# Andrulonis v. United States

> District Court, N.D. New York · December 15, 1989 · 724 F. Supp. 1421

URL: https://www.frixlaw.com/law-library/cases/1467978

## Case

- **Court:** District Court, N.D. New York
- **Decided:** December 15, 1989
- **Citations:** 724 F. Supp. 1421; 1989 WL 123995
- **Precedential status:** Published
- **Opinion:** Opinion
- **Judges:** Munson
- **Cited by:** 22 later opinions in the Frix Law Library

## Citator (automated)

- No negative treatment found by the automated citator. That is not the same as a confirmation that the case is good law; read the citing cases.
- Full citator and citing cases: https://www.frixlaw.com/law-library/cases/1467978

## How later opinions describe it (automated extraction)

- noting that the “neurologic effects of the rabies virus on an infected individual are so severe that the disease of rabies is almost always fatal”

## Opinion text

724 F.Supp. 1421 (1989)
Joanna ANDRULONIS, Individually, and as Conservator of the Property of Jerome Andrulonis, Plaintiffs,
v.
UNITED STATES of America; Glatt Air Techniques, Inc.; Glatt GmbH; Wisconsin Alumni Research Foundation, Inc.; WARF Institute, Inc.; Raltech Scientific Services, Inc.; Ralston Purina Company; Eli Lilly and Company; and John L. Thompson and Sons and Company, Defendants.
UNITED STATES of America, Third-Party Plaintiff,
v.
NEW YORK STATE DEPARTMENT OF HEALTH, Third-Party Defendant.
No. 79-CV-847.
United States District Court, N.D. New York.
October 17, 1989.
As Amended December 15, 1989.
*1422 *1423 *1424 *1425 *1426 *1427 *1428 *1429 *1430 *1431 Roemer and Featherstonhaugh, Albany, N.Y. (James D. Featherstonhaugh and John R. Mineaux, of counsel), for plaintiffs.
Dept. of Justice, Civ. Div., Torts Branch, Washington, D.C. (Leon Taranto and Anthony R. Sherr, Trial Attys., of counsel), and Frederick J. Scullin, Jr., U.S. Atty., N.D.N.Y., Albany, N.Y. (William Fanciullo, Asst. U.S. Atty., of counsel), for U.S.
Robert Abrams, Atty. Gen., State of N.Y., Albany, N.Y. (Kevan J. Acton and Robert Seigfried, Asst. Attys. Gen., of counsel), for defendant New York State Dept. of Health.
Anderson Russell Kill & Olick, P.C., New York City (R. Mark Keenan, of counsel), and Paul F. Donahue Associates, Albany, N.Y. (Alvin O. Sabo, of counsel), for defendant Glatt GmbH.
Carter, Conboy, Bardwell, Case and Blackmore, Albany, N.Y. (Philip J. Danaher, of counsel), for defendant Wisconsin Alumni Research Foundation.
McNamee, Lochner, Titus & Williams, Albany, N.Y. (Earl H. Gallup, Jr., of counsel), for defendants Raltech Scientific Services, Inc. and Ralston Purina Co.
Maynard, O'Connor & Smith, Schenectady, N.Y. (Richard Gershon, of counsel), for defendant WARF Institute, Inc.
Ainsworth, Sullivan, Tracy and Knauf, Albany, N.Y. (Thomas F. Tracy, Frank J. Warner, Jr. and Margaret Comard Lynch, of counsel), for defendants Eli Lilly and Co. and John L. Thompson & Sons & Co.
Galef & Jacobs, New York City (Christopher M. Houlihan, of counsel), for defendant Glatt Air Techniques, Inc.
MEMORANDUM-DECISION AND ORDER
MUNSON, District Judge.
On March 29, 1977 the rabies virus invaded the body of plaintiff Jerome Andrulonis during an experiment conducted by his employer, the New York State Department of Health ("NYSDOH" or "the State"). The experiment was a part of the State's effort to develop a method for immunizing wildlife from the disease the virus causes. Shortly after being exposed to the virus, Andrulonis contracted the disease of rabies, and his central nervous system was ravaged. He survived the disease, thus becoming one of only three individuals in human history to do so, but the neurologic damage he suffered as a result of his illness left Andrulonis without the cognitive ability to appreciate this distinction.
On December 20, 1979 this action was commenced on behalf of Jerome Andrulonis and his wife, Joanna, against the United States of America ("United States" or "the Government") under the Federal Tort Claims Act ("FTCA" or "the Act"), 28 U.S.C. §§ 1346 , 2671-2680, and against various non-governmental defendants, over whom jurisdiction was predicated on diversity of citizenship or the pendant party doctrine. An amended complaint adding additional non-governmental defendants was filed on October 9, 1981. Plaintiffs' claims sounded in negligence, strict products liability, and breach of warranty. The United States made cross-claims against the non-governmental defendants and filed a third-party complaint against NYSDOH, seeking contribution. See N.Y.C.P.L.R. §§ 1401-1404 (McKinney 1976). Subsequently, the court dismissed Joanna Andrulonis' derivative claims against the United States for failure to timely file an administrative claim, as required by the terms of the FTCA. Andrulonis v. United States, No. 79-CV-847, slip op. at 7 (N.D.N.Y. March 8, 1984); see 28 U.S.C. § 2675 (a); *1432 see also id. § 2401(b). [1] A trial on the remaining claims was conducted from February 18, 1987 until March 19, 1987. Before the end of the trial, plaintiffs entered into settlement agreements with all of the non-governmental parties, [2] leaving unresolved the FTCA claims of plaintiff Jerome Andrulonis against the United States and the contribution claims made by the Government. This memorandum-decision constitutes the court's findings of fact and conclusions of law concerning the remaining claims. [3] See Fed.R.Civ.P. 52(a).
I. INTRODUCTION
In some ways, the case of Jerome Andrulonis is aberrational. Andrulonis is believed to be the only person to contract the disease of rabies who prior to any exposure to live rabies virus had developed through vaccination a significant level of rabies antibodies in his blood stream. He is one of only two individuals in this century known to be infected after being exposed to the rabies virus in a laboratory setting. As will be seen, he is one of only four individuals in human history believed to have contracted the disease internasally, through what is referred to as the "aerosol route" or the "airborne route" of infection. [4] Nonetheless, upon examination of what was known about the transmission of the virus by the researchers involved with the experiment of March 29, 1977, what was considered safe and reasonable laboratory practice in the relevant scientific community at that time, and the manner in which the March 29, 1977 experiment was performed, it can only be concluded that Andrulonis' development of the rabies disease was the foreseeable and avoidable result of negligence on the part of the researchers involved with the project.
Because a lengthy narrative is to follow, a brief summary may give some context to the matters discussed. In March 1977 Jerome Andrulonis was a thirty-four year old senior bacteriologist employed by NYSDOH who was primarily involved with research conducted in the rabies laboratory *1433 at the State's Griffin Laboratory ("Griffin"), located near Albany, New York. Because he was constantly exposed to the rabies virus in his work, he had been immunized against the disease of rabies through the administration of a commercial vaccine manufactured by defendant Eli Lilly and Company ("Lilly") and distributed by defendant John L. Thompson and Sons and Company ("Thompson & Sons"). Periodically, Andrulonis received booster shots of the Lilly vaccine, which induced the creation of antibodies to the rabies virus in the blood stream ("serum antibodies"). The effectiveness of the Lilly vaccine was dependent on whether the rabies virus, once transmitted to an immunized individual, came into contact with serum antibodies before entering his central nervous system. In the typical case where the virus is transmitted to an individual by animal bite, the site of the bite wound is covered in the victim's blood, and the antibodies that had been created in the blood stream by the vaccine would have the opportunity to kill the invading virus. In the rare case where the virus is transmitted through the air and inhaled by the victim, however, the Lilly vaccine is probably ineffective. The olfactory nerves within an individual's nasal cavity are exposed to the air. If live rabies virus comes into contact with an individual's olfactory nerve and infects it, the virus could travel the short distance from the olfactory nerve to the victim's brain without ever coming into significant contact with serum antibodies.
At the time Andrulonis was exposed to the virus that ultimately caused his illness, he was attempting to coat sugar nonpareils [5] with a solution containing live rabies virus. The coating process was accomplished through the use of a machine recommended by defendant WARF Institute, Inc. ("WARF"). [6] The machine, known as the "Uni-Glatt," suspended the sugar non-pareils in a stream of upflowing air while various solutions were sprayed onto them. The Uni-Glatt Machine was manufactured by defendant Glatt GmbH and distributed in the United States by defendant Glatt Air Techniques, Inc., and employed an air suspension process that had been developed by Dale Wurster. The process created "aerosols," which are suspensions of microscopic solid or liquid particles in air or gas. The Uni-Glatt machine was not airtight, and when the solution containing live rabies virus was sprayed onto the nonpareils, aerosolized virus escaped from the Uni-Glatt and into the atmosphere of the rabies laboratory at Griffin. The virus was inhaled by Andrulonis, apparently infected one of his olfactory nerves, and then multiplied and travelled from his olfactory nerve to his brain, causing severe and permanent damage.
The experiment in question was conducted under the supervision of Dr. John G. Debbie, a research scientist employed by NYSDOH. Also present during the experiment was Dr. George M. Baer, Chief of the Viral Zoonosis Branch and Rabies Laboratory at the Center for Disease Control ("CDC"), who conducted most of his work in the CDC's laboratories in Atlanta and Lawrenceville, Georgia. The CDC is a part of the United States Department of Health and Human Services, and in March 1977 was a subunit of the Department of Health, Education, and Welfare. The experiment was conducted in furtherance of a joint effort by scientists at NYSDOH and the CDC to develop a method for the mass immunization of wildlife from rabies. During the course of this effort, Debbie requested Baer to prepare a solution of highly concentrated rabies virus for experimental use in the Uni-Glatt machine. The virus "strain" Baer prepared at the CDC's laboratory in Lawrenceville in response to this request was supplied to Debbie on March 28, 1977 and used in the Uni-Glatt machine the next day. At the time of the *1434 March 29, 1977 experiment, it was not known whether the virus Baer supplied was "pathogenic," that is, capable of causing disease in man. The court will find that during the course of the March 29 experiment, Andrulonis was exposed to an aerosol containing the virus Baer had prepared and as a result of this exposure contracted the disease of rabies.
Plaintiffs allege that the laboratory conditions under which the experiment was conducted at Griffin were unsafe, that Dr. Baer should have known this, and that Baer's failure to stop the experiment before Jerome Andrulonis was exposed to an aerosol containing rabies virus constituted negligence that was the direct and proximate cause of the injuries Andrulonis suffered. Plaintiffs also argue that Baer acted carelessly in supplying a highly concentrated virus strain to the comparatively inexperienced researchers at NYSDOH. It is asserted that Baer negligently failed to warn Dr. Debbie of the inherent dangers associated with the virus strain he provided and to which Andrulonis was exposed. Plaintiffs also maintain that the Government is liable because Dr. Baer and Dr. William G. Winkler, Chief of the Viral Zoonoses Section of the CDC's Viral Disease Division, negligently made representations that induced WARF to recommend the use of the Uni-Glatt machine in experimental situations for which the machine was not suited. Finally, plaintiffs introduced evidence suggesting that the March 29, 1977 experiment was a part of a "joint venture" involving CDC and NYSDOH, and consequently that the United States is jointly and severally liable for any negligent acts on the part of NYSDOH employees, including Dr. Debbie. The Government denies any negligence on the part of its employees, and urges that the injuries plaintiff Jerome Andrulonis suffered were the result of his own negligence or the negligent acts of employees of the State or the non-governmental parties.
II. BACKGROUND
Unless the context indicates otherwise, this section of the opinion summarizes facts that reasonably should have been known as of March 29, 1977 by scientists who ventured beyond routine laboratory procedures involving the rabies virus and proceeded into the conception and supervision of experimental research projects involving that virus. Specifically, Drs. Debbie, Baer, and Winkler, whose conduct or representations are relevant to the claims made in this lawsuit, are charged with knowledge of the principles and theories discussed in the pages that follow, as well as familiarity with the research upon which those principles and theories were based. In 1976 and 1977, these men were either members, or engaged in research projects that should only have been undertaken by members, of a select group referred to at trial as the "community of rabies experts," which in the United States numbered between twenty-five and fifty scientists. [7] Whether Jerome Andrulonis reasonably should have been aware of the body of scientific knowledge discussed in this memorandum-decision is more problematical, *1435 and this issue will be discussed separately. [8] For the most part, the scientific literature that is cited by the court in this section predates the March 29, 1977 Uni-Glatt experiment, and the testimony cited concerns knowledge available to the relevant scientific community of rabies experts before that date.
