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The Law Offices of Stanley P. Kops has been involved in polio litigation,
with both the vaccine manufacturer and the United States of America, in
connection with cases involving paralytic poliomyelitis caused by the oral polio
vaccine. Among these cases are the reported cases of Berkovitz by Berkovitz
v. United States; 108 S.Ct. 1954 (1988); Griffin v. United States of
America, 500 F.2d 1059 (3d Cir. 1974); In Re Sabin, 763 F.Supp. 811
(D.Md. 1991); Loge v. United States of America, 662 F.2d 1268 (1981);
Williams v. American Cyanamid, 591 F.Supp. 381 (1984); Campagna v.
American Cyanamid, 767 A.2d 996 (NJ 2001); and numerous other cases.
During the course of the various litigation, documents produced in part dealt
with the issue of SV40. In calendar year 2000, after reading numerous scientific
papers, Stanley P. Kops submitted for peer review an article entitled "Oral
Polio Vaccine and Human Cancer: A Reassessment of SV40 as a Contaminant Based
upon Legal Documents," Anticancer Research 20: 4745-4750 (2000). It is
believed that this is the first instance where an attorney has had an article
published after peer review by medical and scientific experts.
Kops SP. Oral polio vaccine and human cancer: a reassessment of SV40 as a contaminant based upon legal documents. Anticancer Res. 2000 Nov-Dec;20(6C):4745-9. Review. PMID: 11205211 [PubMed - indexed for MEDLINE]
ORAL POLIO VACCINE AND HUMAN CANCER: A REASSESSMENT OF SV40 AS
A CONTAMINANT BASED UPON LEGAL DOCUMENTS.
ABSTRACT
To date, the scientific literature and research examining SV40 and
cancer-related diseases has been based upon an assumption that SV40 was not
present in any poliovirus vaccine administered in the United States and was
removed from the killed polio vaccine by 1963. The basis for this presumption
has been that the regulations for live oral polio vaccine required that SV40 be
removed from the seeds and monovalent pools ultimately produced in the
manufacturing process. The Division of Biologic Standards permitted an
additional two tissue culture passages -- from three to five -- in order to
allow manufacturers the ability to remove this contaminant from the oral
poliovirus vaccines then awaiting licensure. The confirmation of the removal by
one drug manufacturer, Lederle, has been made public at an international
symposium in January 1997, where its representatives stated that all of
Lederle's seeds had been tested and screened to assure that it was free from
SV40 virus. However, in litigation involving the Lederle oral polio vaccine, the
manufacturer's internal documents failed to reveal such removal in all of the
seeds. The absence of confirmatory testing of the seeds, as well as testimony of
a Lederle manager, indicate that this claim of removal of SV40 and the testing
for SV40 in all the seeds cannot be fully substantiated. These legal documents
and testimony indicate that the scientific community should not be content with
prior assumptions that SV40 could not have been in the oral polio vaccine. Only
further investigation by outside scientific and independent researchers who can
review the test results claimed in the January 1997 meeting and who can conduct
their own independent evaluations by testing all the seeds and individual
monovalent pools will assure that SV40 has not been present in commercially sold
oral poliovirus vaccine manufactured by Lederle.
In recent scientific papers in regard to mesothelioma and the role of
SV40, the Simian Virus found in polio vaccines, (1-5) the authors restated a
premise that has been uniformly accepted in the scientific literature in regard
to SV40: that prior to 1963, SV40 was a possible contaminant in poliovirus
vaccine, but after 1963, it was no longer a contaminant. Other cancers, brain
and bone tumors, have also been associated with SV 40 infection being detected
in the tissues. (6) Though these and other articles have stated that both
inactivated vaccine and oral polio vaccine were free of SV40 after 1963, that
premise warrants re-examination in regard to the oral vaccine manufactured by at
least one of the three licensed to produce live oral polio virus vaccine
manufacturers.
