OP#09: The 1971 Smallpox Epidemic in Aralsk, Kazakhstan, and the Soviet Biological Warfare Program

Post on 4 June 2002 by Dave Steiger tagged:


June 2002
Jonathan B. Tucker
Raymond A. Zilinskas

Occasional Paper #9

Read the full Occasional Paper #9:
The 1971 Smallpox Epidemic in Aralsk, Kazakhstan, and the Soviet Biological Warfare Program

The Center for Nonproliferation Studies (CNS) of the Monterey Institute of International Studies today released the first authoritative English translation of an official Soviet report describing a previously unknown outbreak of smallpox in 1971 in the city of Aralsk, Kazakhstan, then located on the northern shore of the Aral Sea.

Public Health Experts’ Commentaries on OP #9:

Related link: Public Health Experts Comment on Analysis of the 1971 Smallpox Outbreak in the Soviet Union.

We thank Dr. W. Seth Carus for giving us the idea for this section containing commentaries.

Contents

Acknowledgement

Foreword

by Bakyt B. Atshabar

Introduction and Analysis

  • Introduction
    by Jonathan B. Tucker and Raymond A. Zilinskas
  • An Epidemiological Analysis of the 1971 Smallpox Outbreak in Aralsk, Kazakhstan
    by Alan P. Zelicoff, M.D.

1971 Smallpox Report

  • Report on Measures Taken to Contain and Eradicate the Smallpox Outbreak Locale in the City of Aralsk (September/October, 1971)
    by E. Sarynov, Deputy Minister of Health of the Kazakh SSR; B. Kulmakhanov, Director of the Outbreak Containment Locale; and Z. Makatov, Chief of Staff
  • Report on Measures Taken to Contain and Eradicate the Smallpox Outbreak Locale in the City of Aralsk, Part II
    by E. Sarynov, Deputy Minister of Health of the Kazakh SSR; and B. Kulmakhanov, Director of the Outbreak Containment Locale
  • Autopsy Reports
    by I. Borisov


Ronald M. Atlas, Ph.D.
Richard Clover, M.D.

The epidemiological analysis of the 1971 smallpox outbreak in Aralsk, Kazakhstan by Alan Zelicoff raises many interesting, troubling, and unanswered questions about the biological weapons program of the former Soviet Union. Clearly this warrants further investigation to determine the real source of the smallpox outbreak at Aralsk. The analogy to Sverdlovsk is great–official reports that deny any association with a biological weapons program and facts that come out years later pointing to Soviet biological weapons activities as having been responsible for a disease outbreak. It seems unquestionable that the Soviet biological warfare program developed the smallpox virus as a biological weapon. Ken Alibek has reported on that program and claimed that it had been scaled to an enormous production capacity. Reports of testing at Vozrozhdeniye Island are consistent with the fact that the Soviet Union had an extensive biological weapons program that must have involved outdoor testing of biological weapons agents. One sign of such programs and testing would be unusual disease outbreaks–such as the 1971 smallpox outbreak in Aralsk.

With regard to the epidemiological analysis by Zelicoff, the data are consistent with exposure of patient 1 between July 29 and 31, 1971. The manifestation of disease in patient 1 was more likely about August 11 rather than the official report of August 6 as this would fit with the occurrence of smallpox onset in patient 2 on August 27; i.e., it would match the approximate 11-15 day incubation period for smallpox and would be consistent with the incubation period of about 2 weeks seen for subsequent patients. If patient 1 had developed disease on August 6 as in the official report there would have been a 21 day lapse from the exposure of patient 2 to the onset of disease in patient 2 and exposure of patient 1 would have had to have been during the portion of the cruise while the ship on which Patient 1 worked was at sea and not near land. While an extended incubation period is possible, as is the possibility that patient 2 was not exposed until several days after onset of disease in patient 1, this scenario is less likely. Hence, exposure of patient 1 seems to have occurred during the period when members of the ship’s crew went ashore in Uyaly on July 29 and again in Komsomolsk-on-Ustyurt on July 31. During this period the ship also passed near Vozrozhdeniye Island on July 30, raising the specter that exposure occurred while patient 1 was on deck during the time the ship passed the island. Knowledge of the wind and weather conditions, as well as how close the ship really came to Vozrozhdeniye Island, could help resolve the likelihood of this scenario. It is difficult 30 years later to resolve the differences between the recollections of patient 1 and the official record regarding whether she went onshore or remained on the ship. More important would be to clarify what activities were ongoing on Vozrozhdeniye Island during that period. That is likely the only way the actual source of exposure will be resolved, as was the case for Sverdlovsk when only official admissions finally exposed the accidental release of anthrax spores from a biological weapons facility.

Regardless of what occurred in late July 1971 in the Aral Sea, the knowledge of the Soviet program, the fear that Iraq, North Korea and, perhaps, other nations possess clandestine stocks of smallpox virus, and given the deadly and contagious nature of smallpox, have catapulted smallpox virus to the top of the biological agents threat list. It has led to the decision by the United States government to stockpile sufficient smallpox vaccine (vaccinia produced in human cell culture) to vaccinate all Americans and the decision by the Advisory Committee on Immunization Practices to recommend that the primary strategy of “ring vaccination” be used in the event of a smallpox outbreak in the United States and that a limited number of health care workers be pre-vaccinated. In the case of a terrorist attack with smallpox, “ring vaccination” would likely extend throughout the community that might have been exposed, i.e., a broad definition of “contacts” would be used in determining who would be vaccinated. Such practice of “ring vaccination” is consistent with the procedure that followed the 1971 outbreak of smallpox in Aralsk, as well as the practice employed in Yugoslavia in 1972. In both cases, restricted movement of people and mass vaccination of potential contacts was used to contain the outbreak and to prevent epidemic spread. Regardless of whether the index case in Aralsk contracted smallpox from an infected individual while onshore or, as suggested by Zelicoff, from an air-release of smallpox virus in a biological weapons test on Vozrozhdeniye Island, the practice of extensive vaccination and isolation was successful in halting the epidemic spread of smallpox in 1971 in Aralsk.

The reasons for the somewhat unusual nature of the Aralsk smallpox outbreak, namely the occurrence in some vaccinated individuals and the high incidence of the deadly hemorrhagic form of the disease, remain unclear. The Soviet vaccination program may have suffered from quality control issues, either with the vaccine or its administration. The data in the report on the smallpox vaccination program indicated that there had been a low immunity–only 31.6% of the residents of Aralsk had been vaccinated. Among first and second grade schoolchildren, 24% had not been vaccinated, and 31.6% showed a primary vaccination reaction when they were vaccinated again following the Aralsk outbreak, indicating a low immunity even among those who had been previously vaccinated. Many of the children who had contacted patient 2 had no vaccination scars even though their medical records indicated that they had been vaccinated against smallpox. Thus, although several of the individuals who contracted smallpox had supposedly received vaccinations, there is evidence that the many receiving the vaccine did not develop immunity. Hence, it seems more likely that there was inadequate immunity in those exposed than the possibility that the strain of smallpox virus was immune-resistant. This viewpoint that proper vaccination would afford protection against the strain of smallpox virus that caused the Aralsk outbreak, even if it came from the Soviet biological weapons program, is supported by the fact that mass vaccination was used to contain the outbreak.

With regard to the high prevalence of the hemorrhagic form smallpox, as Dr. Zelicoff notes, it is not clear whether host factors or the nature of the virus are primarily responsible for causing this form of the disease. Whether or not the smallpox virus came from a natural source as concluded in the official reports or from a biological weapons test on Vozrozhdeniye Island, as Dr. Zelicoff suggests, the virus may well have been especially virulent–although not especially infective. Any suggestion that the virus was genetically engineered, however, is incorrect as the outbreak occurred a decade before the era of recombinant DNA technology began. The strain, though, could have been selected for its virulence from prior natural outbreaks. The assumption of any biodefense program must be that the strain used for a smallpox attack would have a high mortality rate and that an epidemic outbreak from such an attack could cause mass casualties in a susceptible population, such as now exists in the United States. The Advisory Committee on Immunization Practices clearly took this into account when it modified its position to recommend vaccination for some health care workers. The committee held that the basic strategy of vaccinating individuals who may have been exposed after an outbreak remained the best approach based upon prior historical and scientific evidence–including the 1972 outbreak in Yugoslavia. The results of vaccination following the 1971 outbreak in Aralsk would only strengthen the conclusion of the advisory committee; i.e., that a “ring vaccination” strategy that allows for extension to broader vaccination administration (e.g., community-based, target population based vaccination) can be used to stop transmission rapidly following confirmation of a smallpox case. Thus, the epidemiological analysis of the Aralsk outbreak would not alter the claim that a “ring vaccination” strategy can limit the smallpox epidemic and should be used as a primary response strategy.

