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The History of Vaccines

            One of the most important contributions to medicine has been the development and use of vaccinations to prevent disease. Vaccinations easily rank with antibiotics and the purification of water supplies as being one of those contributions that has saved countless lives and prevented a vast amount of disease. While some people may question whether and to what extent vaccinations have been necessary and effective, the vast majority of medical professionals recognize that vaccines have been highly useful. It is hard to deny the triumph over small pox, the elimination of polio, and the prevention of other dread diseases of childhood.[2]

            As with any pharmaceutical products, vaccines have been associated with adverse events.[3]  While vaccines are relatively safe, there have been some notable problems over the years, and all vaccines are capable of causing reactions in some predisposed individuals.  The famous Cutter incident resulted in important verdicts for victims of polio vaccinations.  Rabies vaccines were frequently associated with encephalitis.  The Swine Flu vaccination program in 1976-77 resulted in thousands of cases of Guillain Barre Syndrome (GBS).  DPT vaccines (particularly the whole cell pertussis vaccines) have been associated with seizure disorders and encephalopathy.  Recently, rotavirus vaccines have resulted in intessuseptions.  Numerous vaccines have been credited with causing a variety of autoimmune disorders, such as GBS, encephalitis, transverse myelitis, arthritis syndromes, lupus-like reactions, arthropathies, etc.

            It is important to understand that when dealing with the adverse effects of vaccines, we are often dealing with syndromes and conditions, which have multiple causes, which occur only in a small percentage of those vaccinated and which often have vague or obscure onsets.  All of these factors complicate the ability to prove a causal relationship with the vaccine in question, as will be discussed in more detail below.

The History of Vaccine Litigation and The Swine Flu Program

           Since the early 1960’s, the issue of manufacturers’ liability for the adverse effects of the vaccines they developed, tested, produced and sold has been of great concern to them.  At first cases were rare, and awards were even rarer, but some of them were large, and the trend was toward more cases being filed and winning.  In 1974, the case of Reyes v. Wyeth (498 F.2nd 1264) upheld a jury verdict of $200,000 for a child who developed polio after the Sabin live polio vaccine.  It is not surprising, therefore, that manufacturers began looking for ways to protect themselves from seen and unforeseen liabilities.  Proposals were presented where the government would indemnify for liability in federally sponsored programs.

            This liability issue became critically important in 1976.  After the Christmas holidays, drill instructors returned to their base at Fort Dix, New Jersey to begin training another group of draftees.  It was cold, recruits were crowded into barracks, and the conditions were stressful.  Soon men were reporting to sickbay with upper respiratory infections (URI’s), and a few were even hospitalized.  One recruit, though ordered to bed, disobeyed orders, went on an overnight march and died.  Specimens were routinely sent to the state labs for analysis, and some A Victoria virus was isolated.  Other viruses could not be identified, so Dr. Martin Goldfield[4], civilian epidemiologist with the state, sent the samples on to the CDC for further testing.

            The rest, as they say, is history.  Officials identified an influenza virus that was antigenically similar to the 1918 Spanish flu virus which had killed many people during WW I.  It was a virus which had been observed over the years in pigs, and rarely was transmitted to a farmer or member of a farm family that raised pigs.  The CDC and the WHO mounted a massive surveillance campaign, looking for further evidence of the spread of this strain of virus into humans.  Although no such evidence was found, the political decision to “vaccinate every man, woman and child” was like a snowball rolling downhill.[5]  Large amounts of vaccine were produced for this threat, and ultimately, the decision was made to store the vaccine in people’s arms instead of the refrigerator.

            The Swine Flu Program would never have gone forward without Congressional intervention to solve the problem of liability.  The insurance industry decided that they would not insure the manufacturers of the vaccine for their potential liability, and the manufacturers decided they would not produce the vaccine without adequate protection from liability.  The result was a tort claims bill (PL 94-380) whereby the federal government stepped into the shoes of the manufacturers and assumed their liability.  The statute utilized the mechanisms already in place under the Federal Tort Claims Act for bringing suits against the federal government. 

            The Swine Flu experience was once of those once-in-a-lifetime experiences for epidemiologists.  Never before and never since have so many people received the same vaccination in such a short period of time.[6]  From October 1, 1976 until the program was stopped on December 16, 1976, over forty million people were vaccinated.  It was expected that there would be temporally associated deaths and injuries occurring shortly after immunization in some percentage of these people, just on the basis of normal background rates for such events in the general population.  A passive surveillance system had been set up to monitor potential adverse events, and research had suggested that there might be cases of encephalitis, transverse myelitis and GBS following the vaccines, based on anecdotal reports and biological plausibility. 

            Soon reports were coming in from Minnesota, then Alabama and New Jersey, and then other states.  Before long it became apparent that the rates of GBS being reported among the vaccinated population was exceeding the expected background rate for the syndrome.  With no swine flu virus materializing, and with increasing evidence that GBS was being caused by the vaccine, the decision was made to stop the vaccinations, and an active surveillance (as opposed to a passive system) program was set up by the CDC.  This resulted in the famous “Schoenberger Report” which demonstrated that there was a ten-fold increase in the numbers of cases of GBS after Swine Flu Vaccine (SFV), and the risk appeared to last for up to 10-12 weeks after vaccination.

            The Swine Flu Program was an important milestone in the history of vaccine litigation for several reasons:  (1)  It became a precursor for a no-fault vaccine compensation program; (2)  It was a precursor for federal government involvement in vaccine injury compensation; and (3) It was the advent of what will be called “The Age of Epidemiology.”  To understand what has happened since that time, these three concepts need to be understood.

            While the Swine Flu Program did not start out as a no-fault program, it became  a partial one when the new Secretary of HEW under President Carter, Joseph Califano, announced that anyone who could show that they developed GBS after SFV would not have to prove any theory of liability.  He said this was being done because the government could not have predicted what happened and did not specifically warn about it.  He was probably right in the sense that encephalitis and transverse myelitis were more predictable than GBS, but there were those who had expected to see cases of GBS related to the vaccinations as well.  Furthermore, Califano’s pronouncement had the effect of creating different burdens of proof for different classes of people, dependent only upon which part of their nervous system[7] was injured. 

One of the results of this was that Plaintiffs’ attorneys were often put in the position of arguing that GBS was a syndrome that could include involvement of the central nervous system.  This was important not only to obviate the need to prove liability, but also to bring the case within the epidemiology that is discussed below. 

The second important aspect of the Swine Flu Program was that it was a federal program.  While it used the pre-existing framework of the FTCA, it paved the way for future consideration of other federal programs to compensate victims of vaccinations, which the federal government is actively promoting. 

Finally, the Swine Flu Program elevated the art or science of epidemiology to new levels.  Prior to this time, it would not be at all uncommon for an attorney to prevail before a jury with evidence that the vaccine had been given, there were reports of it having been associated with the condition the plaintiff experienced, a causal relationship was biologically plausible (even though the complete pathogenesis might have remained a mystery), the timing was appropriate, and there was no alternate cause apparent.  Now, however, attorneys were handed insurmountable evidence in the form of epidemiology, and one could not resist using and touting such evidence when it fit the case being tried.  As a matter of fact, Plaintiffs’ attorneys were constantly fighting to be sure that their cases could be defined as GBS, and then fighting to prove that the onset of symptoms occurred within the accepted epidemiological timeframe. 

An interesting category of cases developed which will be referred to as slow, smoldering onset cases.  Sometimes these cases began slowly and progressed gradually to a full-blown case of typical GBS.  Other times they went on to develop waxing and waning courses and were variously referred to as relapsing, recurring, or chronic GBS.  There were analogies for these cases in the animal models, where some animals would have an acute course following an injection with an antigen (like P2 protein) designed to produce experimental allergic neuritis (EAN), an animal model for GBS, but others would develop a chronic, progressive or relapsing course.  Numerous courts adopted this theory of causation, and some of those decisions are attached as Appendix A.[8]

The defense to SFV-GBS cases took several forms.  First of all, an effort was made to narrowly define the syndrome.  In performing the epidemiological studies, it had become apparent that the studies would be stronger if narrow criteria were used to assure that the cases were pure cases of GBS.  These criteria were not intended to define the limits of the syndrome, but the defense chose to use them in that fashion.  Secondly, the government convened a “blue ribbon panel” of epidemiologists to try to refute their own data about whether or not SFV even caused GBS.  The panel struggled mightily to analyze the data in every way imaginable, throwing cases out of the vaccinated group while not applying the same criteria to the expected background rates, but even those efforts were unable to refute the conclusion that GBS was caused by SFV.  The best they could do was suggest that the risk really lasted only 6 weeks and not 12.  A third defense took the form of trying to show that chronic cases were not really cases of GBS at all, but rather a different entity with different causal implications.  Dr. Barry Arnason’s chapter in the famous two-volume text Peripheral Neuropathy, edited by Peter Dyck, was rewritten in its next edition to remove much of the language that plaintiffs’ lawyers had been citing, and a separate chapter was added to deal with CIDP (chronic inflammatory demyelinating polyneuropathy) as opposed to AIDP (acute inflammatory demyelinating polyneuropathy or GBS). 

One thing the Swine Flu Program made clear was that when the government was in charge of defending claims for compensation from vaccine injuries, resources were not a problem for the defense, and getting highly qualified experts was not a problem.  Agreeing to testify for the government, which could pay promptly and which administered the system of grants for medical research, was somehow not fraught with the same dangers as those faced by doctors who were brave enough to testify for Plaintiffs.  For Plaintiffs' experts, jobs were lost and reputations effected.