At the conference held in January of 1997 at which the NIH, the FDA and
the CDC met in Bethesda, Maryland joined by scientists from around the world,
Dr. M. R. Hilleman of the Merck Institute reviewed the historical record of when
SV40 was discovered as a polio vaccine contaminant and what was done to assure
its removal, differentiating between oral and killed poliovirus products. (7)
That meeting was reviewed in Carbone, et al., 1997a. (8)
Dr. Hilleman stated that live poliovirus vaccine manufacturers were
required to assure that their product was free of adventitious agents/extraneous
microbial agents -- including SV40 -- from the start of the manufacturing
process, as this was mandated by the regulations. SV40 had already been detected
prior to the licensure of the first oral poliovirus vaccine in the United States
and had already been discussed at the Pan American Health Conference, PAHO, held
in June of 1960. (9) In August 1960, meetings were held between potential
vaccine manufacturers, members of the Surgeon General's committee, and officials
of the Division of Biological Standards, part of the National Institutes of
Health, which was the regulatory body, all of whose scientists were helping to
write the proposed regulations which were to govern oral polio virus vaccine
manufacture. (10)
In August of 1960, the proposed regulations provided that the oral polio
vaccine sold in the United States could not be more than three tissue culture
passages beyond the original strain material. (11) But when the regulations were
enacted in March of 1961, the language of the final regulations had been
amended, permitting up to five tissue culture passages. (12) The final
regulations which became law on March 25, 1961 provided that virus in the final
vaccine shall represent no more than five tissue culture passages from the
original strain, each of which shall have met the criteria of acceptability
prescribed in Sec. 73.110(b). Whether SV 40 was removed from Sabin Oral Polio
Virus strains, remains a serious and unanswered question.
On March 17, 1961, James Shannon, M.D., then the Director of the National
Institutes of Health, advised the Surgeon General of the United States, Luther
L. Terry, M.D., that the proposed regulations had been amended and two
additional tissue culture passages were being recommended. Permitting five
passages was to enable the manufacturers to remove SV40 from the Sabin original
strains of the three types of oral live poliovirus vaccine and would permit the
seeds to be free of SV40 and any other adventitious agents. "This recommendation
was made by the Surgeon General's Committee on Poliomyelitis control based upon
its judgment that the removal of adventitious agents particularly the
vacuolating and foamy, will necessitate more than three virus passages and that
five passages will not have an adverse effect upon the vaccine." (13)
The Federal Regulations issued on March 25, 1961 also required that "Each
seed virus used in the manufacture shall be demonstrated to be free of
extraneous microbial agents." (12) Similar language can be found in every
subsequent modification of these regulations. (14) The term "manufacture" as
contained in the Regulations is defined as follows: "Manufacturing" means all
steps in propagation or manufacture and preparation of products and includes but
is not limited to filling, testing, labeling, packaging, and storage by the
manufacturer. (15)
In the January 1997 meeting in Bethesda, Maryland, a paper was presented
by the manufacturer of the oral polio vaccine, Lederle, which would lead those
who participated at the meeting, and the readers of the paper that followed that
meeting, to believe that all polio vaccines produced by that company after 1961
were free of the contaminant SV40, or as Lederle put it, "That all subsequent
working seed strains have been prepared in CMK cells and screened to assure that
they are free from SV40 virus." (16) The Brock paper describes in detail the
methods claimed to have been utilized in the testing and screening by Lederle
for SV 40. At that meeting for which a transcript does exist, Lederle discussed
in detail the procedures for neurtralizing the SV 40, testing for SV 40 and the
method utilized. (17) This discussion by Lederle does not indicate that any
tissue culture passages was utilized to remove SV 40, but rather antisera was
utilized in the preparation of the master viral strains. "Master viral strains
(seeds) have been prepared in the presence of SV 40 virus antiserum. All
subsequent working seed strains have been prepared in CMK tissue and screened to
assure they're free of SV 40 virus." There is no indication in this description,
or in the Brock paper subsequently published, that modern molecular techniques
were utilized in this screening process.