Neither the 1971 Aralsk outbreak of smallpox nor the Advisory Committee on Immunization Practices’ recommendation deal with responding to an imminent attack with smallpox (as determined by intelligence sources) nor of the possibility that recombinant DNA technology could be used to make a more virulent form of the virus and even one that was resistant to the immune response. Should the threat of a smallpox attack with a naturally occurring strain of smallpox virus be deemed very high, it would be prudent to consider a wider vaccination program using the stockpiled vaccine. This would have to be done in a manner that would minimize adverse reactions. The Advisory Committee on Immunization Practices likely will need to consider recommendations for that scenario. In the event that a strain of smallpox virus proves to be able to overcome immunity, a separate containment strategy will be necessary. A new generation vaccine might help if it provided multiple epitopes so as to make engineering a resistant virus more difficult. The greater value of a new vaccine may be reducing the rate of adverse reactions.

But, as shown by the IL-4 mousepox experiments in Australia, a new vaccine may not be able to totally eliminate the possibility of engineering a smallpox virus that could totally circumvent the immune system. In such an event, isolation procedures may be the only way of stopping the epidemic spread of smallpox. Joshua Epstein has been modeling such a strategy and it appears that isolation can be as effective as “ring vaccination” in interrupting a smallpox epidemic. Dr. Zelicoff suggests that such isolation may have been an important factor in halting the spread of smallpox in the 1971 Aralsk outbreak.

In conclusion, the analysis of the 1971 Aralsk smallpox outbreak suggests a possibility that the source was an outdoor bioweapons experiment on Vozrozhdeniye Island and that patient 1 (the index case) contracted the disease while on the deck of a ship passing the island on July 30. The outbreak of disease seems to have caused a higher than expected rate of hemorrhagic smallpox. This may indicate that the virus, regardless of its source, had a high virulence. Evidence that the virus may have circumvented immunity induced by vaccination is speculative–a more likely probability is that the vaccination program in the Soviet Union was inefficient and that even vaccinated individuals who were exposed may have had a marginal immune response. Thus, while a continuing investigation as to the nature of the Soviet biological weapons program is warranted, with particular interest in revealing activities on Vozrozhdeniye Island and any smallpox related tests, there is no reason based upon the analyses presented in Occasional Paper # 9 to suggest altering the recommendation of the Advisory Committee on Immunization Practices smallpox for the U.S. vaccination strategy nor of the NIAID Advisory Committee recommendation for a research and development program to develop a new and safer smallpox vaccine.
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Janet R. Gilsdorf, M.D.

Background

Smallpox epidemiology

The epidemiology of smallpox varies with the vaccine status of the population [1]. In areas where smallpox has never occurred, the attack rate is high among all ages and the death rate is highest among older children and young adults, as is the case with the introduction of other viral infections such as varicella and measles into naïve populations.

In endemic areas, children experience higher attack rates, because adults are immune by virtue of past infection.

In populations with active programs of childhood vaccination, young children have low attack rates, because most have been recently vaccinated, while adults have higher attack rates, reflecting their waning immunity.

In populations with recent lapses in childhood vaccination programs, the attack rate in children is relatively high because many are not vaccinated, and relatively low among adults, reflecting immunity from past immunization.

In the Aralsk outbreak, the population was not well vaccinated, and the vaccine status appears to be worse among younger children than among older children (see Table 1).

These data suggest that immunity of the Aralsk population was lowest in younger children, probably reflecting a fall-off in vaccination rates among infants. They also suggest that previous vaccination had not been highly effective. Furthermore, the Aralsk report cites 10 students in patient #2’s classroom who had vaccine scars and yet developed a primary take on revaccination; the number of children examined in this classroom was not given, so the rate cannot be calculated. More information on the efficacy of the vaccines and vaccine strategies used prior to 1971 in Kazakhstan would be critical to understanding the meaning of the Aralsk outbreak.

Thus, in 1971 in Aralsk, the vaccine coverage of the population was sub-optimal (certainly low enough to sustain an outbreak until it was by halted widespread vaccination and quarantine) and the efficacy of the past vaccine must be questioned. This concern is further highlighted by patient #4 who developed classic smallpox in spite of having received a vaccine 2½ years earlier; either the vaccine was of low potency or was different enough antigenically from the infecting strain to render only partial immunity. The other information on poor immunity after prior vaccine supports low potency of the vaccine.

Smallpox virulence

The virulence of variola is dependent on both host and viral factors, which act in concert to determine the outcome of the host-virus interaction. Host factors include:

  1. Acquired immunity, resulting from
    1. Transplacental antibody, which appears to be short-lived, providing strong immunity for the first month after birth and partial immunity for the first four to six months after birth [2].
    2. Passive immunity, from infusions of hyperimmune serum from recipients of smallpox vaccine and was not an issue in this outbreak as it was only used to treat [unsuccessfully] infected individuals with serious disease.
    3. Vaccine-induced immunity, which varies on the ability of the host to mount a robust and specific immune response to the vaccine, on the potency of the vaccine (as a live virus vaccine, it requires fairly rigorous storage to preserve potency), on the time since vaccination or re-vaccination, and on the antigenicity spectrum of the vaccine as compared to an outbreak strain.
    4. Past infection, which may not have been an issue in this outbreak since endemic smallpox may not have occurred in this region for some time.
  2. Innate immunity, which dictates a host’s ability to mount an effective response to the vaccine and to mount a protective response to contain variola infection.
  3. Unknown host factors that alter the host’s response to vaccine or infection, reflecting, for example, polymorphisms in T-cell receptors or genetic variations in immune signaling.

Viral factors include:

  1. Exposure load
    Household contacts in close proximity to infected individuals are exposed to a higher concentration of virus, thus increasing their likelihood to become infected. Similarly, patients are most contagious at the time they are excreting the highest levels of virus. One aspect not addressed in the report is the other crew members of the research ship. Apparently, none of them developed smallpox. Why? It may be as simple (or complicated) as the two women in the U.S. anthrax outbreak for whom no exposure could be identified. The best way to explain those situations is that the level of viral exposure necessary to infect a host is not finite, but varies to include a relatively low level in a very few individuals.
  2. Strain to strain differences in pathogenicity
    Possible variations in pathogenicity of variola strains must be considered in the context of outbreaks rather than in the context of individual patients, because within any outbreak, variation in the severity of the disease is striking and dependent on many factors. The most compelling evidence for strain to strain differences in variola pathogenicity is the existence of geographically defined outbreaks caused by variola major strains (with mortality rates of 5-40%) and variola minor strains (with mortality rates of 0.1 – 2 %) [3]. Biological differences between strains associated with variola major or variola minor have been described, such as differences of haemabsorbtion by infected human cells [3] suggesting these viruses induce different red cell receptors in cells they have infected, pathogenicity for chick embryos, and temperature sensitivity. The relevance of the animal tissue toxicity tests by Sarkar and Mitra [4] remains unknown, but the concordance of toxicity with severity of human disease among the strains tested is intriguing. Rough genetic analyses of viral strains have identified truncated peptides and strain to strain differences in restriction patterns [5], but these studies have not identified viral factors clearly associated with more severe disease. More sophisticated genetic studies weren’t possible when epidemic smallpox was still circulating and, since studies to explore viral genetic traits associated with increased virulence must be done in the context of careful epidemiological studies stratifying patients by clinical outcome, viral virulence factors aren’t likely to be defined anytime soon.

QUESTION 1: Is Dr. Zelicoff’s analysis correct that the source of the Aralsk smallpox outbreak was a field test of smallpox on Vozrozhdeniye Island?

The timing of the initial case and the secondary cases are consistent with this hypothesis. The only uncertainty is the possibility that Patient 1 was indeed exposed to smallpox from another source during the boat trip around the Aral Sea. Since the former (and present) governments of the region have many incentives NOT to report smallpox outbreaks (and did not report this one), relying on the official reports to discount another type of exposure may be misleading.

QUESTION 2: Do the data presented in the Soviet report indicate that the causative virus strain was weaponized to be especially virulent and/or vaccine resistant?

Virulence

Increased virulence is a multifactorial characteristic that may result from increased transmission or increased pathogenicity of the virus. Increased transmission may involve two different scenarios:

  1. Expanded distribution of the virus after an event of mass exposure, such as a terrorist attack or an accidental exposure from a common source.
    Dr. Zelicoff presents compelling data to support the hypothesis that the strain initiating this outbreak was able to infect individuals farther from the source (15 kilometers) than previously thought possible.
  2. Increased transmission from person to person.
    This outbreak does not present data addressing this possibility, as the contacts are poorly described in terms of vaccine status or degree of contact. A virus that had been formulated to increase its survival after a point exposure may not continue to be transmitted from person to person at an increased rate.