The bottom line was that epidemiology became the standard of proof that judges liked to quote.  Dr. Martin Goldfield, who had been largely responsible for discovering the virus in the first place, ended his career analyzing all the data and developing proof that the risk of developing GBS after SFV lasted for at least 26 weeks (and perhaps longer if the data had been collected that far out).  Prior to the Swine Flu Program, most doctors would have speculated that the risk lasted for 2-4 weeks.  The epidemiology performed by CDC shattered that thinking by showing an increased risk out to 10-12 weeks, and, if Dr. Goldfield’s data were to be believed, then the risk lasted even longer. 

            For other vaccines, litigation was continuing, and sizeable verdicts were drawing attention.  There was also growing concern about seizure disorders and encephalopathy following DPT vaccinations, and, in 1985, the book DPT: A Shot In The Dark was published by Harcourt, Brace, Jovanovich.  Harris L. Coulter and Barbara Loe Fisher had done their homework, and they asked the question:

Are we giving our children a shot in the dark?  The pertussis portion of the DPT vaccine may cause a variety of reactions: high-pitched screaming, persistent crying, excessive sleepiness,  shock, brain damage – even death.  For most children the shots are routine first steps in growing up to lead healthy lives.  For others the shots mark the beginning of a lifelong nightmare for child and parents alike.

            On page 354 of their book, Coulter and Fisher describe the experience with DPT vaccines in Japan, where the Ministry of Health, instead of trying to cover up problems with the vaccines chose to find a solution.  By the end of 1981 they had tested and were using an acellular vaccine (as opposed to the whole cell product previously used).  They demonstrated that the vaccine was just as effective in preventing disease, and it produced far fewer side effects.  They quote a Japanese scientist who spoke at a 1982 symposium and tried to answer the question of why Japan switched to the acellular product:  “The situation from 1975 was quite difficult for physicians because of the adverse reactions which became a big problem in Japan, not only in Japan but also in other countries or the world.  And there is one motivation for the change.” 

            It has taken nearly 20 years to get the medical community in the United States to stop giving the whole cell product and use the acellular one.  Even today, manufacturers are distributing the whole cell product to third world countries, undoubtedly because it is cheaper to make.  Coulter and Fisher were absolutely right in their book – money is the bottom line.

            The growing concern about DPT and other vaccinations was of concern to public health officials, parents of injured children, manufacturers of vaccines and administrators of the vaccinations.  Pressure kept growing for the federal government to step in and stop the litigation.

The National Vaccine Injury Compensation Program

            In April of 1982 a group of parents joined together to form a group known as Dissatisfied Parents Together (DPT).  Its stated goals were “to educate parents, doctors, and community leaders about the pertussis vaccine and to encourage both government agencies and physicians to conduct research that will identify high-risk children and develop a safer vaccine.  The group also assists parents by providing information about legal and medical professionals who are knowledgeable about the pertussis.”[9]  Together with the American Academy of Pediatrics, the group came forward with recommendations that formed the basis for a bill introduced into the Senate by Paula Hawkins (R-Florida) and Orrin Hatch (R-Utah) and into the House of Representatives by Henry Waxman (D-California) and others.[10] 

            The result was the National Childhood Vaccine-Injury Compensation Act.  The National Vaccine Injury Compensation Program (NVICP, as it has come to be called) was created by Congress to provide a no-fault, non-adversarial, fair and equitable system for compensating the victims of our country's vaccination programs. Claimants are entitled to file Petitions for Compensation in the United States Court of Federal Claims in Washington, D.C. The respondent for these claims is the Department of Health and Human Services (HHS), and the claims are defended by the Department of Justice. The cases are initially heard by Special Masters (lawyers who are designated by the Claims Court to here the evidence and render decisions), and their decisions are typically upheld on appeal. If claimants can show that a vaccine caused their injuries, then they are entitled to compensation pursuant to the statute.

As is has evolved, the program is highly adversarial, and HHS has made it extremely difficult to prove causation. There are many legal pitfalls that may be encountered along the way, and, because of the limitations on attorneys fees and expenses (which are paid by the program, but only after the case is over), it is difficult to find lawyers who have extensive experience with the program and are willing or able to represent claimants.  Many parents who have been unsuccessful in the program have been extremely disillusioned with the process. 

Because it was unclear at the time the statute was passed whether or not certain injuries were caused by certain vaccines, Congress provided a presumption of causation to certain petitioners if their injuries occurred within a certain time period following vaccination. For instance, there appeared to be an increased incidence of seizure disorders and generalized brain dysfunction following DPT vaccinations. Therefore, Congress enacted a Vaccine Injury Table that provides a presumption of causation if these injuries occurred within three days of a DPT shot. 42 U.S.C.§ 300aa-14(a). Congress also enacted certain "Aids to Interpretation" to assist the special masters in determining whether or not the child's physical manifestations are adequate to afford a petitioner the presumption that his or her injuries are caused by the shot. 42 U.S.C. § 300aa-14(b). Even if a petitioner received the presumption, the government still has the ability to step in and prove that the child's problems were actually caused by some other medical problem, thereby defeating the claim. If a child's injury does not fit within the "Injury Table," then it is necessary to prove that the vaccine caused the injury, using much the same standard of proof as is required in traditional tort litigation.

If the claim ultimately prevails, the legislative history clearly states that the award should be "generous." Those "generous" awards are paid in the Program through a Trust Fund that is funded via a small tax on each vaccine covered by the Program that is given in the U.S. Currently, the trust fund has more than $1.5 billion in it, and it continues to grow at a rapid rate.

In addition to providing petitioners a presumptive Table of Injuries, Congress also gave the Secretary of Health and Human Services the power to change the Table. This included the power to add newly developed vaccines to the Table and to provide new presumptions for the injuries. In late 1994, the Secretary of Health and Human Services ("HHS") proposed certain changes to the Table of Injuries. These regulations became effective on March 10, 1995, and they have devastated the Program. HHS removed the Table Injury of Residual Seizure Disorder all together. In addition, HHS eradicated the congressionally provided definition of "encephalopathy" and put in its place a new definition that is so restrictive that it was believed by petitioners' lawyers familiar with the program that they will never again see an injury to a child that falls within the definition's narrow confines.

The new regulations are not the only downfall of the Program. Until October of 1998, a Petitioner could not file a claim until he or she had incurred $1,000 in out-of-pocket expenses. This statutory requirement had a horrific impact over the years. Numerous petitioners who were on some form of welfare were unable to show that they incurred the necessary amount because their expenses were not considered to have been "incurred" by the petitioners. In addition, petitioners who had access to good insurance coverage were in many cases unable to recover under the Program because their expenses were not "unreimbursable" as that term is understood in this Program. On the other side of the coin, some rather minor "vaccine-related" injuries have been compensated under the Program because the person was financially capable of spending enough money to satisfy the requirement. For instance, one petitioner received more than $150,000 for emotional distress and pain and suffering for a scar left on her leg by a vaccination.

Congress clearly included the $1,000 requirement in the Act as a measure of the severity of a person's vaccine-related injury and to prevent nuisance claims. The results, however, were anomalous, and the provision was removed through the efforts of Senator Daschl. 

Returning to the regulatory changes enacted by HHS, the Vaccine Act establishes an Advisory Commission on Childhood Vaccines. This Commission is composed of a broad base of individuals covering every aspect of the Program. By statute, the Commission includes representatives from the petitioners' bar, petitioners who have been through the Program, representatives from Health and Human Services, etc. The Commission has the power to suggest to the Secretary of HHS any regulatory and legislative changes that should be made to the Program. In addition, any proposed regulatory changes drafted by HHS must be sent to the ACCV for a comment period before they can become effective.

HHS failed to provide a final version of the March 1995 regulations to the ACCV before the effective date as required by the statute. The ACCV never addressed the appropriateness of the definitional change of the word "encephalopathy" in the Aids to Interpretation. Moreover, the ACCV proposed certain additions to the Table of Injuries that have been rejected by HHS. For instance, the ACCV voted to put the Guillian-Barré Syndrome on the Table if the syndrome followed within a certain period of time after a tetanus vaccination. HHS rejected the suggestion.  (See further discussions about this below.)

Petitioners across the country are beginning to feel that resort to the Vaccine Compensation Program is fruitless without some intervention by Congress. The Vaccine Act had been viewed by many as a model for tort reform, and even as a potential model for a tort reform for the tobacco-related injuries, for hemophilia-related AIDS injuries, for Gulf War Syndrome cases, etc. But the Program is ailing from inattention. Its problems are many -- its benefits few. It demands Congressional attention.  As things stand now, it is becoming the poster child for the American Trial Lawyers Association and a perfect example of why tort reform may never work.

            On September 28, 1999, seventeen days after the death of his father, this author had the opportunity to testify before Congress about the need to repair this broken program.[11]  Counsel called upon Congress to amend the burden of proof (utilizing the language from Veterans’ Claims, and more in line with the burden in Workers’ Compensation claims), change the statute of limitations, and provide for interim fees and costs.  While these are not the only issues that need to be addressed, it was thought that they were the most significant.

            Congress does not act quickly.  It was nearly a year before clients could be advised that:  “Two bills were introduced in the House of Representatives on September 28-29,2000. These bills are nearly identical, but one (HR5327) was introduced by a Republican, Dave Weldon of Florida. The other (HR5330) was introduced by Jerrold Nadler, a Democrat from New York. Early consideration and passage of one or both of these bills is critical to the survival of the Vaccine Injury Compensation Program (VICP). It is expected that these bills will be combined and reintroduced in February, 2001.”[12]

            The February date turned out to be a little optimistic, but On March 28, 2001, HR 1287, The Vaccine Injured Children's Compensation act of 2001, was  introduced in the House of Representatives by Congressman Dave Weldon (R-FL) and Congressman Jerrold Nadler (D-NY). Other co-sponsors include Rep. Dan Burton (R-IN), Rep. Barney Frank (D-MA), Rep. Pete Sessions (R-TX), Rep. Jim McGovern (D-MA), Rep. Steve Horn (R-CA), Rep. Karen McCarthy (D-MO), and Rep. Jim Turner (D-TX).  (A copy of this bill can be found on our web site.)

