2014年2月26日 The Public Hearing on Adverse Events following HPV vaccine in Japan
Koji Nabae: We’d like to start. Let us start our discussion on HPV vaccine.
So I’d like to thank the doctors for coming despite your very busy schedules.
Now concerning the introduction of the experts, in the interest of time, we’ll not be introducing them. So please refer to their resumes. And concerning the observation, please make sure that you abide by the rules for observation.
Now I’d like to ask Mr. Sato to say a few words in greeting.
Toshinobu Sato: Good morning, ladies and gentlemen. Thank you very much for coming despite your busy schedule. I belong to a major dep. of Bureau. I am Director General of Health Service Bureau including infectious disease and public health. My name is Toshinobu Sato, how do you do?
So we only have limited time today. So by way of a greeting, I would like to talk about the objectives of holding this meeting today.
To begin with, the HPV vaccine when it comes to the immunization there are various opinions, various cases were reported for adverse reactions. And in the side effect committee for immunization, has been gathering information and various assessments have been conducted by the expert panel. As you know, in December and January in the latest meetings, sufficient discussion was held based upon the gathered information. And as for the cases with side effect the overall picture was illustrated and understood. During that time WHO and the international organizations and foreign authorities have announced statements of safety of the vaccine. And so with regards to the vaccine safety, I think it is almost quite clear.
However, even having said that, there are some concerns and researchers saying that HPV vaccine and the adjuvant that is used together with that, originates specific mechanism. And because of this specific mechanism, the local symptoms as well as the brain and CNS, there is the immunological abnormality that occurs that leads to certain symptoms and certain serious adverse reactions.
We don’t think this is widely received and understood and supported around the world. But these are health-related issues, and also we need to be cautious in considering these various issues and proposals and ideas.
So initially when it comes to these opinions, we think of hearing them in the subcommittee for the adverse reactions of vaccines. But there is some inconvenience in holding that meeting. And also because the subcommittee cannot handle this issue, they had private view exchange meeting held under my authority, the director now of the health service bureau.
And as you see in the material how we predict that there will be very technical matters discussed. So we have very centered actual experts in this field here today. And the chairman would be Professor Kurane of the NIID who is an expert in this field as well.
We only have limited time as I said. So please make your statements concise and easy to understand. And if necessary, we’d like to hold a discussion at the end. And we hope for your consideration and cooperation for the smooth running of the meeting.
As for today’s content, in the adverse reaction subcommittee, Professor Kurane would message the gist of the content to the subcommittee. I ask for your input and for fruitful running of the meeting. Thank you.
Koji Nabae: Thank you very much. As mentioned by Mr. Sato, today’s chairman will be Dr. Ichiro Kurane from the National Institute of Infectious Diseases.
Very sorry concerning the camera recording, we would like to ask you to stop now. We ask for your cooperation.
Koji Nabae: Dr. Kurane, please.
Ichiro Kurane: Good morning. Thank you very much for nominating me as the chair. My name is Kurane from the National Institute of Infectious Diseases. From the secretariat we’d like to ask you to confirm the handout.
Koji Nabae: Materials at hand are first the agenda, second the list of distributed documents, third the names and resumes and forth the seating chart, and also the materials 1 through 5 as well as some reference material. If you do not have any, please inform the staff.
Ichiro Kurane : If everything is okay, then now let us start.
Very limited time, so I would like all these speakers to keep the given time. And by that way, we can finish according to the schedule. First, I’d like to invite Dr. Sin Hang Lee.
Koji Nabae: Together we have Dr. Sin Hang Lee, Dr. Francois-Jerome Authier, and Dr. Harumi Sakai. We would like to ask them to present for 10 minutes each. And from the experts there will be comments to each of the presentations. The time is very limited. So one minute before the time allotted we will ring the bell. So once the bell is rung, we’d like to ask the presenter to wrap up within one minute.
Today we have English and Japanese simultaneous translation. So please use the headphones as necessary. Thank you.
Ichiro Kurane: Well, Dr. Lee, please.
Sin Hang Lee : Thank you very much, ladies and gentlemen. I’m very honored to be asked here to testify in the public hearing. My name is Dr. Sin Hang Lee. I am a former associate professor of pathology at university. But right now I am a pathologist of Milford hospital and director of Milford medical laboratory.
I was involved in this work at the request of a group of American women who believed their daughter’s neurological disabilities and death were related to Gardasil injection and not as a result of psychosomatic reaction. And they asked me to test whether the vaccine contains contaminated viral DNA from the HPV viruses. I did this at a contract of potential payment of one US dollars in the future. Next please.
I received 19 samples of Gardasil from nine countries of the world, and I tested them and every one of the vaccine sample contains residual HPV L1 gene DNA HPV-11 type or type 18 or a mixture of both. Next please.
After I had tested the vaccine, a father and a mother of a New Zealand girl who was 18 years old at the time, who died six months after vaccination in sleep, and they asked me to test the post-mortem blood and the spleen and whether I could find HPV DNA in it related to the vaccine or not. I did find HPV-16 DNA in the spleen and the blood, apparently attached to the microphages. Next please.
Okay. So because I could not find HPV-16 before, then I went back to the vaccine and found the HPV-16 was in a different conformation, and I had to change the method in order to find them in addition to the HPV-11 and 18. The 16 is also in the vaccine. Next please.
So it’s well-known that the HPV vaccination depends on the Gardasil adjuvant. On the left-hand side, the aluminum adjuvant waits for the release of human DNA as a result of inflammation and the cell death. And the human DNA would combine with the aluminum and stimulate the macrophage to enhance the immunogenicity of the vaccine reaction. However, in Gardasil because the HPV DNA was already present in the vaccine when they were injected in these girls, so the viral DNA combined with the aluminum injected to stimulate the microphages. And that is the mechanism I believe to cause cytokine storm and tumor necrosis release. And that would cause hypotension, tachycardia, and sudden death. And other neurological symptom is called acute disseminated encephalomyelitis.
