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Retraction Note: Murine hypothalamic destruction with vascular cell apoptosis subsequent to combined administration of human papilloma virus vaccine and pertussis toxin
Retraction Note: Murine hypothalamic destruction with vascular cell apoptosis subsequent to combined administration of human papilloma virus vaccine and pertussis toxin
The Publisher is retracting this Article because the experimental approach does not support the objectives of the study. The study was designed to elucidate the maximum implication of human papilloma virus (HPV) vaccine (Gardasil) in the central nervous system. However, the co-administration of pertussis toxin with high-levels of HPV vaccine is not an appropriate approach to determine neurological damage from HPV vaccine alone. The Authors do not agree with the retraction.
This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
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Cite this article
Aratani, S., Fujita, H., Kuroiwa, Y. et al. Retraction Note: Murine hypothalamic destruction with vascular cell apoptosis subsequent to combined administration of human papilloma virus vaccine and pertussis toxin.
Sci Rep8, 46971 (2018). https://doi.org/10.1038/srep46971
Causing Cancer & then Milking the Patients for $$$? Politics needs to stay out of Science - let them check the findings & clarify it - you should know by now Cigarettes cause cancer - at one time - it was also "nonsense" for the goats employed by Politicians & Corporates - keep Science clean of Politics! This is people's lives we are dealing with
ranmu
Protest! It is an abusrd decision. The decision is not based on the scientific evidence.
It is the established method to make EAE model effectively in mice using pertussis toxin.
The articles describing this are elsewhere, look at the search results by google scholar below.
Did you consult the expert in experimental neuroimmunology?
Please make contact with Dr Takashi Yamamura about the use of pertussis toxin. Look at his profile below.
Active Induction of Experimental Autoimmune Encephalomyelitis in C57BL/6 Mice In this model EAE is induced in female C57BL/6 mice by immunization with an emulsion of myelin oligodendrocyte glycoprotein (fragment 35–55) in complete Freund’s adjuvant, followed by administration of pertussis toxin in phosphate-buffered saline. EAE is evidenced by ascending flaccid paralysis with inflammation targeting the spinal cord. (fragment 35–55) in complete Freund’s adjuvant, followed by administration of pertussis toxin in phosphate-buffered saline. EAE is evidenced by ascending flaccid paralysis with inflammation targeting the spinal cord.
The problem is not that they used pertussis toxin to induce EAE. The problem is that inducing EAE with pertussis toxin does not enable you to say anything about the role of HPV vaccination - since pertussis toxin alone is sufficent to induce EAE. It's even more problematic to make the leap from saying that pertussis toxin can create neurological damage to saying that the HPV vaccine might be associated with neurological damage ... because you see signs of neurological deficit when you give it together with pertussis toxin. I agree with those who say that the analysis was sloppy and the article should not have been published in its current form - which suggests peer-review was not as rigorous as it should have been.
Dr Alex Vorsters who recently obtained unrestricted educational grants from Merck said "I'm pleased that finally they did manage to retract it, but it was a very long process"
EAE is the most commonly used experimental model for the human MS. However, there is great heterogeneity in the susceptibility to the induction, the method of induction and the response to various immunological or neuropharmacological interventions. These attributes create difficulties and inherently weaken the translation from EAE to the human disease. Without getting into a more critical discussion of the observed outcomes, one needs to take a step back and examine the actual design of the experiments.
These experiments were limited to behavior and anatomical observation. This alone is inadequate to draw conclusions as MS/EAE, well known to be a immunologically-based disease. Without the addition of FACS and cytokine responses, this data is preliminary at best.
Had the authors utilized standard immunological assays, they may have discovered that the HPV vaccine and PTX may have produced synergistic effects which may have provided insight into a number of different possibilities. For example, the ability of PTX to synergize with DAMPs (i.e. lipopolysaccharide) to elicit cellular responses.
The bottom line is that this article in its present condition (based on the methodology) should not have been approved for publication. It is a real shame as it does not reflect well on either the vaccine or the standards of the journal.
Skeptical Raptor
Excellent decision, but I'm afraid it is too little and too late for the men and women of Japan, who could be protected from 10s of thousands of HPV-related cancers.
Why the paper was accepted for publication then? This indicates the serious flaw in the peer review and editorial system. This situation is expected when you publish journals to make money. The publisher should explain why was the paper accepted and what they did from the 5th of May to 11th of November 2016.
ranmu
I refute the decision of retraction from the point of high-levels of HPV vaccine.