This bill provides for changes in three very important areas:

1.  The Statute of Limitations:

In order to file a claim under the Vaccine Injury Compensation Program (VICP), it has to be brought within 3 years of the onset of  the injury claimed to have been caused by the vaccine(s). It does not  matter that the claimants may not have even known that the vaccine  caused their injuries. This bill will amend the statute of limitations to 6 years, provide that the statute of limitations is tolled (stopped) during minority, and add a discovery rule.

2.  The Burden of Proof:[13]

In law, there are different burdens of proof that are required for different things.  For instance, to convict someone of a crime requires proof "beyond a reasonable doubt."  Below that is a level of proof where something has to be proven by "clear and convincing" evidence.  Next down the ladder is the burden used in traditional civil tort litigation, where the plaintiff has to prove something is more likely than not, "by a preponderance of the evidence."  For Veterans' Claims and Workers' Compensation Claims, a lower burden is used, where the benefit of the doubt goes to the claimant.

In HR 1287, the Petitioner's burden of proof is reduced from the "preponderance" standard to the same language used in Veterans' claims. This bill states clearly that the purpose of the program is (as Congress originally intended) to generously compensate the children and other victims of vaccinations.  It was Congress' intent to err on the side of over-compensating, rather than under-compensating, these people.  This bill also makes it clear that this is a remedial program and the government should not raise a claim that this is a "waiver of sovereign immunity" (where the bill would be strictly construed against the Petitioners.)[14]

Finally, the bills make it clear that the government can still raise the possibility of an alternate cause (something other than the vaccination), but they must prove this alternate cause by "clear and convincing" evidence.

3.  Interim Fees and Costs:

One of the reasons so few lawyers are willing to get involved and stay involved in these cases is because the payment for attorneys is extremely low compared to the rewards of traditional civil litigation.  Claimants and their lawyers must often wait years to receive reimbursement of their costs and payment of the attorneys' fees.  Lawyers are expected to compete in a highly litigious environment, where the burden of proof is relatively high, without the benefits of traditional civil discovery, and with small and delayed compensation for their effort.

This bill would make it possible for claimants to petition, no more than once every 90 days, for payment of interim fees and costs.  This will allow experts to be paid in a timely manner, and Petitioners will finally be able to conduct the testing and studies necessary to prove their claims.

Remember that the attorneys for the government are paid every thirty days and the attorneys for the children have to wait until everything is finalized, in many cases waiting for years.[15] In the meantime, the burden of financing the case falls on the shoulders of the family and the attorney. This provision will help level the playing field for the attorneys who are trying to help the families.

The real question becomes whether or not Congress will actually pass legislation to correct the problems with the NVICP, but, even if they do, will it be too little, too late.  For many lawyers who are hanging on to cases in the program, that decision is going to come sooner rather than later.

            For an increasing number of lawyers, the decision has already been made.  They are increasingly taking aim at the vaccine manufacturers through the traditional tort litigation process, and they view the NVICP in much the same way medical malpractice lawyers view mandatory arbitration procedures – as something you have to do to get where you want to be.[16]  With that in mind, what are the areas of potential tort litigation that are opening up for us in the future?

Thimerosal:

            For over 60 years, thimerosal[17] has been used in some vaccines as a preservative to prevent bacterial contamination.  Mercury[18] has been recognized as have toxic effects since the times of ancient Rome and is, in fact, responsible for the term “mad as a hatter.”[19]  There are multiple sources of mercury in the environment, and the most familiar example is risk of ingesting mercury in fish.  Mercury accumulates very well in the aquatic food chain.  The higher up the food chain the fish is, the higher the levels of mercury to be expected.  The most dramatic example of this kind of mercury poisoning occurred in Minimata, Japan in the 1950’s and 1960’s because of industrial discharge of mercury into Minimata Bay over an extended period of time.  The poor people in that area were ingesting high levels of mercury in the fish and shellfish that were the staples of their diets over long periods of time, and they developed terrible injuries, effecting primarily the liver and brain tissues, but also other body tissues.  More recently, there has been considerable literature over the nature and extent of injury caused by dental amalgams containing mercury. 

            Recently, attention has been focused on the amount of thimerosal in many childhood vaccines and what role that may be playing in causing adverse events, including autism.  Many have concluded that there is an epidemic of autism in this country (and the world), and they feel it is directly related to the amount of thimerosal  children are receiving.  The EPA guidelines for the maximum safe dosage of mercury is based on daily exposure to methyl mercury.  When all of the mercury in the thimerosal[20] contained in all of the childhood vaccines is added up, it becomes apparent that many children have been receiving amounts of mercury far in excess of the recommended safe amount.  This exposure is further complicated by four factors;

            1.  EPA guidelines are not adjusted for the extremely low body weight of infants;

            2.  EPA guidelines are based on methyl mercury, not the ethyl mercury being received by the infants in vaccinations; and

            3.  EPA guidelines do not take into account the bolus amounts being received by children who receive multiple vaccinations at the same office visit.[21]

            4.  EPA guidelines do not recognize the fact that young infants have underdeveloped bilary systems and cannot clear mercury from their systems.

            An excellent article describing all of this is Autism and Mercury, a paper prepared by Sallie Bernard, Albert Enayati, B.S., Ch.E., M.S.M.E., Heidi Roger, Teresa Binstock, Lyn Redwood, R.N., M.S.N., C.R.N.P.  This article can be found at http://www.cureautismnow.org/sciwatch/invest.cfm

            In this article, a table presents the symptoms (from the medical literature) of mercury toxicity and compares them with the symptoms of autism.  The similarities are striking.  It is likely that the manufacturers of vaccinations have been aware of the neurotoxicity of thimerosal and the cumulative nature of such exposure from vaccinations for many years.  This is an area that is ripe for civil litigation.

            One of the questions faced by lawyers today is whether or not they must go through the NVICP before they can resort to the civil court system.  A recent decision of Special Master John Edwards in the case of Geppert v. HHS is attached as Appendix C.  SM Edwards raises the issue of whether mercury is a contaminant or adulterant that is intentionally added to the vaccine.  If it is, then under the statute, cases caused by thimerosal could not be brought under the program.  In fact, the Court would not even have jurisdiction.

            The Respondent (Department of Justice) filed a response (also attached as Appendix D), which claimed that the Special Master was wrong, and thimerosal is not an adulterant.  In the same pleading, the Respondent claimed that, while the Court has jurisdiction, causation cannot be proven.  The significance of this position can be better understood when one considers 42 USC Sec. 300aa-22 and 42 USC Sec. 300aa-23 (copies of which are included as Appendix E).  If forced to go through the program and forced to reject the judgment of the Claims Court before filing a civil action, then these provisions come into play and restrict the claims that can be made in such a civil suit.  If  claimants are not required to go through the program because of a lack of jurisdiction, then there would be no such restrictions on the state law that is applied in a civil action.[22]

Influenza Vaccine:

            For years, since the Swine Flu program, there have been occasional cases involving influenza vaccines causing Guillain-Barre Syndrome (GBS) and other autoimmune conditions.  Causation is, of course, an issue in these cases, particularly since the CDC has conducted epidemiological studies suggesting that they cannot observe an increased incidence of GBS after these flu vaccines as they did after the Swine Flu.  There are reasons for this, such as the fact that we have never vaccinated so many people in such a short period of time since then, and the epidemiology has been more passive than what was done after Swine Flu, but causation is something to be addressed in these cases.

            The biggest perceived problem for these cases has been proving some theory of liability against the manufacturer and/or the administrator of the flu vaccine.  Since these vaccines are not covered under the NVICP, it is not required that a claim be filed under that program before proceeding with a civil suit.  Attacking the flu vaccine will require showing that the vaccine is promoted in a deceptive manner.  The vaccine, for most healthy people, is (1) unnecessary;  (2) ineffective;  and (3) capable of causing serious   neurological injuries.  Most cases of so-called flu are not influenza at all, but rather cases involving rhinoviruses and other infections.  Getting the flu, for most healthy individuals is not very serious.[23]  Flu vaccines are admittedly viewed by many in the public health community as being a monetary vaccine, designed to reduce days lost from work.

            The most serious indictment of flu vaccines, however, involves the fact that we are always receiving last year's virus to try to protect us from this year's flu.  Flu viruses change each year, and sometimes the vaccines are prepared with viruses, which are not the same ones that we are trying to protect against.  Despite such mismatches, manufacturers are always quick to sell their product, and recalls are unheard of.  There is evidence that the manufacturers do not even conduct clinical trials for the vaccine each year, despite the fact that the components are changed.

            This is another area that is ripe for litigation.

Whole-cell DPT:

            The story of whole-cell DPT versus the acellular product has been told repeatedly over the years, both in the medical literature and in courtrooms.  When asked whether he would provide assistance with writing this section, Dr. Mark Geier and his son, David, accepted the challenge and provided a detailed history, which is contained at Appendix F.  For lawyers, the most important part of their write-up is contained on the last page:

“. . .only acellular DPT vaccine should have been administered by doctors and healthcare professionals for the last two doses since 1992 and for all doses since 1996. Those doctors and healthcare professionals that continued to administer whole-cell DPT, in light of the current medical and scientific knowledge on the subject, may be liable in civil lawsuits. Additionally, those companies that still manufactured whole-cell DPT, in light of the current medical and scientific knowledge, may be liable in civil lawsuits because whole-cell DPT should have been withdrawn from the market in favor of the less reactive and more efficacious acellular DPT vaccine.”

