incident referred to in the original memorandum concerned discoveries of DBS senior scientist Dr. Calvin Aulisio and not the work of Dr. Kendall Smith." Comment The "contaminants in duck embryo cells" that Morris and Turner state that their original memo was intended to refer to are even less substantial than those of Dr. Kendall Smith. The procedure used by Dr. Aulisio was to treat duck embryo tissue with chicken serum (containing antibodies to avian leucosis) and then after removal of the excess of chicken serum, to attempt to identify chicken antibodies retained in the preparation by staining with fluorescent antibodies directed against chicken gamma globulin. In preparations of duck embryo tissues areas of fluorescence were noted. The fluorescence was of two types: diffuse surface staining of duck cell membranes in an occasional preparation and smaller discrete "particles" in the cytoplasm of some of the duck cells in most preparations. Despite repeated attempts to obtain multiplication such as should be possible with a viral contaminant, Dr. Aulisio was unable to obtain more than the amount of fluorescence with which he started. After a number of fruitless attempts to reach some identification of the fluorescent material, Dr. Aulisio was quite prepared to accept the advice of the group considering the licens ing of rubella vaccine and abandon these studies, a course of action with which he agreed. It is not true that "Since the presentation of the Morris/Turner memorandum, the DBS begun efforts to determine the nature of the particles." The "unexplained deaths of ducks" were presumably unexplained to Morris and Turner (or Dr. Whitman who must have supplied the information), but an adequate explanation of the deaths is available and was known to the ad hoc committee. The deaths were due to trauma with and without superimposed infection. Furthermore the deaths were no more frequent in ducks inoculated with rubella vaccine than in an equal group of uninoculated controls G. Morris/Turner (abbreviated) "Concerning the slow virus problem, the committee again fails to understand the failure of DBS * * *. The point made about DBS was that 'in 1962 it was recognized that "slow viruses" were potential contaminants of cell cultures employed in the manufacture of vaccines for use in man' and that DBS has from that time to the present discouraged all research into slow viruses including and most iportant their ability to contaminate vaccine cell cultures. The discouragement of this research took extreme forms, including destruction of 4.000 mice on long-term scrapie studies ostensibly to make room for other important DBS research. The room from which the mice were removed remained vacant for over one year after their destruction." Comment It is difficult to perceive how the innoculation of 4,000 mice with scrapie can be considered highly relevant to the possible contamination of vaccine cell cultures with slow viruses. If the question under study was the behavior of scrapie virus in a host other than its normal host, then there is adequate reason to doubt the desirability of expending DBS resources for this purpose in view of the extensive studies of slow viruses being carried out by Gajdusek and Gibbs in MINDS and Hadlow in NIAID, the latter including study of scrapie infections in mice. If Dr. Morris had been seeking evidence of slow virus contamination of vaccine substrates one might expect that he would at least have been using such substrates as starting materials and possibly applying procedures such as those used successfully by Gibbs and Gajdusek in the demonstration of slow viruses in Kuru and in Jacobs-Creutzfeld disease. There is no need to discuss the question of who or what was endangered by the introduction of scrapie into DBS laboratories. The fact remains that the introduction had not been authorized, nor had it even been discussed with Dr. Morris' laboratory chief or the Director of DBS. No Department of Agriculture officer can assume this responsibility. H. & I. Morris/Turner statement (abbreviated) 41* * * the committee's belief that there has been no discouragement of important scientific work cannot be supported * * *." Comment Since Morris and Turner here merely restate that they disagree with the ad hoc committee in a matter which must be considered one of opinion, there is no substantial matter requiring comment. J.-1. Morris/Turner statement (abbreviated) "The fact that the varicella vaccine clinical trial was 'completely legal' does not answer the point. DBS wrote to a company asking for the answer to certain questions which the company's investigator felt should have been asked prior to undertaking clinical trials ***. The letter from DBS said 'Your notice of claimed Investigational Exemption for a New Drug * ** has been received and assigned the code number DBS-IND 375 * *.' The legality of the trial is at best confused again by the impression of DBS legal interpretations. However, even if the trial was perfectly legal, that does not mean that the recipients of the experimental vaccine on clinical trial received enough protection Comment Morris and Turner again speak of confusion which can only be in their own minds. Although they misunderstood or misrepresented the regulations governing the matter of the varicella vaccine test, the facts are that (1) DBS has control over only those vaccine investigations in which the vaccine crosses a state line and (2) the regulations in effect at the time required no waiting period between the submission