A. The Nature of the Rabies Virus
Rabies is an acute infectious disease of the central nervous system that imperils a wide range of mammal species, including man. Historically rabies has been one of man's most dreaded diseases, no doubt because of its dramatic symptoms and the severe neurologic effects associated with it.
The Greeks called rabies Lyssa or Lytta which meant madness. The disease in man was described as hydrophobia in which the sick person is tormented at the same time with thirst and the fear of water. The Latin word "rabies" comes from an old Sanskrit word rabhas which translated means "to do violence." The German word tollwut originates with the Indogermanic Dhvar, to damage, and wut from middle German wuot which is rage. The French word for rage is derived from the noun robere, to be mad. [9]
As Jerome Andrulonis noted in his Master's Dissertation, "[e]ven today, the mere mention of this affliction is sufficient to strike terror into the hearts of the general public, for facts and folklore have blended to obscure any true understanding of this deadly malady." [10]
The disease of rabies can develop in an animal after the introduction of the rabies virus into the body of that animal. The rabies virus is an "etiologic agent," in other words, it is an organism capable of causing disease. Infection by the rabies virus in nature usually occurs through the saliva of another infected animal during a bite. Although infrequent, the virus can also be transmitted through the milk of an infected animal or, in rare cases, internasally, if an animal is exposed to an aerosol containing the rabies virus. [11] Not every person or animal who comes into physical contact with an environment containing live rabies virus ("exposure" to the virus) has the live virus introduced into his or her body ("infection"), and not every person or animal infected with the rabies virus subsequently develops the disease of rabies. [12]
A virus is a microscopic organism consisting of genetic material [13] surrounded by a protective protein shell. A virus can reproduce only within a living host cell. [14] The rabies virus is a neurotropic virus, or a virus that proliferates primarily in nervous tissue, although it also has an affinity for certain other tissues of a host that it has infected, including the tissue comprising the salivary and adrenal glands and the epithelial (surface) tissue of the lungs, bladder and urinary tract. [15] In the common case where the rabies virus is transmitted *1436 to a previously uninfected animal through the saliva of an infected animal during a bite, the rabies virus is introduced into the cells of the bitten animal's muscles, connective tissue, or nerves at the site of the bite. [16] Once introduced, the virus may fail to multiply, or may multiply within an infected cell at the location of the bite but not leave that cell, or may spread to other cells locally but fail to invade the infected animal's central nervous system. [17] If any of these contingencies occur, sickness will not develop. On the other hand, if the virus reproduces at the site of infection, leaves that site and invades the victim's central nervous system, it will produce the disease of rabies in the infected animal. [18]
A common progression characterizes those cases where the disease of rabies develops in an animal or man after infection. At the site of exposure and infection, the virus goes through an incubation period lasting from ten days to several months, [19] and then invades nearby nervous tissue. The virus begins to travel along connected nerves until it reaches the central nervous system. The reproduction of the virus within the central nervous system can cause myelitis (inflammation of the spinal cord) or encephalitis (inflammation of the brain). As the animal becomes ill as a result of viral replication in the brain, the virus travels down nerve cells into the mouth and enters the diseased animal's saliva. Frequently, the infected animal will become aggressive or violent because of the encephalitic changes caused by the virus, and this effect will often coincide with the entry of the virus into the animal's saliva. The virus is transmitted to other animal hosts when an agitated rabid animal bites an uninfected animal, introducing saliva containing the deadly virus into the bitten animal. [20]
When rabies virus is introduced into the muscle tissue of an animal as a result of the bite of a rabid animal, the virus has entered by the intramuscular route of infection. The term "route of infection" refers to the manner in which the virus enters the body of an animal. For example, researchers can introduce the virus into a laboratory animal by the "parenteral route" if they inject the virus into the animal intramuscularly, intravenously, or subcutaneously (beneath the skin). In cases of infection by the parenteral route, researchers draw distinctions based on the proximity of the site of the parenteral invasion to the animal's central nervous system. In the laboratory, rabies virus can be introduced into an animal by the "intracerebral route," which is accomplished by injection of a solution containing virus directly into an animal's brain. Most importantly for the purposes of this lawsuit, rabies virus can infect an animal through the "airborne route" (alternatively called the "aerosol route") when the animal inhales aerosol suspensions containing rabies virus.
The chances that the disease of rabies will develop in an infected animal are closely related to the quantity of viral particles [21] to which the animal is exposed. [22] This is true regardless of the route of infection. [23] With respect to the aerosol route of exposure, the "dose" or quantity of aerosolized viral particles to which an animal is exposed is the most important factor in determining whether a rabies virus *1437 will likely cause disease in the animal as a result of this exposure. [24]
As a species, man is not particularly susceptible to contracting the disease of rabies. [25] Nonetheless, between 1958 and 1972 there were an average of 709 reported cases of human rabies per year worldwide (virtually all of which resulted in death), and it is believed that this total significantly underestimates the number of human cases worldwide. [26] The rabies virus is ordinarily transmitted to humans through the bites of wild and domestic animals. Exposure through rabid cats and dogs is still very prevalent throughout the world, although such exposure has been largely minimized in the United States in the past three decades as a result of effective animal control programs and strong policies favoring the vaccination of domestic animals. As a consequence of this development, the number of cases in which humans contracted the disease of rabies in this country decreased from an average of more than forty a year in the 1940s to an average of less than two a year in the 1960s. [27] The most recent cases of human rabies in this country for the most part have been attributable to the bites of bats, skunks, or raccoons. [28]
The disease of rabies in man can be divided into five stages. [29] The first stage is the incubation period, which can last from ten days to several months, depending on the intensity of exposure and the quantity of virus to which the victim has been exposed. [30] The average incubation period is twenty to sixty days. [31] During this initial stage, the infected individual shows no signs of illness, and is usually perfectly well apart from symptoms related to the healing of any wound resulting from an animal bite. [32]
The incubation period ends when the victim experiences the first symptoms of sickness, and the disease enters the prodrome stage. This stage usually lasts between one and five days, and the infected individual suffers from nonspecific flu-like symptoms such as malaise, headache, fever, and fatigue. In cases involving animal bites, pain or numbness at the wound area is not uncommon. The victim may also exhibit anxiety, nervousness, agitation, or irritability. [33]
Shortly after the onset of prodromal symptoms, the disease will enter the acute neurologic stage and produce the unusual symptoms that are suggestive of the disease *1438 of rabies. At this point, the virus has entered the infected individual's brain and is multiplying. Intermittent hyperactivity and violence is common at this stage, and the victim typically suffers periods of agitation, thrashing, running, biting, screaming, or crying. [34] Hyperventilation, excessive salivation, and convulsions usually characterize this stage. [35] Between hyperactive episodes, the victim is lucid, though often anxious. Difficulties with automatic functions — breathing, swallowing, and salivating, for example — commonly arise. Indeed, attempts to drink water often will result in severe, painful spasms of the pharynx and larynx, causing choking and gagging. The victim might develop hydrophobia, a psychic reaction to the sight of liquids causing spasms often resulting in strangulation. Historically, the fact that those who contract the disease of rabies develop great thirst but fear water was one of the most dreaded side-effects of the disease. Today this effect can be avoided by the performance of tracheostomies. [36]
If the victim does not die abruptly of suffocation or heart failure during the acute neurologic phase, paralysis gradually sets in. The victim becomes increasingly disoriented and confused, falls into a stupor, and ultimately slips into a coma. [37] The acute neurologic phase persists for between two and ten days, ending with the onset of coma. Historically, most victims of the disease have died at this stage, probably because of a cessation of breathing, although cardiac irregularities and spasms can occur. [38] If the victim survives, the coma phase can last for a few hours or for several months. At about this point in time, the virus is no longer damaging the victim, but a legion of potentially fatal complications can develop. Among those is an increase in intracranial pressure, cerebral edema (an excessive accumulation of fluid in the brain substance), and internal hydrocephalus (an accumulation of cerebrospinal fluid in the brain). [39] Post-mortem studies of victims of the disease often reveal substantial damage to the brain matter caused by rabies encephalitis. [40]
The above-described neurologic effects of the rabies virus on an infected individual are so severe that the disease of rabies is almost always fatal. In all of human history, only three individuals have survived the coma stage to enter the fifth stage of the rabies disease, the recovery stage. One of those individuals is Jerome Andrulonis.
B. Modern Rabies Research and the Efforts to Control the Disease in Man
Although man's awareness of the disease of rabies dates to antiquity, [41] most scientific knowledge concerning the disease and the etiologic agent that causes it has been acquired within the last century. The roots of modern scientific research concerning rabies can be traced to the work of Louis Pasteur in the late nineteenth century. [42]
*1439 In Pasteur's time, dogs caused most human rabies deaths in the world, and thus Pasteur's initial work with rabies focused on the development of a vaccine for domestic dogs which would prevent the disease in that species by stimulating an active immune response to the agent that caused it. [43] Early in the course of his work, Pasteur observed that dogs which recovered from early symptoms of rabies after inoculation of liquid solutions ("suspensions") containing infected central nervous system tissue into the blood stream were immune to later inoculations. He also concluded that the injection of small amounts of "infective material" — it was not known that a virus caused rabies at the time — would not produce immunity. The problem was finding a way to inject "infective material" into an animal sufficient to yield an immune response without producing disease. Pasteur's solution was to "attenuate" the "infective material" before injecting it into the animal to be immunized. [44] "Attenuation" will be discussed in greater detail below.