1. Administration of 24µg of Gardasil is proper because of:
Gardasil in 0.5 mL includes: HPV type 6 L1 protein：20µg, HPV type 11 L 1 protein：40µg, HPV type 16 L1 protein ：40µg, HPV type 18 L1 protein：20µg; total 120µg
In the experiment 0.1mL of Gardasil was administered, this means the 24µg (120/5) of Gardasil.
Please look at the method of following article that murine model of HPV type 16 L1 immunization. They use 20µg of Gardasil.
References A recombinant human papillomavirus (HPV) type 16 L1–vaccinia virus murine challenge model demonstrates cell-mediated immunity against HPV virus-like particles. Journal of General Virology 80: 2471-2475, doi: 10.1099/0022-1317-80-9-2471 To examine the T cell response to VLP-16, groups of 6–8-week-old BALB/c mice (Animal Unit, University of Cape Town) were immunized intraperitoneally (i.p.) either with a single dose of 20 μg VLP-16 or with three consecutive weekly doses of 10 μg VLP-16.
2．I add the reference articles of the pertussis toxin for making EAE in mice. It is a usual method to facilitate BBB to be damaged in order to effectively to induce EAE. In EAE model, by using pertussis toxin, the research of EAE progressed remarkably.
References 1. Suppression of Experimental Autoimmune Encephalomyelitis by Ghrelin. Immunol 2009; 183:2859-2866 Shortly after immunization and 48 h later, the mice were injected i.p. with 200 ng of pertussis toxin (List Biological Laboratories). Clinical scores of EAE were daily assigned as follows:
2. Ben-ning Zhang, Takashi Yamamura, Takayuki Kondo, Michio Fujiwara, Takeshi Tabira：Regulation of Experimental Autoimmune Encephalomyelitis by Natural Killer (NK) Cells. J Exp Med 1997
Booster immunization with an identical emulsion was given at both sides of the flank 1 wk later. They were intravenously injected with 500 ng of pertussis toxin (PT) in 500 μl of PBS shortly after, and 48 h after first immunization.
Lastly, The reason of the retraction is not based on scientific basis. I am not a personally anti-vaccine. I hope the establishment of Precision Medicine, which includes the vaccinomics, adversomics. To elucidate the genetic and other factors for rare adverse reactions is necessary, that leads to the establishment of the vaccine confidence.
(https://www.ncbi.nlm.nih.go... Vaccinomics, adversomics, and the immune response network theory: Individualized vaccinology in the 21st century)
Mice are usually 20-30g and humans are 30-40kg at the age of vaccination. Therefore, 24ug for mice is 0.2kg for human. 300 time overdose. This level of overdose can not be justified.
I beg your pardon, I rewrite this according to the community guidelines. In this paper, they wrote as below:
【 In fact, “seven times” more TUNEL-positive cells were observed in mice treated Gardasil and Ptx, while “four times” more apoptotic cells were found in mice treated with Gardasil alone than that apoptotic cells in vehicle mice.】
Where did they derive the definite values such as “seven times” or “four times” from? I couldn’t find any such data in the article. We are only presented with numerous microscopic pictures in Figure 3: “Detection of apoptosis by TUNEL in mouse brains”. Although apoptotic cells are indicated by arrows in this figure, I could hardly find those cells (=TUNEL-positive cells) even in the full size images.
If they write “seven times” or “four times”, actual numbers should be presented. Their pathological studies are lacking for any quantitative or statistical analysis, and therefore lacking in objectivity, reproducibility and credibility.
They really wrote as below: >Groups of 11 week-old female C57BL/6 mice were intramuscularly administrated 100 μl of Gardasil or phosphate-buffered saline (PBS) for a total of five times.
100μl × 5 times=500μl=0.5 ml, that is equivalent to one dose of Gardasil for a girl. The average body weight of a pubertal girl is about 30 to 40 kg, and that of a mouse is 20 to 40 g. When the total dose for a mouse is compared with three times of inoculation of Gardasil (1.5 ml) for a girl, it is 250 to 667 times larger per body weight, much greater than 44 times as you wrote. At least they should have tried additional experiments with lower doses.
>I speculate that the questions you raised were already solved during the review process of the long time period.