of an IND and initiation of clinical trials. The latter regulation has now been revised to require a waiting period for the regulatory agency to respond or require additional information. Although most pharmaceutical manufacturers do not limit their testing to the state of manufacture in order to avoid regulation, the only additional protection that can be legally enforced requires action on the part of the state. In any case, the central point at issue in the DBS letter, cited by Morris/Turner, was that the varicella vaccine not be given by mouth. Participants in the study were given the vaccine by another route and thus protected against any potential hazard of oral administration. J-2. Morris/Turner statement (abbreviated) "The committee addresses the fact that one industry researcher had doubts about the use of mumps vaccine because the seed strain might be neurovirulent by citing another DBS memorandum. That memorandum states that 'the attenuated mumps virus did not replicate in monkeys even in the central nervous system (CNS) and that, although there were lesions of the choroid plexus and ependyma, they were not caused by replication of the mumps virus since no virus could be recovered from these tissues.' This is an exceedingly dangerous reasoning. Non-replicating measles virus gives exactly the same experimental results in monkeys *** but can cause an extremely neurovirulent disease SSPE (subacute sclerosing pan encephalitis) in man * * *. The ad hoc committee's comments on Rubin's procedure for detecting Resistance Inducing Factor (the RIF test in controversy) reveals how DBS officials were once again able to mislead the committee ***. Specifically, the committee failed to consult with the official responsible for conducting the RIF test at DBS, Dr. Calvin Aulisio * * *. Since the release of the Morris/Turner Memorandum, the DBS has moved to improve its procedures to detect the presence of avian leucosis viruses in vaccines. The committee states that 'while this virus (avian leucosis) is oncogenic in chickens, no evidence has yet been observed of an adverse effect on man "The implication of the statement that a virus which causes cancer in animals should not be considered dangerous until it is shown to cause cancer in humans. This is the position which the committee took in reference to the SV40 contamination of polio and adenovirus vaccine. Once again to maintain that position it had to pick and choose the evidence it received. In a memorandum to the Director of NIH concerning vaccine safety with respect to contamination by oncogenic viruses, Dr. Wallace Rowe *** addresses this problem * * *. Dr. Rowe says 'I see no solution other than establishing a truly first rate basic research program on oncogenic viruses within DBS ***.' The failure of the ad hoc committee to note Dr. Rowe's observations reveals that the committee's comments on cancercausing contaminants of vaccine did not fully respond to the serious nature of the potential harm." Comments The "rebuttal" here seems to be, in part, to a memorandum made available to the committee rather than to the statement of the ad hoc committee itself since the latter did not comment on the non-recovery of the virus from the lesions. The committee did note that the material in the vaccine that was associated with the production of the lesions was separable from the virus on a density gradient. If 77-615 O 7251 the material was not a virus to begin with the possibility of a non-replicating virus like that said to be involved in SSPE is not a real consideration. The fact that the material producing a cellular response on injection into monkey brain was not a virus renders the use of the term “neurovirulence” inappropriate and, since vaccines are not generally administered intracerebrally to man, makes the finding of the cellular response irrelevant to the safety of the vaccine. The so-called lesions seen in the central nervous system (CNS) of some monkeys after intracerebral inoculation of several live virus vaccines such as mumps, measles and rubella are slight perivascular cuffing by lymphocytes and lymphocytic infiltration of the choroid plexus. These lesions are a universal response of the monkey central nervous system to irritants. Not only is there no evidence of replication of the mumps virus in the central nervous system but, in contrast to SSPE in man, no evidence of the fingerprints of the virus can be seen, either by recovery of the virus by cocultivation of the brain tissue with sensitive indicator cell culture systems, by fluorescent antibody techniques or any other known methods. The lesions seen in the central nervous system of some monkeys after inoculation of mumps vaccine are similar to those seen in about 0.5 per cent of uninoculated monkeys and are similar to those described by the subcommittee on Monkey Testing of Poliomyelitis Vaccine chaired by Dr. David Bodian as published in the American Journal of Hygiene, 1956. No significant neuropathologic lesions have been seen in all the years of testing lots of measles, mumps and rubella vaccines. It is difficult to understand why the statement is made by Morris/Turner that the committee failed to consult Dr. Aulisio when in the second subsequent paragraph it is stated (correctly) that the committee had the benefit of a detailed memorandum from Dr. Aulisio, the memorandum having been prepared at the committee's request. A reasonable reading of the statement of the committee (to the effect that avian leucosis virus has not been found to produce