By 1885, Pasteur had reported success in developing immune responses in experimental dogs after injecting them with a series of inoculations of suspensions of an attenuated rabies virus strain. [45] That same year, Pasteur relented to the pleas of the mother of a young boy who had been bitten by a rabid dog numerous times and administered a series of injections of the solution he had developed for dogs to the boy. The boy never developed rabies, and as a result of this apparent success Pasteur's work became so influential that it defined in large part the direction of modern rabies research well into the second half of the twentieth century. Many of the techniques used by Pasteur in his early work persisted in modern rabies investigation through 1976 and 1977, the time period in which the events most relevant to this lawsuit transpired, and discussion of these techniques will give context to terms used throughout the remainder of this opinion. [46]
1. The "Passaging" of Virus
In his efforts to develop a canine vaccine, Pasteur was the first rabies investigator to utilize a laboratory procedure known as "passaging" in order to adapt the etiologic agent that caused the disease of rabies (the rabies virus) to animal species other than the dog. After a certain number of "passages," a virus, through a process of natural selection, can become "virulent" (extremely pathogenic) for the host for which it is adapted. However, if a solution containing the passaged virus is injected into an animal with a cell structure different than that of the animal species for which the virus has been adapted, it is possible that the passaged virus will lack the capacity to cause disease in that animal. [47] Nonetheless, in some cases a suspension of passaged virus in an animal for which the virus has not been adapted will act as an antigen, a substance capable of inducing the animal's immune system to produce antibodies to the rabies virus. [48] An antibody is a protein with a structure such that it interacts only with either the antigen that induced its creation in the first place or an antigen closely related to the inducing antigen. If a passaged virus is capable of spurring the creation of antibodies, those antibodies once produced will be present to neutralize any rabies virus to *1440 which the immunized animal is subsequently exposed in the wild. [49]
Basically, a "passage" is a defined period of growth for a virus through replication and mutation within a particular cell system. An animal, an embryonated egg, or a tissue culture is infected with a solution containing a given concentration of viral particles. The virus is allowed to incubate under certain conditions for a specified period of days, during which time the virus will multiply and mutate randomly. Presumably, viral particles well-adapted to the host animal or tissue culture will replicate more readily than viral particles that might be better adapted to other species or cell systems during the short-term evolution that takes place during the passage. A virus that multiplies more readily will also mutate more frequently. After a specified period of days has elapsed, live rabies virus will be "harvested" from the animal or tissue culture within which it was grown. [50] Under modern laboratory practice, passaging often transpires in tissue culture maintained in test tubes and bottles, and "harvesting" constitutes the removal of liquid containing live viral particles from the cells of the tissue culture. This liquid containing viral particles is called a "supernate." [51] Through passaging, rabies investigators seek to develop a "modified live virus rabies strain" with certain predictable qualities. A "modified live virus" is any virus strain that has been altered through some laboratory process such as passaging and possesses certain constant, identified characteristics. [52]
In developing his vaccine, Pasteur isolated rabies "street" virus (the virus as it occurs in the wild) from the brain of a rabid cow in 1882. The street virus was injected intracerebrally into a rabbit, and after a certain amount of time had elapsed the virus was harvested. The harvested virus was then itself injected intracerebrally into another rabbit. This process was repeated until the virus had been passaged in rabbits ninety times. [53] The resulting virus strain was more pathogenic to rabbits than street virus, and had a fairly constant incubation period of six to seven days when injected intracerebrally into rabbits. This virus strain proved to be less pathogenic than street virus for dogs, however, and it was repeatedly demonstrated in the laboratory that dogs inoculated with a series of injections of suspensions containing the virus strain not only did not develop disease but resisted disease after subsequent infection with a strain of rabies virus virulent to dogs (a so-called "challenge"). [54]
The modified live virus strain Pasteur developed was a "fixed virus" with respect to rabbits but an "attenuated virus" with respect to dogs. A virus is deemed "fixed" for a particular species when it has a fairly specific incubation period — which is ordinarily comparatively short — and is always lethal to that species. [55] The characteristics of a fixed virus are more predictable than those of a street virus. [56] A virus is "attenuated" *1441 for a certain species if it is less pathogenic for that species than street virus when introduced into an animal by a specified route. [57] Almost invariably, when scientists attempt to attenuate a live virus for a particular species, it is done in an attempt to develop a vaccine against rabies for that species. [58]
A rabies vaccine is a suspension of either attenuated live rabies viral particles (a "modified live rabies virus vaccine") or inactivated rabies viral particles (a "killed virus vaccine") which is administered to an animal host in order to stimulate an immune response in that host without inducing disease. [59] Strictly speaking, the term "vaccine" is properly used to describe a specific suspension that has been licensed for use as a vaccine for a particular species. [60] It is important to note that a virus strain, particularly an attenuated live virus strain, that has been tested and approved for use as a vaccine for one animal species may be pathogenic if introduced into another species. [61] Moreover, a virus strain that has been shown to be a safe and effective vaccine when introduced into an animal by a specified route may prove to be pathogenic when introduced into the same animal by a different route. [62] This is not surprising given the process by which a live virus is attenuated in order to make a vaccine: to make the virus non-pathogenic for one species, the virus is made to thrive in a cell culture different than that of the species for which the vaccine was developed. [63] As a general rule, only by conducting laboratory tests in which a particular modified live virus strain is introduced into a particular species by a specified route can it be reliably determined whether that virus strain is attenuated for the species in question when infected by the virus through the route specified. [64]
2. Control of Human Rabies in the United States: The Mass Immunization of Canines and the Lilly Vaccine
The immunization method developed by Pasteur required multiple inoculations, and was never adopted for the mass immunization of dogs. It was not until the early 1920s that a practical one-dose vaccine for dogs was developed in Japan. [65] The virus strain used in the vaccine had been fixed for rabbits and then inactivated, [66] a process by which the biological activity of the virus is destroyed either through exposure to heat, chemicals, or ultraviolet irradiation. [67] Although this vaccine proved effective in controlling rabies in dogs in Japan and was used in other countries, use of the vaccine in the United States was sporadic. [68] In the late 1920s, it was discovered that some lots of that vaccine contained live virus, and thereafter different methods of inactivation *1442 were tested. In the course of these tests, it was found that inactivation rendered many lots of vaccine ineffective in stimulating an immune response in animals. Since there was no reliable way to determine the antigenic efficacy of a particular vaccine lot before it was used, efforts to implement an effective mass immunization programs were frustrated. [69]
The obstacle to mass immunization posed by the inability to pre-determine vaccine efficacy was overcome in the 1940s with the development of reliable standardized tests for both the evaluation of vaccine potency and an animal's immune response to the administration of a vaccine. [70] These tests, known as "titrations," are used to yield a standardized number called a "titer." In essence, "titer" is a term that is used to indicate a measure of a substance's ability to cause some defined result. By assigning a titer to a particular solution containing a virus, for example, researchers can compare that virus solution to other solutions containing the same virus with respect to the ability to cause the result contemplated.
When rabies researchers measure the "titer" of a rabies virus strain, they are measuring the ability of that virus strain to kill laboratory mice after intracerebral injection of a solution containing that virus strain. [71] The titer of a rabies virus strain is measured in units of "50% mouse intracerebral lethal doses per .03 milliliters (MICLD-50/.03 ml)," a reference to the number of dilutions of the virus strain that could be injected intracerebrally into a group of mice in .03 milliliter suspensions and induce disease in fifty percent of the mice injected. [72] A virus strain with a high titer has a greater capacity to kill mice than a virus strain with a low titer. [73] The titer is commonly expressed exponentially, with a base number of ten raised to a certain power. For example, a virus strain could have a titer of ten raised to the power of 3.5 MICLD-50/.03 ml. The "common logarithm" of the titer represented by the foregoing mathematical expression is 3.5. For the remainder of this memorandum-decision, the titer of a virus strain will be expressed by reference to its common logarithm.
Rabies investigators also measure an animal's immune response to a vaccine by reference to the term "titer." Here, "titer" is a measurement of neutralizing antibodies in an immunized animal's blood stream. [74] Blood serum isolated from a blood sample of the immunized animal is added to a solution containing the challenge virus standard ("CVS"), a fixed standardized rabies virus strain with constant characteristics derived from the original Pasteur virus. This mixture is incubated and then inoculated into mice. The measure of antibodies in the blood serum is determined by evaluating their ability to neutralize the viral particles present in the CVS strain and prevent mouse deaths. Serum neutralizing antibody titer is usually expressed as a ratio, such as 1:5. The higher the second number in the ratio, the greater the amount of viral particles that can be neutralized by the immunized animal's serum antibodies. [75] Hereafter in this opinion, references to "titer" allude to the measure of the ability of a rabies virus strain to kill laboratory mice, while the phrase "antibody titer" will be used to refer *1443 to the level of neutralizing antibodies in an animal's blood stream.
As a general rule, if the titer of a particular virus strain is increased by some laboratory procedure, the pathogenicity of that virus strain is increased for species for which it has not been attenuated. [76] It appears that the most important factor determining the magnitude of the titer of a suspension of a modified live virus strain is the quantity and concentration of viral particles in the suspension. [77] The titer of a particular virus strain can be increased either by passaging or by concentration. [78] By passaging a virus strain in animals, embryonated eggs, or cell cultures, the virus replicates within the vehicle chosen for passaging, thus increasing the quantity of virus obtained. [79] By concentrating a virus strain through one of a variety of available laboratory techniques, live viral particles are condensed into a smaller volume of virus solution. [80] Passaging a virus strain results in a changed virus strain that can be more pathogenic for a particular species either because of the mutations that the virus underwent during passaging, or because of an increase in the number of viral particles in a given volume of a suspension of the virus strain. [81] Concentration of a virus strain will not result in viral replications and mutations, [82] but does increase the number of viral particles in a given volume of a suspension. Because the pathogenicity of a rabies virus exposure is dose-related, concentration can also increase the pathogenicity of a virus strain. [83]
After the development of a reliable and convenient means of pre-testing the antigenic efficacy of a particular vaccine lot, a demonstrably effective mass canine immunization program was carried out in the United States for the first time. The program, instituted in Memphis, Tennessee in 1948, combined mass vaccination of dogs and strict animal control measures. [84] In the two decades that followed, similar programs were instituted throughout the United States, severely limiting the incidence of rabies in domestic dogs. [85] With the control of rabies in domestic dogs, reports of the disease in humans in this country dropped to near zero. [86]
Just as the control of rabies in dogs markedly reduced the incidence of human exposure to the rabies virus in the United States, significant improvements were made in the vaccines available for the treatment of those humans who were exposed to the virus. Until the 1950s, the vaccines developed for human use were variations of the Pasteur vaccine that originally had been intended for use in dogs and later *1444 adapted for human immunization. [87] The Pasteur vaccine had been developed through viral passages in the brains of living rabbits, and the modified live rabies virus strain that resulted was suspended in solutions of the spinal cords of rabbits. [88] The administration of any vaccine containing adult animal nervous tissue presents a risk of inducing allergic reactions resulting in neuroparalytic disorders. [89] In an effort to avoid this serious side-effect, defendant Lilly developed a vaccine in the 1950s that did not contain the nervous tissue of adult animals. [90]
The duck embryo vaccine ("DEV" or "the Lilly vaccine") was produced by passaging the CVS fixed virus strain in seven-day-old embryonated duck eggs, a process which yielded a high-titer supernate upon harvest. [91] The virus was inactivated and prepared for use as a vaccine. Similar to the original Pasteur vaccine, DEV was to be administered in a series of fourteen to twenty-one inoculations, and when it was licensed and first distributed in 1957, it was intended exclusively for post-exposure treatment. [92] In the mid-1960s, defendant Lilly amended the package insert that was routinely distributed with the lots of the vaccine it manufactured and recommended it for pre-exposure use for "high-risk" individuals. [93] Among those considered "high-risk" were veterinarians, spelunkers, and laboratory personnel working with rabies virus. [94] It was common practice by the early 1970s for scientists and laboratory technicians engaging in rabies research to maintain a minimum level of serum antibodies through periodic inoculations with the Lilly vaccine.
Although other non-nervous tissue vaccines were available for use in man, DEV was the vaccine of choice for human use in the United States from the late 1950s until 1980. [95] When the Lilly vaccine was being tested for safety and effectiveness before it was licensed, defendant Lilly focused on whether DEV would provide protection against disease in the event of human exposure to the rabies virus through a bite or scratch wound or a pre-existing abrasion after contact with the saliva of an infected animal (hereinafter collectively referred to as the "bite route" of exposure). [96] At the time, the bite route was the only known means of transmitting the virus in nature, [97] and thus the protectiveness of the Lilly vaccine against development of the disease of rabies after infection through a non-bite route was not investigated. [98] Specifically, no tests concerning the effectiveness of DEV against aerosol exposures to the rabies virus were conducted. [99]
*1445 C. The Airborne Transmission of the Rabies Virus
The belief that the rabies virus was transmitted in nature only through the introduction of the saliva of an infected animal into a bite wound or open lesion of another animal persisted until the late 1950s or early 1960s. [100] This opinion had endured in the scientific community despite scattered reports in the early medical literature indicating that animals could acquire the disease of rabies by inhaling the virus. [101] In the late 1950s, scientists began to question the assumption that direct contact with the saliva of an infected animal was necessary in order for the rabies virus to be transmitted to another animal.