Not solved at all. They may be among the most serious flaws of this article.
Human 3 times in total Mouse 5 times in total 32.5x5/3= 54.2 times (BW 35kg: 28.4X5/3=47.3)
Please read the article I referred.
You should learn Animal Equivalent Dose.
The dose of 50 times is reasonable dose to test the toxicity of the drug.
The information by Dr. Rokuro Hama, Non-Profit Organization “Japan Institute of Pharmacovigilance” was sent to me.
From the Textbook of toxicity in general:
Maximum dose of drug group is definite toxicity including death. Minimum dose is no toxicity. Intermediate dose is between them, and test the dose -response relation. Intermediate dose is 30~50 times of human equivalent dose (HED), showing some toxicity. When there is no toxicity with minimum dose of about 10 times of HED, this dose of about 10 times is NOAEL ( No Observed Adverse Effect Level) without toxicty. Safety factor is 10 times means NOAEL without toxicity is about 10 times. Thus, dose with toxicity is 30~50 times of HED. When there are no adverse reactions with 10 times of HED, dose of practically harmful is several times of 10 times that is 30~50 times. Definite toxicity including death is its 3~5 times , 90~150 times.
Please listen to the press interviews held May 22, 5 pm.
Everything will be diclosed, including the answers to your questions.
I have understood what you have meant. You are talking that we should use an equivalent dosage based on body surface area, and, in that way, their mice were given several score times dose of Gardasil compared with human dosage.
Thank you for teaching it. However, it is still too high dosage and they should have tested additionally with one digit lower dosage even based on a body surface area if they want to investigate its adverse effects on a human being.
What you are telling us is if there is increased dosage - the vaccine will cause cancer? Is that NOT a problem?
How can you certify this? Man you people cannot read or write genetic code - you just cut & paste genes & pray - really - this is your science - more like Mental patients playing with themselves & lives of others - Can you write genetic code for One Blue arm & one White arm - no, its too sophisticated for you - your engineering vaccines are prone to do more damage because of Low Level tech you employ - its like baboons using Stone to open a container. Until you guys can credibly read/write genes - you need to stay away from genetic engineering - there is considerable increase in cancer world wide because of Big Pharma - this is FACT.
Causing Cancer, to Milk the Dying patients + some Leftist Mental Bull S**t about Population control
The real problem is when you are RICH, ELITE - you get isolated from Other Normal Humans & Develop Mental medical Conditions - this creates Delusions & because you have Money & thus Political Power - you start projects to "Control" population - this is why we need to Check Elite Rich & politicians for MEDICAL MENTAL problems arising due to Isolation & negligible Human contact
We dont want a crazy Rich guy obsessed with "Controlling Population" giving Cancer Causing vaccines to entire populations with Poorly written genetic code
We pretty much appreciate this work - Do not get discouraged or pressured by Big Pharma - we want to know if there is truth to link between Big Pharma vaccination & cancer - there may be efforts to purposefully cause illness to sell more cure - the Politicians & Corporates work hand in hand here - there is more politics here than science.
22nd May - please clear up the subject
(For Others: THIS IS SCIENCE - NOT POLITICS - keep Politics out of science. Period. What is really important is TRUTH - we must accept even if Big Pharma will be at loss - people are more important than the Elite Politicians & Pharma Corporates making money from Cancer)
You wrote this 6 years ago. I wonder how you feel about politics being kept out of science now, after the fake Covid pandemic and deadly Covid Vaccine being pushed by every government agency on the planet. It's as if you could see the future.
Rokuro Hama
I would like to comment again with some revision because I cannot see my comment posted on 14th May. Retraction of this excellent paper by two reasons (1. co-administration of pertussis toxin, 2. with high-levels of HPV vaccine) is an unbelievable wrong decision.
Methods using pertussis toxin is an established method for detecting autoimmune disorders in the brain as discussed by others. I would like to examine specifically whether the dose was too high for animal toxicity tests or not. For human equivalent dose (HED) and duration of animal toxicity test, see Guidance for Industry by FDA [a] a) Guidance for Industry by FDA https://www.fda.gov/downloa...