Dr. Zelicoff’s hypothesis of increased pathogenicity of the virus rests on the observation that in the Aralsk outbreak three of the ten cases (one adult and two infants, 4 and 9 months of age) — the three unvaccinated cases — died and had the hemorrhagic form of smallpox. He cites evidence from the studies of Rao in India that the hemorrhagic form is rare in infants, which is enigmatic considering that the death rates in patients studied by Rao are highest in young children [2]. The diagnosis of hemorrhagic smallpox may be subjective and open to question; for example, plate 2 in Dr. Rao’s book [2] is labeled flat type smallpox lesions on day eight of illness and yet many of the lesions appear hemorrhagic, consistent with the late type of hemorrhagic smallpox (as opposed to the early type, which is purpuric, most likely reflecting a generalized bleeding diathesis that occurs just as the rash is emerging). Since so many questions surround the designation “hemorrhagic” smallpox, a better endpoint to consider as a measure of serious disease is death.

Although the role of host susceptibility versus viral pathogenicity in the highly fatal hemorrhagic form remains unresolved, two pieces of data support the fact the hemorrhagic disease is the result of host factors.

  1. The hemorrhagic form occurs in equal proportions among patients with variola major and in patients with variola minor, suggesting that the hemorrhagic form of the disease does not correlate with strain pathogenicity as reflected by death rates associated with the variola major and variola minor strains of the virus.
  2. The hemorrhagic form occurs in equal proportions among vaccinated and non-vaccinated patients. The interpretation of this observation is difficult, but it may reflect the hemorrhagic form occurring in patients with altered T-cell function who don’t generate optimal immunity from vaccine and don’t contain the virus well when infected with either variola major or variola minor (a so-called lacular defect).
    The hemorrhagic forms of smallpox need to be better understood in light of the host innate immune system, possibly using meningococcemia as a model. The various clinical forms of meningococcal disease, ranging from fever and bacteremia with or without petechial rash through bacteremia and meningitis to overwhelming sepsis with disseminated intervascular coagulation and death, do not appear to be strain dependent.

Vaccine resistance

Microbial antigenic variation, in which a vaccine that contains antigens from one strain provides only partial immunity against other strains, is well known for viruses that recombine readily with related viruses, the most infamous being influenza virus. We know too little about variola and its interactions with other poxviruses to suggest a mechanism for antigenic shift and too little about its natural genetic variation to support significant antigenic drift. Other potential (and probably more likely) explanations for vaccine failure are poor quality of the vaccine, host inability to mount an optimal viral-specific immune response, or waning immunity with time since vaccination.

Thus, the Aralsk report includes too few patients and too little information on the vaccine status of the contacts and their degree of contact to the cases to make strong statements about transmissibility, virulence, or vaccine resistance of the virus.

QUESTION 3: Does the Soviet report have implication for international biological arms control?

While the Soviet report and Dr. Zelicoff’s analysis do not prove that this outbreak represented exposure to a hypervirulent or particularly hearty virus, they do remind us that we understand very little about the activities of the former Soviet Union in developing biological weapons and would be wise to consider many possibilities.

QUESTION 4: Does the Aralsk outbreak have implications for the development of a national smallpox vaccine strategy?

No one familiar with the currently available smallpox vaccine (prepared using 1950s or earlier technology) would be satisfied with this vaccine as the sole method of preventing smallpox should outbreaks be likely. The Federal Government appears poised to devote significant resources to improve our understanding of variola and its potential pathogenic and immunogenic factors, with the goal of developing safer, yet highly effective, vaccines. In this context, information concerning variola antigenic variation, both naturally acquired and biologically engineered, is critical to developing newer vaccine components.

References

1. Banks, H.S., Smallpox, in The Common Infectious Diseases. 1945, Edward Arnold & Co.: London. p. 209-223.
2. Rao, A.R., Smallpox. 1972, Bombay: The Kothari Book Depot. 220.
3. Fenner, F., et al., Smallpox and Its Eradication. 1988, Geneva: World Health Organization. 1460.
4. Sarkar, J.K. and C. Mitra, Virulence of Variola Virus Isolated From Smallpox Cases in Varying Severity. Ind. Jour. Med. Res., 1967. 55(1): p. 13-20.
5. Dumbell, K.R., et al., A variant of variola virus, characterized by changes in polypeptide and endonuclease profiles. Epidemio Infect, 1998. 122: p. 287-290.
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Dr. D. A. Henderson

Dr. Zelicoff’s analysis of the Aralsk outbreak and interpretation of the findings are regrettably flawed. Had his report been presented in an appropriate venue with suitable discussion, I believe it could have been seen in appropriate perspective. Unfortunately, it appears to have been presented with media coverage in mind. While he couches his summary conclusions in terms of “unanswered questions,” he leaves little doubt as to his beliefs:

The answers to these and many other questions will almost certainly have a profound effect on civilian and military biodefense efforts… (O)ur complete reliance on a single vaccine (unmodified vaccinia) represents a serious potential vulnerability. Only a detailed analysis of the Aralsk strain with the most modern tools of molecular biology can guide public health officials and defense planners in formulating appropriate polices and prophylaxis which may include a concerted effort to produce new vaccines based on entirely novel approaches, along with testing of anti-viral drugs in animal models.

The report reveals that a hitherto publicly unknown outbreak of 10 smallpox cases occurred in Aralsk and that infection of the single index case possibly resulted from exposure to aerosolized smallpox virus from the Vozrozhdeniye Island test site in the Aral Sea. These findings are of interest but hardly dramatic or unexpected. Does the outbreak provide information that should heighten our concern or alarm? If there is something there, I cannot identify it.

Have we been aware that the Soviets worked to prepare smallpox virus as a biological weapon? Yes. Alibek has been quite explicit about this.

Have we been aware that an aerosolized preparation of smallpox virus can infect at a distance and at low dosage? Studies during the 1960s in England and the U.S. document the survival of vaccinia as a fine particle aerosol. The 1970 Meschede, Germany, outbreak provides better and more ample illustrative documentation of the potential of a smallpox aerosol.

Have we been aware that the Soviets performed tests of smallpox aerosols? Again, Alibek has been quite specific in telling us this. Further, former Vice-Minister of Health Burgasov, as quoted in a November 2001 Moscow newspaper article, stated that there had been an outbreak in Aralsk related to testing on the island.

Could this be an especially engineered, more virulent strain of smallpox? The only case apparently resulting from exposure to the aerosol was a 24-year-old woman whose rash was sufficiently atypical as not to be recognized as smallpox. Dr. Zelicoff indicates her onset to have been August 11 but, interestingly, as he points out, she recovered so quickly that she left Aralsk 4 days later to get married. This case would not appear to qualify even as “ordinary” smallpox. Meanwhile, none of her shipmates became ill according to Dr. Zelicoff. This is difficult to explain if the virus was indeed more virulent than normal strains and capable of evading the immune protection provided by ordinary vaccinia.

If this were an especially virulent virus, one might have anticipated that a hemorrhagic case might have given rise to other cases but not one of the three did so. Rao (1972), in has classic book on smallpox, points out that in his series of 385 cases of hemorrhagic smallpox, not once did a second hemorrhagic case occur among contacts of a patient with the hemorrhagic form. In other words, the Aralsk transmission pattern was not unexpected.

That 3 of the 10 cases were hemorrhagic is higher than usual but how much can be said with such small numbers. Two points are to be made: first, that the manifestation of hemorrhage is thought to relate to host factors rather than to the virus per se and, second, variation in the frequency of hemorrhagic cases varied widely from outbreak to outbreak. Rao found that of 85 hemorrhagic cases occurring among unvaccinated persons, 24 (28%) were 0-4 years of age (a more detailed breakdown by age is not provided) and 18 (21%) were in the 20-24 year age group. These were the highest numbers for any of the 5-year age groups and, interestingly, the deaths in the Aralsk outbreak corresponded with this distribution.