And may I ask the respectable chairlady, to allow my colleague to present our case from Connecticut and has the MRI changes and histological changes because she knows personally the case. Not me, I work in a lab. So Mrs. Chairlady, may I have your permission to allow Dr. Norma Haja to present.
Koji Nabae: The chairman is the Professor Kurane. Kurane is now the chairman today.
Sing Hang Lee: So to allow her present the initial slides because I’m not a clinician, please.
Koji Nabae: Please ask to Dr. Kurane for his permission.
Sing Hang Lee: I please ask for your permission.
Ichiro Kurane: Could you explain the slide by yourself? Is it impossible? Because you are the invited speaker.
Sing Hang Lee: Okay, all right, I’ll present myself. Okay, please continue on Dr. Haja’s—okay.
This is a 16-year-old girl who suffered hemiparalysis in Connecticut. This happened in Connecticut, in the state of Connecticut, and suffered from visual loss and left hemiparalysis following vaccination. Next please.
On admission, the MRI shows parietal occipital enhancement indicating myelitis in the brain, encephalomyelitis and chiasma changes here to indicate the lesion involving the optic nerve. Next please.
So the brain biopsy shows demyelination of the brain with inflammation of the blood vessel and surrounded by macrophages. And presumably some of the macrophages may be carrying the HPV DNA into the brain causing this reaction. Next please.
You have to call attention to the presence of the lymphocytes also. Right, and also the lymphocytes and the macrophages inflammation. Next please.
So at three months there is resolution of the parietal occipital lobe lesion and the diminishing reaction in the chiasma. Next please.
The 18 months and the resolution of the brain lesion, but the chiasma lesion still persist.
Okay, that’s the end of it. So this person and my colleagues assured me that clinical—this person, the girl has lost her vision completely. The complication is blindness in all her life. And I do not believe that this could be due to psychosomatic reactions as a pathologist.
Thank you very much for your patience.
Ichiro Kurane: Thank you very much. Thank you very much, Dr. Lee. Then I would like to invite Dr. Helen Harris. I would like to ask the comment from Dr. Helen Harris from Auckland University, New Zealand. Dr. Harris, five minutes comment please.
Helen Harris: Thank you. As I understand, Dr. Lee has tested some vials of Gardasil vaccine and also post-mortem tissue samples from a single person for the presence of HPV DNA sequences and has apparently detected those. And he goes on to propose that the HPV vaccine may have caused death due to a complex of vaccine constituents, the adjuvant and residual DNA. I strongly question the methods, his interpretation and conclusions derived from his work, and I just want to briefly address some of what I believe to be the key issues. Next slide, please.
We expect the vaccine to contain traces of vaccine type DNA. And this is consistent with the manufacturing process. But there are a number of problems with these facts. Firstly, the tests are not transparent or validated and they’ve certainly not been replicated by any international source. And this is a vital part of the scientific process.
Now PCR is an extremely sensitive test and a nested PCR is much more so. It’s used to detect extremely minute quantities of genetic material. But there is also an inherent high risk of amplifying other DNA sequences. And certainly the use of what we call degenerate primers, which he’s used, increases sensitivity but also increases the risk of amplifying other DNA sequences. And this reduces your specificity for what you are looking for. It’s like throwing in a wildcard. And give that the exact genetic code of the vaccine gene is known, it’s a strange thing to do, which I find quite concerning. Next slide, please.
I also have concerns of the testing of post-mortem samples and the interpretation of those. And this is the young girl who died unexpectedly six months after receiving Gardasil. In this case there is no indexed controls used, and that’s a vital part of the scientific process. We do not know if everybody would present with the same results after death. So samples from other post-mortem examinations are essential. In this case only water was used.
Also the inclusion of degenerate primers reduces the ability to only detect the vaccine type gene. Also if Dr. Lee tested for the plasmid DNA and yeast DNA, which are also components of the vaccine process, then he might have more evidence for his hypothesis. But he’s not done that.
Also by Dr. Lee’s own admission, the amount of residual DNA in the vaccine is miniscule. So it’s all very tiny and it required extraordinary measures to detect them. How can such a small amount of DNA then be detected dispersed throughout the body tissue with vast and reduced concentration? It’s not biologically possible for the HPV DNA to integrate into the host genome. It does not have the necessary sequences. So that really can’t happen.
So what we’ve got here—next slide please—is an extraordinary hypothesis. Dr. Lee’s supporting a hypothesis whereby HPV DNA is bound irreversibly to the aluminum adjuvant, which is a theory, taken up by macrophage, which is a theory, and caused an inflammatory response leading to death, again which is a theory. In addition he contends that these complexes can be detected in post-mortem tissue samples and that they were carried there by macrophage. But he has little evidence for these hypotheses, which if true, need to be tested using a rigorous scientific process.
So we need convincing proof at every single one of these steps in order for the hypothesis to stand including the binding effects in DNA to the adjuvant carriage by the macrophage, deposition in tissues, and inflammatory immune cascades, which include a tumor necrosis factor. No one else has replicated the findings and they’re not supported by the extensive research on both the immunology and epidemiology of the HPV vaccine safety. Next slide, please.
I just want to touch on the immune response also following vaccination with protein-based vaccines such as the HPV vaccine. And this has been overlooked. After the vaccine is injected and the immune cells such as macrophage take the vaccine up, the antigen and the adjuvant, the aluminum, at the injection site—
Ichiro Kurane: Helen, you have only one minute left, please.