[1] Toxic dose is only 27 times higher than human dose Gardasil per one dose used in the authors' experiment was 0.1 mL in mice (20g). Human equivalent dose (HED) of the one dose is 0.40 mL/kg (for 20 g mice: 0.1/0.02/12.3). Human dose for 33 kg (more precisely I found average body weight of Japanese girls aged 10 years was 31 to 35 kg) for Gardasil is 0.015 (0.5/33). Hence the dose (HED) used is approximately 27 times higher than the human dose. In this dose, tail paralysis was observed in 12 among 21 animals.
[2] Non toxic dose may be far lower One third (0.03mL per mouse) dose could induce tail paralysis. If one third dose does not induce tail paralysis at all, the non-adverse effect dose (NOAEL) may be 9 times higher than human dose. If one third dose induced tail paralysis, NOAEL may be only 3 time higher than human dose. Hence the dose used is not too high for animal toxicity test.
[3] Duration of test is too short or repeated dose is too few FDA recommends one month toxicity tests for an agent which is clinically used as a single dose or repeated for up to two weeks. Hence, 5 doses given in the authors’ experiments may be too few for animal toxicity test for an agent which is given 3 times in human.
[4] Exagerated dose and duration are necessary to detect potential toxicity in humans A researcher Zbinden (1963 [b]) at Roche Pharmaceutical said in 1963 “In order to increase the chances of recognizing possible toxic properties, the dose is raised above the therapeutically useful range, the duration of treatment is often lengthened.--- Thus, the toxicity experiment tries to imitate the clinical use of the drug and although bold exaggerations with respect to dose and duration of treatment are common and permissible, it is important that the future therapeutic applications in man guide the planning of a toxicity study” This means that toxicity studies should be conducted in exaggerated doses and periods of treatment in order to predict rarely occurring reactions in humans using a small number of animals.
[b] Zbinden G. Experimental and Clinical Aspects of Drug Toxicity. Adv Pharmacol. 1963;2:1-112.
Please also refer my review paper on the toxicity of oseltamivir [c]. [c] Hama R, Bennett C. The mechanisms of sudden-onset type adverse reactions to oseltamivir Version of Record online: 30 JUN 2016. DOI: 10.1111/ane.12629 https://onlinelibrary.wiley...
[5] “treatment-related response” suggests real toxicity of HPV vaccine Last but not least, I would like to add a phenomenon of a “treatment-related response” so to say, in the experiment. Tail palarysis was not observed in vehicle group (0/6) and pertussis toxin (Ptx) group (0/7) but 2 among 12 animals were observed in Gardasil (G) only group and 12 among 21 animals were observed in G+Ptx group. Chi square for linear trend was 13.85 (p=0.0002). This indicates that Gardasil alone could induce brain damage and in certain circumstances where blood brain barriers were damaged, HPV vaccine may damage human brain.
Best regards Rokuro Hama
SgtBarrett
And now in 2024, we have 2020 vision of the past to see how toxic most current vaccines truly are. And this HPV vaccine was one of the worst as proven in court cases and scientific papers, yet not nearly as bad as the Covid vaccine has proven to be. They are a tool for population control and reduction. But most people are too stupid to understand this even after all these facts have been laid bare across the globe in full daylight, repeatedly. May God have mercy on us.
Jean Oliveira
Unfortunately, too late...
Samuel Jones Replied to Jean Oliveira
Too late for what?
Causing Cancer & then Milking the Patients for $$$?
Politics needs to stay out of Science - let them check the findings & clarify it - you should know by now Cigarettes cause cancer - at one time - it was also "nonsense" for the goats employed by Politicians & Corporates - keep Science clean of Politics! This is people's lives we are dealing with
ranmu
Protest! It is an abusrd decision. The decision is not based on the scientific evidence.
It is the established method to make EAE model effectively in mice using pertussis toxin.
The articles describing this are elsewhere, look at the search results by google scholar below.
Did you consult the expert in experimental
neuroimmunology?
Please make contact with Dr Takashi Yamamura about the use of pertussis toxin. Look at his profile below.
https://www.ncnp.go.jp/nin/...
Active Induction of Experimental Autoimmune Encephalomyelitis in C57BL/6 Mice
In this model EAE is induced in female C57BL/6 mice by immunization with an emulsion of myelin oligodendrocyte glycoprotein (fragment 35–55) in complete Freund’s adjuvant, followed by administration of pertussis toxin in phosphate-buffered saline. EAE is evidenced by ascending flaccid paralysis with inflammation targeting the spinal cord. (fragment 35–55) in complete Freund’s adjuvant, followed by administration of pertussis toxin in phosphate-buffered saline. EAE is evidenced by ascending flaccid paralysis with inflammation targeting the spinal cord.
