The public health danger posed by potentially pandemic-causing viruses escaping from laboratories has become the subject of considerable discussion, spurred by “gain of function” experiments. The ostensible goal of these experiments—in which researchers manipulate already-dangerous pathogens to create or increase communicability among humans—is to develop tools to monitor the natural emergence of pandemic strains. Opponents, however, warn in a variety of recent research papers that the risk of laboratory escape of these high-consequence pathogens far outweighs any potential advance.
The danger of a manmade pandemic sparked by a laboratory escape is not hypothetical: One occurred in 1977, and it occurred because of concern that a natural pandemic was imminent. Many other laboratory escapes of high-consequence pathogens have occurred, resulting in transmission beyond laboratory personnel. Ironically, these laboratories were working with pathogens to prevent the very outbreaks they ultimately caused. For that reason, the tragic consequences have been called “self-fulfilling prophecies.”
Modern genetic analysis allows pathogens to be precisely identified, and because all circulating pathogens show genetic changes over time, the year that a particular example of a pathogen emerged can generally be determined, given a sufficient database of samples. If a pathogen appears in nature after not circulating for years or decades, it may be assumed to have escaped from a laboratory where it had been stored inert for many years, accumulating no genetic changes—that is, its natural evolution had been frozen.
The swine flu scare of 1976 and the H1N1 human influenza pandemic of 1977. Human H1N1 influenza virus appeared with the 1918 global pandemic and persisted, slowly accumulating small genetic changes, until 1957, when it appeared to go extinct after the H2N2 pandemic virus appeared. In 1976, H1N1 swine influenza virus struck Fort Dix, N.J., causing 13 hospitalizations and one death. The specter of a reprise of the deadly 1918 pandemic triggered an unprecedented effort to immunize all Americans. No swine H1N1 pandemic materialized, however, and complications of immunization truncated the program after 48 million immunizations, which eventually caused 25 deaths.
Human H1N1 virus reappeared in 1977, in the Soviet Union and China. Virologists, using serologic and early genetic tests, soon began to suggest the cause of the reappearance was a laboratory escape of a 1949-50 virus, and as genomic techniques advanced, it became clear that this was true. By 2010, researchers published it as fact: “The most famous case of a released laboratory strain is the re-emergent H1N1 influenza-A virus which was first observed in China in May of 1977 and in Russia shortly thereafter.” The virus may have escaped from a lab attempting to prepare an attenuated H1N1 vaccine in response to the U.S. swine flu pandemic alert.
The 1977 pandemic spread rapidly worldwide but was limited to those under 20 years of age: Older persons were immune from exposures before 1957. Its attack rate was high (20 to 70 percent) in schools and military camps, but mercifully it caused mild disease, and fatalities were few. It continued to circulate until 2009, when the pH1N1 virus replaced it. There has been virtually no public awareness of the 1977 H1N1 pandemic and its laboratory origins, despite the clear analogy to current concern about a potential H5N1 or H7N9 avian influenza pandemic and “gain of function” experiments. The consequences of escape of a highly lethal avian virus with enhanced transmissibility would almost certainly be much graver than the 1977 escape of a “seasonal,” possibly attenuated strain to a population with substantial existing immunity.
Smallpox releases in Great Britain. Eradication of natural smallpox transmission made the prospect of reintroduction of the virus intolerable. This risk was clearly demonstrated in the United Kingdom. From 1963-78 the U.K. saw only four cases of smallpox (with no deaths) occurred that were imported by travelers from areas where smallpox was endemic. During this same period at least 80 cases and three deaths resulted from three separate escapes from two different accredited smallpox laboratories.
The first recognized laboratory escape, in March 1972, occurred with the infection of a laboratory assistant at the London School of Hygiene and Tropical Medicine. She had observed the harvesting of live smallpox virus from eggs used as a growing medium; the process was performed on an uncontained lab table, as was then routine. She was hospitalized, but before she was placed in isolation, she infected two visitors to a patient in an adjacent bed, both of whom died. They in turn infected a nurse, who survived, as did the laboratory assistant.
In August of 1978, a medical photographer at Birmingham Medical School developed smallpox and died. She infected her mother, who survived. Her workplace was immediately above the smallpox laboratory at Birmingham Medical School. Faulty ventilation and shortcomings in technique were ultimately implicated.
Investigators then re-examined a 1966 smallpox outbreak, which was strikingly similar. The initial 1966 infection was also a medical photographer who worked at the same Birmingham Medical School facility. The earlier outbreak was caused by a low-virulence strain of smallpox (variola minor), and it caused at least 72 subsequent cases. There were no deaths. Laboratory logs revealed variola minor had been manipulated in the smallpox laboratory at a time appropriate to cause the infection in the photographer working a floor above.
Venezuelan equine encephalitis in 1995. Venezuelan equine encephalitis is a viral disease transmitted by mosquitoes. It intermittently erupts in regional or continental-scale outbreaks that involve equines (horses, donkeys, and mules) in the Western Hemisphere. There are often concurrent zoonotic epidemics among humans. VEE in humans causes a severe febrile illness; it can occasionally be fatal or may leave permanent neurological disability (epilepsy, paralysis, or mental retardation) in 4 to 14 percent of clinical cases, particularly those involving children.
There were significant outbreaks of VEE every few years from the 1930s to the 1970s. Modern analysis revealed most outbreaks were genetic matches to the original 1938 VEE isolation used in inactivated veterinary vaccines. It was clear that many batches of the veterinary VEE vaccines had not been completely inactivated, so residual infective virus remained.
From 1938 to 1972, the VEE vaccine caused most of the very outbreaks that it was called upon to prevent, a clear self-fulfilling prophecy.
In 1995 a major VEE animal and human outbreak struck Venezuela and Colombia. There were at least 10,000 human VEE cases with 11 deaths in Venezuela and an estimated 75,000 human cases in Colombia, with 3,000 neurological complications and 300 deaths. VEE virus was isolated from 10 stillborn or miscarried human fetuses.
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