Helen Harris: It’s the initiation of the inflammatory immune response. The cells have become activated and migrate via the lymph to a local lymph node not the spleen. They will stay in the local lymph node to present the antigen to T and B cells. And it also might be useful to note that the half-life of a macrophage is about six days. Macrophage do not cross the blood-brain barrier with the exception of some of the disease states. So these facts together do not support potential for the presence of adjuvant HPV in DNA in either blood or spleen and certainly not in the brain.
Our work here at the University of Auckland has demonstrated that the immune activation on the uptake of HPV vaccine does not include and increase inflammatory factors including TNF in the serum, even in vaccines with large injection site reactions at the time of local inflammation. Next slide please.
In our case in New Zealand the testing for other abnormalities—
Ichiro Kurane: Dr. Harris, sorry, time is running out. So I need to ask you to stop here.
Helen Harris: Okay, I’ll just refer you to my last slide.
Ichiro Kurane: Thank you very much. And then we need to ask—I would like to ask Dr. Yoshikura who is very knowledgeable on this type of issues.
Hiroshi Yoshikura: I enjoyed the presentation by Dr. Lee and the intervention by Helen. Most of the audience is Japanese, so I speak in Japanese. Concerning Dr. Lee’s presentation, the HPV gene in the vaccine, my understanding is that it’s only natural that it’s included. And HPV capsule protein, well, this is well-known regardless of the DNA, it can be uptaken very efficiently. So the gene, the HPV capsule being used to introduce DNA, that is commonly done in the United States. So from that perspective it is natural.
And Gardasil vaccine uses bread yeast, and about 100 to 150 plasmid L1 DNA is included, and the core protein is reproduced or expressed, and the VLP virus like particles is reproduced. The cell is collapsed and it is generated by doing so. So same as with HPV DNA, there’s a lot of yeast DNA included as well. To what extent do HPV DNA—what is the ratio of yeast DNA? I don’t refer to any complicated calculation. But HPV DNA and the yeast DNA, the ratio is about 1 to 100 if you calculate the number of copies. So even if DNA is included, HPV DNA 100 times of that is the yeast, bread yeast DNA. Whether it’s HPV DNA or bread yeast DNA, DNA is the same chemical substance. So why is it so special? That will have to be explained. And today it was not explained in detail. Aluminum compound as well as the L1 protein capsule protein, it’s like the Trojan horse. HPV DNA is taken in and the papillomavirus DNA is carried to the brain.
So this paper, as Dr. Helen also said, refers to brain tissue antibody specificity—I think there is an issue with that. But there are many unknowns about this. But in any case, concerning HPV DNA the Trojan horse with the HPV DNA, why is it going to be used from the injection site to the brain? Maybe it’s taken in by microphage. But in order for the cell to be transported toxicity is required. So the macrophage with VLP, it is attracted to the brain.
But aside from that, as we mentioned about the ratio of the papilloma DNA and the yeast DNA, if there is one transporting HPV DNA, then there are about 100 Trojan horses transporting the yeast DNA. And if one is strong and DNA enters the brain, then the brain may be filled with yeast DNA. And if the genes are expressed, then the brain might turn into bread. But yeast DNA doesn’t work within human cells so that is fine. So that is how my fantasy expands.
In terms of vaccine inoculation, of course there is the issue of side effect. Vaccine inoculation, that is always our problem. So something that occurs among 1 in 10,000, if there are 1 million people, then there would be 100 such cases. For those people who are inflicted, all of these people have received vaccines, so what to do about that? So this is a never-ending story. The Trojan horse has the tail and feet. These are going to be visible going forward.
Ichiro Kurane: Thank you very much, Dr. Yoshikura. Shall we go to program number one?
Harumi Sakai: Professor Kurane? Dr. Sin Hang Lee, do you have any opinions or response to the comments made?
Ichiro Kurane: Other part of this meeting. So I’d like to proceed to the next.
Harumi Sakai: I understand.
Ichiro Kurane: Then we would like to move to the next speaker. I would like to invite Dr. Francois-Jerome Authier from France. For 10 minutes please.
Francois-Jerome Authier: I will present briefly. I am a neurologist and neuropathologist in charge of the Neuromuscular Center in the university hospital. I am a professor at Paris XII University in France. So—
Ichiro Kurane: It’s a Paris university?
Francois-Jerome Anther: Yes, it is. So I will speak about macrophagic myofasciitis and how these conditions will provide new insight of the long-term safety of aluminum adjuvants. Next please.
Macrophagic myofasciitis is characterized by specific lesions in deltoid muscle. And this lesion is evidenced by deltoid muscle biopsy. As you can see on the left cartoon, it’s made of focal infiltration by macrophages. And these macrophages at electron microscopy appeared fulfilled by crystal inclusions. And microanalysis of this crystal inclusion revealed that they correspond to aluminum hydroxide crystals and in vivo aluminum hydroxide crystals from aggregate. And these aggregate are captured by macrophages. Next please.
So this lesion was observed in patients presented with clinical syndrome that has been characterized as follows. First these patients received significant number of aluminum vaccinations during the past 10 years before the onset of symptoms. And this mean number was 5.2 and we observed up to 17 aluminum shots in these patients. The onset of clinical symptom is delayed from the last shot of aluminum containing vaccines and the mean delay was 12 months, that is one year. Another important finding is that the delay between the muscle biopsy and the last shot is the mean delay is 66 months. And this finding assesses long-term persistence of MMF lesions within muscle tissue and body and therefore the long-term persistence of aluminum hydroxide within body.