1. The Discovery that Animals Can be Infected after Exposure to Aerosols Containing Rabies Virus
In 1956, a thirty-eight year old public health worker contracted the disease of rabies soon after being exposed to the atmosphere of various bat caves in the south-western region of the United States. One of the caves this worker had entered was the Frio Cave in Uvalde County, Texas, which was known to shelter rabid bats. While the public health worker had worked with the rabies virus on occasion in a laboratory setting, there was no clear evidence that he had been exposed to the virus either by animal bite or laboratory accident. [102] In 1959, a mining engineer who was examining guano deposits in various bat caves in the Southwest developed the disease. Before his death, the engineer insisted that he had not been bitten or scratched by a bat or other animal. This individual had also explored Frio Cave, and thus was exposed to the atmosphere of a cave housing rabid bats. [103] The deaths of these two men suggested that it was possible that an unknown method of rabies virus transmission existed. [104] A number of field studies and laboratory experiments followed. The most important of these was a series of experiments conducted on behalf of the CDC under the direction of Dr. Denny G. Constantine in which various mammals were exposed to the atmosphere of Frio Cave. [105]
Frio Cave is a large multi-chambered cavern which provides shelter for three species of bats. Most numerous are the Mexican free-tailed bats, whose numbers varied seasonally *1446 from between two and upwards of twenty million. [106] Millions of bats, primarily lactating females and their suckling, flightless young, were present in just one chamber of the cave (the "nursery chamber") from June until early August. Most of Constantine's work was conducted in this chamber. [107] The bats in the nursery chamber clung to a ceiling that ranged from four to ten feet in height. The concentration of bats in the nursery chamber varied from three hundred to four hundred per square foot. [108] The ventilation in the chamber was poor, and a continual rain of saliva, urine, and feces fell from the bats to the ground. [109]
In July 1960, thirteen carnivores confined in mesh cages were placed in the nursery chamber, where they remained for a period of seven days. A number of rodents were placed in the same chamber for lesser periods of time. While none of the rodents contracted rabies, four of the carnivores were killed by the disease. [110] Although Constantine could not rule out the possibility that the animals were bitten through their mesh cages by diseased bats or other animals present in the nursery, [111] the suggestion that the caged animals contracted rabies as a result of exposure to rabies viral particles suspended in the atmosphere of Frio Cave was strong. [112]
In experiments conducted in Frio Cave in July 1961, elaborate steps were taken to assure that some of the animals exposed to the atmosphere of the nursery chamber would not be subject to other exposures from animal bites or arthropods. [113] These animals — four coyotes and four grey foxes — were confined in the chamber between twenty-four and thirty days. All subsequently died of rabies. [114] From these and other experiments conducted at Frio, Constantine concluded that it was "apparent that transmission of rabies virus from free-tailed bats to other animals occurs by air." [115]
Constantine's experiments were conducted in poorly ventilated caves that contained an unusually large number of bats. [116] Any intimation that the airborne transmission of the rabies virus was limited to the unique environment of Frio Cave, however, was quickly dispelled. In 1967, a spontaneous outbreak of rabies occurred in the laboratory animal colony of the United States Public Health Services's Southwest Rabies Investigation Station at Las Cruces, New Mexico. Caged foxes, coyotes, and opossums which were never exposed to direct physical contact with a rabid animal began dying of rabies. Over a little less than ten months, sixty-four animals died, and thirty-nine of those animals had never been intentionally exposed to the rabies virus by researchers. [117] After an extensive investigation *1447 led by Dr. William G. Winkler of the CDC, it was concluded that the outbreak was most likely attributable to the airborne transmission of the rabies virus. [118] Animals that had been exposed to rabies virus in experiments were moved in and out of a room where animals that had not been exposed were housed, and infective virus was probably circulating in that room during the period of the outbreak. It was believed that the aerosols were generated either by the exposed animals themselves or as a result of a cage cleaning procedure that utilized a high-pressure spray. [119]
In 1973, the death of a fifty-six year old veterinarian underscored the potential hazard aerosols containing rabies virus posed to laboratory workers. The victim had no known animal bite exposures prior to falling ill, and no lesions on his body were observed during an autopsy performed after his death. [120] The veterinarian was an employee of a commercial laboratory in Texas that was involved in the preparation of various anti-viral vaccines. In preparing an experimental lot of animal rabies vaccine, he used a common "kitchen-type" blender to homogenize goat brains that had been infected with the CVS rabies virus strain. The blender produced aerosols, and it was hypothesized that the veterinarian "inhaled substantial amounts of virus" while transferring the homogenized goat brains from the blender to other containers. [121] The liquid homogenate in the blender had a titer of 6.5. [122] The veterinarian had had no other known contact with the rabies virus for a number of years before his death, and he succumbed to the disease of rabies shortly after this laboratory incident. [123] The veterinarian, who apparently was not effectively immunized against rabies, [124] was the first individual suspected to have died as a result of an aerosol exposure to a fixed strain of virus rather than a wild or "street" strain. [125]
2. The Pathogenesis of Airborne Rabies Infection
The death of the Texas veterinarian provided dramatic evidence that the newly-discovered route of infection could have important ramifications for laboratory workers using rabies virus strains. Even before this incident, however, there was some evidence suggesting that aerosols containing rabies virus could pose a threat to man different in kind than that presented by the more common exposures through animal bites or accidental injection in the laboratory. Constantine advised that "the term `susceptibility' in reference to transmission by air route may constitute a marked departure from the term in its usual connotation regarding rabies." [126] At the time Constantine prepared his report summarizing his studies in Frio Cave, "[n]o attempt [had] been made to determine the actual virus invasion sites" in the two men who were suspected to have died as a result of their exposure to the rabies virus in Frio Cave in the 1950s. [127] It was recognized that a proper assessment of the danger *1448 which aerosols containing rabies virus posed to man and other animals would require study of the means by which the virus travelled through the body of an animal from the site of exposure to the site where the virus causes fatal encephalitis — that is to say, the "pathogenesis" of airborne rabies infection would have to be studied. In the late 1960s and early 1970s, experiments designed to reveal the pathogenesis of airborne rabies were conducted. [128]
Two important findings resulted from this research. First, it was demonstrated that an animal's susceptibility to developing sickness as a result of an airborne exposure to the rabies virus was closely related to the amount of viral particles in the aerosols to which that animal was exposed. [129] Rabies has long been considered a "dose-related" disease; in the case of airborne exposures, it was concluded that the quantity of viral particles to which an animal was exposed was the most determinative factor governing the chances the virus would infect that animal and cause disease. [130] Second, important evidence was collected concerning the path the virus takes in invading an animal's central nervous system after infection through the airborne route.
It was known that some viruses transmitted through aerosol suspensions can cause encephalitis in the animals they infect after they are inhaled into the nasal region by spreading along the olfactory nerves and enter the olfactory bulb, the region of the brain that controls an animal's sense of smell. Other viruses replicate in the lower respiratory tract and lungs after being inhaled through the mouth and nose before attacking the central nervous system. [131] The results of experiments conducted in the late 1960s and early 1970s involving laboratory animals such as mice, guinea pigs, and rabbits indicated that when those animals were infected after an exposure to an airborne suspension of rabies virus, the olfactory region was of primary importance in the spread of the virus to the central nervous system. [132] It was found that the virus attached itself to the olfactory nerves of the exposed animals, reproduced there, and quickly spread to the brains of those animals. [133] It was also concluded that while "[t]he participation of lung tissue as the primary site of virus multiplication in inhalation rabies cannot be excluded[,] ... [the test findings] suggest that the pulmonary route of virus spread into the [central nervous system] plays no important role in the pathogenesis of rabies in experimental animals infected *1449 by inhalation." [134] Results pointing to the same conclusion were obtained regardless of whether street or fixed viruses were used. [135]
These findings indicated that the pathogenesis of rabies virus transmitted to man through an aerosol exposure might be significantly different than the pathogenesis of the virus when transmitted through animal bites or scratches. As noted above, the rabies virus proliferates primarily in nervous tissue. When a human being is exposed to the virus through the bite of an infected animal, the muscles, connective tissue and nervous tissue at the site of the bite wound will be bathed in blood. If the victim of the bite has been immunized against rabies and as a result has developed rabies antibodies in his blood stream, those antibodies would have the opportunity to neutralize the virus before it invaded the victim's central nervous system. [136]
This is not necessarily the case when an individual is infected through the airborne route. From studies relating to biological warfare conducted by Dr. Arnold Wedum at Fort Detrick, it was known that pre-existing antibodies circulating in the blood stream might not provide protection against aerosol exposure to some viruses. [137] A human's olfactory nerves at one end rise out of the mucosal epithelium cells that line the olfactory region inside the nose and at the other extend directly into the region of the brain known as the olfactory bulb. [138] The olfactory nerves are the only nerves in a vertebrate animal such as man that emanate directly from the brain and are exposed to the air. [139] Because the olfactory nerves are superficial structures, the only protection they have against neurotropic viruses in the environment to which they are exposed is provided by the nasal mucosa. [140] The olfactory nerves do not ordinarily come into significant contact with the blood stream, and thus a virus infecting them would not come into contact with pre-existing antibodies circulating in the blood stream. [141] Consequently, absent the presence of a significant level of antibodies in the mucosa, a virus that infects the olfactory nerves can replicate and travel the short distance to the afflicted individual's brain unimpeded by neutralizing antibodies. [142]
Some but not all vaccines produce antibodies in surface membranes such as the nasal mucosa as well as in the blood stream. [143] In 1976 and 1977, it was not known whether the Lilly vaccine produced surface antibodies in the nasal mucosa sufficient to provide protection in the event of an aerosol exposure to the rabies virus. [144] Defendant Lilly did not undertake investigations concerning the effectiveness of DEV against infection by the airborne route at any point in the 1960s or 1970s, even after reports surfaced concerning the laboratory-related death of the veterinarian in 1973, [145] nor were such studies conducted by other researchers. Despite the uncertainty concerning DEV's effectiveness against infection through the aerosol route, the package insert distributed with DEV was not amended at any time to alert users *1450 that the vaccine might not protect against disease in the event of such exposures. [146]
In light of the existing knowledge concerning the peculiar vulnerability of the olfactory nerves to infection and the lack of knowledge concerning the effectiveness of the Lilly vaccine in protecting against aerosol exposures to rabies virus, safe laboratory practice in 1976 and 1977 mandated the avoidance of such exposures. If possible, the creation of aerosols containing rabies virus in the laboratory was to be avoided. If the creation of such aerosols was necessary to the accomplishment of the purposes of a particular study, safe laboratory practice required that the aerosols be physically contained. [147] The physical "containment" of an aerosolized etiologic agent is achieved through the use of one of several methods of separating the environment in which the aerosols are created from the environment to which laboratory workers are exposed. Many of these methods were technically feasible in 1976 and 1977, and in fact were commonly employed. The use of an apparatus known as a "laminar flow containment hood" was probably the most common method of "containing" an etiologic agent. This apparatus, as well as other containment methods, will be discussed in greater detail below.
III. THE EXPERIMENTS WITH THE UNI-GLATT MACHINE
This section of this memorandum-decision and order focuses on those aspects of the research conducted by NYSDOH and CDC scientists regarding wildlife immunization relevant to this lawsuit. The research concerning the aerosol transmission of the rabies virus was performed contemporaneously with studies directed at developing a rabies immunization program of an unprecedented scale. With the substantial reduction of the incidence of rabies in domestic animals and man in the United States in the 1950s and 1960s, the attention of a number of rabies experts turned to the control of the disease in wild animals and commercial livestock. Among the animal species particularly susceptible to acquiring and passing on the disease of rabies are foxes, coyotes, skunks, raccoons, and bats. [148] Whether eradication of the disease of rabies can be accomplished ultimately will turn on science's ability to control the spread of the rabies virus in these and other species found in the wild.
A. Wildlife Immunization Research
In 1973, a report prepared by experts under the auspices of the World Health Organization ("WHO") noted that the "massive reduction" of those species responsible for the perpetuation of the rabies disease within a given ecosystem through extermination programs was "the only method available for wildlife rabies control." [149] Such population reduction programs are effective only in "suitable, limited areas," [150] and even where possible such programs have adverse environmental and economic effects. [151] The WHO report noted that immunization of wildlife was not then practicable, and recommended that "[s]tudies in this direction should ... be intensified.... Immunization could reduce the susceptible host population to a point where no further rabies spread is possible." [152]
One of the earliest experiments concerning wildlife immunization had been conducted between 1961 and 1963 by Dr. George M. Baer of the Center for Disease *1451 Control. Baer performed these experiments while he was a visiting epidemiologist at the New York State Department of Health's Griffin Laboratory. [153] Baer attempted the oral vaccination of foxes by shooting a fixed rabies virus strain into the mouths of the animals with a mechanical device. [154] Six of the fourteen foxes vaccinated in this manner experienced rises in serum neutralizing antibodies and survived subsequent challenge with the CVS rabies virus strain. [155] The encouraging results obtained in this experiment and in others conducted in the 1960s [156] fueled discussion of the possibility that non-domestic animals could be immunized by consuming bait distributed in the wild that would contain live rabies virus. [157] Baer himself became a vocal advocate of this approach to rabies control. [158]
Baer reasoned that if bait containing live rabies virus strain were to be distributed in the field safely and also be effective in producing rabies antibodies in the animals that consumed them, the virus strain used would have to be highly attenuated with respect to a wide range of animal species while maintaining its immunizing capability when highly diluted. [159] Baer believed that it was possible to develop such a strain by further modifying a licensed modified live virus vaccine known as ERA. [160]
The ERA commercial vaccine was derived from the SAD virus strain, which had been developed at the University of Toronto's Connaught Laboratories ("Connaught"). [161] The SAD virus strain had been derived from street virus that had been isolated from a rabid dog in Montgomery, Alabama in 1935 by passaging it over fifty times in the brains of mice. [162] In the early 1960s, scientists at Connaught passaged the SAD virus strain an additional four times in the brains of mice to make a virus strain called SAD-4. Dr. Melvin K. Abelseth and two other researchers at Connaught then passaged the SAD-4 virus strain twenty-five times in tissue culture taken from the kidneys of hamsters, ten times in embryonated chicken eggs, and an additional six times in tissue culture isolated from the kidneys of pigs. [163] The virus strain that resulted from this passage history was designated ERA. [164] A modified live virus strain, ERA was found to be attenuated for dogs, cats, horses, cattle, sheep, and swine, and in the 1960s was licensed for use as a modified live virus vaccine for those species. [165] Thereafter, *1452 ERA, which usually attains titers ranging from 3.5 to 4.5, was widely used as a commercial vaccine.
