Animal Experimentation Issues

Poliomyelitis

Polio (short for poliomyelitis) is an example of how human clinical research, along with advancements in cellular research, led to the near eradication of an epidemic. The disease also points up the limitations of animal experiments, which were slow and cumbersome, and misled researchers.

Polio is a viral disease which reached its height in the U.S. in 1916, when cases numbered over 29,000.¹ The virus is contracted by mouth, and passes into the digestive tract. Initially, it produces a mild or symptomless systemic infection. At this stage, most people produce antibodies and eliminate the virus. In a small percentage of patients, the virus is not killed, and it spreads to the spinal cord and brain, causing fever, headache and stiffness, followed by mild to severe muscular weakness. Fatality can occur from respiratory paralysis. Treatment consists of supportive care, analgesics for muscle pain, and support for severely weakened muscles to prevent limb distortion. Convalescence can be prolonged and consists of muscle retraining and massage.

Prevention is available through two vaccine types: the Salk, or killed injectable vaccine, and the Sabin, or live attenuated oral vaccine.

Human Clinical Research Shows How the Disease Is Transmitted

Knowledge of the symptoms of poliomyelitis and its mode of transmission was obtained by studying human patients, beginning as far back as 1840, when Jacob von Heine provided the first detailed description of the disease.² Clinicians described two phases of the disease—systemic and neurologic—and found that systemic cases were often responsible for the spread of the disease from one person to another.¹

The virus was found in the contents and walls of human small intestines, suggesting transmission via the digestive tract.¹ Population studies led to the theory of naturally acquired immunity, which held that exposure to the virus causes immunity to later infection. Antibodies, indicating immunity to the poliovirus, were found in healthy and convalescing patients.¹

In 1948 and 1949, John Paul studied isolated Eskimo villages and determined that once immunity was gained (through a minor or symptomless infection), it persisted for years. A few years later, researchers at Johns Hopkins and Yale detected the virus in patients’ blood before neurological signs were seen.¹

Together, these human findings not only helped establish the route of transmission, but also indicated that more serious cases could be prevented, pointing the way to vaccine development.

Animal Experiments Give False Leads

Animal experiments in the early 1900s seriously misled researchers. Monkey experiments suggested that polio was transmitted via the nose, directly into the brain.^1,3 This was incorrect, and it caused scientists to overlook emerging human clinical research implicating the oral route of transmission. In 1937, researchers tried to prevent polio by spraying children’s noses with chemicals. The trial was failure, and some of the children lost their sense of smell permanently.⁴

Another false lead occurred when researchers immunized monkeys against polio by the intraspinal injection of serum from recovered monkeys. Variations of this technique were tried in people in 1910 and 1914. It wasn’t until 1931 that controlled human studies proved the futility of passive immunization for prevention or treatment.^1,3

Animal experiments also led to other vaccine failures. In 1934, John Kolmer of Philadelphia and Maurice Brodie’s group in New York City developed vaccines from infected monkey spinal cords. Of over 20,000 children vaccinated, twelve were paralyzed and six died. The vaccine was withdrawn.³ Progress might have been much faster without the confusing data provided by animal experimenters.

Experimenters who were working with the animal “model” of the disease cultivated the virus in monkey nerve tissue. This resulted in laboratory strains of virus which preferentially attacked the brain and spinal cord. Data obtained from these laboratory strains supported the incorrect concept of a direct nose-to-brain route of infection. Finally, in 1949, John Enders and his associates cultivated the virus in human non-nervous tissues, and discovered characteristic changes in the cells, which helped replace the older animal tests used to determine virus presence. They won the Nobel prize in 1954.⁵

Vaccines: Technology Evolves from Animal Experiments to Cellular Techniques

The Salk vaccine was developed in 1954 using killed poliovirus. The virus was isolated from humans and grown in monkey kidney cells.⁶ Tissue culture methods for determining whether a virus was completely killed were still under development at that time, so Salk tested the vaccine on live monkeys. Unfortunately, the vaccine, at first, was not as safe as one would have hoped. Of the 650,000 people who received the vaccine and their family contacts, over 200 contracted polio, causing eleven fatalities.³ Researchers now recommend cultivating the virus in human connective tissue cells. Human cell-derived vaccines are at least as effective as animal cell-derived vaccines, are less expensive, and eliminate the serious danger of animal virus contamination.⁷

The Sabin live vaccine followed in 1955. The vaccine uses a live virus which is modified in order not to cause disease. Originally the vaccine was grown in monkey kidney tissue and tested on monkeys and chimpanzees.⁸ Today, live vaccines can be produced using human cell culture,⁹ but Sabin vaccine manufacturers still test the vaccine to see if it causes polio by injecting it into the spinal cords of living monkeys. These tests are painful, time-consuming, and expensive, and do not perfectly predict human exposure risk.¹⁰ In fact, between 1973 and 1984, the Sabin vaccine caused 101 out of the 138 cases of paralytic poliomyelitis in the U.S.¹¹ Researchers have developed a laboratory method of determining safety which may provide a better test, based on the detection of virus mutations commonly associated with neurovirulence.¹²

The further researchers move away from reliance on non-human animal data for testing and production of vaccines, the safer the vaccines become. New research focuses on understanding the causes and treatment of post-polio syndrome, seen only in humans 25 to 35 years after the original attack.

Summary

Human clinical research was vital to the understanding of poliomyelitis. Case studies and human data provided a complete picture of the disease, including the nature of its transmission and the mechanisms of immunity. Based on this information, successful vaccines were developed.

Animal experimentation led to a faulty interpretation of disease transmission, sidetracked progress, and caused human injuries and even fatalities. Vaccines can now be produced and tested for safety using human cells in culture.

References
1. Dowling HF. Fighting Infection. Cambridge, Massachusetts, and London, England: Harvard University Press, 1977.
2. Paul JR. A History of Poliomyelitis. New Haven and London: Yale University Press, 1971.
3. Parish HJ. Victory with Vaccines. Edinburgh and London: E&S Livingstone Ltd., 1968.
4. Sabin AB. Oral poliovirus vaccine. JAMA 1965;194(8):872-6.
5. Enders JF, Weller TH, Robbins FC. Cultivation of the Lansing strain of poliomyelitis virus in cultures of various human embryonic tissues. Science 1949;109:85-7.
6. Salk JE. Studies in human subjects on active immunization against poliomyelitis. JAMA 1953;151(13)1081-98.
7. Hayflick L. Human virus vaccines: why monkey cells? Science 1972;176:813-4.
8. Ramsay AM, Emond RTD. Infectious Diseases. London: William Heinemann Medical Books Ltd., 1978.
9. Beale AJ. The use of tissue cultures for testing vaccines. J Royal Soc Med 1978;71:681-6.
10. Hennessen W. Replacement of animals in manufacture and control of vaccines. Develop Biol Standard 1980;45:163-73.
11. Murph JR, Grose C, McAndrew P, et al. Sabin inactivated trivalent poliovirus vaccine: first clinical trial and seroimmunity survey. Pediat Infect Dis J 1988;7(11):760-5.
12. Chumakov KM, Powers LB, Noonan KE, Roninson IB, Levenbook IS. Correlation between amount of virus with altered nucleotide sequence and the monkey test for acceptability of oral poliovirus vaccine. Proc Natl Acad Sci 1991;88:199-203.

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