These patients, patients with MMF at muscle biopsy present three types of symptoms. The most common symptom observed were first chronic muscle pain, second chronic fatigue, and third cognitive impairment. And in this patient we observed abnormally high level of autoimmune diseases, 20%. And among this autoimmune disease, we observed multiple sclerosis in 9% of these patients. The significant association between the symptom muscle pain and the presence of the histopathological lesions, MMF was demonstrated in a paper published in 2001 and for a case-control study.
The significant association between the syndrome fatigue and the histopathological lesions was demonstrated in a case control study conducted by the AFSSAPS. AFSSAPS is the French equivalent of the FDA. And in this study as investigators observed that fatigue was most frequent in MMF patients in control at onset of the disease, that total and cognitive fatigue scores were higher in MMF patients than in controls, and that the controls had a higher amount of medical antecedents than in MMF patients. And they conclude that they were two distinct subsets of patients. This study is currently available on the net. And we also showed that MMF patients fulfilled criteria for chronic fatigue syndrome, and most patients fulfilled the international criteria for chronic fatigue syndrome. Next please.
So the introduction of the antipapillomavirus vaccine in France was followed by the observations of macrophagic myofasciitis in vaccinated girls. And we observed—I got referred to Henri Mondor Hospital for chronic fatigue syndrome. And as you can hear the age at onset was between 15 and 18 years whereas the age at evaluation was between 16 and 23 years. And all these differences witness the chronicity of the clinical symptoms. And all these girls received Gardasil , HPV vaccine.
In seven patients we performed deltoid muscle biopsy and observed macrophagic myofasciitis in two of them. In the left panel, I showed the clinical story of patients, and you can see the dot of vaccine—please go back. And you can see the different shot of vaccines. And a few months after the last Gardasil shots, occurrence of muscle pain and asthenia and cognitive disorder. We performed biopsy and as shown in the bottom, we observed typical macrophagic myofasciitis injuries. And we confirmed that Gardasil was able to induce MMF lesion by injecting Gardasil into a mouse. And as you can see in the right panel, we produced the pathological lesions in animals. And Morin staining confirms a presence of aluminum within macrophages. Next please.
The main, very important feature of macrophagic myofasciitis is the presence of cognitive dysfunction. That is a classic, constant stereotype of this executive type is roughly similar to that observed in patients in workers exposed to aluminum inhalations. And it is cognitive deficiencies are well correlated with abnormality to functional imaging, brain functional imaging, for example with the SPECT finding. Next please.
After injections of a single dose of aluminum based vaccine in a mouse, we observed the entry of aluminum—sorry, I need to end please.
Ichiro Kurane: Time is over. So please close.
Francois-Jerome Anther: So we observed entry of aluminum within brain tissue. It’s a very important tissue. Next please. And so the neuro migrations of aluminum particle is an active process. The particles can be transported by monocyte cells to the lymph node, to the blood, and spleen and enter to the brain using an MCP1 mechanism. This occurs at a very low rate in normal condition, probably explaining the good overall tolerance of aluminum despite the neurotoxicity, the neurotoxic potential of its components. But if you—in case of escalating doses of this adjuvant in the population, we may be faced to adverse effect, especially in case of over-immunizations, immature altered blood-brain barrier or high constitutive MCP1 CCL2 production. Thank you for your attention.
Ichiro Kurane: Thank you very much. Then next I would like to invite Dr. Jean Beytout from France for your opinion. Five minutes, please.
Jean Beytout: Thank you, Mr. Chairman, ladies and gentlemen. Next slide please.
The experience of aluminum vaccines is very long and it comes from everywhere in the world. Safety concerns were rare and the use of aluminum salts was never contested for safety reason. Next slide.
Professor Authier, your team from Creteil described MMF, and you established a relation between the granuloma and the vaccines which are inoculated into the deltoid. But you are the only team to recruit these patients. And you have many patients. Next slide.
On this slide you can see that the symptoms which conducted the diagnosis were rather disparate. You can say miscellaneous. But some of the patients had already a diagnosis of multiple sclerosis. We remark that the case adults despite children receive more frequent vaccinations than adults. Next slide.
On this slide are the vaccines involved. And once again, it is hepatitis B vaccine with charge. At period where in France this vaccine was charged—was wrongly charged for multiple sclerosis cases, it looks like a sort of harassing campaign. Next slide.
The epidemiological study that you recalled from AFSSAPS, and I think to which you participated, did not demonstrate any relation between immunization with aluminum vaccines and the occurrence of MMF syndrome. Deltoid granuloma is supposed to be a sort of tattoo witness of aluminum salt inoculation. And GACVS from WHO repeats it is not associated with specific clinical entity. Next slide.
You tried to find an explanation of your theory. What would be the cause of MMF disease? Is it muscle autoimmunization process? Is it something near idiopathic chronic fatigue syndrome? Is there a direct cerebral toxicity due to aluminum deposits? Or is it a mix of direct toxicity and autoimmune process, just like in the ASIA syndrome? Next slide.
Your recent studies refer to chronic fatigue syndrome. Here is the clinical definition of this syndrome. And in it we can remark that the most frequent and chronic symptoms are directly related with fatigue and weakness. Next slide. I should not comment on this slide because it is work you already presented. But I shall point out some critical aspects in the next slide. Next please.
You demonstrated psychological and neurological involvement in patients who complained of chronic fatigue. But how do you explain the other symptoms of which MMF patients suffer, especially myalgia or peripheral neurological involvement?
Do Rhodomin label beads, latex beads really reflect the becoming of aluminum of macrophage in mice with genetic blood-brain barrier fragility.
Ichiro Kurane: Dr. Beytout, could you wrap up, please?
Jean Beytout: Yes, all this present of this experiment are on mice with genetically fragile blood-brain barrier. I think no deduction can be transposed to patients suffering from MMF, especially to the possible presence of aluminum inclusions in the CNS. It does not mean neurotoxicity. Next slide. That’s why the French ICSP assumes that the safety of aluminum vaccine is not called in question. We still recommend the continuation of immunization with aluminum containing vaccines. But evaluating the safety may be pursued. Thank you.