            Obviously, many whole-cell DPT claims are successfully pursued through the NVICP, but lawyers need to be on the lookout for claims that fail[24] and that fit the criteria set forth in this analysis.

Hepatitis B vaccines:

            Hepatitis B vaccinations are now routinely given to newborn babies, whether or not they are at risk of contracting hepatitis B.  The primary risk factors for contracting hepatitis B are the same as for AIDS, and the vaccines are promoted for those individuals as well as for health care workers.  More and more reports are appearing in the literature associating hep B vaccination with injuries to various body systems, including (1) neurological, such as post-vaccinal encephalitis[25], neuropathies (like GBS), transverse myelitis; (2) rheumatological, such as arthritis syndromes, inflammation and lupus-like syndromes; (3) dermatological, including alopecia, dermatitis, etc; (4) hematological; (5) endocrine; (6) vascular/cardiovascular; (7) nephric; and (8) thyroid.  Most of these cases in adults appear to be immune-mediated.  In children, hepatitis B vaccines are actually causing more febrile reactions that whole-cell DPT vaccine.  At first this was a puzzle, until one realizes that hepatitis B vaccine contains one of the highest levels of thimerosal of any vaccine.

The other significant factor in some of the hepatitis B claims involves the concept of “positive rechallenge.”  This concept was heavily relied upon in the paper where the CDC determined that there was a causal relationship between hepatitis B vaccines and alopecia.[26]  Many of the hepatitis B claimants whose cases have been reviewed to date are cases where there was a reaction after one vaccination in the series[27] and then a much more severe reaction after the next shot in the series.  These cases provide very strong proof of a causal relationship.[28] 

            Until recently, it was this author’s impression that hepatitis B claims were going to be nearly impossible to win in the NVICP.  There were many reasons for this concern, but one example will suffice.  In a case under the NVICP, counsel has presented evidence concerning a perfectly healthy woman who developed GBS within 3 weeks of a tetanus vaccination.  At the first hearing in the case, well-qualified experts testified that more likely than not, the vaccination was the cause of the GBS.  The government conceded that tetanus vaccine is capable of causing GBS[29] (satisfying the “can it” test), but they contested that Petitioners could show that it did so in this case (the “did it” test).  There was no evidence of an alternate cause, although one of the government experts raised the possibility of a camphylobactor jejuni infection.  There was no proof of such an infection, so this was mere speculation.

            At trial, the government called upon an epidemiologist who went through extensive computations to demonstrate that in any given year, given the number of people who get tetanus vaccinations, one would expect to see 3 cases occurring by chance alone within 6 weeks of vaccination.[30]  On cross examination, this expert conceded that by this logic, one would expect to see 1.5 such cases occurring within 3 weeks of vaccination by chance alone.  When confronted with numerous cases from the VAERS[31] for the year in which the Petitioner was vaccinated[32], the expert started going on and on about small numbers, and how you couldn’t use statistics like this to prove causation to the magic “95% confidence limits.”[33]

            After the hearing, the Special Master made it clear that he was on the fence and needed something to push him over the 50% line.  Testimony from epidemiologist made it clear that performing the kind of epidemiological studies necessary to satisfy the Court would be cost-prohibitive.  Likewise, it was too long after the acute phase of the GBS to find autoantibodies to test in an effort to find some biological marker.  For a long time, counsel felt the case was simply dead in the water.

            A recent ruling from this Special Master in another case may offer hope for this claim and for a lot of other claims under the program, including the hepatitis B claims.  In Stevens v. HHS, 99-594V, Ron Homer[34] moved for a summary judgment (or judgment on the record).  While the motion was not successful in that case, Chief Special Master Gary Golkiewicz set forth a 5-prong test for determining causation in hepatitis B (and presumably other) vaccine claims.  The Stevens case is attached as Appendix G, but here is our analysis of those 5 prongs:

Stevens v. HHS

No. 99-594V

Ruling on Petitioner’s Motion for Summary Judgment, dated March 30, 2001

Prong One:           Proof of medical plausibility

Met by showing that “it is medically plausible for the vaccine received to cause the injury alleged.”

“This is done by proffering a theory of biologic mechanism by which a component of the vaccine can cause the type of injury suffered.”

“This is not a rigorous burden.”

This is typically provided by some expert report

You are not responsible for showing that literature associates the vaccine itself with the injury. That is left to Prong Two.  All that is needed here is a theory.

Prong Two:          Proof of confirmation of medical plausibility from the medical community and literature.

“Here, petitioner must establish that peer-reviewed literature reports that the vaccine is related in some sense to the injury alleged.”

“The court is concerned with the fact that a relationship is reported, rather than how that relationship is defined or by what criteria.”

“This is not a demanding burden.”

Proof here can include “epidemiological studies, animal studies, case series, case reports, anecdotal reports, journal articles, manufacturing disclosures, Physician Desk Reference citations, and institutional findings, like those reported by the Institute of Medicine.”

“The court would be hard-pressed to find causation in an individual case if the medical community is not even witnessing or contemplating a causal relationship.”

“Petitioner’s successful satisfaction of these two prongs also complies with Daubert which seeks to ensure that petitioner presents a medical theory based on medically or scientifically valid concepts, and ones preferably rooted in published or peer-reviewed literature.”

Prong Three:        Proof of an injury recognized by the medical plausibility evidence and literature.

The case scenario at hand must conform to the medical evidence presented in Prongs One and Two.

This evidence typically comes from the medical records.

Prong Four:          Proof of a medically acceptable temporal relationship between the vaccination and the onset of the alleged injury.

The relationship must be medically acceptable rather than just temporally acceptable. (i.e., it must make good medical sense).

“The medically acceptable time frame is defined through peer-reviewed literature, most likely submitted to establish Prong Two.”

“In practice, this prong has proven easily satisfied as the experts are cognizant of and routinely testify to medically accepted time frames for the onset of injuries.”

Prong Five:     Proof of the elimination of other causes.

Must show that “there is no reasonable evidence that an alternate etiology is the more probable cause of the alleged injury.”

“Petitioners may successfully support this prong with evidence from a treating physician indicating that alternate causes were considered and eliminated as the more likely causative agent; this evidence may include oral testimony, written reports, and/or contemporaneous medical records showing the completion of a differential diagnosis.  Reasonable efforts to rule out known alternate causes is sufficient to meet the preponderance standard.”

Only a showing of reasonable efforts to rule out known causes is necessary.

“[P]hysicians may eliminate a sub clinical infection through laboratory testing.  However, a spontaneous or asymptomatic infection or illness which cannot be tested through laboratory or other means is necessarily speculative, and the court refuses to require that petitioners eliminate speculative alternate causes.”

      All of the prongs must be met to prove causation.[35]

It remains to be seen how this decision will be interpreted by all of the Special Masters in the program, and the government will probably appeal the decision, but this does offer a slight glimmer of hope to Petitioners in all claims, whether or not Congress steps forward to alter the burden of proof.

Diabetes:

            An interesting area of future litigation involves the assertion by Dr. Bart Classen that many of the vaccines being used today contribute to the development of juvenile onset diabetes.  His studies can be accessed online at www.vaccines.net and demonstrate relative risks for numerous vaccines.  The issues involved in these types of cases are several and complicated.  First of all, in most cases, looking at just one vaccine would involve a relative risk of less than two.  In order to develop relative risks greater than two (and thereby meet the more likely than not legal standard) requires combining the effects of multiple vaccines.  Secondly, unlike many reactions to vaccines, with diabetes we are often looking at a relationship that develops two and a half to three years after vaccinations.  Thirdly, while going after multiple manufacturers of multiple vaccines many not be a problem under the NVICP, it could pose interesting problems in the context of any civil litigation. 

LYMErix vaccines:

            Class action litigation has been filed against SmithKline Beecham claiming that the vaccine for Lyme Disease causes autoimmune arthritis.  This has been previously reported in the Mealey’s Litigation Report, and more will be presented on this area of litigation by Mr. Lawrence Cohen.