Mark Doc Replied to ranmu
The problem is not that they used pertussis toxin to induce EAE. The problem is that inducing EAE with pertussis toxin does not enable you to say anything about the role of HPV vaccination - since pertussis toxin alone is sufficent to induce EAE.
It's even more problematic to make the leap from saying that pertussis toxin can create neurological damage to saying that the HPV vaccine might be associated with neurological damage ... because you see signs of neurological deficit when you give it together with pertussis toxin.
I agree with those who say that the analysis was sloppy and the article should not have been published in its current form - which suggests peer-review was not as rigorous as it should have been.
ranmu Replied to Mark Doc
Please look at Figure 1.
https://www.nature.com/arti...
There was no clinical findings in mice administered pertussis toxin alone.
ranmu
Link to the articles about pertussis toxin to
make EAE in mice.
https://scholar.google.co.j...
Lucy Hill
Dr Alex Vorsters who recently obtained unrestricted educational grants from Merck said
"I'm pleased that finally they did manage to retract it, but it was a
very long process"
https://www.sciencedirect.c...
Conflict of interest
AV (Alex Vorsters) University of Antwerp obtained unrestricted educational grants from GSK, Merck and SPMSD
Andrea Boccelli
Sacred cow of the western medicine. The vaccine. Safe and effective by definition.
Samuel Jones Replied to Andrea Boccelli
Exactly
Kaos_vs_Control
EAE is the most commonly used experimental model for the human MS. However, there is great heterogeneity in the susceptibility to the induction,
the method of induction and the response to various immunological or
neuropharmacological interventions. These attributes create difficulties and inherently weaken the translation from EAE to the human disease. Without getting into a more critical discussion of the observed outcomes, one needs to take a step back and examine the actual design of the experiments.
These experiments were limited to behavior and anatomical observation. This alone is inadequate to draw conclusions as MS/EAE, well known to be a immunologically-based disease. Without the addition of FACS and cytokine responses, this data is preliminary at best.
Had the authors utilized standard immunological assays, they may have discovered that the HPV vaccine and PTX may have produced synergistic effects which may have provided insight into a number of different possibilities. For example, the ability of PTX to synergize with DAMPs (i.e. lipopolysaccharide) to elicit cellular responses.
The bottom line is that this article in its present condition (based on the methodology) should not have been approved for publication. It is a real shame as it does not reflect well on either the vaccine or the standards of the journal.
Skeptical Raptor
Excellent decision, but I'm afraid it is too little and too late for the men and women of Japan, who could be protected from 10s of thousands of HPV-related cancers.
https://www.skepticalraptor...
Suresh Panthee
Why the paper was accepted for publication then? This indicates the serious flaw in the peer review and editorial system. This situation is expected when you publish journals to make money. The publisher should explain why was the paper accepted and what they did from the 5th of May to 11th of November 2016.
ranmu
I refute the decision of retraction from the point of high-levels of HPV vaccine.
1. Administration of 24µg of Gardasil is proper because of:
Gardasil in 0.5 mL includes:
HPV type 6 L1 protein：20µg, HPV type 11 L
1 protein：40µg, HPV type 16 L1 protein ：40µg, HPV type 18 L1 protein：20µg; total 120µg
In the experiment 0.1mL of Gardasil was administered, this means the
24µg (120/5) of Gardasil.
Please look at the method of following article that murine model of HPV
type 16 L1 immunization. They use 20µg of Gardasil.
References
A recombinant human papillomavirus (HPV) type 16 L1–vaccinia virus murine challenge model demonstrates cell-mediated immunity against HPV virus-like particles. Journal of General Virology 80: 2471-2475, doi: 10.1099/0022-1317-80-9-2471
To examine the T cell response to VLP-16, groups of 6–8-week-old
BALB/c mice (Animal Unit, University of Cape Town) were immunized
intraperitoneally (i.p.) either with a single dose of 20 μg VLP-16 or with
three consecutive weekly doses of 10 μg VLP-16.
http://jgv.microbiologyrese...
2．I add the reference articles of the pertussis toxin for making EAE in mice.
It is a usual method to facilitate BBB to be damaged in order to effectively to induce EAE. In EAE model, by using pertussis toxin, the research of EAE progressed remarkably.