In the course of litigation conducted on behalf of persons with paralysis
claimed to have resulted from exposure to the live Orimune polio vaccine product
manufactured by Lederle, documents were obtained indicating that some of these
statements claiming removal of SV40 from the vaccine seeds should be re-examined
and critically reviewed. The content of these legal documents question the
assumption that oral polio vaccine produced after 1961 by at least Lederle, one
of the three United States manufacturers, was fully tested at every stage of the
manufacturing process and that the results of these tests indicate that they
were free of SV40.
Between 1961 and 1976 there were three manufacturers of oral poliovirus
vaccine in the United States. In the early 1970's, Wyeth Laboratories withdrew
its vaccine from the marketplace. By the end of 1976, Pfizer stopped
manufacturing vaccine for sale in the United States. From the latter part of
1977 until the end of 1999, only Lederle has manufactured this product for the
United States market. In the year 2000, the Centers for Disease Control no
longer recommended the use of Oral Polio Vaccine in the United States. (18)
Whether it is still being manufactured and available for sale, is unknown by
this author.
In an internal document of Lederle dated November 8, 1961, approximately
eight months after the live oral polio virus regulations became effective, test
results disclosed three out of the first fifteen vaccine pools it had utilized
to secure both its monovalent license (in 1962) and its trivalent license (in
1963) may have contained SV40 at the PCB 2 level. A monovalent dose of oral
polio vaccine contains only one type of each of the three types of polio
viruses. A trivalent dose is where all three types of oral polio virus vaccines
are combined into a single dose. The specific pools that were identified as
having this possible contaminant were lots number 114 of Type I, 216 of Type II
and 317 of Type III. All three of these pools were utilized in vaccine
commercially sold for several years following licensure in the United States,
both in the monovalent and trivalent form of the product. (19) Dr. Roderick
Murray, Director of the Division of Biologic Standards, the regulatory agency
who has the ultimate authority to enforce the federal regulations for all
vaccines manufactured and sold in the United States, from 1961 until 1972, was
aware, according to this internal documentation, of the presence of SV 40.
The PCB 1 level is attained when the pooled fluids are taken from 25% of
the production control vessels at the time of harvest. The PCB 2 level is when
pooled fluids are taken from 25% of the production control vessels 14 days after
viral inoculation of the production vessels. All of this testing is mandated in
the regulations and becomes part of the final protocol submitted to the
government for approval.
The Lederle representatives in the January 1997 meeting described the
mandated testing as follows: "Viral harvest samples are sent to the quality
control laboratory for evaluation and the rest of the harvested fluids are
stored frozen until testing is completed. Fluids from these bottles are again
tested to detect the presence of any transmissible microbial agent in CMK for 14
days, followed by a subculture in CMK for another 14 days. Viral harvest fluids
are also tested again in Rhesus monkey kidney cells, rabbit kidney cells, and
BSC-1 cells, all for 14 days. Samples are also tested to demonstrate the absence
of microplasma. Quality assurance releases a virus harvest for further
processing when all testing has been completed with satisfactory results - for
the original cell culture, the cell culture fluid testing and subcultures, and
the viral harvest samples. In summary, over four thousand individual cell
culture observations are made during the quality control testing of a single
trivalent bulk lot. Any product contamination observed at any point, results in
rejection." (17)
The licensing lots utilized by American Cyanamid for both its monovalent
and trivalent licenses were Type I, lots numbered 113 to 117; for its Type II,
lots numbered 213 to 217; and for its Type III, lots numbered 313 to 317. (20)
Testimony of Dr. Mary Ritchey in 1998, then Vice President of Operations
for the Wyeth-Lederle Vaccines and Pediatric Business Group, was that American
Cyanamid could not now determine that all of the polio vaccine seeds and strains
were tested for SV40, as Lederle did not have protocols in its possession for
all of its strain and seed materials. (21) Dr. Ritchey testified that there were
no protocols for any of the three master seeds, Type I, Type II and Type III.