Rotavirus:

            On October 15, 1999, Wyeth-Ayerst's  rotavirus vaccine (RotaShield) was withdrawn from the market.  This vaccine had taken 23 years to develop, but the Centers for Disease Control and Prevention (CDC) concluded that the vaccine increased the risk of a type of bowel obstruction known as intussusception in infants.  Much of the work on this vaccine was done at the NIH, and until the facts became unavoidable, the government advocated that every child should receive the vaccine.  CDC immunization spokesman Dr. John Livengood said that the decision to withdraw the vaccine recommendation was the result of a review of scientific evidence, which showed that the rotavirus vaccine appeared to cause intussusception in approximately 1 in 5,000 recipients, and that vaccinated babies were 25 times as likely to develop intussusception three to seven days after the first dose as those who did not receive it.  What is so shocking about this admission is that the high rate of intussusception was known before FDA approval in August 1998.  The raw data were kept secret and the CDC went ahead with its recommendation. Another disturbing piece of news is that, of the federal health advisory  panel's 12 members, only 4 voted, all for the recommendation to withdraw use of the vaccine. We are told that the others were absent "because of emergencies or abstained because of ties to the  manufacturer or other conflicts of interest."[36]

Other vaccines:

            If anyone thinks that the future of vaccine litigation is limited, think again.  Here is just a partial list of vaccines that are currently being developed:

Candida - http://www.ligocyte.com/article2.html

Cytomegalovirus (CMV) - http://www.deafblind.com/cmv1.html

Chlamydia - http://hopkins.med.jhu.edu/NewsMedia/hnf/hnf_1050.htm

E Coli - http://www.nichd.nih.gov/newsreleases/ecoli.html

Genital Herpes - http://www.henderson-morley.com/research/vaccine.html

Hepatitis E - http://www.info-nepal.com/p-review/2000/02/10022000/newvaccine.html

Strep - http://www.groupbstrep.org/GBS/vaccine.html; http://ur.utenn.edu/context/july97context/features/strep.html

Periodontal Disease - http://webmd.lycos.com/content/dmk/dmk_article_40068

RSV - http://aepo-xdv-www.epo.cdc.gov/wonder/prevguid/m0050267/m0050267.htm

Staph-http://www.abcnews.go.com/sections/living/DailyNews/staph_vaccine990527.html

New TB - http://www.hivdent.org/researcht/resnewstvus0799.htm

Malaria - http://www.epimmune.com/start.html

Nicotine - http://www.nida.nih.gov/MedAdv/99/NR-1217.html

Hepatitis C -  http://www.epimmune.com/epi-flash.html

Herpes Simplex - http://www.midwconfimmunol.org/midwinter99/posters/mourich.htm

Ragweed - http://www.jhu.edu/~gazette/janmar97/mar0397/briefs.html

Behavioral (e.g., Cocaine) - http://abcnews.go.com/sections/living/SecondOpinion/secondopinion_92.html

Rheumatoid Arthritis - http://www.dnavaccine.com/new.html?aid=125

Peanut Allergy - http://www.sciencenews.org/sn_arc99/4_3_99/fob4ref.htm

Childhood Diabetes - http://www.theindychannel.com/sh/health/conditionsaz/news-health-990513-192647.html

Allergy - http://www.bioportfolio.com/erbi/Peptide_2.htm

Multiple Sclerosis - http://www.usc.edu/hsc/info/pr/1vol5/526/ms.html

Anti-cholesterol - http://wrair-www.army.mil/depts/mbc/dmbpbl8.htm

Syphilis - http://www.businessweek.com/bwdaily/dnflash/sep2000/nf20000920_834.htm

Listeria - http://www.centerwatch.com/patient/studies/stu17896.html

H Pylori - http://www.peptide.co.uk/Sci/SciProdHpylori.htm

Cat Allergy - http://www.avma.org/onlnews/javma/jul97/s071597f.html

Ringworm - http://www.otago.ac.nz/Microbiology/Smith.html

Gonorrhea - http://www.biospace.com/news_rxtarget.cfm?rxtargetID=92&SR=11

            The importance of good vaccinations should not be minimized, but some caution might be appropriate.  All vaccines must be weighed on the scales of justice to determine:

1.                  Necessity

2.                  Alternatives

3.                  Efficacy

4.                  Safety

To this list must be added some very important ingredients.  How do we measure the long-term effects of vaccines?  Many, if not all, safety studies are limited to short timeframes, which are not designed to pick up rare reactions, nor reactions that develop slowly.  Furthermore, in a situation like the one where hepatitis B vaccination is given to newborn babies before they are discharged from the hospital, how can a lawyer ever prove causation.  There is no before and after to compare.  Any problems that a baby develops are going to automatically be blamed on genetics or birth trauma or anything but the vaccine.

Exciting things are happening with vaccines.  The development of aerosol vaccines, patches, and other methods of administration may make vaccines safer.  On the other hand, we may be faced with a whole new set of  problems that cannot be foreseen right now.  Someone has to start looking at the impact of giving multiple vaccines over a short period of time.  How do the viruses, bacteria and other constituents of the vaccines interrelate?  This is seen with the cumulative effect of thimerosal and with the theories of Dr. Wakefield about combined vaccines causing problems that single doses might not.

It has become increasingly apparent that the government, despite the enactment of the NVICP, is not going to conduct the research necessary to identify adverse effects of vaccines, nor to try to identify children at high risk, either because of a genetic marker or some other risk factors.  It is also clear that the NVICP is denying compensation to a large percentage of the people filing claims, without giving them access to the funds necessary to hire experts and develop medical proof, and without giving them access to the traditional discovery available in traditional tort litigation.

For the reasons stated, this then is a “call to arms” for the plaintiffs’ bar.  The time is ripe for returning to the civil court system and litigating issues that will protect the rights of future generations.

            Clifford J. Shoemaker 

Overview: Stealth viruses are defined as cytopathic viruses able to establish a persistent infection because of deletion and/or mutation of specific genes which, if expressed, would evoke effective anti-viral cellular immunity (1-5). This presentation will mainly focus on stealth viruses derived from African green monkey simian cytomegalovirus (SCMV). Federal health authorities have been slow in addressing the potential transmission of stealth viruses in live polio viral vaccines.

Bief History of Poliomyelitis: Epidemic paralytic polio began to appear towards the end of the 19th century (6). The first report of a major outbreak was made by the Swedish pediatrician Dr. Carl Medin in 1889. Polio epidemics soon appeared throughout Europe. Attempts at animal transmission failed until 1908 when Dr. Carl Landsteiner (of blood group fame), inoculated two monkeys with a spinal cord extract obtained at autopsy from a 12 year-old boy. One monkey died acutely while a Rhesus monkey became paralyzed.

A major outbreak of paralytic polio occurred in the United States in 1916 affecting nine thousand individuals in New York City (7). Each summer there were reported clusters of polio in various parts of the United States. An unusual polio-like illness affected California in 1934. One hundred and ninety eight medical personnel at the Los Angeles County Hospital became sick (6). They were not paralyzed, but instead developed a chronic fatigue syndrome (CFS)-like illness. Attempts to isolate polio virus were unsuccessful. A class action suit was settled in 1938 for several million dollars, supposedly with the stipulation that there be no publicity to suggest that caring for polio patients could possibly be hazardous.

Basic studies showed that (i) polio virus initially infected the alimentary tract; (ii) Only a small percentage (<1%) of infected individuals actually developed paralysis; (iii) there were 3 serologically distinct Types (1, 2 and 3); (iii) most cases of paralytic polio were due to Type I, as exemplified by the highly virulent Mahoney strain; (iv) serum from a previously infected individual contained protective type-specific antibodies; (v) polio virus could be passed in monkey and mouse brains but "brain adapted" polio did not grow well in non-nervous tissues (6).

A major breakthrough occurred in 1948 when Dr. John Enders showed that by using antibiotics, it was possible to culture intestinal cells on which polio virus could be propagated and could produce a quantifiable cytopathic effect (CPE).

Development of Polio Vaccines: There were two competing approaches to vaccine development. The influenza vaccine model involved the use of inactivated (killed) virus. The yellow fever vaccine model involved the use of a weakened or attenuated strain as a live viral vaccine. Several unsuccessful efforts were made in the 1930's using these approaches with the polio virus grown in monkey or mouse brain.(6).

Following the work of Dr. Enders, Dr. Jonas Salk was commissioned in 1953 by Basil O'Connor, Director of the National Foundation for Infantile Paralysis (March of Dimes Foundation), to produce an inactivated polio vaccine (IPV). Dr. Salk grew virulent polio viruses on Rhesus monkey kidney cells and inactivated the harvested viruses using a 1:4,000 dilution of formaldehyde. Serious questions concerning (i) the necessity of using the Mahoney isolate for Type 1 polio, (ii) the dynamics and completeness of formaldehyde inactivation and (iii) statistical analyses of the early trial data using experimental vaccine lots were smothered by O'Connor's powerful Public Relations campaign and by the public's eagerness for a vaccine. The Federal Laboratory of Biological Safety (a component of the National Institutes of Health) licensed polio vaccine on April 12, 1954. This occurred in spite of Dr. Bernice Eddy notifying her supervisors that several monkeys developed paralysis from the vaccine made at Cutter Laboratories.

Soon after the launching of the commercial vaccine lots in April 1955, there were 10 deaths and 192 cases of vaccine induced paralytic polio. Most of the cases were traced to the Cutter vaccine. Vaccine lots from Park Davis and Eli Lilly were also found to contain live virus and the Industry knew that Dr. Salk's assumptions about formaldehyde were invalid. Efforts were made to single out Cutter as the only defective vaccine, while at the same time improve upon the inactivation protocol. The vaccine program was halted on April 27th and resumed on May 27th, hopefully still in time for the anticipated July onset of natural polio cases. By November, new manufacturing safeguards were introduced, such as an additional filtering step, without any recalls of existing lots. The Laboratory of Biological Safety was reorganized and placed under the Food and Drug Administration (FDA) as the Division of Biological Standards. For her good work, Dr. Eddy was removed from polio vaccine testing!

Although the efficacy of IPV was exaggerated by changing the clinical definition of paralytic polio and other maneuvers, it led to a significant reduction in polio cases. It still probably caused several cases from residual live virus. Public Health critics of the program were shunned and their protests nullified by legislating compulsory vaccination. Dr. Albert Sabin, Dr. Hilary Koprowski and others were more interested in developing an attenuated polio virus which could be administered as a live vaccine. Dr. Koprowski conducted extensive human and animal trials in Central Africa. A 1956 trial in Ireland was marred by the occurrence of polio in vaccine recipients. Dr. Sabin had more success, mainly because he made use of Dr. Renato Dulbecco's technique of plaque purifying attenuated viral isolates. By 1960, Dr. Sabin had convinced much of Europe that his vaccine was less expensive and created more rapid and longer lasting immunity than did IPV. Moreover, excretion of live vaccine virus indirectly vaccinated others within a community and helped out-compete virulent viral strains.