References
1. Suppression of Experimental Autoimmune Encephalomyelitis by Ghrelin. Immunol 2009; 183:2859-2866
Shortly after immunization and 48 h later, the mice were injected
i.p. with 200 ng of pertussis toxin (List Biological Laboratories). Clinical
scores of EAE were daily assigned as follows:
https://pdfs.semanticschola...
2. Ben-ning Zhang, Takashi Yamamura, Takayuki Kondo, Michio Fujiwara, Takeshi Tabira：Regulation of Experimental Autoimmune Encephalomyelitis by Natural Killer (NK) Cells. J Exp Med 1997
Booster immunization with an identical emulsion was given at both
sides of the flank 1 wk later. They were intravenously injected with 500 ng of
pertussis toxin (PT) in 500 μl of PBS shortly after, and 48 h after first
immunization.
http://jem.rupress.org/cont...
3. Look at the video presentation.
https://www.jove.com/video/...
4. Search of key words by Google Scholar, you can find many articles
https://scholar.google.co.j...
Lastly,
The reason of the retraction is not based on scientific basis.
I am not a personally anti-vaccine. I hope the establishment of Precision
Medicine, which includes the vaccinomics, adversomics. To elucidate the genetic and other factors for rare adverse reactions is necessary, that leads to the establishment of the vaccine confidence.
(https://www.ncbi.nlm.nih.go...
Vaccinomics, adversomics, and the immune response network theory: Individualized vaccinology in the 21st century)
정진원 Replied to ranmu
Mice are usually 20-30g and humans are 30-40kg at the age of vaccination. Therefore, 24ug for mice is 0.2kg for human. 300 time overdose. This level of overdose can not be justified.
ranmu Replied to 정진원
Please look at the answer to Dr. Kinugasa.
Toshie Ikeda
We will have a press conference on the paper of animal experiments on HPV vaccine that was forcibly retracted by Scientific Reports.
Date, 22th May Tuesday
Place, Press Club of Ministry of health, labor and welfare List of attendees;
Dr. Kusuki Nishioka, Dr.Toshihiro Nakajima, Dr.Yoshiyuki Kuroiwa, Dr. Shumpei Yokota, Dr. Satoko Aratani and Mr.Ikuro Nakamura.
Organizer, Japan Medical Research Foundation Contact;
info@jmrf-nanbyou.org Nakamura
Masato Kinugasa
I beg your pardon, I rewrite this according to the community guidelines.
In this paper, they wrote as below:
【 In fact, “seven times” more TUNEL-positive cells were observed in mice treated Gardasil and Ptx, while “four times” more apoptotic cells were found in mice treated with Gardasil alone than that apoptotic cells in vehicle mice.】
Where did they derive the definite values such as “seven times” or “four times” from? I couldn’t find any such data in the article. We are only presented with numerous microscopic pictures in Figure 3: “Detection of apoptosis by TUNEL in mouse brains”. Although apoptotic cells are indicated by arrows in this figure, I could hardly find those cells (=TUNEL-positive cells) even in the full size images.
If they write “seven times” or “four times”, actual numbers should be presented. Their pathological studies are lacking for any quantitative or statistical analysis, and therefore lacking in objectivity, reproducibility and credibility.
ranmu Replied to Masato Kinugasa
I speculate that the questions you raised were already solved during the review process of the long time period.
The decision of the retraction was based two facts.
1. Administration pertussis toxin
—This is right procedure as I listed the several references, and proved my assertion.
2. Excessive amount of Gardasil
—I listed one article before.
I show another article about a simple practice guide for dose conversion between animals and human.
24μg of Gardasil is overdose or not?
Human Girl 120μg/40kg, 3μg/kg (BW 35kg; 120μg/35kg, 3.43μg/kg)
To calucule AED, animal equivalent dose
3x12.3=36.9μg/kg (Look at Table 2) (BW35kg; 3.43x12.3=42.2μg/kg)
Body weight of mice 20g
36.9x0.02=0.738μg (BW35kg; 42.2X0.02=0.844μg)
24/0.738=32.5 (BW35kg; 24/0.844=28.4)
Almost everyone criticize that dose of more than 1000 times were administered by too simple comparison of the body weight between human and mice.
