placebo. In most placebos, aluminum adjuvants were used and it was hard to detect the significant difference between each group because the adjuvants group tends to show adverse reactions. Those connected with Cochrane Library are beginning to plan the inquiry to this point.
- We cannot judge various symptoms in combination in the current standard of the study. They examine a single symptom for comparison. A large number of observational case studies are important to analyze the rare serious adverse reactions.
- CAUSALITY ASSESSMENT OF AN ADVERSE EVENT FOLLOWING IMMUNIZATION (AEFI) User manual for the revised WHO classification WHO/HIS/EMP/QSS. MARCH 2013
With inadequate or incomplete data, an AEFI can be deemed unclassifiable. However, it should also be noted that AEFI causality may be indeterminate due to lack of clear evidence for a causal link, or conflicting trends, or inconsistency with causal association to immunization. It is nevertheless important not to disregard the above reports of AEFI because at some point they may be considered a signal and may lead to hypotheses regarding a link between a vaccine and the event in question, with specific studies designed to test for a causal association. Pooling of data on individual cases is very helpful in generating hypotheses.
- Ogawa Y et al. Safety of HPV vaccines in healthy young women: a meta-analysis of 24 controlled studies, J Pharmaceutical Health Care and Sciences 2017 3:18 https://doi.org/10.1186/s40780-017-0087-6
Table1. The number of subjects in 20 reports were less than 4,000 (100～500 subjects in 9 reports、500～1,000 subjects in 4 reports、1,000～2,000 subjects in 5 reports、2,000～3,000 subjects in 1 report、3,000～4,000 subjects in 1 report、more than 5,000 in 4 reports（5,762、6004、12,167、18,644）
- Chandler, R.E. Safety Concerns with HPV Vaccines Continue to Linger: Are Current Vaccine Pharmacovigilance Practices Sufficient? Drug Saf 2017. https://doi.org/10.1007/s40264-017-0593-3
- Jefferson T, Jørgensen L. Human papillomavirus vaccines, complex regional pain syndrome, postural orthostatic tachycardia syndrome, and autonomic dysfunction – a review of the regulatory evidence from the European Medicines Agency. Indian J Med Ethics 2017; 2:30–37.
- Hendrickson JE, et al. Human papilloma virus vaccination and dysautonomia: consideration for autoantibody evaluation and HLA typing. Vaccine 2016; 34:4468.
- Palmieri B, et al: Severe somatoform and dysautonomic syndromes after HPV vaccination: case series and review of literature. Immunol Res. 2016. doi:10.1007/s12026-016-8820-z.
- Geier DA, Geier MR. Quadrivalent human papillomavirus vaccine and autoimmune adverse events: a case-control assessment of the vaccine adverse event reporting system (VAERS) database. Immunol Res. 2016. doi:10.1007/s12026-016-8815-9.
- Blitshteyn S, Brook J: Postural tachycardia syndrome (POTS) with anti-NMDA receptor antibodies after human papillomavirus vaccination. Immunol Res (2016) DOI 10.1007/s12026-016-8855-1
- Inbar R et al: Behavioral abnormalities in female mice following administration of aluminum adjuvants and the human papillomavirus (HPV) vaccine Gardasil. Immunol Res (2016). doi:10.1007/s12026-016-8826-6
- Martínez-Lavín M. Hypothesis. Human papillomavirus vaccination syndrome — small fiber neuropathy and dysautonomia could be its underlying pathogenesis. Clin Rheumatol. 2015; 34:1165-1169.
- Kinoshita T, et al. Peripheral sympathetic nerve dysfunction in adolescent Japanese girls following immunization with the human papillomavirus vaccine. Intern Med. 2014; 53:2185-2200.
- Blitshteyn S. Postural tachycardia syndrome following human papillomavirus vaccination. Eur J Neurol. 2014; 21:135-139.
- Sobue group report of the epidemiology about the various symptoms after HPV vaccination. Look at pp42. (Written in Japanese)
- Hama R. Harm assessment of HPV vaccine and“frailty exclusion bias” or“healthy vaccinee effect”: A theoretical basis and practical influences on Nagoya City Study Nagoya City Study of HPV vaccine
http://www.npojip.org/chk_tip/No65-file06.pdf (In Japanese)
• It is highly suspected that the interim report of Nagoya City Survey indicates harmful effect of HPV vaccines.
• We recommend that Nagoya City withdraw the interim report and disclose raw data
so that the third party could analyse the data.
• We also recommend that Nagoya City itself reanalyse the data by appropriate methods. English)
- “National epidemiological survey” Lawyer comment on additional analysis results.
- Martínez-Lavín M et al. Serious adverse events after HPV vaccination: a critical review of randomized trials and post-marketing case series. Clinical Rheumatolog36: 2169–78, 2017
The safety issues about vaccines are common, and the investigators who report the adverse reaction of vaccine are jeopardized as shown in the articles below. The articles by Muranaka acted to kick off the academic position of Dr Ikeda and the one who carried out the mice experiment, under the lawsuit to maintain the position in the university.
- Bragazzi NL et al. Debate on vaccines and autoimmunity: Do not attack the author, yet discuss it methodologically. Vaccine 35: 5522-6, 2017
- Vernon LF. How Silencing of dissent in science impacts woman. The Gardasil® Story. Advances in Sexual Medicine 7: 179-204, 2017