Is there evidence of resistance to the immunity provided by the vaccine? The answer is an unequivocal “no”. Dr. Zelicoff expresses concern that all 7 patients who recovered had all been previously vaccinated. Five of the seven were 24 years of age and older (24, 33, 36, 38 and 60). Note that all 7 are recorded as having been vaccinated only once and that in childhood. No mention is made as to whether any had a vaccination scar as evidence of having been successfully vaccinated. From Jenner’s time, it has been recognized that a single vaccination does not provide lifetime immunity. Dr. Zelicoff’s assertion that “the efficacy of the smallpox vaccine is usually described as being in excess of 90 percent” may be correct for the first several years after vaccination but the protection afforded by a single inoculation wanes over time. After 20 to 30 years, protection against infection is minimal. In a country that was quite rigorous in enforcing vaccination, is it surprising that most of the cases had once been vaccinated?

Summary: This interesting smallpox outbreak provides further documentation that the Soviets were actively engaged in developing the smallpox virus as a biological weapon. There is nothing in the report to suggest that the strain used was either more virulent than other south Asia strains and certainly nothing that suggests that it resisted the immunity provided by conventional vaccinia infection.

Reference

Rao, A.R. (1972) Smallpox, The Kothari Book Depot, Bombay.
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Dr. Peter B. Jahrling

Dr. Zelicoff’s analysis of the Aralsk smallpox outbreak is extremely valuable in that it provides strong circumstantial corroboration of suspicions that Soviet bioweaponeers conducted open air testing of smallpox virus on Vozrozhdeniye Island in the Aral Sea. This documentation elevates the theoretical concerns about variola virus as an agent of mass destruction to a new level.

Dr. Zelicoff presents a convincing argument that the index case of the outbreak in Aralsk in 1971 could only have become infected while living and working on a research vessel that she never left during the entire potential exposure and incubation period for smallpox disease. The vessel sailed within 15 km of Vozrozhdeniye Island in late July 1971. This timing corresponds closely with a suspected open-air release of smallpox virus on the island. The circumstantial evidence that she was exposed to variola in the form of an aerosol cloud that drifted downwind is compelling.

A former Soviet bioweapons program official has acknowledged that the release of 400 grams of a weaponized smallpox formulation was associated with a civilian outbreak. Dr. Zelicoff’s analysis suggests that the index case was the only individual infected by exposure to the aerosol cloud; subsequent cases arose by conventional transmission mechanisms. That she was the only victim among twelve occupants on the ship can be explained by her duties, which required her to be the deck for long periods of time, including nighttime, in contrast to other crewmembers. The protection against aerosol exposure provided by very modest shelter conditions was documented during the Sverdlovsk anthrax incident (another Soviet BW experiment gone awry) in 1979.

Although we don’t know whether the 400-gram payload was disseminated from a point source or a line dissemination device, the dilution of virus over a 15 km radius is substantial; yet sufficient infectivity remained to infect the index case. Had the release been over a densely populated area instead of open water, it is conceivable that many hundreds if not thousands of index cases might have occurred simultaneously. This contingency dramatically impacts the projections for the spread of disease and the feasibility of containment strategies based on ring vaccination. Even the most conservative epidemiological models suggest that ring vaccination alone, after an attack of this magnitude, would be totally inadequate to contain the subsequent outbreak. The plausibility of such an attack is increased by Dr. Zelicoff’s analysis. Failure to plan for the contingency of smallpox virus being dispersed by aerosol methodology over U.S. communities would be irresponsible. This realization should prompt a reevaluation of the benefit-to-risk equation for mass immunization. Crash development of a less reactogenic vaccine, and effective antiviral drugs to treat individuals who develop smallpox, regardless of immunization status, are also worthy investments.

Considerable controversy has surrounded Dr. Zelicoff’s further suggestion that the smallpox virus strain associated with the Aralsk outbreak apparently caused disease in previously immunized adults and hemorrhagic disease in non-immune children. The numbers are too small for definitive statistical analysis, and alternative explanations can be invoked for the apparent vaccine breakthrough infections and the hemorrhagic diathesis, but the concern that this strain was hotter than average should not be dismissed out of hand. We know that the Soviet bioweapons development program attempted to select natural strains of increased virulence and that one of the selection criteria was hemorrhagic diathesis in mice and embryonated eggs. Overwhelming vaccine induced immunity could be explained by sub-standard vaccine quality or administration; conversely, the weaponized strain could have been selected on the basis of vaccine evasion, although the eventual containment of the Aralsk outbreak by use of the vaccine in question argues against this contingency.

Many of the questions pertaining to the weaponized strain could be addressed if reference materials from this outbreak could be located and analyzed. Dr. Nelja Maltseva, who was associated with the Institute of Viral Preparations (IVP) in Moscow in 1971, was involved in the Aralsk outbreak investigation and it is likely that clinical materials from which variola virus was isolated (as documented in the clinical reports) were archived in the IVP collection. Since that reference repository was moved in 1994 to the more secure Vector facility in Koltsovo, Siberia, it would be helpful if our Vector colleagues would scrutinize the records to determine if any of the isolates can be traced back to the Aralsk outbreak. Neither Vector nor its home agency Biopreparat existed in 1971, so no one associated with that program can be held accountable for the misdeeds of the Ministry of Defense (MOD) pre-1972 bioweapons program. But since western scientists still do not have access to the MOD laboratories, which remain a concern since they still carry out secret work, our Vector colleagues remain our best hope for cracking the case. Even if relevant, infectious materials cannot be identified and located, tissues from the victims of the Aralsk outbreak are likely to exist, preserved in formaldehyde and paraffin-embedded blocks. If so, they can be analyzed by modern techniques of immunology and molecular virology to give insight into the nature and phylogeny of the causative virus. A similar approach, used to analyze pathology specimens associated with the Sverdlovsk anthrax outbreak in 1979, yielded information valuable to infectious disease specialists. By analogy, similar cooperation between knowledgeable Russian and western scientists might answer the disturbing questions raised by Dr. Zelicoff’s incisive analysis of the documented smallpox outbreak and its association with Vozrozhdeniye Island.
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Dr. Serguei Popov

Dr. Alan Zelicoff’s chapter “An Epidemiological Analysis of the 1971 Smallpox Outbreak in Aralsk, Kazakhstan,” in Occasional Paper No. 9, The 1971 Smallpox Epidemic in Aralsk, Kazakhstan, and the Soviet Biological Warfare Program, edited by Jonathan B. Tucker and Raymond A. Zilinskas, June 2002, describes and analyzes previously unknown information on a smallpox outbreak in the former Soviet Union. Several hypotheses are carefully considered regarding the origin of this epidemic, which caused 10 cases of smallpox among the population of Aralsk city. Dr. Zelicoff concludes that the most probable origin of the epidemic was a release of aerosolized smallpox virus at the military testing ground at Vozrozhdeniye Island in the Aral sea. This conclusion is well substantiated and represents the first clear circumstantial evidence that the Soviet Union succeeded in weaponizing the smallpox virus as early as 1971.

The highly classified nature of the Soviet biological warfare program makes it extremely difficult to collect direct evidence about its activities. One also has to take into account the strong counterintelligence efforts undertaken by the Soviet security apparatus to provide the program with innocuous “cover stories.” However, Dr. Zelicoff’s conclusion as to the origin of the outbreak comes as no surprise to people who were directly involved in the Soviet bioweapons program. From personal knowledge acquired during more than 16 years of performing research at Biopreparat facilities I am well aware that a weaponized version of smallpox virus was developed in early 1970s and was tested at the Vozrozhdeniye Island field test site. The relatively high incidence of the most severe hemorrhagic form of the disease, as well as the indication of high vaccine resistance by the virus that caused the Aralsk epidemic, represent additional evidence in favor of the deliberate release of the virus. The choice of an especially virulent strain for weaponization was dictated by the military requirement to pre-select a strain of virus in laboratory conditions for superior “tactical and technical characteristics.”

A new biological warfare program named “Ferment” was established in the mid-1970s; one of its primary goals was to further improve the smallpox virus weapon. Genetic manipulation of the virus was considered as the major approach to increase its virulence and ability to defeat the existing vaccine. In particular, there was a high interest in creating strains of hemorrhagic smallpox virus using the new methods of molecular biology. Evidence of this can be found in several publications by Soviet scientists. For example, they describe methodology for creating a highly hemorrhagic vaccinia virus, which then was used as a research model of smallpox virus.[1] Studies on methods to design deadlier smallpox virus strains continued with considerable success until the collapse of the Soviet Union in early 1990s. For example, one publication describes how a harmless vaccinia virus became as lethal in experimental animals as the smallpox virus in humans.[2]

In my opinion, Occasional Paper No.9 is an accurate and reliable document revealing a small part of the Soviet biological warfare program’s history. A more detailed knowledge of what happened more then 30 years ago in Aralsk is required to answer the question of what we can expect from a biological weapon based on the smallpox virus and in what form such a weapon can emerge in today’s environment where concerns about biological terrorism are prevalent among the public and government officials.