(21) She testified there were no protocols for any of the following seed
numbers: 3101, 3102, 3107, 1102, 45B51, 2107, and 45B52. (21) Dr. Ritchey also
testified that over the years, American Cyanamid had utilized intermediate
seeds, in addition to the aforementioned seeds, in the manufacturing process of
its oral polio virus vaccine. There are no records that these seeds were tested
for SV40. (21)
It is this history which brings into question the assumptions heretofore
made by the scientific community based upon prior assurances of safety testing
and results that indicated that all of the seeds had passed the screening
process as stated in the January 1997 meeting in Bethesda, Maryland.
In documents submitted to Congress prior to the licensing of the Orimune
product and prior to the enactment of the regulatory system governing the
production and sale of the oral polio vaccine, Merck & Co. specifically declined
to manufacture the Sabin vaccine, in part because of its concerns about the
question of the contaminant SV40. In a letter addressed to the Surgeon General
of the United States, Merck & Co. stated the following:
"We have, however, once again reviewed our decision in the light of your letter and of the standards for live poliovirus vaccine published in the Federal Register. Our scientific staff have emphasized to us that there are a number of serious scientific and technical problems that must be solved before we could engage in large-scale production of live poliovirus vaccine. Most important among these is the problem of extraneous contaminating simian viruses that may be extremely difficult to eliminate and which may be difficult if not impossible to detect at the present stage of the technology." (22) |
Dr. Albert Sabin had been advised that the testing performed by Merck &
Co. on his original seed strains for the presence of SV40 may not detect the
presence or absence of SV40, and so informed American Cyanamid in correspondence
in 1962. (23)
In 1979, American Cyanamid's technical superintendent of polio vaccine
production, when preparing to submit documents to a foreign licensing authority,
stated the following in an internal memoranda: "It should be made clear that
Lederle did not test the original Sabin seeds for extraneous agents or
neurovirulence since only 50 ml or less of each seed were provided by Dr.
Sabin." (24)
The import of this testimony and the referenced Lederle internal
documents challenge the conclusions previously advanced in scientific journals
that people born after 1963 who tested positive for SV40 either became
contaminated as a result of human-to-human transmission, or of placental
transference. The scientific community, having been assured by the principal,
and eventually sole, OPV manufacturer that SV40 had been removed never conducted
research to determine whether or not that was accurate. No investigation is
contained anywhere in the literature to verify the results of testing of all of
the seeds of the Orimune manufacturer, Lederle, by independent scientific
investigators to determine whether the seeds, including intermediate seeds, were
free of SV40.
There has been no scientific literature which has reviewed and critically
analyzed the Lederle documents submitted to the government and/or Lederle's own
internal documents showing that each and every seed, including intermediate
seeds, were tested and free from SV40 contamination.
There has been no scientific investigation to determine whether or not
the post-1963 mesothelioma and other cancerous condition cases in which SV40 has
been detected or isolated from tissue samples were caused by vaccine that
individual was given or through contact with someone who had been recently
administered a vaccine that may have contained the SV40 contaminant.
The scientific community should now require an inquiry into whether all
the seeds utilized in production of the Orimune product were tested for SV40 and
what the test results revealed for each of the seeds utilized in the
manufacturing process, including intermediate seeds. Unfortunately, there is no
documented evidence that either Lederle or the FDA could produce to substantiate
the claim that all the seeds were tested and that they all passed the mandated
standards. In litigation, demands were made both on the United States in the
In Re Sabin Litigation, and on American Cyanamid in numerous cases now
pending, and the documents still have not been furnished, showing the testing of
each and every seed utilized by American Cyanamid in its manufacturing process
for the product Orimune. Further investigation should be conducted to determine
whether any of the seeds of each of the three types of the monovalent pools
comprising the trivalent vaccine given to every newborn in the United States for
decades did have SV40 as a contaminant in any of the strains, seeds and
monovalent pools. Only if all tests are negative can there be any assurance that
SV40- contaminated vaccine did not reach the vaccinees and/or their contacts.
The scientific literature indicates that mesothelioma can be initiated,
promoted, and/or accelerated by a combination of various factors including SV40.