Ichiro Kurane: Thank you very much. Two scientists from Japan—first I would like to invite Dr. Ishii.
Ken Ishii: I’d like to thank both of you from France to come over and we’re really happy to. I really enjoyed your talk as well here. So let me also speak in Japanese. I’m sorry because the audience is all in Japanese.
My comment would be that was mentioned by the two speakers. The aluminum adjuvant, this mode of action, why is it efficacy? Why is it effective? And why does it work as an adjuvant? And why not as adjuvant does it cause adverse reaction and lesions? And I think you understood that the understanding has not advanced to a high level yet.
So we’re having a discussion today, and on the other hand there’s a possibility or a risk of patients suffering from adverse reaction. There is still a gap in between. There’s a consideration that these are rare phenomena, rare cases. And how can we link that with the animal experiments? I for a long time have questioned how to link that in terms of how mechanism, whether they are linked. It was mentioned toward the end by Dr. Beytout. But going forward, the adjuvant vaccine or the vaccine itself, the adverse reaction, experiment, or research was epidemiological studies need to be conducted for all these components in order to elucidate the mechanisms.
Another point, the issue of MMF, of course it was valuable how this question was raised. But invasive muscle biopsy is said to be necessary for the diagnosis. And on that point when it comes to reproduction and pursuit of future research, it’s quite challenging. So if we had the steps to diagnose the criteria for MMF, why don’t we develop a non-invasive type of diagnostic criteria? I strongly recommend such a research so that the other countries, other hospitals can follow suit and do the same.
And another point that aluminum adjuvant according to Dr. Lee’s presentation as well, it was mentioned that it has been used for the past 80 years or more. But the mechanism action was not known. However, there has been rapid elucidation of knowledge and research recently. And so the effect as well as the adverse effect in both these aspects regardless of it being negative or positive finding, there is progress. And so we should pay attention to the future research. There were two or three disorganized comments—I apologize for that. But that concludes my comment.
Ichiro Kurane: Back to invite Dr. Tetsuo Nakayama for your comment.
Tetsuo Nakayama: My name is Nakayama. I would like to comment the mouse animal test was mentioned and as was mentioned last time in the mice. The vaccines with and without aluminum was inoculated and in the muscular cytokine as well as various pathological findings were observed. Local muscle where it was injected there is inflammatory cytokine that grew—that rose until two days post inoculation. And the inflammatory cytokine level is quite high. However compared to other vaccines, it is quite high.
But on the other hand, the in blood cytokine, Cervarix and Gardasil, there are other—regardless of whether aluminum is included in vaccine, the same level of cytokine was observed. So concerning local pain after inoculation maybe there is an effect. However, concerning general effects, cytokine cannot be explained. And long-term—for about one year, long-term observation has been done. Local aluminum—in local areas aluminum is observed. However, the cell—if we look at the cell functions, arginase, these proteins are not impacted. So after six months to one year, the joint remain but there is no finding to support the inflammatory symptoms. So various vaccines and local pain and may be related to cytokine. However, after that continuous, persistent, chronic fatigue or chronic pain concerning those, there is no data to support that.
Six months post-inoculation, there may be some pain in the local area. However in the non-inoculated site, if we looked at the tissue there, there was no transfer of aluminum. So the aluminum, we have not been able to observe any aluminum going to a remote area site. So aluminum vaccine may create a local inflammation however not general systemic inflammation. And as mentioned earlier on, the CNS related symptoms and fatigue symptoms at this point in time cannot be explained yet, and the correlation is still questionable. So MMF and these diseases, I think we need to proceed as separately. MMF may reflect the history of aluminum vaccine inoculation. That is all. Thank you.
Ichiro Kurane: Thank you very much. Then we’d like to move on. But I’d like to ask the secretariat, I think we would be going overboard with the time. We will go beyond 11 o’clock. Is it all right?
Toshinobu Sato : We heard Dr. Sin Hang Lee volunteer to speak and give his response later on. And also there is a final presentation still to be made. And so if we can—I think it’s all right to extend the time.
Ichiro Kurane : We would like to move on to the next speaker, Dr. Harumi Sakai. I will give you 10 minutes for your presentation.
Harumi Sakai: Thank you very much. I used to be at Tokai University Medical School. My name’s Harumi Sakai. Can you darken the room a little bit? Today I would like to present the data. And the data source is from MHLW. The data is published on MHLW.
This is material for the adverse events subcommittee and also GlaxoSmithKline webpage. There is official data from their webpage as well. And the third source of data is the cervical cancer victim association. There are some cases that have been reported to that association. So this is from GlaxoSmithKline, the rather recent Lancet Oncology data.
I asked GlaxoSmithKline, for example, the serious adverse events and new onset of chronic diseases, there are some cases that have been double counted. So here I have only—I would like to narrow down only on serious adverse events. So the count of serious series of adverse events is 9.0%. This is a clinical study. So there is a certain number of patients and for four years, these patients were observed. And this number’s the result of that. So within four years after inoculation, there were 9.0% of SAEs. And what are the SAEs? I officially asked GSK. There was no response. So please refer to the following slide.
I went to the MHLW website and I looked at the side effect subcommittee. So ever since this drug was launched in to March of 2013, Cervarix adverse events, I created a database myself because there are some double counts, and for one number there may be two patients. So all of these were included and put into the database. I sorted out and I found that for Cervarix AE, there were 1,708 in total. And I have classified these in my own way. So SAE and new onset of chronic diseases and new onset of autoimmune diseases meant other medically significant conditions. So I have classified these into these categories so all kinds of diseases are included.