The ERA vaccine is the first rabies virus strain discussed in this opinion that was developed in part through passage in animal tissue cell culture rather than wholly through passage in live animals or embryonated eggs. Virus strains adapted to cell systems generally replicate readily, growing large quantities of virus during passaging. After modern concentration and purification techniques are employed, virus strains grown in cell systems yield higher titers of "pure" virus (virus preparations free of non-viral cellular impurities) than can be obtained from the brains of infected animals after passage, concentration, and purification. [166] For all of its advantages, however, virus strains adapted to tissue culture did increase one hazard associated with the laboratory use of rabies virus strains: studies had indicated that such strains were more effective at inducing the disease of rabies after inhalation than strains of identical origin grown in mouse brains. [167]
The ERA vaccine was considered particularly well-adapted for growth in cell culture, rendering the highest yields of "pure" virus of all of the cell culture-adapted strains available in the 1960s and 1970s. [168] Moreover, a virus strain derived from the ERA vaccine tended to have a high "specific infectivity." In any rabies virus strain, most of the viral particles will not penetrate an animal's cells and replicate. As a rule, an unusually high percentage of the viral particles in an ERA-derived strain were capable of infecting an animal's cell system. [169] An ERA-derived strain of virus was considered a strong candidate for use in any wildlife vaccination program in part because of its high infectivity. Baer noted at an early juncture that the immune response in animals injected with the commercial ERA vaccine "apparently result[ed] from multiplication of virus" in the animal to which the vaccine is administered. [170] Because the live virus in the vaccine evidently replicated without spreading to the central nervous system and causing disease in animals for which the vaccine was attenuated, it retained its immunizing ability when highly diluted. [171] Equally important was the fact that the ERA vaccine was not lethal to foxes, the primary target for the wildlife immunization program that Baer sought to develop because of their role in perpetuating the disease of rabies in the United States. [172] Finally, because the ERA vaccine had proven to be a "safe and effective immunizing agent in six species of domestic animals," [173] it was hoped that a derivative of the commercial vaccine could be developed that would be attenuated for the much wider range of species that could consume baits containing live rabies virus distributed in the wild.
In 1969 or 1970, Baer attempted to produce serum neutralizing antibodies in a grey fox by dropping on the tongue and cheek of the animal one milliliter of ERA strain rabies virus grown on a cell system *1453 originating from the kidneys of baby Syrian hamsters and subsequently altered in the laboratory. This cell "line" was known as BHK/21. [174] The passaging of the ERA vaccine on BHK/21 cells resulted in a virus strain designated ERA-BHK/21; the ERA-BHK/21 strain administered by Baer in the grey fox experiment had a titer of 6.8. [175] Antibodies were produced. Buoyed by the success of this experiment, Baer ventured north in 1970 to meet with Dr. Abelseth, by this time the Director of Laboratories within NYSDOH's Division of Laboratories and Research, and Dr. John G. Debbie, an NYSDOH scientist who worked directly under Abelseth, in an effort to interest the NYSDOH scientists in his project. [176]
Among the laboratories maintained by the Division of Laboratories and Research was Griffin Laboratory, located in a rural area west of Albany, New York. At Griffin, animal research and diagnostic work related to human disease was performed, and animals were raised for use in experiments conducted in NYSDOH's other laboratories. [177] Dr. Debbie headed the rabies laboratory at Griffin. [178] Debbie was responsible for assuring that all procedures performed in that laboratory were conducted safely, in accordance with good laboratory practice as recognized by the scientific community at the time. [179] Among those working under Debbie was Jerome Andrulonis, at the time a bacteriologist with NYSDOH. [180]
At the 1970 meeting with Abelseth and Debbie, Baer related the promising results obtained in his grey fox experiment, and it was then decided that because NYSDOH had access to foxes for experimental use, further research concerning the oral vaccination of wildlife would be pursued at Griffin. [181] Funding for this study was provided by the State of New York, not by the CDC. The virus strain used in this study was supplied from the CDC by Dr. Baer. [182] The CDC commonly prepares and supplies various viral strains, including strains of rabies virus, to approved private and state operated laboratories for use in research projects. [183] The CDC did not in the 1970s and does not now make routine safety inspections of the laboratories to which etiologic agents are supplied. [184]
For the first tests performed at Griffin, Baer supplied Debbie with an ERA virus strain grown on BHK/21 cells. This virus strain had a titer of 7.0. Debbie administered the virus in liquid form to the tongues and cheeks of six red foxes. [185] Andrulonis aided Debbie in this procedure. [186] All six foxes developed serum-neutralizing antibodies, and survived a challenge from a street virus that killed four out of five foxes in a control group. [187] A short time thereafter Debbie repeated the experiment using the ERA vaccine that *1454 had been licensed for commercial use. The vaccine used had a titer of no greater than 3.7. A significant percentage of the foxes which were administered the commercial ERA vaccine developed antibodies and survived challenge. [188] Again, Andrulonis assisted. [189]
Encouraged by the successful results obtained in these experiments, researchers from the CDC and NYSDOH sought to determine what effect an ERA-derived virus strain would have on animal species other than foxes. The researchers wanted to determine whether immune responses could be triggered by an ERA-derived strain in other wildlife species. More importantly, it was necessary to determine whether other animals which might ingest a bait containing an ERA virus in the wild would develop the disease of rabies as a result, since a rabies virus that is attenuated for one species might be pathogenic to another. The researchers were also interested in determining whether a liquid containing live rabies virus could be passed on to foxes and other species in a bait of some sort. [190] The survival of the virus under field conditions was problematic, and thus the development of a bait suitably protective of the virus was another focus of research. [191] Research conducted at Griffin investigating these areas of concern was supported in part by a grant from the CDC, [192] although the CDC did not direct the day-to-day operations of the project, devise protocol for the work, or otherwise control the manner in which the work conducted at Griffin was to be performed. [193]
Subsequent attempts to orally vaccinate skunks and raccoons at Griffin with an ERA-derived virus strain, as well as efforts to produce antibodies in mongooses administered an ERA-derived virus strain at the CDC laboratories in Lawrenceville, were not as successful as the experiments involving the oral vaccination of foxes. [194] Foxes apparently can be immunized by an attenuated virus strain that invades through the lingual and buccal mucous membranes of the tongue and cheek. [195] These other animals tested, however, evidently were not susceptible to infection by the same route. [196] Moreover, it was believed that the modified live rabies virus that was being administered to the animals was being killed by the acids of the animals' stomachs. [197] Consequently, the attention of the researchers at Griffin turned to the development of a method of vaccination through the so-called "enteric route," whereby the virus would be absorbed through the intestines of the animals that ingested it rather than through the tongue and cheek. [198] This would be accomplished by applying an "enteric coating" [199] to a live virus which would protect the virus from the stomach acids of the animal consuming it but would disintegrate once it reached the animal's intestine, allowing the virus to multiply there and induce an antibody response. [200]
*1455 Initially, Debbie applied enteric coating to gelatin capsules containing rabies virus that had been stabilized through a process known as "lyophilization" [201] and administered the capsules to foxes. The capsules proved too large, however, and failed to pass out of the stomachs of the foxes and into their intestines. [202] In or around September 1975, Debbie attended a WHO-sponsored collaborative meeting of scientists, including Baer, concerned with the oral vaccination of wildlife. At this meeting, Debbie discussed this enteric coating experiment in informal presentations. It also appears that Debbie spoke with Baer of the problems he was having with the size of the capsules he had prepared, since Baer subsequently sent Debbie a copy of a patent that had been obtained for an enteric coated capsule containing a modified live virus intended to create antibodies for a contagious viral disease that attacked swine. [203] The patent described a process through which a virus was coated onto processed sugar nonpareils with diameters measuring less than 2.5 millimeters. The virus-coated nonpareils were then enterically coated with a compound of alcohol and an acetic acid known as cellulose acetate phthalate. Debbie sought more information concerning the enteric coating process alluded to in the patent, and was advised by someone at the Albany School of Pharmacy to communicate with the coating department at the WARF Institute, Inc., located in Middleton, Wisconsin. [204]
Debbie contacted a representative of WARF and sought information about the available coating techniques that might be used to create a smaller capsule containing a live rabies virus. [205] In response, Debbie received a letter from Thomas M. Hinkes, the director of WARF's coating department, and an enclosure describing the "Wurster air suspension coating process," which will be discussed in detail below. In his letter, Hinkes indicated to Debbie that "[a]s we agreed, I will check with people at WARF Institute regarding the safety of handling the vaccine, and you in turn will contact the parties in Atlanta, Georgia," [206] those parties being Drs. Baer and Winkler of the CDC. [207]
At some point, Debbie contacted Baer and Winkler, seeking assurances about the safety of the ERA rabies virus and its derivatives. Baer responded with a letter addressed to Debbie dated November 7, 1975, which included the following passage:
ERA rabies vaccine appears to be one of the most attenuated animal rabies vaccines available. We have used it in this laboratory for years, not only as a commercial product but also as a concentrated BHK tissue culture supernate, with a titer 100 to 1000 times the original vaccine. In working with the material we take the usual laboratory precautions, primarily having those persons in direct contact with the vaccine vaccinated against rabies. [208]
A copy of Baer's letter was forwarded to Hinkes. Shortly after forwarding Baer's letter to WARF, Debbie received a letter from Dr. Winkler. Unlike Baer, Winkler confined his discussion to the commercial ERA vaccine, and did not discuss derivatives of the vaccine. In his letter, dated December 3, 1975, Winkler related that there was limited data regarding the dangers posed by the ERA vaccine to man, but that the accidental exposures to the vaccine that had been recorded did not result in "problems of any kind." Further, animal studies indicated that the ERA vaccine was *1456 "at least as safe" as another animal rabies vaccine that had proven to be "innocuous in man." [209] This opinion was also related to WARF officials. [210] Whatever apprehensions WARF officials had concerning the project were apparently mollified: arrangements were made for a demonstration of the Wurster air suspension process to be conducted by a WARF representative at Griffin. [211]
B. The Initial Uni-Glatt Experiments
On March 30, 1976, WARF representative Harlen Hall arrived at Griffin to demonstrate how a machine known as the Uni-Glatt could be used to coat sugar nonpareils first with a modified live rabies virus strain and then with an enteric coating. [212] The Uni-Glatt machine, which effectuated the air suspension coating process developed by Dale Wurster, was manufactured by defendant Glatt GmbH and distributed by defendant Glatt Air Techniques, Inc. Debbie was sufficiently impressed with the machine to use it on three occasions subsequent to the Hall demonstration in attempts to develop an enterically coated pill containing live rabies virus. The last Uni-Glatt experiments performed at Griffin were conducted on March 29 and 30, 1977. Funding for the Uni-Glatt experiments conducted after the Hall demonstration was provided by the CDC, in exchange for which Debbie was to provide the CDC with some of the coated nonpareils prepared in the course of the Uni-Glatt experiments. [213] Other than providing the funds for the enteric coating experiments, however, officials from the CDC were not directly involved in the manner in which the Uni-Glatt experiments were performed, nor did they seek to control the means through which those experiments were carried out. [214]
The Uni-Glatt machine [215] was designed to suspend solid pellets or pills in a column of upflowing air so that coating materials *1457 could be sprayed onto them. [216] It was commonly used for the sugarcoating of candy or pharmaceutical products. [217] The Uni-Glatt consisted of a console which was approximately three feet in length, two and one-half to three feet in depth, and about two and one-half feet in height, a large pressurized air tank, a long transparent column that sat atop the console, a peristaltic pump that was attachable to a valve located at the bottom of the column, and a long flexible exhaust duct that was attachable to the top of the machine. [218]
The machine's console had gauges and control dials on its front, and inside it was a labyrinth of tubes and switches which enabled the machine to suspend solid materials within the transparent column. [219] Some of those tubes led to the large air tank which supplied pressurized air to the bottom of the console when the machine was in operation. [220] The column, which was comprised of two sections of rigid, transparent plastic tubing, fit into an opening on the top of the console. [221] Approximately one-third of the length of the column would fit below the surface of the console, while the remainder protruded upward. [222] The lower part of the column was conical in shape, increasing in diameter from the surface of the console upward. The upper section of the column was cylindrical, and was attached to the conical section by a metal collar. [223] A cloth filter was placed over the top of the column and was held fast by a metal ring, allowing air as well as other gasses to be passed through and vented out of the machine but preventing the solid materials suspended within the column from escaping. [224] An opaque, sleevelike cap was placed over the filter and secured to the top of the column, and the exhaust duct ran out of the top of this cap. [225]
The exhaust duct was expected to direct the air expended from the Uni-Glatt out of the laboratory in which the machine was operated. [226] However, the machine operated under positive pressure, with the air pressure within the machine's column becoming greater than that outside the machine once the machine was activated. Consequently, any opening to the external environment would be the path of escape for gases and other airborne suspensions within the machine. [227] Since the Uni-Glatt machine was not airtight, leaks from the machine were forced out into the atmosphere surrounding it. A substantial leak of air occurred where the metal collar joined the conical and cylindrical sections of the transparent column and where the opaque cap was fitted onto the top of the column. [228] Despite this permeability, the Uni-Glatt was never operated at Griffin within any of the various physical containment systems that were available in 1976 and 1977, [229] and thus anyone working in close proximity to the machine while it was *1458 in operation was exposed to any aerosols created within the Uni-Glatt's column.