This breakthrough in scientific research now requires a complete appraisal of
whether the oral vaccine used in the United States from 1961 until 2000 could
have been a contributing cause. The determination of where the SV40 which has
been isolated in post-1961 cases in conjunction with various cancers came from
is an essential step in continuing any meaningful scientific investigation into
these cancers.
The answer to many of the questions raised herein is available from the
vaccine manufacturer or the regulatory agency, presently the Food and Drug
Administration. They can furnish their records and the seed stocks and
monovalent pool stocks in their storage facilities to the scientific community.
They should furnish to the scientific community their internal records including
all test results showing that each of the strain, seeds and intermediate seeds,
as well as the monovalent pools derived therefrom, without exception, were
tested and that these results revealed that SV40 had been successfully and
completely eliminated from oral polio vaccine.
Federal regulations required that protocols be kept of all tests
performed by the manufacturer, including those to determine whether or not SV40
was present in its product. (25) In an affidavit filed in another litigation
case, Lederle swore that every seed was submitted to the government for the
government's review and approved by the government. (26) This sworn statement,
and the Brock paper (16) and presentation (17) conflicts with the sworn
testimony of Dr. Ritchey. (21) Only demands by the scientific community
requesting the actual documents, protocols and test results can fully answer
this apparent contradiction. If these protocols exist, then the data should be
made available for review to the medical community at large. If they do not
exist, then the medical community should be so informed.
Capability to test with more precision and accuracy for SV40 has
increased as scientific knowledge has advanced. (27) Therefore, testing of seed
material, including intermediate seed material and monovalent pools, should be
performed to determine whether today's enhanced testing technology reveals the
presence of SV40 in any product and in any seed that was used in the
manufacturing process from 1961 until the present.
Full details of how the SV40 present in the oral polio vaccine was
removed from the original strains, seeds and final product, should now be fully
disclosed to the scientific community. Only then can epidemiologic and oncologic
analysis and discussion of the role, if any, of SV40 in tumor processes be based
upon a fully informed scientific community which is the best available
information on this important area of on-going scientific study and research.
REFERENCE
(1) Murthy, S.S., Testa, J.R., Asbestos, Chromosomal Deletions, and Tumor
Suppressor Gene Alterations in Human Malignant Mesothelioma. J.Cell. Physiol.,
180: 150-157 (1999)
(2) Butel, J. and Lednicky J., Cell and molecular biology of simian virus 40:
implications for human infections and disease. J. National Cancer Inst.,
91: 119-134, 1999
(3) Carbone, M., Simian Virus 40 and Human Tumors: It is Time to Study
Mechanisms. J.Cell. Biochemistry, 76: 189-193 (1999)
(4) Shivapurkar, N., Wiethege, T., Wistuba, I., Salomon, E., Milchgrub, S,
Muller, K., Churg, A, Pass, H. and Gazdar, A., Presence of Simian Virus 40
Sequences in Malignant Mesotheliomas and Mesothelial Cell Proliferatios.
J.Cell. Biochemistry, 76: 181-188 (1999)
(5) Waheed, Guo, Chen, Welser,Nguyen, and Schrump, Antisense to SV40 early gene
region induces growth arrest and apoptosis in T-Antigen - positive human pleural
mesothelioma cells. Cancer Research 59, 6068-6073, 1999.
(6) Carbone, M., Fisher, S., Powers, A., Pass, H.I., and Rizzo, P. New molecular
and epidemiological issues in mesotheliomas: role of SV40. J. Cell. Physiol.,
180: 167-172, 1999.
(7) Hilleman, M.R., Discovery of Simian Virus 40(SV40) and its Relationship to
Poliomyelitis Virus Vaccines. Dev. Biol. Stand., Basel, Karger, 1998,
vol. 94, pp. 183-190.
(8) Carbone, M., Rizzo, P., Pass HI, 1997a. Simian virus 40, poliovaccines, and
human tumors: a review of recent developments. Oncogene 15:1877-1888.
(9) Sweet BH, Hilleman MR: 6. detection of a "non-detectable" simian virus
(vacuolating agent) present in rhesus and cynomolgus monkey-kidney cell culture
material. A preliminary report. Second International Conference on Live
Poliovirus Vaccines, Pan American Health Organization and the World Health
Organization, Washington, DC 6-7 June, 1960, pp 79-85.