adverse effects in man despite its inadvertent inclusion in yellow fever vaccine) does not lead to the inference that the committee holds that a substance that "causes cancer in animals should not be considered dangerous until it is shown to cause cancer in humans." Nor is this the position that "the committee took in reference to the SV40 contamination of polio and adenovirus vaccine." The statements of the committee with respect to both types of contamination were based on an assessment of the evidence of possible harm done during more or less long periods during which vaccines containing unrecognized adventitious agents had been administered to man. The fact that no ill-effects were produced gives a certain amount of relief from fears of the dangers of the particular contaminants involved, but has nothing whatever to do with whether a substance that causes cancer in animals should be considered dangerous until it is shown to cause cancer in man. If the agent is recognized, it is to be avoided and there is nothing either in the statements of the committee (or in the actions of DBS) that can lead to an honest inference to the contrary. Since the committee did not take the position attributed to it, it is also not true that the committee "had to pick and choose the evidence it received" in order "to maintain" the alleged position. Dr. Rowe is a scientist respected generally as well as by the members of the committee, but it is difficult to take seriously his conclusion that DBS needs a basic research program on oncogenic viruses when DBS is imbedded in an environment in which there is a most extensive program in the study of oncogenic viruses and when work in that field is being supported to the tune of tens of millions of dollars. That DBS must be alert to the possible presence of oncogenic viruses in vaccines is an obvious truism with which neither the committee nor DBS could possibly differ. Furthermore DBS has had (since 1965) a modest program of research aimed at the detection of possible oncogens in vaccines. The J.-3 comments relate largely to Dr. Morris' grievance, a matter currently under adjudication in the Office of the Secretary. They will not be discussed at this time. EXHIBIT 58 MAY 10, 1972. To: Dr. Robert Q. Marston, Director, National Institutes of Health. From: James S. Turner and Dr. J. Anthony Morris. Subject: Scientific Mismanagement at DBS-Comments on Two Documents entitled: (1) Comments on Morris and Turner "Rebuttal" to Ad Hoc Committee Report on DBS Scientific Management, and (2) Staff Analysis of Morris and Turner "Rebuttal" to Ad Hoc Committee Report on DBS Scientific Management. 1. The second of these two documents appears to be an edited form of the first in which some of the more unscientific personal language has been removed. The first document is unsigned and undated, while the second states only Office of the Director of National Institutes of Health. It is unclear who drafted either; however, apparently the Director's Office takes responsibility for both For that reason this set of comments on the two documents is directed to you. 2. It is unclear why one version was submitted to the Senate Appropriations Committee and another version given to the press. However, since the scientific substance of both memos is essentially the same, the errors of one are essentially the scientific errors of the other. For that reason they are responded to jointly. A. Release of vaccine containing live polio virus.-The NIH drafters miss the point again. If they say "Dr. Eddy's detection of live virus in lots 154, 254, and 354 *** (gave) a false sense of security in the adequacy of the tests to detect live virus," why did the government laboratories allow lots of polio vaccine to reach the public without any testing? The drafters claim that "it is difficult to see how one could claim that information concerning contaminated lots was kept from these committees * * *." However, it was the NIH Ad Hoc Committee that created such an implication by releasing what purported to be summaries of all the meetings of the expert committees held on polio showing that the last discussion of live polio contamination of the vaccine occurred more than six months prior to Dr. Eddy's discvery of the three contaminated lots. The NIH drafters also failed to mention that several other laboratories were reporting live polio in vaccine lots; and that Dr. Sven Gard, the vaccine control officer of Sweden, pointed out that "in 1954 at the Congress in Rome, the proceedings of which were recently (1955) published by NEIP, I presented evidence to show that the Salk theory of formalin inactivation might be fundamentally wrong. We (he and his colleagues) have been piling up evidence ever since." Nor did the NIH drafters point out that Dr. James Shannon, in 1968, identified what he considered to be a fundamental error in the American development of the 1955 polio vaccine. The error he defined was the secret decision of the polio foundation to place all its effort into the killed vaccine that contained the live polio contamination that Sven Gard and others had warned about and which Dr. Eddy had isolated in her laboratory. It is unfortunate that the NIH holds so tenaciously-even to the point of altering the facts relied on by its own Ad Hoc Committee-to the argument that NIH has no responsibility for the 1955 polio vaccine tragedy. Now is the time for NIH to say openly what so many others know to be the case. Incidentally, lots marked “experimental" were used in field trials for people, and the lots Dr. Eddy found live polio in were specifically intended for people according to her recollection. This is so, she believes, because the laboratory was backed up with work and she was the only person testing materials that were intended for human use. B. DBS failure to act promptly to eliminate SV40 contamination of adenovirus vaccinc.