The correct estimate is about 32.5 times in girl of 40kg ( 28.4 times in girl of 35kg)
To examine the rare and serious adverse reactions, the dose given to mice is permissible.
In conclusion, the decision of the retraction of the article is false, indicating the poor abilities of the reviewers and editorial board.
https://www.ncbi.nlm.nih.go...
Masato Kinugasa Replied to ranmu
I'm afraid you have mistaken a calculation.
They really wrote as below:
>Groups of 11 week-old female C57BL/6 mice were intramuscularly administrated 100 μl of Gardasil or phosphate-buffered saline (PBS) for a total of five times.
100μl × 5 times=500μl=0.5 ml, that is equivalent to one dose of Gardasil for a girl. The average body weight of a pubertal girl is about 30 to 40 kg, and that of a mouse is 20 to 40 g. When the total dose for a mouse is compared with three times of inoculation of Gardasil (1.5 ml) for a girl, it is 250 to 667 times larger per body weight, much greater than 44 times as you wrote. At least they should have tried additional experiments with lower doses.
>I speculate that the questions you raised were already solved during the review process of the long time period.
Not solved at all. They may be among the most serious flaws of this article.
ranmu Replied to Masato Kinugasa
Human 3 times in total
Mouse 5 times in total
32.5x5/3= 54.2 times (BW 35kg: 28.4X5/3=47.3)
Please read the article I referred.
You should learn Animal Equivalent Dose.
The dose of 50 times is reasonable dose to test the toxicity of the drug.
The information by Dr. Rokuro Hama, Non-Profit Organization “Japan Institute of Pharmacovigilance”
was sent to me.
From the Textbook of toxicity in general:
Maximum dose of drug group is definite toxicity including death.
Minimum dose is no toxicity.
Intermediate dose is between them, and test the dose
-response relation.
Intermediate dose is 30~50 times of human equivalent dose (HED), showing some toxicity.
When there is no toxicity with minimum dose of about 10 times of HED, this dose of about 10 times is NOAEL ( No Observed Adverse Effect Level) without toxicty.
Safety factor is 10 times means NOAEL without toxicity is about 10 times.
Thus, dose with toxicity is 30~50 times of HED.
When there are no adverse reactions with 10 times of HED, dose of practically harmful is several times of 10 times that is 30~50 times. Definite toxicity including death is its 3~5 times , 90~150 times.
Please listen to the press interviews held May 22, 5 pm.
Everything will be diclosed, including the answers to your questions.
Masato Kinugasa Replied to ranmu
I have understood what you have meant. You are talking that we should use an equivalent dosage based on body surface area, and, in that way, their mice were given several score times dose of Gardasil compared with human dosage.
Thank you for teaching it. However, it is still too high dosage and they should have tested additionally with one digit lower dosage even based on a body surface area if they want to investigate its adverse effects on a human being.
Samuel Jones Replied to Masato Kinugasa
What you are telling us is if there is increased dosage - the vaccine will cause cancer? Is that NOT a problem?
How can you certify this? Man you people cannot read or write genetic code - you just cut & paste genes & pray - really - this is your science - more like Mental patients playing with themselves & lives of others - Can you write genetic code for One Blue arm & one White arm - no, its too sophisticated for you - your engineering vaccines are prone to do more damage because of Low Level tech you employ - its like baboons using Stone to open a container. Until you guys can credibly read/write genes - you need to stay away from genetic engineering - there is considerable increase in cancer world wide because of Big Pharma - this is FACT.
Causing Cancer, to Milk the Dying patients + some Leftist Mental Bull S**t about Population control
The real problem is when you are RICH, ELITE - you get isolated from Other Normal Humans & Develop Mental medical Conditions - this creates Delusions & because you have Money & thus Political Power - you start projects to "Control" population - this is why we need to Check Elite Rich & politicians for MEDICAL MENTAL problems arising due to Isolation & negligible Human contact
We dont want a crazy Rich guy obsessed with "Controlling Population" giving Cancer Causing vaccines to entire populations with Poorly written genetic code
Samuel Jones Replied to ranmu
We pretty much appreciate this work - Do not get discouraged or pressured by Big Pharma - we want to know if there is truth to link between Big Pharma vaccination & cancer - there may be efforts to purposefully cause illness to sell more cure - the Politicians & Corporates work hand in hand here - there is more politics here than science.