I’ve classified them concerning SAEs. They are very, very serious. Death, miscarriage, and CNS, very severe symptoms. Of these, 1,708 in total, 1,002 all together comprised of these diseases I just mentioned. Meaning that for these people, they may be bedridden or they have may physical disabilities throughout their lives or serious brain damage. If there are 15 years of age now, for the remaining 75 years of their life they will have to suffer. And the same thing can be said for their families. The next slide please.
This shows new onset of autoimmune diseases. The fact that there is onset, this is reported by the ministry, MHLW. And earlier on we talked about the optical diseases. There were some reports of vision loss. Of the 1,708, I just picked up the cases where there was loss of vision. That is nine. But not only loss of vision, but for example there may be other loss of consciousness and also dizziness. There was dizziness, vertigo, and cardiopulmonary arrest. So very serious CNS related symptoms, not only visual loss. There are nine such cases.
And this has been reported to the patient group for cervical cancer vaccine. Only these are for visual loss, four cases. Not only visual loss but there are various other related central nervous disease symptoms, peripheral nerve system disease. Just looking at these symptoms, the list of symptoms, you cannot imagine that they will recover and lead a happy life.
Same thing for this patient, not only visual loss but muscle arthralgia, generalized severe pain syndrome and other CNS symptoms. And this patient as well in motor gait disturbance, loss of memory and also pain, arthralgia. Same thing for this person as well. Visual loss means that CNS is damaged. So the other brain functions may be damaged in various combinations.
This shows—this is reported to the victim association from vaccine inoculation to onset. The interval until the first symptom is shown within one year there were some patients whose symptoms did occur. But more than one-third of these symptoms occurred after one year. So the one-year threshold will not serve to capture all the patients. Concerning this vaccine we don’t know when the symptoms will occur. It may be in five years. It may be in 10 years. There are serious side events.
And this was from GSK webpage. Dr. Ryo Konno premarketing clinical study data on the top this is classification of SAEs and others. But there is no sufficient data. So please refer to the bottom. Of the 519 patients within observation after two years, 46 became pregnant of which, well, with natural pregnancy 10% were miscarried. So spontaneous miscarriage, 11% is normal. But there is abortion 30%. So if they had not been vaccinated, after nine months, a healthy baby should have been born. However, because they were vaccinated, there was some trouble. So they had to abort the pregnancy, 30%. So 30% of babies were not born. Thank you for the slides. May I ask Dr. Sasaki to comment?
Ichiro Kurane: We have invited you so we would like to ask you to comment.
Harumi Sakai: Well, Dr. Sasaki says that there is causality between inoculation and severe pain. And the conclusion is 9% of girls have become impaired. In Japan we need to depend on the women in the labor force. So 9% of the young women are in the productive age. However, they cannot remain active. And also concerning babies to be born, from this data as you can see, birth rate will come down by 30%. The number of babies will go down and the number of children in Japan is very small. So this is a very serious issue. 2.3 million people have been vaccinated with this vaccine, of which 9% we have seen serious adverse event or potentially may suffer from SAEs. This is calculated from GSK data, 200,000 people. So we ask for their relief. Thank you.
Ichiro Kurane: Thank you very much.
Harumi Sakai: There’s an additional comment if I may.
Ichiro Kurane: Please be brief.
Harumi Sakai: There’s a request that I would like to make. There are free coupons that are distributed. Because these are publically funded vaccination programs and the municipalities have these coupons. So a follow-up survey should be conducted for two or three years. Even if you start now, two or three years of follow-up is possible. That is my request.
And also there was a muscle biopsy mentioned that this is too invasive. So please then why don’t you measure their visual field as well as acuity? They may have a loss of acuity. They may have narrow visual field. So that will indicate an impact on the CNS. So please test that if you want a non-invasive system. Thank you.
Ichiro Kurane: Thank you very much. Is it ok with you?
Harumi Sakai: Ok.
Ichiro Kurane: So we have—there was a presentation of data by Dr. Sakai. There is a number of comments to be made by the secretariat.
Tetsuya Miyamoto: With the rest of the data, in the original presentation there was a lot of data. So I would like to point out a number of related points, especially with regard to the confirmation of safety of drugs there are basic procedures. So going to the floor, I would like to explain out of presentation, there is a number of relevant points relevant to the presentation on page four. This is material number 6, number 6 to the bottom where Dr. Sakai had mentioned related data how is shown, and this is a breakdown of SAEs.
This shows the Cervarix efficacy testing. A clinical trial was conducted and there was a lottery here to randomize people into those inoculated and those that were not vaccinated. And looking at the efficacy of the vaccine, also the adverse events were counted. And although not mentioned in the presentation by Dr. Sakai the deaths as well as SAEs and chronic new occurrence of chronic diseases were captured. And I would like to highlight the important points. And so if I can go to page 7—I’m sorry.
So Dr. Sakai has introduced this portion of the data on slide 7, page 4. So can you go back, yes, this is the slide I am talking about. It’s on page 4 and the slide is number 7. If you look at the data, death and SAE and how new occurrence of chronic disease and also new occurrence of autoimmune disease. And so between the vaccinated and the non-vaccinated, the group does a comparison, each of them says no difference. And the initial clinical trials says when they confirm the safety there were no such issues.
And Dr. Sakai’s explanation included the outcome on pregnancy. She talked about the Japanese data. But in this clinical trial, how the outcome over pregnancy also is disclosed and also not only several expert also Gardasil as well, clinical trial also outcome is disclosed. In any case those vaccinated and non-vaccinated, there were no differences in the outcome of pregnancy. And SAE, there is a high incidence of SAE according to Dr. Sakai but there are only two groups to compare. So there is no other outcome to share.