-Again the NIH drafters failed to consider the meaning of their own argument. They state that,in 1964, production of adenovirus vaccine was stopped for two reasons. First, if the SV40 in the vaccine was killed, the potency of the vaccine became unacceptable; second, that the oncogenic property of certain adenoviruses made them a potential problem even when they had been killed. These are sound observations of scientific fact. The facts existed in 1961 as well as in 1964. In 1961, if the DBS standard requiring all SV40 to be killed were applied, then the potency of the vaccine would have been too low to give protec tion. Therefore, if the 1961 standard had been applied, it would have been impossible to produce adenovirus vaccine lots free of SV40 and with sufficient potency to protect against the disease. In addition, since the potential oncogenic danger of adenoviruses posed problems requiring non-production of the vaccine, whether the viruses were live or dead, the potential oncogenic problems of SV40 for regulatory purposes, whether it was live or dead, remain the same. Both of these points are made by the NIH drafters of the "comments" and analysis" but their importance is overlooked. In essence, the NIH drafters support the fact that proper application of the 1961 DBS standards would have resulted in an end to the production of potent adenovirus vaccines. Fraumini is cited by Innis. Both the Fraumini papers come to the conclusion shared by Innis and by the Morris/Turner papers. Namely, "there is still no clear answer to the question of how SV40 contamination might have affected its recipients." The fact that SV40 has recently been recovered from the autopsied brains of two patients makes the need to conduct such follow-up studies even more urgent than when the Morris/Turner papers were written. C. Continued reliance by DBS-NIH on the CCA test.-However much the NIH drafters wish to believe otherwise, there must be an inconsistency in the following two statements. Dr. Edwin D. Kilbourne calls the CCA test "archaic and unsatisfactory." The Ad Hoc Committee, on which he served, says "the CCA test appears to be a satisfactory procedure for estimating the content of the major influenza virus antigens in a vaccine." But even more is wrong about the NIH position on the CCA test. "Within a relatively short time," the NIH drafters assert, "Dr. Tauraso had found the source of the variability in the CCA test and eliminated it." This statement is untrue. A DBS investigator, on two separate trips to check manufacturers' procedures, reported variations in CCA testing as high as 100%. He also reported that manufacturers were deliberately excluding the highest figures obtained in the conduct of the test. When manufacturers were summoned to NIH to show how the test could be reproduced, the results again varied dramatically and far in excess of 15%. The reliance of NIH on Dr. Tauraso's alleged improvement of the CCA test not only reveals the unscientific nature of its deliberation but leads to a failure to protect the public health properly. Of all the issues in this controversy, the reliance of the DBS, the NIH, and all other HEW officials and the Ad Hoc Committee of "experts" on the incorrect and self-serving statement of one man is the issue approached with the least scientific integrity by the NIH. D. Confusion on the regulation of preservatives.—As pointed out by the NIH drafters, some lots of vaccine exceeded specified concentrations of mercury by as much as 31%. The laboratory books showing this fact, by the way, have never been made available to anyone other than those defending DBS-NIH. More to the point, the NIH drafters claim that since the manufacturers' license application had to indicate the preservative added, there was no point in requiring them to repeat the information with each lot. What the drafters did not point out was that the DBS regulations required preservatives in limited amounts. There is no indication, either from DBS or NIH sources, just how the government regulators planned to monitor the amounts of preservative used in vaccines. In fact, this failure, rather than a 62% error in test methods, might more accurately explain the excessive amounts of mercury in vaccines. The information that benzathonium chloride does not appear in vaccine came from Dr. Ruth Kirschstein, who provided a large portion of the information relied upon by the Ad Hoc Committee. It does seem strange that a vaccine, used in people, contains a substance which a DBS official recommended should be removed from vaccines because it causes cancer in animals. Further, the assertion that thrombin is not intended for oral use, shows just how weak the regulatory activity of the DBS actually is, since the package insert for thrombincopy enclosed-shows thrombin indicated for oral use. The DBS confusion about preservative use and regulation is so extreme as to require a special investigation in itself. E. Ineffectiveness of influenza vaccine.-The ineffectiveness of the influenza vaccine in the civilian population is so well accepted that the NIH's own consultant on the question stated it as a fact. The CDC has repeatedly reported the |