22nd May - please clear up the subject
(For Others: THIS IS SCIENCE - NOT POLITICS - keep Politics out of science. Period. What is really important is TRUTH - we must accept even if Big Pharma will be at loss - people are more important than the Elite Politicians & Pharma Corporates making money from Cancer)
SgtBarrett Replied to Samuel Jones
You wrote this 6 years ago. I wonder how you feel about politics being kept out of science now, after the fake Covid pandemic and deadly Covid Vaccine being pushed by every government agency on the planet. It's as if you could see the future.
Rokuro Hama
I would like to comment again with some revision because I cannot see my comment posted on 14th May.
Retraction of this excellent paper by two reasons (1. co-administration of pertussis toxin, 2. with high-levels of HPV vaccine) is an unbelievable wrong decision.
Methods using pertussis toxin is an established method for detecting autoimmune disorders in the brain as discussed by others. I would like to examine specifically whether the dose was too high for animal toxicity tests or not. For human equivalent dose (HED) and duration of animal toxicity test, see Guidance for Industry by FDA [a]
a) Guidance for Industry by FDA
https://www.fda.gov/downloa...
[1] Toxic dose is only 27 times higher than human dose
Gardasil per one dose used in the authors' experiment was 0.1 mL in mice (20g). Human equivalent dose (HED) of the one dose is 0.40 mL/kg (for 20 g mice: 0.1/0.02/12.3). Human dose for 33 kg (more precisely I found average body weight of Japanese girls aged 10 years was 31 to 35 kg) for Gardasil is 0.015 (0.5/33). Hence the dose (HED) used is approximately 27 times higher than the human dose. In this dose, tail paralysis was observed in 12 among 21 animals.
[2] Non toxic dose may be far lower
One third (0.03mL per mouse) dose could induce tail paralysis. If one third dose does not induce tail paralysis at all, the non-adverse effect dose (NOAEL) may be 9 times higher than human dose. If one third dose induced tail paralysis, NOAEL may be only 3 time higher than human dose. Hence the dose used is not too high for animal toxicity test.
[3] Duration of test is too short or repeated dose is too few
FDA recommends one month toxicity tests for an agent which is clinically used as a single dose or repeated for up to two weeks. Hence, 5 doses given in the authors’ experiments may be too few for animal toxicity test for an agent which is given 3 times in human.
[4] Exagerated dose and duration are necessary to detect potential toxicity in humans
A researcher Zbinden (1963 [b]) at Roche Pharmaceutical said in 1963 “In order to increase the chances of recognizing possible toxic properties, the dose is raised above the therapeutically useful range, the duration of treatment is often lengthened.--- Thus, the toxicity experiment tries to imitate the clinical use of the drug and although bold exaggerations with respect to dose and duration of treatment are common and permissible, it is important that the future therapeutic applications in man guide the planning of a toxicity study” This means that toxicity studies should be conducted in exaggerated doses and periods of treatment in order to predict rarely occurring reactions in humans using a small number of animals.
[b] Zbinden G. Experimental and Clinical Aspects of Drug Toxicity. Adv Pharmacol. 1963;2:1-112.
Please also refer my review paper on the toxicity of oseltamivir [c].
[c] Hama R, Bennett C. The mechanisms of sudden-onset type adverse reactions to oseltamivir Version of Record online: 30 JUN 2016.
DOI: 10.1111/ane.12629
https://onlinelibrary.wiley...
[5] “treatment-related response” suggests real toxicity of HPV vaccine
Last but not least, I would like to add a phenomenon of a “treatment-related response” so to say, in the experiment. Tail palarysis was not observed in vehicle group (0/6) and pertussis toxin (Ptx) group (0/7) but 2 among 12 animals were observed in Gardasil (G) only group and 12 among 21 animals were observed in G+Ptx group.
Chi square for linear trend was 13.85 (p=0.0002). This indicates that Gardasil alone could induce brain damage and in certain circumstances where blood brain barriers were damaged, HPV vaccine may damage human brain.
Best regards
Rokuro Hama
SgtBarrett
And now in 2024, we have 2020 vision of the past to see how toxic most current vaccines truly are. And this HPV vaccine was one of the worst as proven in court cases and scientific papers, yet not nearly as bad as the Covid vaccine has proven to be. They are a tool for population control and reduction. But most people are too stupid to understand this even after all these facts have been laid bare across the globe in full daylight, repeatedly. May God have mercy on us.