[1] Totmenin, A.V., Gashnikov, P.V., Shchelkunov, S.N., and Sandakhchiev, L.S., “The use of the gene responsible for formation of hemorrhage as a phenotypic marker in creating hybrid variations of vaccinia virus (in Russian). Dokl. Akad. Nauk SSSR, vol. 305, pp. 1246-1248 (1989).
[2] Shchelkunov, S.N., et al., “Viral chimeric protein including a determinant of myelin basic protein is capable of inducing allergic encephalomyelitis in guinea pigs.” Biomed. Sci., vol. 2, pp. 493-497 (1991).
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Dr. Jack Woodall

In this commentary I analyze the four hypotheses proposed for the origin of the 1971 smallpox epidemic in Aralsk. Thus, the official 1971 USSR report proposed three alternative scenarios, and a 2001 report from Russia suggested a fourth.

1. Port Source

The first official scenario was that the index case, a fisheries researcher, became infected with smallpox when she went ashore at one of three port cities visited by the ship. But in 2002 the scientist said she never went ashore and that female passengers were in fact expressly prohibited from doing so (no explanation for the prohibition was provided). The official report further stated that she had bought a towel, some fabric, and a dress at the market in Muynak on August 4. Contaminated fabrics are well known to transmit smallpox viruses; viz. the contaminated blankets distributed to American Indians in the past. But although she remembers the port call at Muynak, she denies going ashore, let alone buying anything there. However, it is presumably possible that she asked somebody else to get those items for her, and she simply has forgotten that.

As the translators note, the official report contains many conflicting dates. The most important for purposes of analysis are those of the port calls and the arrival in Aralsk at the end of the voyage. To quote the official report (p. 26):

The expedition was conducting research at 20 stations in the Aral Sea from June 15 to August 8, 1971. Members of the crew and of the research team went ashore on July 29 in the town of Uyaly in the Kzyl-Orda region, on July 31 in the town of Komsomolsk-on-Ustyurt, and on August 4 in the town of Muynak in the Karakalpak ASSR… On August 11 upon her arrival in Aralsk … the physician … was called to the house, and he noted that the patient complained of the following: headache, cough, and a fever up to 39 degrees. He completed a form releasing her from work from August 11 to August 17.

Further on (p. 29):

Thus, consistent with the average incubation period, it is presumed that [Patient 2] contracted the disease sometime between August 10 and August 20, 1971, when his older sister came home from her trip… As has been mentioned before, she was sailing the Aral Sea from July 18 to August 8 and went ashore on July 29 and 31, 1971, and August 4, 1971. She became ill on August 6. It can be presumed that she became infected with smallpox in one of the two locations [where she went ashore]. Judging by the incubation period, these locations were Uyaly and Komsomolsk [-on Ustyurt]. This is confirmed by the absence of the illness among the other crewmembers of the vessel and among the researchers.

In fact, Patient 1 did state in her phone interview that no one on board the Lev Berg developed illness or fever. But the official report states on p. 29: “Patient 1 and her friend P., who fell ill a day earlier, associated their illness with the fact that they had felt very cold a few days prior, when they were casting nets from the boat.” P.’s blood was tested but the results are not included in the report. It seems unlikely that P. would have been blood tested if she had not been ill.

Note that the port dates are consistent in the two sections of the report, but the arrival date varies between August 8 and 11, and the onset of illness between August 6 and 11.

Thus the official report excludes Muynak as the place where the index case contracted smallpox. Zelicoff also excludes Muynak on the grounds that the incubation time is too short, quoting a period of 11-15 days (95% CI). Based on their onset dates in relation to the earliest appearance of rash — and therefore of infectivity — in their contacts, Patients 6, 8, and 9 could have had incubation periods as short as eight days. Therefore, if Patient 1 fell ill on August 6, as stated in the official report, there was only enough time for her to have become infected during the port call on July 29, not at the one on July 31 or at Muynak on August 4. On the other hand, if her illness began on the day of her return home to Aralsk, as she recalls — while not remembering the actual date — whether that was August 8, 10, or 11, it brings the July 31 port call into contention (assuming that the port dates are correct). It seems unlikely that she would have forgotten being confined to her bunk for the last 5 days of the voyage, as the official report has it and which she denies.

Whatever the reality of the dates, it seems that the ship was visiting ports and sailing in waters south of the island test range during dates that would fit the incubation period of her illness.

According to the second scenario (below), teams from the Aralsk shipping company were sent to the port of Termez, where they transferred ship cargos from Afghanistan to trains, and one such team was en route back to Aralsk from Termez during August. Could a team (not necessarily the same one), northbound from Termez to Aralsk, have been in one of the ports at the same time that the ship called?

2. Trade Route Source

The second scenario was that the virus originated in Afghanistan, where smallpox was still endemic at the time, and reached Aralsk from the southern border regions of Kazakhstan by land or waterway. This scenario differs from the first in that it postulates direct infection of Aralsk from the south without involving other Aral Sea ports and land transit points.

Atshabar, in the Foreword, states that this hypothesis is less plausible because the disease could only have been transported from Afghanistan to Aralsk through Tajikistan and Uzbekistan. If people had become ill with smallpox in those republics, he says they certainly would have been detected, yet no such cases were reported. Zelicoff states: “In and of itself, the failure of the Soviet Union to notify the World Health Organization (WHO) of the 1971 outbreak suggests a sinister source for the epidemic.” But non-reporting of infectious disease outbreaks in the USSR was routine at the time — see the Introduction: “Epidemics in the Union of Soviet Socialist Republics (USSR) often went unreported because they undermined the propaganda image of the socialist workers’ paradise.” On Zelicoff’s premise, every failure to report cholera to the WHO would suggest a sinister source.

The USSR reported importations of smallpox into the region from Afghanistan to the WHO in 1959 (one non-fatal case arrived by land at Termez in July) and 1961 (one non-fatal case arrived by land at Kirovabad in October), and none thereafter [1]. However, the big breakout of smallpox from Afghanistan to the west began in 1970, when the disease first reached Mashhad, which is located on Iran’s northern border with the USSR, in October. From there it followed trade routes south to the Persian Gulf and west to Iraq, arriving in that nation by the end of 1971. Smallpox then spread through Turkey to Yugoslavia by 1972 [2]. It is logical that in the same time frame the disease would also have followed the road north from Mashhad, along the west coast of the Aral Sea to Komsomolsk-on-Ustyurt and Aralsk, and the Amu-Darya River from the Afghan border to Muynak on the Aral Sea and across it to Aralsk.

The official report states (p. 30):

According to World Health Organization reports, there were 1,030 cases of smallpox in Afghanistan in 1970, and 482 cases during the first eight months of 1971. The disease could have reached the territory of the Tajik and Uzbek Soviet Socialist Republics, which were economically linked to the city of Aralsk. Large quantities of cotton, melons, and other agricultural products from the Uzbek and Tajik republics were shipped north to Aralsk via the Amu-Darya River and the Aral Sea, whereas grain, coal, and other items were shipped south.

Workers from Aralsk and other cities and towns in the region serviced the Uch-Say transshipping facility. Periodically, teams from the Aralsk shipping company were sent to the port of Termez, where they transferred cargo from Afghanistan from ships to trains. Such a team arrived in Aralsk from Termez on August 29-30. Nevertheless, its members could not have been the source of infection for Patient 1 because of the time discrepancy.

Since Patient 1 was already ill before August 29, as was her brother, Patient 2, and all subsequent cases were linked to her household, this scenario is effectively ruled out.

3. Fomites in the Aralsk Market as a Possible Source

According to the third hypothesis presented on page 30 of the official report:

A scenario of infection via the open-air market has also been thoroughly checked. As a matter of fact, individuals bring to the city of Aralsk large quantities of produce from the Uzbek and Tajik republics. However, no evidence was established that people with smallpox arrived from those regions and visited the home of [the father of Patients 1 and 2] or the market’s director [also the father], or that goods such as rugs and other wool artifacts were bought or sold there.

It would be entirely possible that the disease could reach the territory of the Tajik and Uzbek SSRs [Soviet Socialist Republics]. These regions are connected to the city of Aralsk economically, as large quantities of cargo are conveyed via the Amu-Darya River and the Aral Sea. Cotton, melons, etc. are shipped to the north, while grain, coal, and other items are shipped to the south.”

But an artifact does not have to be made of wool to carry smallpox virus — clothing and laundry have frequently been incriminated in the past as carriers of the virus. Imported raw cotton was suspected of causing some outbreaks in England [3]. But in any case, no smallpox case was recognized in Aralsk before Patient 1’s arrival there, and all subsequent cases could be traced back to her household.