But if you look at slide number 6, this one, this is Japanese data, it is just for your reference. According to the patient survey, it shows the annual generation of hospitalization rate for different age brackets on an annual basis. Between 15 years to 19 is 2.7%, about 30 years old 4.7% would undergo hospitalization per annum. So this is a natural population, natural situation. So with regards to the pregnancy as well, in the young generation 10 to 15%, in the healthy population undergo abortion and also miscarriage. And with the older aged women, there is 40% miscarriage rate according to the Japanese data. And looking at the clinical data as well the risk has not been found or identified.
According to the adverse event report, I don’t have a slide to show you but the mechanism or the procedure for the report is that we hope to capture information as widely as possible. In other words according to certain criteria, the physicians will determine whether they should report or not. And for each of the cases that were reported, whether it is influenced by the vaccination regardless of the judgment, the report is to be submitted. And if there are specific patterns identified, we would magnify and go into detail the assessment. And this is like a post marketing survey that is generally conducted around the world. This is general practice. And within the subcommittee for adverse reaction of vaccine, these issues have been taken up.
The committee has investigated adverse event reports on condition that all SAEs are not caused by vaccines; it is different from what Dr. Sakai mentioned. In the data there is the cohort observation study. And many of the subjects, this is a large sample size survey, very characteristic of the survey analysis. And this is slide number 8. In terms of pages, it is page 5. And beyond that this is U.S. situation cohort safety monitoring study. And also slide 10, this is a Danish as well as Swedish data in the teenage women. And neurological as well as autoimmune diseases and all these categories there have been no risks identified in all these studies. That’s all. Thank you.
Ichiro Kurane: Thank you. So now we would like to ask Dr. Okabe to comment on Dr. Sakai’s presentation.
Nobuhiko Okabe: Dr. Sakai, thank you very much. So from the secretariat there were some data presented, the SAEs, at the committee meetings various vaccines we have many discussions on SAEs. And the same thing can be said for the health survey as well.
Harumi Sakai: Excuse me, but it is wrong.
Ichiro Kurane: We’d like to hear from Dr. Okabe first.
Nobuhiko Okabe: So the serious adverse events, the secretariat also explained, however, our understanding of SAE is that is if there is an event whether it be vaccination or not, after that there is observation and various symptoms that occur afterwards is broadly captured. Like VAERS in the U.S. same thing is done. And the side effect report in Japan as well due to the allusion of vaccination. But the definition of SAE equals side effect. That may be how it is perceived. So I’d like to take this opportunity to say that within the vaccination law, serious adverse events or side effects, so I think it definitely should be clarified further for these terms.
And in your presentation it was not included. However in your material you talked about adjuvant. And in your publications I think you mentioned that squalene can be a cause of SAEs. But judging from this, aluminum adjuvant maybe is an issue as well. Concerning aluminum, the issues concerning that has also been commented on by the other experts. So this is something we would like to discuss going forward. Thank you.
Ichiro Kurane: Thank you. It is a quarter passed 11. If we can invite additional comments, I’d like to open the floor. A comment from the speakers or commentators and just I would like to ask a very short comment because we are running out of time, and one minute comments please. And if you can raise hand. Okay, Dr. Lee.
Sin Hang Lee: Thank you. My method of detecting DNA is not challenged, flawless, is based on DNA sequencing of the publication the FDA agreed that there is a DNA left, recombined DNA left in the vaccine. But the FDA has not responded that this is combined with aluminum or not because they have no data on it. And I don’t, as a pathologist, my job is to find out how the patient died and how to explain the lesion, the pathological lesions we find in the brain. And there is no, in my opinion, there is no explanation for psychosomatic reaction causing inflammation in the brain. So that’s why I don’t think anybody of you, if any of you, the scientists here believe psychosomatic reaction can cause inflammation in the brain, just raise your hand. No?
Ichiro Kurane: Thank you for your comment.
Sin Hang Lee: That’s my comment.
Ichiro Kurane: Thank you for your comment. One minute comments, Dr. Authier, one minute comment, please.
Francois-Jerome Authier: Yes, I will stress three points. First only a part of vaccines are adjuvanted with aluminum cells. All vaccines are not containing aluminum. And second it is aluminum hydroxide is supposed to be safe because it was used for decades. But its safety has not been clearly studied, in particular long-term safety was never in-depth evaluated. So it’s impossible to claim clearly that aluminum hydroxide is safe. And may I?
Ichiro Kurane: Short comment.
Francois-Jerome Authier: All patients, all vaccinated patients do not have macrophagic myofasciitis only a subset of patients.
Ichiro Kurane: Thank you very much.
Tetsuya Miyamoto: Just additional comment that I made, Dr. Sakai’s explanation included the SAE. There is 9% incidence of SAE according to Dr. Sakai. What I wanted to comment is that the definition of serious is that for example hospitalization is necessary. There is some impairment that remains of.
And looking at the hospitalization, if I can go back one page, there is data for each of the age categories. There’s like 3% or 5% or so. This is one-year data. So if it is two-year, it can reach 9%. It is quite natural. This is Japanese data for a reference. So this is the level of SAE that we normally see. And talking of the definition of seriousness, it widely includes causes which correspond to hospitalization, car accident as an example. And those are also included in these numbers. So please understand these data to mean that.
Ichiro Kurane: Thank you. Are there any other comments?
Ken Ishii: One last point. The people suffering from adverse events are potential patients, to these patients and these families. From their perspective, we need to continue these kinds of discussions. And also on the other hand, people with VPD because vaccine opportunity was lost, there may be some negative effect. That is also another point we need to be mindful of.