The subtle nucleotide changes, mainly within the 5' non-coding region, that distinguish attenuated from wild type virus have recently been identified. Much of the difference involves a single nucleotide substitution. The attenuated strains can revert to more pathogenic variants, and even approved vaccine lots contain some revertants. This problem occurs more frequently with the least altered, Type 3 polio vaccine strain.

SV40 Contamination: From 1957 Dr. Eddy was involved in pioneering work with Dr. Sarah Stewart on the ability of a mouse Polyoma virus to induce tumors in hamsters. Dr. Eddy was suspicious that monkey kidney cells might have a polyoma-like virus. In April 1960, she reported to her supervisor, Dr. Joseph Smadel, that extracts from Rhesus monkey kidneys induced tumors in hamsters similar to those induced with Polyoma virus. Her work was dismissed by Dr. Smadel. Moreover, she was severely chastised for subsequently mentioning her findings at a Polyoma virus conference held in New York in August, 1960. She was instructed that all future utterances had to be written and submitted for approval by Dr. Smadel.

Dr. Maurice Hillerman of Merck was also concerned that the Rhesus monkeys being used for polio vaccine were becoming increasingly infected with unknown viral agents. He asked the Director of the Washington D.C. Zoo to arrange a shipment of a different species of monkey, imported separately from the usual routing. He received African green monkeys from Africa via Madrid and Baltimore. Extracts from Rhesus monkeys produced a strong vacuolating cytopathic effect on the African green monkey kidney cells. The responsible virus was the 40th virus isolated from Rhesus monkeys and called SV40. It was subsequently shown to be the same virus as found by Dr. Eddy to cause cancer in hamsters.

SV40 is endemic in Rhesus monkeys, producing very little CPE. It does not occur naturally in African green monkeys and when present, it produces a strong CPE. With suppressed publicity, FDA undertook a major effort to switch the polio vaccine seed lots from Rhesus to African green monkeys using anti-SV40 antibodies to neutralize the contaminating virus. Brief and belated mention of the problem occurred in the press; even Dr. Eddy was subsequently allowed to publish her findings. She had, however, lost her laboratory and her research support.

The SV40 issue was initially seen as a problem for the live viral vaccine. Unfortunately, the virus was not inactivated by 1:4,000 formaldehyde and parental inoculation created more infections than oral administration. However, since there were no apparent ill effects, the concern over this virus subsequently waned. Yet, recently there have been reports of SV40 virus in both childhood choroid plexus brain tumors (8) and in mesotheliomas (9). The children were too young to have received SV40 directly from a vaccine and in all likelihood this virus is now circulating within the human population.

Live polio virus vaccine was licensed to Lederle (American Cyanimid) as Orimune(R) in 1961 and has since largely replaced inactivated vaccines. Occasionally (8-10 cases per year in the United States), the Type 3 vaccine polio reverts to virulence and induces disease.

Viral Contamination of Live Polio Virus Vaccines: During early vaccine developments almost 50% of the kidney cultures established for polio vaccine production were discarded because of obvious viral contaminants (mainly foamy retroviruses but also adenoviruses and non-identifiable agents). Few if any of these adventitious agents were thought to be pathogenic for man. An exception was the monkey B virus, a herpes simplex-like virus known to cause a fatal encephalitis. Another major scare arose in 1968 in Marburg, Germany when monkeys intended for vaccine production transmitted an acute hemorrhagic illness to their caretakers. Renewed efforts went into screening for unknown viruses. In 1968, Dr. Kendall Smith, an electron microscopist at FDA Division of Biological Standards, detected viral-like agents in some batches of polio vaccines. He unsuccessfully argued for the use of a fluorescence focus assay using sera from monkeys tested on their own kidney cell cultures. Consideration was given by Lederle to switching from monkeys to human cells for vaccine production. This approach was taken by Pfizer, an English pharmaceutical company. Their product was called Diplovax and was derived from human diploid cells.

In a joint Lederle/Bureau of Biologics study conducted in 1972 "All eleven monkeys studied demonstrated the presence of CMV-like agents. These monkeys all originated from Kenya over a short period of time. Seven of these monkeys would have passed our existing test standards." In a "Cytomegalovirus Contingency Plan", dated August 4th, 1972, Dr. Vallancourt from Lederle argued that "Unless and until Pfizer's Diplovax is in abundant supply, the BB [Bureau of Biologics] cannot risk Lederle being off the market." On March 16th, 1973, Dr. Vallancourt wrote to the President of American Cyanamid, "I do not believe our problems with the slow release of specific lots of Orimune(R) are a result of a Pfizar influence..... Furthermore, if the Bureau wanted to restrict us they could bring up the subject of CMV (Cytomegalovirus) in our substrate (i.e. African green monkey kidney tissue) which they have not done, even though they have told us the monkeys in the collaborative study performed in 1972 were all positive for this agent."

In 1977 assays for retroviral reverse transcriptase activity were applied to some polio vaccines. Certain vaccine lots tested positive and this activity could be transmitted to cell cultures which developed an atypical CPE. It is now known that many of the African green monkeys used were infected with simian immunodeficiency virus (SIV). Interestingly, African green monkeys brought to the Caribbean earlier this century were not infected with SIV, raising the possibility that SIV is a more recent infection than generally thought and possibly of experimental vaccine origin. Discussion at the time of possible Type C retroviruses in polio vaccines led to more detailed electron microscopy. Particles were seen in polio batch 3-444, but were considered more likely to be cell debri than actual viruses. I worked at the time as Director of the Viral Oncology Laboratory at the Bureau of Biologics. In 1978, Dr. G. Aulakh and I confirmed that a bulk monopool of polio vaccine contained a considerable amount of DNA, not all of which could be accounted for as simple cellular debri. I was not provided any information on the earlier concern about CMV, but was told that the monopools were submitted only to determine if they met the mutually approved and mandated tests for polio vaccines. In other words, they were not available to continue this line of experiments. I still remember the project terminating statement from the Bureau's Director: "Stop worrying about it, every time you eat an apple you ingest foreign DNA."

The issue of probable contamination of polio vaccines with adventitious viruses was difficult for anyone to contradict. Maintaining support for the established vaccine program was, however, variously argued: (i) The continued use of primary cultures from kidney cells would help avoid any suggestions that established cell lines may have progressed towards cancer and may contain "oncogenes". (ii) The polio vaccine had been administered to many millions of individuals without apparent adverse effects. It was, therefore, unnecessary and anyhow too late, to correct the situation; (iii) The viruses detected were not the dreaded Marburg agent or the much feared Type C cancer associated retroviruses and were, therefore, of little significance and were probably destroyed when passing through the stomach; (iv) The pharmaceutical industry had to be encouraged to manufacture vaccines and the public had to be encouraged to take vaccines for the government-sponsored immunization programs to be successful. (v) The programs were predicated on existing costs and profit margins and could be threatened if additional testing was imposed. (vi) Many companies had ceased vaccine manufacturing within the United States and any further reduction could make the country more vulnerable to threatened germ warfare, etc., etc.

Neuropsychiatric Illnesses: It is generally believed that the incidence of chronic brain dysfunctional disorders has steadily increased over the last several decades. Conditions such as chronic fatigue syndromes, fibromyalgia, migraine, attention deficit hyperactivity disorder, autism, mental depression, dementia, schizophrenia, etc., are being increasingly diagnosed. Our society has somewhat complacently accepted these conditions as inevitable consequence of "progress". Moreover, compared to efforts aimed at clinical management of these diseases, relatively little effort has gone into identifying their etiology. The involvement of basic researchers has been especially hampered by the imposition of confusing clinical case definitions. Medical specialists have somewhat arbitrarily segregated various facets of neuropsychiatric illnesses into a wide array of nosologically distinct, territorily protected, clinical entities. The ever increasing multiplicity of named dysfunctional brain syndromes may simply reflect the complexity of the brain, rather than imply the presence of innumerable etiologic processes.

Search for Viral Infections in Neuropsychiatric Diseases: I initiated a project in 1986 to see if patients diagnosed as having the chronic fatigue syndrome (CFS) were virally infected (1). Early findings using the polymerase chain reaction (PCR) with primer sets cross-reactive with all of the known human herpesviruses gave weak positive signals with one third of CFS patients, but not with any of several laboratory controls (10). I later found that many CFS patients would also give low, but detectable PCR responses using primers designed to amplify the tax gene of human T lymphocytotropic viruses.

The potential significance of the marginal responses seen in CFS patients became clearer in 1990 when strikingly positive PCR responses occurred with cerebrospinal fluid (CSF) samples from two patients and on a brain biopsy of a third patient. All three patients had unexplained severe encephalitis-like illnesses. The brain biopsy came from a school teacher who had gradually lost her capacity for written and oral communication, but was otherwise alert with no localizing neurological signs. She did, however, have an abnormal MRI with periventricular lesions. The brain biopsy showed mild gliosis with no inflammation. Complete and incomplete forms of herpesvirus-like particles were present in several of the glial cells. Some of the virus positive cells showed marked vacuolated changes and lipid accumulation (11). The PCR positive CSF samples were acellular, indicating an absence of inflammation. One had come from a newborn infant with delayed neural development. The other from an adolescent with residual severe brain dysfunction following what was called an atypical herpes simplex encephalitis.