(10) Transcript of Proceeding of Department of Health, Education and Welfare, U.
S. Public Health Service, NIH, Conf. On Production and Testing Requirements for
Live Poliovirus Vaccine, Thurs. and Fri., August 18 & 19, 1960, Bethesda, MD.
U.S. Exhibit No. 353-354 - In Re Sabin Polio Vaccine Litigation, MDL 780,
U.S.D.C., MD - Baltimore, Maryland.
(11) Proposed Regulations, August 1960. Plaintiff's Exhibit No. 43 - In Re
Sabin Polio Vaccine Litigation, MDL 780, U.S.D.C., MD - Baltimore, Maryland.
(12) Federal Register, Saturday, March 25, 1961 at page 2565-2568, Sec. 73.110,
et seq.
(13) Memorandum from Director of N.I.H. to Surgeon General of the United States
dated March 16, 1961. Defendant's Exhibit No. 33 - In Re Sabin Polio Vaccine
Litigation, MDL 780, U.S.D.C., MD - Baltimore, Maryland.
(14) 21 Code of Federal Regulations 630.10(b)(3): "Each seed virus used in
manufacture shall be demonstrated to be free of extraneous microbial agents
except for unavoidable bacteriophage."
(15) 21 Code of Federal Regulations, 600.3(u).
(16) Brock, Kelleher and Zlotnick, Developments in Biologic Standardization,
Simian Virus 40 (SV40): A Possible Human Polyvirus; Product Quality Control
testing for the Oral Polio Vaccine. 217-219, 1998
(17) Transcript of Proceedings 300-307 of the Developments in Biological
Standards, January 1997.
(18) Recommendation of the CDC's Advisory Committee on Immunization Practices,
June 17, 1999.
(19) Lederle internal memorandum from Dr. Biddle to Dr. Danielson dated November
8, 1961, submitted in response to discovery requests in the polio litigation.
(20) Letter of submission of American Cyanamid to the United States dated
November 6, 1961. Defendant's Exhibit No. 57- In Re Sabin Polio Vaccine
Litigation, MDL 780, U.S.D.C., MD - Baltimore, Maryland.
(21) Testimony of Mary Ritchey, Ph.D., Vice President of Operations,
Wyeth-Lederle Vaccines and Pediatrics Business Group, dated April 14, 1998, in
the U.S.D.C. for the E.D. of Ohio, Civil Action No. 94-423 and 94-425.
(22) Letter from John T. Conner of Merck & Co. to Dr. Leroy Burney, Surgeon
General of the United States, dated 12/16/60 - Plaintiff's Exhibit No. 54 -
In Re Sabin Polio Vaccine Litigation, MDL 780, U.S.D.C., MD - Baltimore,
Maryland.
(23) Letter from Albert Sabin, M.D. to Dr. I.S. Danielson, Lederle Laboratories,
dated October 8, 1962 - Plaintiff's Exhibit No. 178 - In Re Sabin Polio
Vaccine Litigation, MDL 780, U.S.D.C., MD - Baltimore, Maryland.
(24) Lederle internal memorandum dated March 14, 1979 - Plaintiff's Exhibit No.
483 - In Re Sabin Polio Vaccine Litigation, MDL 780, U.S.D.C., MD -
Baltimore, Maryland.
(25) 21 Code of Federal Regulations § 630.17(e).
(26) Sworn affidavit in Stuart v. American Cyanamid Co.,
U.S.D.C.,S.D.N.Y. 95 Civ. 4940 dated 2/5/96 by Lederle's Senior Director and
Responsible Head Regulatory Affairs and Technical Assessment.
(27) Rizzo P, DiResta I, Powers A, Rattner H, and Carbone M. Unique strains of
SV 40 in commercial poliovaccines from 1955 not readily identifiable with
current testing for SV 40 infection. Cancer Res. 59:60103-6108, 1999.