On March 30, 1976, Harlen Hall met Debbie and his assistants, including Andrulonis, at Griffin's rabies laboratory. An unassembled Uni-Glatt machine had been transported to the laboratory by two of Debbie's assistants. Hall first showed the NYSDOH employees how to assemble the machine. [230] The Uni-Glatt was placed on a table near a window of the laboratory, and the exhaust duct ran from the machine out the window. [231] Hall then conducted a test "run" of the machine. Spherical sugar nonpareils with a diameter of approximately two millimeters were blown upward and suspended in the Uni-Glatt's transparent column. On the initial demonstration run, a rabies virus strain developed by passaging ERA vaccine twice in the brains of suckling mice ("ERA-SMB") was siphoned from a one-liter flask by the peristaltic pump into the valve at the bottom of the transparent column and sprayed through a nozzle upward into the column and onto the air-suspended nonpareils. [232] The process created an aerosol containing live viral particles of the virus strain used. The nonpareils would darken in color as the virus solution was sprayed onto them. [233] The aerosolized virus solution itself, though colorless like water, [234] could be visualized within the column as it was being sprayed onto the nonpareils. [235] Leakage of the virus aerosol from the Uni-Glatt into the atmosphere of the laboratory, however, apparently was not visible to the unaided eye and left no trace outside the machine. [236]
Nonetheless, on occasion nonpareils would leak out of the machine and into the laboratory environment. [237]
Once the virus solution had been sprayed upon the nonpareils, the Uni-Glatt machine was disassembled and the nonpareils were removed and sifted to break up clumps. [238] The machine was then reassembled and a flask containing water soluble 5% methylcellulose was attached to the machine's peristaltic pump. The nonpareils were again suspended by upward air flow in the column, and the methylcellulose solution was sprayed onto the virus-coated nonpareils. [239] This coating was intended to protect the virus from a third coating that was applied to the nonpareils consisting of hydroxy methylcellulose phthalate, a cellulose dissolved in a volatile ethyl alcohol solvent. [240] After the second coating had been sprayed onto the nonpareils, the machine was again disassembled and the nonpareils were sifted. [241] The third coating, which was intended to protect the virus from the stomach acids of animals that would subsequently consume baits containing the nonpareils, was then applied. The application of this cellulose solution to the nonpareils created a reddish dust that leaked out of the Uni-Glatt machine during this part of the coating process. The leak was readily perceptible to the human eye. [242]
These three coating procedures together constituted a "run," and it took between four and six hours to complete a run. [243] The sugar nonpareils tended to stick together as they were being suspended within the Uni-Glatt's transparent column, *1459 frustrating effective application of the material being sprayed onto them. On occasion, the machine would be stopped in the middle of one of the three phases of a coating run and disassembled so that clumps of nonpareils could be broken up manually. [244] Moreover, while the machine was in operation, it was necessary to watch the nonpareils constantly. A laboratory worker, usually Debbie or Andrulonis, would sit close to the machine while it was in operation and tap the transparent column with the handle of a screwdriver to prevent the nonpareils from sticking together. [245] Andrulonis was masked and gloved when he performed this function. [246] Commonly, Andrulonis would place his face within six to twelve inches of the column while tapping it, and would remain that close to the Uni-Glatt machine for minutes at a time. This task was performed repeatedly over the course of a run. [247]
Because the Uni-Glatt was not airtight and was not operated within a physical containment system, Andrulonis experienced a substantial aerosol exposure to the virus strains that were propelled through the machine when he was monitoring the nonpareils in this manner. After the initial demonstration run, moreover, the researchers at NYSDOH knew that the machine was not airtight. This was evident from the reddish dust deposited around the machine during the third phase of a coating run, as well as from the fact that nonpareils occasionally escaped from the machine's cylinder. [248] Even so, the only precautions taken by the NYSDOH workers during the subsequent Uni-Glatt experiments were the use of masks and gloves when working around the machine and the maintenance of a high level of antibodies in their blood system through periodic inoculations with the Lilly vaccine. [249] Dr. Debbie's testimony indicated that he believed that an individual with a sufficiently high antibody titer would be protected against any laboratory exposure to the rabies virus. [250]
Debbie remained in fairly constant contact with Baer after the first use of the Uni-Glatt in March 1976, conferring with Baer once or twice a month. [251] Debbie testified that at some point after the March 1976 demonstration run and before the final Uni-Glatt experiments conducted in March 1977 he told Baer of the reddish dust that was deposited about the laboratory during the third phase of the coating run. [252] Baer denied this, testifying that Debbie did not tell him of the dust before the March 29, 1977 Uni-Glatt experiment. Baer claimed that he did not learn that the Uni-Glatt was not airtight until he became aware of the results of tests that were conducted on the machine approximately three months after the March 29 experiment. [253] For reasons set out in detail below, [254] the court accepts Debbie's testimony and rejects that of Dr. Baer.
*1460 During the initial demonstration run conducted with Hall present in March 1976, the NYSDOH investigators used an ERASMB virus strain prepared by Andrulonis at Griffin. Prior to coating, the virus strain had a titer of approximately 6. [255] As the virus was propelled through the machine and sprayed onto the nonpareils, the heat generated by the machine killed most of the viral particles. [256] After the virus strain had gone through the three-stage coating process, its titer had been reduced to approximately 1. [257] Debbie fed the coated nonpareils to laboratory animals kept at Griffin, including foxes, skunks, and raccoons, and was able to develop only an irregular and uneven level of serum antibodies to rabies in those animals. [258] Similarly sporadic results were obtained in dogs and mongooses which were fed the coated nonpareils at the CDC's laboratories in Georgia. [259]
Another Uni-Glatt experiment was conducted at Griffin in July 1976. Once again, an ERA-SMB virus strain with a titer of 6 was used. As in the initial experiment involving the Uni-Glatt, the end-product had a greatly reduced titer, thereby limiting its effectiveness at producing rabies antibodies in animals that consumed it. [260] The coating experiment was repeated in September 1976, and this time two coating runs were completed, one using an ERA-BHK/21 virus strain obtained from the CDC which had a titer of approximately 5.5, and one using an ERA-SMB with a titer of approximately 6. A substantial loss of titer occurred during the course of the coating process in both runs. [261]
In evaluating the results obtained from these experiments, Debbie reasoned that if a virus solution with a higher titer was used, an end-product with a sufficiently high titer to effectively produce antibodies in animals could be obtained, even if the heat generated by the Uni-Glatt machine during the coating process killed most of the virus. [262] The researchers at Griffin, however, were unable to obtain a titer much higher than 6, the titer that had been achieved in the ERA-SMB strains which they had prepared for the earlier Uni-Glatt experiments. This titer level had proved inadequate in three prior coating runs. Debbie again turned to Dr. Baer in Georgia, who agreed to prepare a rabies virus strain with a higher titer than could be obtained by the workers at NYSDOH. [263]
C. The Virus Strain Prepared by Dr. Baer and Used in the March 29, 1977 Uni-Glatt Experiment
To prepare a high titer virus strain, Baer chose a virus strain that had been derived from the ERA vaccine and had been passaged in BHK/21 tissue culture numerous times. Baer passaged the virus an additional time in the BHK/21 cell system. [264] The result was a virus strain several passages removed from the ERA commercial vaccine from which it was derived.