From about 1987, I had devised several approaches to try to grow human herpes virus-6 (HHV-6) from CFS patients using cord blood lymphocytes. Routine human fibroblast cultures were also established. The latter cells frequently showed a delayed, transient CPE somewhat suggestive of human CMV. Buoyed by the PCR findings in the severe encephalopathy cases, efforts were again undertaken to culture a virus from a PCR positive CFS patient (D.W.). After 6 weeks of culture, enlarged, rounded, vacuolated cells suddenly began to appear in both human and monkey derived cell lines. Cell syncytia were easily recognized. The CPE could be passed to many other cell types and to cells of multiple species. By electron microscopy, numerous complete and incomplete herpesvirus-like viral particles were seen. The foamy, vaccuolated cells did not, however, stain with antisera specific for the immediate-early gene of human CMV. Nor did the cells stain with antisera specific for HSV, HHV-6/7, VZV or adenoviruses. PCR assay using the HTLV tax gene primer gave two well defined products. Sequencing of one of the PCR products (GenBank accession # U09212) identified a region of partial sequence homology to the UL34 gene of human CMV. The sequence of the other PCR product (GenBank accession # U09213) was suggestive of a possible herpesvirus origin but could not be aligned with any of the known herpesviruses (3). Viral DNA was isolated and cloned. A region of sequence homology to African green monkey simian cytomegalovirus (SCMV) was first found in early 1994. Unrelated to our work, Dr. Gary Hayward of Johns Hopkins University submitted additional sequence data on SCMV to GenBank in December 1994. From his sequence data, it was unequivocal that the CFS patient's virus had originated from SCMV (5).

In 1991 I coined the term "stealth" to describe the viruses I had been seeking. I used this term primarily because it carried the connotation that the viruses could occur in the absence of inflammation. The SCMV-derived virus was designated stealth virus-1. A closely related virus (stealth virus-2) was isolated in early 1991 from the CSF of a patient with an acute severe encephalopathy following a 4 year history of a manic depressive illness. The patient (B.H.) has remained in a vegetative state since 1991. DNA sequencing of a PCR amplified product from her infected cultures has identified the virus as being similar but not identical to the SCMV-derived stealth virus-1. Numerous other stealth viral isolates have been obtained and are awaiting resources to perform the necessary sequencing analyses.

Animal Studies: Stealth virus-1 induces an acute neurological illness when inoculated into cats (12). The early manifestations developed within a week and included gingivitis, bloody ocular and nasal discharge, lymphadenopathy, pupil dilatation with photophobia (squinting in response to light) and nuchal hair loss from rubbing against the cage. There was a reduction in body temperature beginning in the second week which averaged 0.6oF at 2 weeks and 0.8oF at weeks 3 and 4. Most striking was the marked behavioral changes in all of the virus-inoculated cats. They lost the playfulness that was present prior to injection and became reclusive and irritable. They resisted being handled and the animal caretakers resorted to wearing leather gloves. By palpation, the enlarged lymph nodes and various muscle groups were identified as being painful for the animals. The severity of the illness peaked at around 4 weeks with definite improvement noted in the cat necropsied at 6 weeks. A cat that was maintained to 15 weeks had resumed normal activities by week 10 and appeared to be symptom free. Histological examination of animals' brain tissue showed foci of cells with cytoplasmic vacuolization and an absence of any inflammatory reaction. Electron microscopy on several cats confirmed the presence of occasional herpes-like viral particles and, more commonly, the presence of variable patterns of accumulations of viral-like granular and other membranous structures suggestive of subgenomic viral expression.

Unstable, Fragmented Nature of the Stealth Virus-1 Genome: Restriction enzyme digests of stealth virus-1 have been cloned and partially sequenced. The genome appears to comprise multiple fragments of approximately 20 kilobase pairs. The virus displays an unusually high degree of sequence microheterogeneity suggesting infidelity of DNA replication or an alternative replication strategy (13). The concept of a fragmented, unstable viral genome is consistent with electron microscopic observations (14). It has important implications for the approaches to be taken in using molecular techniques to screen for these viruses. It also raises concerns about the possible oncogenicity of stealth viruses (16).

Stealth Viruses Isolated from Patients with Severe Encephalopathy: Since the beginning of these studies, a number of patients have been identified with strongly positive cultures and complex clinical case histories. While the initial focus was on CFS patients, the more recent emphasis has been on patients with severe encephalopathy. In many of these cases, a preceding CFS-like illness was present. The clinical observations support the concept of potentially infectious neuropsychiatric illnesses attributed to varying degrees of dysfunction of different regions of the brain (2). Brain biopsies have been obtained in five patients and have shown many of the characteristic changes noted in the infected cats. In some of the biopsies, there is an additional vasculitis component. Possibly, the most promising clinical aspect of these illnesses is the recovery process seen in several, but not all, severely ill patients. The mechanism of recovery is the most important goal of stealth virus research. In a step towards this goal, I am hoping to obtain sufficient sequence data on isolates from severely ill adult patients and from autistic children, to determine which, if any, have originated from African green monkeys. I realize that while monkey cells have been used for polio and adenovirus vaccines; dog and duck kidney cells have been used for rubella vaccines; chicken cells have been used for measles and mumps vaccines; and a very wide range of animals cells have been used for animal vaccines. Unfortunately, only limited sequence data are available on most animal viruses. Some stealth viruses may simply have originated by the down sizing of known human viruses, especially human herpesviruses. In these endeavors, I have so far unsuccessfully sought the help of both the FDA and the CDC.

Notification to CDC, FDA and Lederle: CDC was notified in early 1991 that a repeat positive culture was obtained on patient D.W. and a similarly positive culture was obtained on the comatose patient B.H. An invitation to visit my laboratory to see the cultures was declined. CDC was again notified in mid 1994 when the sequence data on stealth virus-1 showed a greater relatedness to SCMV than human CMV. FDA Center for Biologics Evaluation and Research (CBER) was contacted in March of 1995 and the President of Lederle sent a letter in July, 1995. Prompted by FDA personnel, unsolicited requests for collaborative and financial assistance were sent to CDC and to FDA in June 1995, followed by visits to both agencies. The unsolicited proposal format is designed to protect an agency from the accusation that it has given a competitive advantage to someone seeking government funds. The proposals included detailed clinical descriptions of 12 cases of severe, otherwise unexplained, encephalopathy. In the FDA proposal, I asked to do a surveillance study to determine the prevalence of simian CMV-derived stealth viruses in humans and in the monkeys used for polio vaccine production. I also wanted to test some vaccine monopools. In the CDC proposal, I asked for help in sequencing the viral isolates from the 12 patients.

Response from CDC Received 5 Months After Submission: "Reviewed by the National Immunization Program (NIP) and the National Center for Infectious Diseases (NCID) of CDC. It was determined that the proposal did not address NIP research needs at this time. There was also the comment from NCID that "The twelve patients reported have variable clinical histories with no obvious epidemiological links between them. The evidence that a virus can be isolated from these cases is unconvincing. No independent confirmation has been reported in the results described in this proposal and the evidence for the existence of an infectious agent which the offeror (sic) calls a 'stealth virus' remains unconvincing."

Unofficially, I was told that Ms. Joanne Patton, now working in Dr. John Stewart's laboratory at NCID, recalled hearing of a patient becoming infected with SCMV which had contaminated a rubella virus vaccine grown on African green monkey cells. From discussions with Ms. Patton and Dr. Stewart, there seems to be some regret that CDC had not made efforts to pursue this event. A request for a brief statement in the Mortality and Morbidity Weekly (MMWR) on atypical viral encephalopathy was also denied.

Response from FDA Received 7 Months after Submission: "Request for support to screen for the prevalence of simian cytomegalovirus derived stealth viruses in humans is best sought from an agency such as the NIH, rather than the FDA.Requests to screen the monkey colonies that are used in vaccine production for the presence of stealth viruses. These are studies that would need to be conducted with the manufacturers.

Request to screen polio samples (the bulk mono-pools) for stealth viruses. Screening of these samples, if done, should be carried out in CBER's own laboratories. We are evaluating the types of studies that might be best done using PCR-based techniques. However, even if such sequences are found in a PCR-based assay, the question whether transmissible, replication competent viruses are present would still need to be addressed.

We appreciate your informing us and others, not only in your submitted proposal but also at the FDA Workshop on cell substrates and at the IOM meeting on vaccine safety, about your concerns vis-a-vis simian cytomegalovirus and potential related viruses in the polio vaccine. We will be addressing this concern in our Laboratories".

Other Relevant Actions: The Advisory Committee on Immunization Practices (ACIP) had made a recommendation to move from a series of four injections of live polio vaccine to a split protocol of two injections of inactivated vaccine (IPOLTM, produced by Pasteur Merieux-Connaught Laboratories) followed by two injections of live vaccine. This was obstensibly to help reduce the occurrence of the approximately 8-10 cases a year of poliomyelitis from Type 3 vaccine revertants. Although not cited as a reason, such a move would expand the production of inactivated vaccines should a subsequent total switch to inactivated vaccine be recommended. A decision to delay the implementation of this plan was made at the February ACIP meeting. There will be opportunity for public input at the June meeting.

FDA has held open meetings to discuss possible hazards of interspecies bone marrow therapy in AIDS patients and interspecies liver and other organ transplants. FDA was unable to muster support to restrict the first baboon bone marrow trial.

Summary: The concepts that certain stealth viruses may have arisen as contaminants of live viral vaccines, and that vaccinations may have had untoward consequences, have not been embraced by either vaccine manufacturers or Public Health agencies. As the experimental data unfold, however, the existence and the clinical importance of stealth viral infections are less easily reputed. Indeed, stealth viral infections may explain a wide range of neurological and neuropsychiatric diseases, serving as a common thread linking these diseases, and possibly accounting for their ever increasing prevalence.