4. The Biological Weapons Field Test Site on Vozrozhdeniye Island as a Possible Source

This scenario is based on information derived from an interview with Burgasov’s published in 2001. Burgasov’s spreading of the disinformation that the source of the 1979 Sverdlovsk anthrax outbreak was contaminated meat had earlier destroyed his credibility. Is he trying to re-establish it now by claiming that this outbreak was the result of a biological weapons test? Zelicoff points out there are inconsistencies in Burgasov’s account of the Aralsk incident, as he remembered it 30 years later; for example, his assertion that all the smallpox victims died. Another is his statement that the researcher was collecting plankton, when both the official 1971 report and the researcher interviewed by Zelicoff agree that she was collecting fish. So why should we now believe his statement that the research ship sailed inside the 40 km exclusion zone?

Although D.A. Henderson recently has stated that it is possible to dry the smallpox virus and add stabilizers so it can persist a long time in the air like anthrax [4], it is improbable that the technology to do so had been invented by 1971. The state of the art at the time was published in a 1970 WHO report; airborne viruses could not be expected to retain their lethality for aerosol transmission of more than 1 km — in contrast to Bacillus anthracis spores with a range of more than 20 km [5]. So even if the ship did come as close as 15 km to the island, as stated by Burgasov, it is unlikely that airborne infection could have occurred after the virus had traveled that distance.

Referring to the virulence of the virus that caused the 1971 outbreak, I quote from the official report:

According to a September 29 report from Guryev and Alma Ata (where both Patient 1 and friend P. had gone — JW), neither woman had any traces of smallpox on their skin. They were completely healthy. Both had vaccination scars. However, blood-serum tests on Patient 1, conducted in Moscow, showed high antibody levels, indicating recent exposure to the smallpox virus. Obviously, she had been sick with the mild form of the disease — varioloid.

Alternatively, it could have been that her previous vaccination protected her, as well as the three other mild cases that had previous vaccinations. Further, “The source of the infection was [Patients 1 and 2’s] family, from which the infectious agent spread to four households. By September 27 (i.e., within 5 days), the outbreak was contained.” Taken together, this does not suggest that a laboratory-produced strain with enhanced virulence caused the Aralsk outbreak.

Summary

I start from the premise that, when interviewed in 2002, Patient 1 had no reason to falsify her recollection of events in 1971, whereas if the outbreak was suspected of being linked to secret experiments, the writers of the 1971 reports had every reason to alter events to fit a version that excluded the possibility of airborne infection at sea.

There are major discrepancies between the 2002 recollections of Patient 1 and the 1971 official report. If the official report was an attempt at a cover-up, the authors went to extraordinary lengths. According to Patient 1, they fabricated a story that she went ashore at all three ports, bought textiles at the August 4 port call — even though, by their own calculations, that was already too late to have been the day of infection (so why invent it? To give an air of verisimilitude?) — that she and a female friend called P. both fell ill on board, and that she was bunk-ridden for five days before the ship’s arrival back in Aralsk. Was this all false, designed to bolster the hypothesis that the infection was contracted on July 29 or 31 at one of those port calls rather than at sea?

The translators noticed that dates in the original reports are inconsistent. Was this the result of alterations designed to place the ship at a port within the supposed incubation period, or was it simply bureaucratic sloppiness? I recall that the written U.S. response to the Cuban allegation that an American aircraft had sprayed Thrips palmi insects over their island was so full of contradictions that it looked suspiciously like a badly designed cover-up [6].

If Patient 1 had contracted smallpox in a year when there was no smallpox activity in any neighboring country, it would have been reasonably conclusive of an unnatural origin. But smallpox was spreading in the region, and the absence of any reporting from the USSR was not unusual.

Recall that examination of autopsy specimens from the 1979 Sverdlovsk epidemic revealed multiple strains of anthrax in the same patient, an unnatural finding [7]. In that case, the location downwind of a military laboratory was definitive. On the other hand, after a hitherto unknown strain of hantavirus appeared in humans in 1993 in the region of several military proving grounds in western U.S.A., field research demonstrated that the strain was widespread in humans and wild rodents nationwide, and had been so for years previously [8], thus reducing the likelihood that it was an escapee from a military test. The location of the outbreak therefore appears to have been coincidental to the virus’ natural range. Likewise, the location of the 1971 smallpox outbreak in Aralsk could have been coincidental to the presence of the smallpox virus in Afghanistan and other nearby countries.

In spite of the two deaths from hemorrhagic smallpox, there is evidence for the strain involved not having been exceptionally virulent. Unless nucleic acid sequences can be obtained from the autopsy specimens, it will be impossible to say whether the smallpox strain involved was the Afghanistan 1970-71 strain or a laboratory strain. Of course, if an isolate from the Aralsk outbreak still exists in a deep freeze somewhere, and can be shown to be significantly different from the contemporary Afghan strain, then all would be clear.

To conclude, my opinion is that there is at present insufficient evidence to decide between scenarios 1 and 4. Suggestions follow as to how the issue might be clarified.

Further questions to Patient 1:

  1. Does she remember hearing about an exclusion zone? If so, how big was it? Did the ship enter it? If so, why? How near did it approach the island? To the north, south, east or west?
  2. If not, how near did the ship approach to the south end of the island while sailing between Uyaly and Komsomolsk?
  3. Why were female passengers not allowed ashore at ports?
  4. Did she receive on board a towel, clothing or fabric from one of the ports — perhaps obtained for her by someone who went ashore?
  5. Does she remember a female passenger named P. and, if so, was P. sick on board? If P. was sick, how long before the ship’s return to Aralsk did symptoms appear?

Suggestions for further research:

  1. Try to obtain the ship’s log to verify dates; failing that, check harbormaster logs at the three ports visited by the Lev Berg.
  2. Try to locate the Lev Berg’s laboratory journal at its home fisheries institute.
  3. Try to obtain the reports of the contemporary epidemiological investigations mentioned by Sarynov as in process in the three port cities.
  4. Obtain wind force and direction data from Aralsk airport for the relevant dates, through the International Meteorological Organization, Geneva, Switzerland.
  5. Try to obtain autopsy material, or better, the strains isolated during the outbreak, for nucleic acid sequencing of the causative virus.

References

[1] Fenner, F., Henderson, D.A., Arita, L., Jezek, Z., and Ladnyi, I.D. Smallpox and Its Eradication (Geneva: World Health Organization, 1988), Table 23.2.
[2] Ibid. Fig. 23.5.
[3] Ibid. p. 1343.
[4] Rowland, R. Panel: Smallpox vaccine not for everyone; CNN.com/Health, <http://www.cnn.com/2002/HEALTH/conditions/06/20/smallpox.vaccine/index.html>. Accessed July 11, 2002.
[5] World Health Organization, Health Aspects of Chemical and Biological Weapons (Geneva: World Health Organization, 1970), Table 10.
[6] United States, Documents in Support of United States Presentation Regarding Cuban BW Allegations, Geneva, Switzerland, 25 August 1997 (Geneva: United States Delegation, 1997).
[7] Jackson, Paul J.; Hugh-Jones, Martin E.; Adair, Debra M., et al., “PCR analysis of tissue samples from the 1979 Sverdlovsk anthrax victims: The presence of multiple Bacillus anthracis strains in different victims.” Proceedings of the National Academy of Sciences, USA, vol. 95, pp. 1224-1229 (1998).
[8] Nichol, S.T.; Spiropoulo, C.F.; Morzunov, S., et al., “Genetic identification of a Hantavirus associated with an outbreak of an acute respiratory illness.” Science vol. 262, pp. 914-917 (1993).

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Alan P. Zelicoff, M.D.

I am grateful to the Center for Nonproliferation Studies (CNS), Monterey Institute of International Studies, for soliciting commentary on my analysis of the 1971 Aralsk smallpox outbreak. For too many years, discussions about smallpox — destruction of existing stocks, threat analysis, contingency planning — have failed to take into account advances in molecular biology as well as the scope and accomplishments of the former Soviet Union’s offensive biological warfare (BW) program. With this publication, the CNS has revitalized the debate over these difficult issues.