And aluminum adjuvant effect and side effect, this and the rare population you mentioned subset earlier on, there may be some special or maybe it’s a limited number people are suffering from these symptoms. Why is that and how can we identify the cause? And how can we predict this and prevent this? We need to do more positive looking study and contribution. Thank you.
Ichiro Kurane: Thank you. Dr. Sakai, you were raising your hand.
Harumi Sakai: Thank you very much. May I speak?
Ichiro Kurane: Please be brief.
Harumi Sakai: The biggest issue to this vaccine is that this unprecedented adjuvant containing vaccine that has never been used in human. We’re not just criticising aluminum like the others. This is specific aluminum in DNA fragment is including that. And we know that for Gardasil. And also the other is aluminum hydroxide. And I think you’re an expert. But MPL we call it, the Salmonella outer membranes endotoxin is included in this vaccine. So human immune reaction can be stimulated severely and dramatic stimulation of the immune system is that it can lead to a severe adverse reactions. Please understand this situation.
And also these are novel compounds. And so what how will trigger, what symptom after immunization is unknown. So not just try to identify causality from the beginning, but why don’t you collect all the information that you see and to identify what is happening? We should start from there. And then for the first time you are able to know the effect and the adverse effect of this toxin as whole.
This vaccine you don’t know the timing of the onset of the adverse reaction. You don’t know the site and you don’t know the symptom that will manifest. It can affect various organs in various types of ways and symptoms. And we don’t know when it will be the onset, maybe it will be 10 years later. Macrophage has eaten it up and taken it up and it exists in the whole body. And so 20, 30 years we need to have a longer time span for follow-up.
Ichiro Kurane: Thank you. We are running out of time. So lastly, I would like to summarize our discussion today. First of all, Dr. Sin Hang Lee said with an HPV vaccine there is derivative DNA fragment is included. And from the sudden death patient that virus was detected. And that may be a cause of a huge side effect. That was presented.
Concerning that, Dr. Harris said that I think there were about three points that were mentioned. First of all, concerning the presentation, there was no control. So that was pointed out. So there was no control. So we question the result. That was the issue. And also another point that was cited is HPV L1 gene fragment binds with the adjuvant and cause inflammation. So concerning that hypothesis there is no sufficient proof for that. So that was the rebuttal. So it was just an accumulation of various theories.
And also another, even if there is a DNA fragment; it is very tiny. So due to that, the DNA moving throughout the body causing severe inflammation is not conceivable. And the Japanese expert Dr. Yoshikura said that concerning DNA fragment the HPV and yeast DNA is a ratio of 1 to 100, and the macrophage that transports the DNA, if that exists, then that is also transporting yeast DNA, more of the yeast DNA. So it may go into the brain. Due to the mechanism there may be—so all of these moving into the brain and causing side effect is not conceivable.
And concerning the second presenter from France, Dr. Authier, aluminum included in the macrophage will cause MMF. And the MMF is relevant to adverse event and chronic fatigue. Or aluminum may exist in the brain. And concerning that, Dr. Beytout said that until now concerning these we have experienced in France and aluminum including vaccines have been widely used throughout the world for more than 80 years. Safety has been confirmed. And concerning the cases of Dr. Authier, some of these were already diagnosed as a certain illness.
And as for MMF, even if it may cause some disease, Dr. Authier has been changing the concept time to time; chronic fatigue syndrome, ASIA and so on. There may be a variety. There is a lack of variety. And also he commented inflammation site will induce systemic symptom. There is a lack of evidence; how can the local inflammation move to the whole body? That was not explained. So the comment was quite negative.
And from Dr. Ishii, the adjuvant mechanism of action is being unclarified, and based on science analysis needs to be done. This is something that needs to be done going forward. And Dr. Nakayama said that aluminum may cause local inflammation but systemic inflammation maybe not. So MMF, even if MMF exists, it should be local phenomenon and it’s inconceivable that it can move throughout the entire body.
Dr. Sakai, talked about the SAEs. Based on clinical studies the adverse event possibility was presented. And also Dr. Sasaki’s comment was included. Loss of vision or CNS or pregnancy comments concerning those were cited.
From the secretariat, all of the adverse events are reported regardless of whether or not the cause is a vaccine. So we will have to interpret the number carefully. It may cause side effects at a higher percentage. However, concerning adverse events, if there is an abnormality, I think there was an extreme sample of traffic events, a traffic accident is included. All of the events are captured. So the term adverse event will have to be interpreted and understood properly before the analysis is done. And that was explained.
And the woman in this age is hospitalized at a high percentage rate, regardless of the vaccination. It was 4% or so I think per annum. So you need to look at the baseline data. Hospitalization can occur, that is counted as an SAE regardless of the vaccination.
And Dr. Sakai, in your presentation you talked about the pregnancy and they undergo abortion. There is not much difference from control group, and also in other countries survey there is no difference in adverse reaction in terms of pregnancy, no difference with the normal healthy population.
And Dr. Okabe has said that the term “adverse event (Yugai-jisho)” and the “side effect (Fukuhannou)”, what do they each mean in terms of what is the nature and content of the data. We need to clarify that. There is data regardless of vaccination included in certain sets of data. So we need to have an understanding of the overall situation.
We heard various hypotheses as well as definite ideas from different experts today. And the experts from abroad as well as from Japan, there were various questions posed and also denials were made as well. We only had very limited time to meet today. However, I think we had a very fruitful discussion today hearing various opinions. And it is time for us to close. I would like to turn to the secretariat.
Koji Nabae : Thank you very much ladies and gentlemen for your participation. We’d like to close today’s meeting.
There’s a request to the observers. The elevator hall is very small and the number of elevators is limited. So we would like to give the first priority to the expert speakers here to leave first. So please, if you are an observer, please remain seated for a while. Thank you.