If a vaccine program were to be initiated today, one would surely not import wild monkeys from Africa, create short term primary kidney cultures, add a human virus and administer the crude gamish derived from the virally infected cells to virtually every child in the country. Nor would one want to withhold applying the many molecular biological techniques developed over the last 30 years to assess vaccine purity. Yet this is essentially the situation with live polio vaccine and comparable arguments can be made for other human and animal viral vaccines.

Various meetings, phone calls and document exchange have uncovered a sense of frustration within the Federal Public Health System, Industry, and the general public with what appears to be a resistance of those in authority to face the issue of prior, if not also present, vaccine contamination. If animal viruses have been inadvertently introduced into humans, the sooner we find out the better. I would very much appreciate continuing to hear about patients with seemingly complex infectious and/or neuropsychiatric illnesses. Volunteers are needed to help bring these patients to the attention of the Public Health System. Work on the in vitro efficacy of stealth virus inhibitors needs support so that clinical therapeutic trials may soon become a reality. Phone and FAX messages can be left at 818 799-4500 and 818 799-1700 in the Los Angeles area and at 510 222-9466 and 510 222-9466 in the San Francisco area. The e-mail address is wjmartin@mizar.usc.edu

References

1. Martin W.J. Viral infection in CFS patients. in "The Clinical and Scientific Basis of Myalgic Encephalomyelitis Chronic Fatigue Syndrome." Byron M. Hyde Editor. Nightingdale Research Foundation Press. Ottawa Canada pp 325-327, 1992.
2. Martin W.J. Stealth viruses as neuropathogens. CAP Today 8 67-70, 1994.
3. Martin WJ, Zeng LC, Ahmed K, Roy M. Cytomegalovirus-related sequences in an atypical cytopathic virus repeatedly isolated from a patient with the chronic fatigue syndrome. Am J Path. 145: 441-452, 1994.
4. Martin WJ. Stealth virus isolated from an autistic child. J Aut Dev Dis. 25:223-224, 1995.
5. Martin WJ, Ahmed KN, Zeng LC, Olsen J-C, Seward JG, Seehrai JS. African green monkey origin of the atypical cytopathic 'stealth virus' isolated from a patient with chronic fatigue syndrome. Clin Diag Virol. 4: 93-103, 1995.
6. Paul JR. A history of poliomyelitis. Yale University Press, New Haven, 1971.
7. Gould T. A summer plague. Polio and its survivors. Yale University Press. New Haven, 1995.
8. Lednicky JA et al. Natural simian virus strains are present in human choroid plexus and ependymoma tumors. Virology 212: 710-717, 1995.
9. Cristaudo A, et al. Molecular biology studies on mesothelioma tumor samples: preliminary data on H-ras, p21 and SV40. J. Environ Path 14: 29-34, 1995.
10. Martin WJ: Detection of viral related sequences in CFS patients using the polymerase chain reaction. In Hyde B ed. The Clinical and Scientific Basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Nightingale Res Found. Ottawa Canada, pp278-282, 1992.
11. Martin WJ. Severe stealth virus encephalopathy following chronic fatigue syndrome-like illness: Clinical and histopathological features (submitted)
12. Martin WJ, Glass RT. Acute encephalopathy induced in cats with a stealth virus isolated from a patient with chronic fatigue syndrome. Pathobiology 63: 115-118, 1995.
13. Gollard RP, Mayr A, Rice DA, Martin WJ. Herpesvirus-related sequences in salivary gland tumors. J Exp Clin Can Res.15: 1-4, 1996.
14. Martin WJ. Genetic instability and fragmentation of a stealth viral genome. Pathobiology (in press).

PRESENTATION TO INSTITUTE OF
MEDICINE MEETING ON VACCINE SAFETY

NOVEMBER 6th, 1995

Dr. W. John Martin. Thank you very much for this opportunity to discuss with you work on atypical herpes viruses in chronic neurological diseases.

I will begin with clinical descriptions of two patients, and then move to in vitro culture work, and conclude with data showing that some atypical herpesviruses have sequences of African green monkey simian cytomegalovirus origin.

This first slide is the attempts at drawing a clock and a house by a 39-year-old school teacher from Palm Springs. This was in 1990. Her illness began one year earlier, when she merely noticed the inability to spell some words. She was treated for a stress-related disorder, but her condition deteriorated within the year. An MRI showed bilateral periventricular lesions. She was referred for a stereotactic brain biopsy. The next slide illustrates the brain biopsy. Noteworthy, is the absence of any inflammatory response. Electron microscopy, however, showed vacuolated glial cells, as seen on the next slide, with some atypical structures consistent with herpesviruses.

I chose to mention this patient because the biopsy was performed way back in 1990. I have encountered a number of patients since then with atypical neurological illnesses attributable to a viral encephalopathy. One of the last, but unfortunately not the last brain biopsy that I have examined, is this biopsy from a 30 year old dentist who was asymptomatic midway through last year. Her condition slowly deteriorated, especially affecting her work performance and social demeanor. Again, her initial illness was simply ascribed to stress. Essentially she had what is called chronic fatigue syndrome. Her illness became quite severe in May of this year. Following a request to her mother for help, she was admitted to a psychiatric hospital with a psychosis. Her condition further deteriorated and she became deeply comatose. She had a brain biopsy which showed the characteristic vacuolated cellular appearance seen in this slide. For two months, she remained deeply comatose. She has since, however, shown significant improvement but is still quite incapacitated.

I will now describe the in vitro culture findings of viral induced cytopathic effects. This next slide demonstrates the typical effects seen when blood and other samples are cultured with human fibroblasts. The fibroblasts develop vacuolated changes similar to those in the brain biopsies.

I want to emphasise that in the various patients from whom we have had positive cultures, routine testing for human viruses have yielded negative results. It is only by careful culturing that we pick up the cytopathic effect. By regular refeeding, the cytopathic effect progresses to yield large syncytial cells, that can look like foamy cells. Such cultures clearly show a very marked cytopathic effect. Strongly positive cultures have now been seen using blood, brain and CSF samples from a large number of neurologically impaired patients.

The important question is, what is causing the in vitro cytopathic effect, and can we relate it to what is going on in the brains of patients, with milder degrees of brain dysfunction than those in whom brain biopsies were performed.

We now have answers to some of these questions. This is the in vitro cytopathic effect on human fibroblasts induced with cerebrospinal fluid of a 23 year old woman admitted in early 1991 to the Los Angeles County Hospital. Her illness had began when she was 19 years old, with an initial diagnosis of schizophrenia, subsequently changed to bipolar manic depression. She deteriorated in early 1991, to the extent that she became comatose, developed seizures and had a brief cardiac arrest. She was treated initially as if she had a herpes simplex encephalitis. But as with several other patients, a confounding finding was the lack of any inflammatory reaction in her cerebrospinal fluid. So the conclusion was reached that she probably had overdosed on some medication. This particular patient has never recovered from her comatose state. Similar to the school teacher, this patient has remained in a vegetative state. She is awake, but has had no cerebral functions since 1991 when she was admitted to the hospital. I'll come back to this patient in a while.

Cultures showing these types of vacuolating cells have been obtained from patients who have had less severe, but still persisting, neuropsychiatric illness. Many of these patients have been simply characterized clinically as having the chronic fatigue syndrome.

This is one such patient's in vitro culture showing the vacuolated cytopathic effect. In her case, electron microscopy revealed numerous viral particles. They looked like herpesviruses, particularly cytomegalovirus even showing typical dense bodies. Yet when we performed specific serological and polymerase chain reaction based tests to see if they were human cytomegalovirus, human herpesvirus 6, Epstein-Barr virus, varicella zoster or human herpes simplex virus, we obtained negative results.

Another striking feature of the cytopathic effect seen with this virus, was that it was not restricted to human cells, but instead had an extremely wide host range. The cytopathic effect could be transmitted to cells from a variety of species, even down to the level of insect cells, inducing the same transmissible vacuolating cytopathic effect.

The wide host range allowed me to undertake animal studies with Dr. Tom Glass of the University of Oklahoma. We wanted to see what would happen if we inoculated the virus into cats. What will be published soon, is the description of the severe acute encephalopathy which occurred in the cats inoculated with this virus. We did the study in cats becaus of epidemiological data and anecdotal reports of unexplained illness in pets of chronic fatigue syndrome patients.

The virus was pathogenic and able to induce an acute encephalopathy in animals. The inoculated cats changed dramatically from friendly, frisky animals to very irritable, disturbed animals. Yet routine histopathological analysis of the brains of the animals showed rather subtle changes, for which most neuropathologists would exclude infection, especially since the changes occurred in the absence of inflammation.

If one looks for cellular details, one can see the same characteristic vacuolated cells with distorted nuclei as seen in the human brainn biopsies mentioned before. Moreover, by electron microscopy, one can see viral particles often accompanied by a lot of extraneous viral-like products. It is the lack of inflammation that led to the term "stealth virus, referring to viruses that were disregarded by the immune system yet retain the ability to disrupt cellular function, particularly within the brain.

The next major issue was to come to grips with what kind of viruses were we dealing with and where had they come from.

I, therefore, proceeded with molecular studies. I was able to isolate DNA from the viral cultures, clone it and begin to do sequence analysis. Last year, we reported that the initial sequence data clearly indicated a relationship to cytomegalovirus.

Only limited sequence data are available on animal cytomegaloviruses, unlike human cytomegalovirus which has been completely sequenced. What we did find was only a 50 to 60 percent homology to human cytomegalovirus. But by serology and PCR it clearly was not identical to human cytomegalovirus.

This situation persisted until we could obtain additional sequence data covering regions of the virus where there were corresponding sequence data available for various animal cytomegaloviruses.

This analysis led to a definitive indication that the virus we were characterizing had a very high level of sequence homology to the simian cytomegalovirus of