It was not surprising that Baer chose an ERA-BHK/21 virus strain for use in the Uni-Glatt experiments. By the 1970s, the BHK/21 cell line had become a favorite *1461 medium for the preparation of rabies virus strains because of its "extreme susceptibility to the virus." [265] The BHK/21 cell system tended to yield high quantities of viral particles when a virus strain was grown on it, particularly when the virus strain had a prior history of passage on animal tissue cell culture, as did the ERA vaccine. [266] Moreover, there was evidence indicating that an ERA-BHK/21 virus strain would have a greater ability to withstand the heat generated by the Uni-Glatt machine. In the early 1970s, an ERA virus strain passaged four times on BHK/21 cells was found to be very efficient at replicating at comparatively high temperatures, while remaining less pathogenic, though still lethal, when inoculated intracerebrally into suckling mice than other strains which were not capable of reproducing at higher temperatures. [267]
Notwithstanding the perceived advantages associated with the ERA-BHK/21 virus strain, relatively little was known about it in March 1977. The ERA vaccine virus strain had been derived through passage in the cell systems of three animal species—hamsters, chickens, and pigs. In creating ERA-BHK/21, additional passages on an altered cell system originating from baby Syrian hamsters were performed. Any time a virus strain is passaged, the potential to change its characteristics exists, and this change is fairly unpredictable: the virus may become more or less pathogenic for a specific species after it has been passaged. [268] The changes resulting from the mutations that occur during passaging are particularly unpredictable when a virus strain adapted to the cell system of one species is passaged in cells isolated from another species. [269]
By March 1977, a handful of studies involving the ERA-BHK/21 virus strain had been conducted. The results of those studies were mixed. In 1975, it was reported that safety testing that had been undertaken indicated that the ERA-BHK/21 strain "would probably be non-pathogenic" for red foxes if ingested orally. [270] The titers of the virus strains tested ranged from 6.5 to 7.0. [271] However, ERA-BHK/21 virus strains with similar titers produced disease in white mice, Norway rats, and cotton rats when fed to animals of those species either in liquid form or after incorporation into sausage baits. [272] In an experiment conducted by Dr. Baer, solutions containing ERA-BHK strains were injected into the cerebrospinal fluid of the central nervous systems of rhesus monkeys, which like humans are of the order of primates. An ERA-BHK strain is similar to an ERA-BHK/21 strain except that the former is prepared on baby hamster kidney cell lines as they are configured in nature, while the latter is prepared on altered cell lines. The ERA-BHK virus strains used in Baer's experiment had titers ranging from 4.5 to 8.5, and death resulted in virtually all *1462 of the monkeys injected. [273] A study conducted in France using the ERA-BHK/21 strain and another strain created by passaging ERA-BHK/21 in another cell line indicated that a highly pathogenic strain of virus could result when the ERA-BHK/21 strain was allowed to mutate in a cell line different from that to which it had been adapted. [274] At a symposium held in Atlanta in September 1976, two German investigators reported that the oral administration of ERA-BHK/21 produced disease in Syrian hamsters, brown rats, and field mice. [275] These researchers noted that tests involving other ERA derivative strains revealed a "marked difference in susceptibility of closely related species," making it difficult to assess the range of species for which an ERA-derived virus strain might prove pathogenic. [276]
It was not known with certainty whether man was susceptible to developing the disease of rabies as a result of infection by ERA-derived virus strains. [277] The ERA vaccine was widely considered non-pathogenic to man. [278] But with regard to modified live rabies virus strains derived from the ERA commercial vaccine (including ERA-BHK/21), there was "no reliable information on which to judge the risk" that attended human exposure to such strains, and in a 1976 publication the CDC recommended that such virus strains "should be regarded as potentially virulent for purposes of managing the treatment of exposed humans." [279]
While the danger to man posed by any ERA-BHK/21 virus strain was unknown in March 1977, the particular strain prepared by Baer for the Uni-Glatt experiment had an added element of risk: it had been concentrated to an extraordinarily high titer. The virus strain that was ultimately used in the Uni-Glatt experiment conducted March 29, 1977 had been developed by passaging the ERA commercial vaccine in BHK/21 cells between two and twenty-five times, with the virus reaching a titer of 6.7. The virus strain was then concentrated, and the volume of the solution containing the viral particles was reduced from approximately 950 milliliters to approximately seventy-five milliliters. This procedure increased the titer of the virus strain to 8.1. [280] This was the highest titer of any rabies virus strain Baer had transported *1463 out of the CDC's laboratories in Georgia. [281] This strain was over one hundred times more pathogenic to mice than any of the virus strains used in the earlier Uni-Glatt experiments, and was approximately 10,000 times more pathogenic to mice than the commercial ERA vaccine from which it was derived. [282]
D. The March 1977 Uni-Glatt Experiments
Dr. Baer wanted to witness the coating process accomplished through the use of the Uni-Glatt machine first hand, so he decided to personally deliver the high-titered virus strain he had prepared in Georgia to Dr. Debbie in Albany and stay to observe the Uni-Glatt machine in operation. [283] On the evening of March 28, 1977 Baer travelled to Albany by air and was met at the airport by Debbie. Baer had brought the virus strain with him, and that evening he and Debbie took the virus to Griffin and stored it in a laboratory freezer. [284] Baer informed Debbie that the virus was an ERA-BHK/21 strain and that it had a titer of 8.1. [285] This information was related to the other laboratory workers involved in the Uni-Glatt experiments prior to the experiment conducted the next day. [286] At no time prior to the use of the virus in the Uni-Glatt experiment conducted March 29, 1977 did Baer disclose to Debbie or any other NYSDOH employee how the virus had been prepared, how many times the virus had been passaged in BHK/21 cells, or of any dangers that might inhere in the use of the virus in an experiment in which aerosols containing the virus would be created. [287]
Consistent with ordinary CDC practice, Baer did not conduct a safety inspection of the rabies laboratory at Griffin before the virus he had prepared was supplied to Debbie. [288] As noted above, the CDC did not exercise control over the manner in which the March 29 Uni-Glatt experiment was conceived or carried out. The court finds, however, that Dr. Baer retained the power to prevent Debbie from using the virus strain he had prepared in the March 29 experiment even after he had surrendered possession of the strain to Debbie on the evening of March 28, and that he could have reclaimed the virus strain at any time prior to its use in the Uni-Glatt experiment conducted that day. [289]
On the morning of March 29, Baer accompanied Debbie to the rabies laboratory at Griffin. The Uni-Glatt machine had already been assembled in the laboratory and had been filled with sugar nonpareils by the time they arrived. Debbie retrieved the ERA-BHK/21 virus solution from the laboratory freezer, and it was set out to thaw. [290] While the virus strain was being prepared for use by Andrulonis, Debbie activated the air currents of the Uni-Glatt and the nonpareils within the machine's transparent column began to circulate. [291]
Baer testified that in this initial period in which the Uni-Glatt was operated — before any rabies virus solution had been introduced into the machine — he observed nonpareils *1464 exiting the exhaust duct and entering the laboratory environment, and that Debbie repaired the leak in the duct with adhesive tape or electrician's tape. [292] This testimony lacks credibility. It was established at trial that a cloth filter placed at the top of the cylindrical portion of the Uni-Glatt's column at the point where the exhaust duct was attached prevented the nonpareils from exiting the column and entering the duct. [293] This filter was not defective, and it did not pose problems during the Uni-Glatt experiment conducted March 29, 1977. [294] Thus it was impossible for Baer to have observed nonpareils escaping from the exhaust duct. Rather, the court concludes that Baer observed the nonpareils escape from the column within which the nonpareils were suspended, and that Baer observed this leakage before any virus solution was aerosolized into the column of the machine.
This initial "warm-up" period in which the Uni-Glatt was operated before any solutions were introduced into it lasted approximately fifteen minutes. [295] During this time, Andrulonis removed a small portion of the virus solution Baer had supplied so that the titer of the strain used could be verified subsequent to the experiment. [296] The remaining portion of the virus solution was placed in a flask, and the flask was attached to the Uni-Glatt's peristaltic pump. [297] Baer testified that he realized that the virus solution was going to be sprayed onto the nonpareils within the Uni-Glatt's transparent column even before the solution was attached to the pump, and that by forcing the solution through the nozzle at the base of the Uni-Glatt's column an aerosol would be created. [298]
After the flask was attached to the peristaltic pump, the virus solution was slowly introduced into the Uni-Glatt's column, and the upward air current within the column was again activated. [299] The virus was applied to the nonpareils within the column for a little more than an hour. [300] Debbie and Andrulonis worked in close proximity to the machine, adjusting the air flow and the rate at which the aerosolized virus solution was sprayed onto the nonpareils. [301] From time to time, either Debbie or Andrulonis would tap the column with a screw driver handle to prevent the nonpareils from sticking together and from adhering to the side of the column. [302] Baer witnessed the NYSDOH researchers periodically deactivate the Uni-Glatt and disassemble it in order to sift the nonpareils. [303]
Baer observed most of the coating run in which the ERA-BHK/21 virus strain he provided was incorporated into enterically coated baits. [304] Baer observed the coating procedure closely, and he himself was often within a foot or two of the machine while it was in operation. [305] The following day, after Baer had returned to Georgia, another coating run was completed, this time using an ERA-SMB virus strain with a titer of approximately 5.5 that had been prepared by Andrulonis at Griffin. [306]
*1465 As with the previous Uni-Glatt experiments, the Uni-Glatt machine was not operated within a physical containment system of any kind during either of the coating runs conducted in March 1977. [307] The researchers who worked in close proximity to the machine had been immunized against rabies. [308] Specifically, the level of rabies antibodies present in Jerome Andrulonis' blood stream at the time of the March 1977 Uni-Glatt experiments was higher than the minimum that was recommended by the CDC in the Laboratory Safety Manual distributed widely to research laboratories across the United States. [309]
E. The On-Set of Illness
On April 14, 1977, approximately two weeks after the last experiment involving the Uni-Glatt machine, Jerome Andrulonis was sent home from work with a headache and a temperature. That night he became violently ill, but by the next morning his condition had improved and he went to work. Over the next five days, Andrulonis would suffer cyclical flu-like symptoms of greater and lesser severity, until finally he decided to visit a physician, who was unable to determine the cause of Andrulonis' illness. [310] Over the subsequent two days, Andrulonis became very listless, having some difficulty walking and becoming somewhat unresponsive to verbal stimuli. By April 20, Andrulonis was unable to dress himself, and his wife Joanna, upon the recommendation of a family doctor, took her husband to the Albany Medical Center Hospital ("AMCH") to consult with a neurologist. [311]
Within a short time after his arrival at the AMCH emergency room, Andrulonis started to act confused and was unable to answer questions posed by hospital personnel. [312] A battery of tests were ordered, including a series of CAT scans of the brain, examinations of spinal fluid, tests to measure brain waves (electroencephalograms, or EEGs), and tests to detect heart abnormalities (electrocardiograms, or EKGs). [313] Although the CAT scans taken April 20 were considered normal, Andrulonis' abnormal spinal fluid and changes in consciousness the day he was admitted to AMCH pointed to a form of encephalitis, or *1466 inflammation of the brain. [314] The physicians who initially examined Andrulonis quickly concluded that he was most likely suffering from encephalitis caused by a viral infection. [315] Andrulonis was admitted to AMCH following the examination conducted in the hospital's emergency room and was placed in the intensive care unit. [316]
At some point on April 21, the day following his admission to AMCH's intensive care unit, Andrulonis became extremely agitated and hospital personnel were required to use arm restraints to confine him to his bed. [317] Andrulonis' medical records indicate that he suffered delusions, was disorientated, and was unable to understand what was said to him. [318] This period of agitation soon passed, however, and Andrulonis became increasingly lethargic and unresponsive to outside stimuli, [319] finally slipping into a coma. [320] Andrulonis was placed on a respirator, was administered various fluids intravenously, and was provided intensive nursing care. He received medications to control a persistent fever and to prevent convulsions. [321]
An EEG taken on April 21 was reported as markedly abnormal with diffuse, slow brain waves, supporting the initial diagnosis of encephalitis. An EEG taken the next day revealed a progression of wave patterns consistent with a viral cause of the encephalitis. [322] Although it was known that Andrulonis had been exposed to the rabies virus in his work, the attending physicians at AMCH did not immediately conclude that Andrulonis had contracted the disease of rabies. In his work at Griffin, Andrulonis had been exposed to a number of viruses; moreover, blood tests conducted during Andrulonis' first two days of hospitalization did not reveal an increase in Andrulonis' serum antibodies to rabies. [323] Possibly because of the uncertainty concerning the cause of Andrulonis' illness, no post-exposure treatment with the Lilly vaccine was attempted. [324]
During his first week at AMCH, Andrulonis developed pneumonia. [325] He remained unconscious, and required full respiratory support. On May 3, a tracheostomy was performed, and a metal tube was placed in Andrulonis' throat to assist breathing. [326] Andrulonis suffered significant paralysis, rendering two of his extremities useless. [327] Doctors at AMCH continued to attribute Andrulonis' condition to viral encephalitis, cause unknown. [328] Laboratory tests designed to ascertain the etiologic agent that had caused Andrulonis' illness continued.