In reference to the commentaries, Dr. D.A. Henderson’s critique of my article centers on the assertion that there is “nothing new” in the findings of my analysis of the Aralsk outbreak. Specifically, he states:

  • It has always been known that smallpox could be aerosolized and disseminated over long distances. Besides, Henderson argues, Dr. Ken Alibek made us (actually, only our intelligence community at that time) aware of Soviet smallpox biological weapons research shortly after he defected in 1992.
  • Former Soviet Vice-Minister of Health Pyotr Burgasov already had given an interview to a Moscow newspaper in November 2001 stating that the Aralsk smallpox outbreak was to the result of a biological weapons test.
  • Because hemorrhagic smallpox has occurred before in other epidemics, it is “not unexpected” that 3 out of the 10 victims of the Aralsk outbreak would have had the hemorrhagic form of the disease.
  • The apparent vaccine resistance of smallpox in Aralsk is consistent with other outbreaks in which, despite successful vaccination, immunity waned after 10 years.
  • The index case had a mild rash and was “well in four days,” thus casting doubt on the diagnosis of virulent smallpox.
    In response:

The knowledge in the West of the details of the Soviet “work” with smallpox virus are what are at issue here. It is one thing to grow variola virus in chick embryos, and quite another to deliver it as an aerosol over a distance of several kilometers while maintaining virulence. Alibek did not provide any information on the aerosol testing of a smallpox biological weapon on Vozrozhdeniye Island to the general public until after Burgasov was interviewed, which was nine years after his defection. This omission suggests that Alibek’s knowledge of the Soviet Union’s smallpox program was incomplete, consistent with its highly compartmentalized nature. Indeed, if Dr. Lev Sandakhchiev and Dr. Sergei Netesov (Director and Deputy Director, respectively, of Vektor, in Koltsovo, Siberia) are to be believed, even they were unaware of the test. This is significant because they, unlike Alibek, worked exclusively on viruses for the Soviet BW program, with a concentration on the smallpox virus.

Burgasov’s interview was, indeed, the first public revelation of the Aralsk outbreak, but many people doubt Burgasov’s credibility — including commentator Dr. Jack Woodall. Burgasov is infamous for having lied to and successfully duped American scientists in the past and, besides, it turns out he was wrong on the details of the outbreak’s effects (he stated, for example, that everyone on the research ship Lev Berg died). I think the scientific community deserves better than the isolated testimony of one ex-Soviet official in characterizing the scope of the threat of use of smallpox virus as a weapon.

The only data ever published on the aerosol survivability of an orthopox virus is found in an article by G.J. Harper, “Airborne micro-organisms: survival test with four viruses,” Journal of Hygiene 59:479-486 (1961). The Soviet aerosol test did not take place until more than ten years after this article appeared, and given that they had a robust bioweapons development program, it is possible that the virus particles they weaponized were microencapsulated to, for example, harden them against ultraviolet radiation and other environmental stresses, which would have been a more effective protectant than the horse serum used in Harper’s experiment. Thus, the Aralsk outbreak raises the question of how far virulent smallpox viruses can be disseminated as an aerosol plume. Harper’s data suggest that high relative humidity destroys the virus (under a reasonable range of temperatures) in hours or less. Indeed, Henderson stated at the National Academy of Sciences (NAS) meeting on June 15, 2002, when I first presented the Aralsk data publicly, that it was not possible for an aerosol of variola viruses to have been transported in the open environment as far as allegedly occurred in 1971. Given that the Aralsk experiment took place in a very warm, high-humidity environment (August in Central Asia), relying on Harper’s data alone would bolster Henderson’s contention. But, the realization that infectious viruses did travel at least 15 kilometers (and perhaps even further) downwind from their point of release strongly suggests that there is indeed something new to be learned from an analysis of the Aralsk outbreak.

The index case did not have a mild, atypical rash (as described in the Official Report); rather, she had a severe rash — so severe that she was concerned she might miss her marriage date on August 30 (not August 14 as stated in the Official Report). I believe it is reasonable to assume that she is the more accurate source of information as to the date of her marriage.

Regarding the three hemorrhagic cases (33% of the Aralsk victims), the statistical analysis does not support Henderson’s contention that the Aralsk outbreak was similar to other outbreaks in the percentage of hemorrhagic cases (particularly among infants, where it is decidedly rare) or in the ease with which the virus propagated in households where everyone was vaccinated.

One would not expect an aerosol cloud to necessarily penetrate into the interstices of the ship, especially at night (when, for technical reasons, it is most likely that the aerosol was dispersed in the Soviet field test). Two phenomena help to explain why this would be the case. First, at night metal surfaces are cooler than the surrounding air due to black-body radiation into the night sky (you can convince yourself of this by putting your hand on the hood of a car on a hot summer’s night — you’ll be amazed how cool it is compared to the ground or wooden objects). Second, aerosol particles will impact and stick on cooler surfaces (that is, cooler relative to the air than carries them). This phenomenon is called themophilic attraction, and is manifested in our everyday experience as dust on windows (especially in the winter). Thus, a thin aerosol cloud of virus particles would be greatly diminished by thermophilic attraction as it approached a cool surface.

Finally, as Henderson knows, I presented my analysis to the NAS staff organizing the June 15th, 2002 public meeting and more than two dozen people at the Centers for Disease Control and Prevention (CDC) to solicit their opinion as to whether or not the Aralsk data warranted presentation (Henderson was invited to participate in the telephone conference, but chose not to). There was consensus (with only a few detractors) that the Advisory Committee on Vaccination Policy should learn about the outbreak and see my statistical analysis before the round of public hearings came to a close.

Dr. Ronald Atlas and Dr. Richard Clover make the following points in their critique:

  • The data in the report on the smallpox vaccination program indicated that there had been a low immunity — only 31.6% of the residents of Aralsk had been vaccinated. Among first and second grade schoolchildren, 24% had not been vaccinated, and 31.6% showed a primary vaccination reaction when they were vaccinated again following the Aralsk outbreak, indicating a low immunity even among those who had been previously vaccinated. Hence, it seems more likely that there was inadequate immunity in those exposed than the possibility that the strain of smallpox virus was immune-resistant.
  • The viewpoint that proper vaccination would afford protection against the strain of smallpox virus that caused the Aralsk outbreak, even if it came from the Soviet biological weapons program, is supported by the fact that mass vaccination was used to contain the outbreak.
    In response:

It is indeed difficult to ascertain the presence of successful vaccination (of those in whom vaccination was undertaken anytime before the outbreak) in most of the victims. The Official Report makes clear that the index case had a vaccination scar yet came down with a severe case of smallpox.

The Official Report refers to an older Report (“No. 86”), from which Atlas and Clover quote:

“During the years from 1966 to 1970, according to Report No. 86 of the epidemiological monitoring station, a total of 69.7% of the district’s population and 31.6% of the residents of the city of Aralsk were vaccinated (vaccination and re-vaccination), which is obviously insufficient.”

However, there may have been a vaccination effort in the interim, that is, between 1966 and the outbreak in 1971, that could have raised the number of vaccinated persons. This possibility is substantiated by the actual findings on examining individuals during the vaccination campaign in Aralsk (some 49,000 people were vaccinated in a little over two weeks), which revealed:

“As a result of an examination of 1,383 schoolchildren, carried out in order to determine their immunization status by randomly checking the nature of their skin reaction to revaccination, it was determined that 161 of these children (11.6%) did not have vaccination scars. Among the first- and second-grade students, 24% had not been vaccinated, while among the third- to tenth-grade students — 15%. Of 370 adults examined, 37 (10%) did not have vaccination scars, i.e., had not been previously vaccinated. At the same time, a significant percentage (20.6%) had primary skin reactions, indicating an absence of immunity. A low-immunity segment was observed among first- and second-grade students, where the primary reaction percentage was 31.6%.”

Thus, it appears, that in Aralsk, the rate of vaccination “take” before the re-vaccination (or primary vaccination) campaign was closer to 70 — 75%.

Next, assuming that in other, earlier smallpox outbreaks (e.g., in India and Pakistan) the vaccination “take” among household contacts was similar, then all other things being equal, my statistical analysis shows that smallpox was more likely to spread within households in Aralsk where there was a high percentage of vaccinated people, thus indicating a propensity of the Aralsk strain to spread more easily than was “usual” in vaccinated hosts. That the number of smallpox victims is small does not negate this statistical conclusion.

Finally, Atlas and Clover make a mistake in assessing the effectiveness of vaccination in managing an outbreak when they say that “mass vaccination contained the outbreak,” but make no mention of quarantine. I emphasized in my analysis that the Aralsk authorities imposed a quarantine that was massive in scope and duration: no movement in and out of the city for many weeks, hundreds of inhabitants formally hospitalized in observation units, and restriction on movement of inhabitants within the city. Therefore, in Aralsk it was the combination of vaccination and quarantine that was effective in stemming the outbreak.

Woodall opines that importation of smallpox from Afghanistan (or somewhere along the well-established trade routes into the Central Asian portion of the then-Soviet Union) could have accounted for the outbreak. But since the Soviet Union had reported importations in 1961 and 1962 into Moscow (after indigenous smallpox had been declared eradicated before World War II), why not report the Aralsk outbreak if it was imported? After all, it was the Soviet Union that initiated the global smallpox eradication campaign in the first place, and key to its final success was the reporting of all cases, imported or indigenous.

Alternatively, Woodall posits the possibility of fomites (objects contaminated with variola virus, such as imported fabrics) as the cause of the outbreak. But epidemiologists looked for other cases of smallpox in the Aral Sea region and found none. I find it difficult to believe that smallpox would behave in this way; i.e., to present a small cluster of cases in complete isolation. The more reasonable explanation for the Aralsk outbreak is that a secret biological weapons test on Vozrozhdeniye Island was the source of the outbreak.

Woodall also wonders why the Official Report was so riddled with inconsistencies, opining that this was as a result of an effort to cover-up the real source of the outbreak. He then likened this alleged cover-up to the clumsily “written U.S. response to the Cuban allegation that an American aircraft had sprayed Thrips palmi insects over their island, which was so full of contradictions that it looked suspiciously like a badly designed cover-up”. Well, maybe so, but the difference is that the Cuban allegation has been authoritatively analyzed and found baseless[1] and, unlike the Soviet Union, the United States presented its version of how the Thrips episode occurred in an open, special session of states parties to the Biological Weapons Convention that was held in 1997. But, I agree with Woodall that there are puzzling aspects of the Official Report that require clarification. This is precisely why I, along with others[2], have called on our colleagues in Russia to provide answers to questions such as those posed by Woodall, as well as samples of the Aralsk smallpox strain. To date, they have not been forthcoming.

In summary, the statistical evidence strongly suggests that the strain of smallpox virus (or, perhaps, quasi-species) responsible for the Aralsk outbreak behaved differently than most strains recovered from earlier outbreaks in that the hemorrhagic manifestation was more common. Moreover, relative vaccine resistance may also have been in the nature of the Aralsk strain. The small numbers of cases involved in the outbreak are, of course, to be noted, but the statistical inferences are nonetheless robust. Given the epidemiology of the outbreak, the wind patterns, the likely infection of the index case on an ecological research vessel traveling down-wind of a secretive Soviet military bioweapons testing ground, and the absence of any other cases of smallpox in the region that could have provided a source for the epidemic, the origin of the Aralsk outbreak cannot be in doubt.

[1] Zilinskas R.A. “Cuban Allegations of Biological Warfare by the United States: Assessing the Evidence.” Critical Reviews in Microbiology 25(3):173–227 (1999).
[2] Lederberg, J., Monath, T., Jahrling, P., and Zelicoff, A.P. Letter to Lev A. Sandakchiev, Director of the All Russian Institute of Virology and Biotechnology (Vektor), Koltsovo, Russia, July 15, 2002.

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Peter B. Merkle, Ph.D., P.E.

Thank you for providing a forum for this type of “forensic epidemic analysis.” Dr. Zelicoff has done a great service by careful research of the actual circumstances of the outbreak. I think such studies are critical to meeting the many challenges of defending against biological warfare (BW) and bioterrorism. In all these matters, I commend the editors for your restraint with the press. Panic and fear will be equal adversaries to the virus itself if a new epidemic emerges.

I wanted to share my thoughts on this, especially regarding Dr. Zelicoff’s “unanswered questions.” The prevalence of hemorrhagic-type disease in a smallpox epidemic is not necessarily indicative of selection for virulence. In a 1945-46 hospital-centered outbreak among U.S. military personnel in Japan, Agerty reported 17 adult cases, with 10 fatalities of the hemorrhagic type. Many of the deceased had been vaccinated within three years of the outbreak, presumably with faulty technique or degraded vaccine, according to Agerty.[1] I analyzed this outbreak as reported, and supplied some figures and comments to Dr. Zelicoff after the New York Times article of June 15, 2002.[2] For the 1999 modeling study by John Bombardt I managed at DTRA[3], Dr. Horst Agerty was interviewed (then nearly a centenarian, but sharp as a tack). The outbreak he reported upon was extremely unusual. He noted that smallpox was endemic in the area among the local and transient population of post-war Japan.

Having 10 hemorrhagic cases out of 17 total in a hospital-centered outbreak is by any standard an outlier. I do not know why some outbreaks are more virulent than others, aside from the “host factors” reason that is the commonly accepted theory. Logically, the Agerty outbreak was either “natural” or “unnatural.” I have no reason to believe that the index case(s) were deliberately infected with a strain especially selected for virulence, or that the strain in circulation was somehow unnatural, other than pure conjecture. I do know that genetic technology to enhance the virus did not exist at that time. I must conclude that, absent new findings about smallpox in post-war Japan, there were a completely natural series of epidemics in progress. In comparison with the Agerty outbreak, I cannot conclude even qualitatively that the Aralsk outbreak involved “an especially virulent strain” with its 2 hemorrhagic cases out of 10 cases. Note that it is reasonable to assume that any BW program would select strains of any disease organism for virulence, if that indeed were the weapon’s intended characteristic.

In the context of the Aralsk smallpox virus strain, the “unanswered question” section comments that our reliance on a “single vaccine (unmodified vaccinia) represents a serious potential vulnerability.” However, all wild and thus presumed natural strains of smallpox virus were extinguished as epidemics by such vaccines, including the Agerty strain. It is regrettably unclear from this portion of the text if the implication is that the Aralsk strain, or perhaps others in the Soviet program, have been genetically modified to evade the vaccine, or that there were wild strains that were known to have overwhelmed potent vaccine when administered properly, repeatedly, and in advance of infection (as was done for WHO personnel in epidemic eradication). I defer to those with field experience in smallpox eradication on this point.

The “unanswered questions” section includes the statement “…the Soviets not only ‘weaponized’ smallpox but succeeded in aerosolizing it and, it appears, ‘hardening’ the virus so that it maintained its infectivity…” The vocabulary used here does not reflect the terminology of former offensive BW practitioners, to my knowledge. It implies that “weaponization,” “aerosolizing,” and “hardening” the virus are distinct activities. In fact, they are not. This same imprecise vocabulary caused a great deal of confusion during the anthrax mail attacks. The process of “weaponization” encompasses the entire process of strain selection, strain enhancement, and strain compatibility with aerosolization mixtures and environmental factors upon release. The text implies “weaponization” is something separate; is it solely this genetic modification or strain enhancement, as in “new forms never encountered”? Weaponization is not synonymous with genetic modification or even strain selection for virulence. As a process, it may include genetic modification. Aerosolizing the formulation is integral to the weaponization process, as is making the aerosol robust against environmental stress during dispersal. At its simplest, infecting someone with the variola virus and sending them to a target population or onto an airplane is “weaponization,” albeit nontechnical. I think this vocabulary issue is something that needs to be communicated to researchers in the policy field. Not understanding BW-related terminology can lead to tremendous misunderstandings and, in the press, outright mistaken reporting.

I must comment further on the statement “That smallpox is still with us is obvious, perhaps in forms we never encountered…” It is obvious that smallpox virus cultures exist in the two authorized repositories. To suggest that new unnatural forms exist is to suggest that someone has genetically modified the variola virus in some fashion, unless the contention is that natural outbreaks or reservoirs still exist where the smallpox virus is undergoing genetic change, or that undiscovered strains exist. I think the intended meaning is to suggest that genetic manipulation or assisted selection of some kind has taken place. I agree that this would be an extremely dangerous situation, yet I know of no public and substantiated reports of any specific individual or organization in any location having done so, or even holding an unauthorized natural variola virus culture today. I would welcome education on this point. If there is nonpublic information of this kind, I think that anyone not otherwise restricted should report it openly so that the threat may be addressed directly by the international community.[4]

References

[1] Agerty, H.A. “An Outbreak of Smallpox in American Military Personnel in Japan.” N Engl J Med 237:305-09 (1947).

[2] Merkle, P.B. ”Observations on Models and Outbreaks,” presentation to the 2002 DIMACS Working Group on Mathematical Sciences Methods for the Study of Deliberate Releases of Biological Agents and their Consequences, May 2002.

[3] Bombardt Jr., J.N. “Smallpox Transmission and BW Casualty Assessments,” Institute for Defense Analyses Paper P-3550 (Defense Threat Reduction Agency, Advanced Systems and Concepts Office, Fort Belvoir, VA, 2000).

[4] The opinions expressed here are the author’s own and do not necessarily represent those of the U.S. Government or the Sandia National Laboratory.

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