During the next week, Andrulonis went through the deepest part of his coma before gradually becoming more responsive to stimuli. [329] On May 5, Andrulonis had been unresponsive to even painful stimuli; on May 10, Andrulonis opened his eyes, and by May 17, his spontaneous movements had increased, though he remained "quite rigid" and unconscious. [330] During this phase of his illness, Andrulonis exhibited an erratic pulse and unstable blood pressure, temperature, and respiration, and was *1467 administered medication to control this instability. Andrulonis also developed a condition known as myoclonus, a tetanic spasm of the muscles, and was placed on medication intended to control these spasms. [331] On May 27, a gastrostomy was performed, through which a plastic tube was surgically inserted through Andrulonis' abdominal wall and into his stomach. Attempts to feed Andrulonis through tubes that had been inserted through his nose had not been very successful because of difficulties Andrulonis had had in swallowing. The gastrostomy was performed to avoid this problem by permitting the administration of food directly to the stomach. [332]
Initially, serum neutralization tests did not reveal any noticeable elevation in Andrulonis' rabies antibody titer. [333] On April 26, however, Andrulonis' rabies antibody titer was measured at 1:64, a significant rise. [334] On May 9, Andrulonis' antibody titer was measured at an astronomical 1:65,536; by the end of May, Andrulonis' antibody titer was consistently recorded at 1:200,000. [335] Ultimately, Andrulonis' antibody titer would rise to more than 1:1 million, the highest rabies antibody titer ever recorded in man. [336]
Doctors concluded from the marked increase in Andrulonis' rabies antibody count that the rabies virus had invaded his body and caused his illness. [337] Andrulonis did not receive post-exposure treatment with the Lilly vaccine at this point because his treating and consulting physicians concluded that Andrulonis' antibody titer was so high that administration of the vaccine would have had negligible beneficial effect, while the risks associated with post-exposure vaccination would have remained undiminished. [338] Andrulonis was placed in strict isolation in order to minimize the risk of transmitting the virus to others in the hospital. [339] Studies were then conducted to determine whether a deficiency in Andrulonis' immune system may have contributed to the development of his illness. Those studies showed that Andrulonis had resisted other secondary infections and indicated that his immune system was probably intact when he fell ill. [340]
F. The Cause of Jerome Andrulonis' Illness
Although the point is not conceded by the Government or the State, the court finds it manifestly clear that Jerome Andrulonis contracted the disease of rabies, necessitating his hospitalization on April 20, 1977. [341] Andrulonis' antibody titer reached levels vastly exceeding that which could have been achieved by any vaccination program, indicating that Andrulonis' immune system was responding to the presence of rabies virus which had entered his body from some source other than the vaccination regimen to which Andrulonis adhered. [342] Similarly astronomical measures of rabies antibodies in Andrulonis' cerebrospinal fluid evidenced that the rabies virus had invaded his central nervous system. [343]
Moreover, the course of Andrulonis' illness tracked the typical symptomatic progression of the disease of rabies in man as *1468 summarized earlier in this opinion. [344] The first signs of illness Andrulonis exhibited were the flu-like symptoms associated with the prodromal stage of the disease, and these symptoms persisted for five days, as might be expected in a case of rabies exposure. [345] At the time he was hospitalized, Andrulonis was beginning to enter the acute neurologic stage of the disease, and by April 21 Andrulonis was exhibiting the agitation and hyperactivity associated with that stage. [346] Finally, Andrulonis entered the coma stage, although some of the symptoms associated with the acute neurologic stage persisted into the coma stage. [347] The damage to Andrulonis' brain, which is discussed in greater detail below, is consistent with rabies encephalitis. [348]
It is not known with absolute certainty which specific exposure to the rabies virus Jerome Andrulonis experienced caused his illness. [349] However, "[a] plaintiff is not obligated to eliminate all possibility that the injuries resulted from causes other than a defendant's negligence." Ledogar v. Giordano, 122 A.D.2d 834, 837 , 505 N.Y. S.2d 899, 902 (2d Dept.1986). Plaintiffs have demonstrated by a fair preponderance of the evidence that Andrulonis contracted the disease as the result of an aerosol exposure to the ERA-BHK/21 rabies virus strain during the March 29, 1977 Uni-Glatt experiment conducted at Griffin Laboratory in the presence of Drs. Debbie and Baer. [350]
The incubation period of the rabies virus after it has infected a human is variable, lasting from ten days to several months. [351] After it was learned that Andrulonis had contracted rabies, officials from NYSDOH as well as from the CDC investigated the actual or potential exposures to the rabies virus Andrulonis had experienced in the several months preceding April 14, 1977, the day Andrulonis first exhibited symptoms of the disease. [352] These inquiries failed to uncover any possible exposures to the rabies virus Andrulonis might have had outside of his work. [353] Andrulonis constantly encountered the virus, however, in the course of his employment at Griffin; indeed, all of his work there involved the rabies virus.
In the regular course of his employment, Andrulonis was required to inoculate live animals and to care for live animals which had been exposed to the rabies virus during various research projects. In his diagnostic work, Andrulonis was exposed to specimens taken from animals suspected of having rabies. Andrulonis frequently performed a number of routine laboratory procedures involving the rabies virus, including the preparation of slides for antibody tests, the titration of virus strains used in research projects, the homogenization of virus preparations in a blender, the lyophilization of virus preparations in an apparatus known as a "lyophilizer," and the concentration and purification of rabies virus through the use of a centrifuge which would spin a tissue culture infected with the virus at high speed. [354] In connection *1469 with the Uni-Glatt experiments conducted under the supervision of Dr. Debbie in March 1976, July 1976, September 1976, and March 1977, Andrulonis was responsible for preparing the solutions containing rabies virus strains which were to be sprayed onto the nonpareils suspended within the transparent column of the Uni-Glatt machine. This involved transferring solutions containing virus from vials to flasks and taking samples from those solutions and performing titrations. [355] Finally, Andrulonis was exposed to aerosols containing various rabies virus strains during the Uni-Glatt experiments conducted at the Griffin rabies laboratory in 1976 and 1977. [356]
It is not likely that Andrulonis contracted the disease of rabies as a result of an exposure that may have occurred while he carried out his routine daily responsibilities at Griffin. Such exposures regularly occurred in laboratories throughout the United States before March 1977, and none of the individuals exposed — many of whom had immunization histories and work exposure histories substantially identical to that of Andrulonis — developed the rabies disease. [357] The experience of rabies researchers indicated that the Lilly vaccine would offer protection against an exposure to the virus through a bite from an infected animal, accidental self-inoculation, or exposure of a cut or skin abrasion to the virus. [358] Further, the body's own defense mechanisms were probably adequate to defend against the mild aerosol exposures that occasionally occurred during routine laboratory procedures. [359]
The court's conclusion that Andrulonis did not develop disease as a result of an exposure while he performed routine laboratory procedures is bolstered by the evidence offered concerning Andrulonis' work habits. Andrulonis was considered by his superiors and co-workers to be diligent and conscientious in completing the tasks assigned to him. He was a careful worker, adept at performing tasks that required finesse, and was safety conscious in carrying out his work. [360] There was an unwritten policy at Griffin requiring workers to report laboratory accidents or unintended exposures to virus, and Andrulonis had not reported any such accident or exposure. [361] When all of the factors are considered together, it is unlikely that Andrulonis was accidentally infected by rabies virus while performing the routine laboratory tasks for which he was responsible. Andrulonis' illness was more likely the result of an "unusual" exposure. [362]
The exposure Andrulonis had to the virus when the Uni-Glatt machine was in operation during the four enteric coating experiments conducted at Griffin was certainly "unusual." [363] The aerosols containing rabies virus that were created during the Uni-Glatt experiments were not contained. The Uni-Glatt machine leaked heavily, a large quantity of virus was aerosolized in each experiment and Andrulonis worked in close proximity to the machine for long periods of time during each experiment. Whatever exposures Andrulonis had to aerosolized virus while performing routine laboratory procedures — and the evidence is inconclusive that such exposures occurred at all [364] — were dwarfed by the magnitude of *1470 the exposures that occurred during the Uni-Glatt experiments, and it was during these experiments that Andrulonis more likely than not came into contact with the virus strain that caused his illness. [365]
Given the variable incubation period associated with the rabies virus, it is conceivable that any of the exposures that occurred during the various Uni-Glatt experiments conducted at Griffin between March 1976 and March 1977 could have resulted in Andrulonis' infection and disease. Nonetheless, the evidence that the exposure that caused his illness occurred during one of the two coating runs conducted in March 1977 is compelling. The other Uni-Glatt experiments were conducted six or more months before Andrulonis exhibited the first symptoms of this illness, and an incubation period of such a length, though theoretically possible, is well outside the average range of twenty to sixty days. [366] Only fourteen percent of all cases have incubation periods exceeding ninety days, regardless of route of exposure or the proximity of that exposure to the central nervous system. [367] Because an aerosol exposure was likely the cause of Andrulonis' illness and because an individual's olfactory nerves are but a short distance from the brain, a short incubation period was more probable than a long one. [368] The aerosol exposures Andrulonis experienced during the Uni-Glatt experiments were intensive, and this factor also argues for a short incubation period rather than a long one. [369] In short, the timing of the onset of Andrulonis' illness indicates that he was exposed to the virus strain that caused his illness during the Uni-Glatt experiments of March 1977. [370]
There is one factor that not only further supports the conclusion that Andrulonis' disease was the result of an exposure in March 1977 but also establishes that it is likely that the exposure occurred during the use of the ERA-BHK/21 virus strain Baer had prepared. That factor is the extremely high titer of the strain supplied by Baer. The titer of the ERA-BHK/21 virus strain used in the March 29 Uni-Glatt experiment was 8.1; the titers of the other virus strains used in the Uni-Glatt did not exceed 6, and the titer of the ERA-SMB strain used in the Uni-Glatt machine on March 30, 1977 was 5.5. [371] Thus, the ERA-BHK/21 virus strain contained over one hundred times as many rabies viral particles per given volume than any other virus strain used in the machine, and was almost 400 times as concentrated at the ERA-SMB strain used March 30, 1977. The discrepancy in the intensity of the exposure to airborne virus during the March 29 experiment and the other Uni-Glatt experiments may have been magnified by the fact that the heat generated by the Uni-Glatt machine while it was in operation had been killing most of the viral particles in the virus strains previously used in Uni- *1471 Glatt experiments. [372] The ERA-BHK/21 strain is more resistent to heat than other strains, such as the ERA-SMB, which were usually used in the previous Uni-Glatt experiments. Further, the virus strain used in the March 29 experiment had been passaged and concentrated to an extremely high titer for the very purpose of assuring that a significant number of viral particles would survive the heat of the machine during the coating process. As a consequence of all of these factors, Andrulonis' exposure to rabies viral particles during the March 29 coating run was markedly greater than during the runs conducted with the other virus strains.
As noted above, the quantity of viral particles to which an animal is exposed is the most important variable governing the chances that rabies virus will infect the animal after an airborne exposure; [373] Andrulonis' exposure to aerosolized viral particles during the experiment in which the ERA-BHK/21 virus strain with a titer of 8.1 was used could fairly be characterized as "massive." [374] The extraordinary difference in the magnitude of the exposure to aerosolized virus Andrulonis experienced on March 29, 1977 and the exposure experienced during the other coating runs was a critical consideration that led those experts who testified about the cause of Andrulonis' illness to conclude that it was the March 29 exposure that most likely resulted in infection and disease. [375]
In sum, the court accepts the opinion testimony of the various experts that it could be said with a reasonable degree of medical and scientific certainty that Andrulonis contracted the disease of rabies as a result of his exposure to the aerosolized ERA-BHK/21 virus strain used in the March 29 Uni-Glatt experiment. [376] Plaintiffs have established by a fair preponderance of the evidence that the likelihood that the injuries suffered by Jerome Andrulonis were caused by his exposure to aerosols containing the ERA-BHK/21 virus strain that escaped from the Uni-Glatt machine on March 29 far outweighs the combined prospects that his injuries were caused by some other exposure, either potential or actual, either known or unknown.
IV. LIABILITY
The only claims made by plaintiffs that remain unresolved in this case are those of plaintiff Jerome Andrulonis against the United States under the Federal Tort Claims Act. By enacting the FTCA, Congress waived the Government's sovereign immunity in a broad class of cases by permitting a private person to maintain a suit for damages against the United States
for injury or loss of property, or personal injury or death caused by the negligent or wrongful act or omission of any employee of the Government while acting within the scope of his office or employment, under circumstances where the United States, if a private person, would be liable to the claimant in accordance with the law of the place where the act or omission occurred.
28 U.S.C. § 1346 (b); see also id. § 2674. The court concludes that the substantive law of New York is applicable in the present case because most of the acts or omissions on the part of Government employees that had "the most significant causal effect" in reference to the injuries suffered by Jerome Andrulonis occurred in Albany, New York. See Bowen v. United States, 570 F.2d 1311, 1318 (7th Cir. 1978). [377]
*1472 Because the only unresolved claims by Jerome Andrulonis are against the Government, if the court does not find that an employee of the United States breached a duty owed Andrulonis and that that negligence was a substantial cause of the event which produced his injuries, see Derdiarian v. Felix Contracting Corp., 51 N.Y.2d 308, 315 , 434 N.Y.S.2d 166, 169 , 414 N.E.2d 666, 670 (1980), the culpable conduct of the other parties involved in this case, including that of employees of the State of New York, would be irrelevant. Nonetheless, it is easier to understand Andrulonis' claims against the Government if the negligent conduct imputable to NYSDOH is reviewed first. Accordingly, the court will examine the basis for the Government's third-party claim for contribution against the State before turning to Andrulonis' claims against the United States.
A. The Culpable Conduct Attributable to NYSDOH
When the Government is sued under the FTCA, it may commence a third-party action against another party seeking contribution, provided that such an action is allowed under loca

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Source: Frix Law Library, https://www.frixlaw.com/law-library/cases/1467978. Public record. Not legal advice.