Selected Quotes from Vaccines

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Taken from: "Polio - Historical" by Frederic C. Robbins, M.D., in the 1988 edition of Vaccines a.k.a. "The History of Polio Vaccine Development" in Vaccines, 1999.

Pretissue Culture Era

In the 40-year interval from the isolation of the virus in monkeys to the development of tissue culture techniques, considerable progress was made in understanding the disease.  Evidence was presented to suggest that the virus multiplied in the gastrointestinal tract and that infection could be transferred by the fecal-oral route.  Monkeys had been shown to develop immunity to challenge with active virus, and the various efforts had been made to prepare experimental vaccines.  The starting material was infected monkey central nervous system tissue treated in a variety of ways.  Although some success was reported the experiments were inconsistent, and the results were disappointing overall.  In spite of the ambiguous animal data, two investigators, in 1936, independently conducted field trials in children and some adults of vaccines prepared form monkey spinal cord.  Brodie and Park used a formalin-treated preparation, whereas Kolmer treated the spinal cord suspension with ricinoleate in order to "attenuate" the virus.  Kolmer made the assumption that it was necessary to use live virus in order to achieve immunity.  By modern standards, these trials were ill conceived.  The scientific base was woefully inadequate to justify human trials.  Appropriate tests for safety and efficacy were lacking, and, indeed, there seems to have been little concern for the known risk attendant with injection of central nervous system tissue.  Furthermore, it was not yet known whether or not there was more than one type of poliovirus, and there was no readily available means to diagnose infection.  Thousands of subjects received these vaccines, some of whom developed paralysis soon after inoculation, often in the inoculated limb.  These findings raised the specter of persistence of live virulent virus in the vaccine, and the trials were terminated.

The Cutter Episode

Interest in the vaccine was high, and many communities organized specific programs, which obtained widespread coverage.  However, not long after the vaccine had become general available, cases of paralytic disease were reported in recipients.  On the basis of the time between vaccine and onset of disease and the fact that paralysis usually occurred in the inoculated limb, it was suspected that these cases were due to active virus in the vaccine.  Epidemiological investigation revealed that almost all the cases occurred in children who had received vaccine made by the same manufacturer - Cutter.  On further investigation, it was established that certain lots of Cutter vaccine were particularly implicated.

The Public Health Service immediately suspended vaccination, recalled the Cutter vaccine and launched an intensive investigation, including a careful review of the regulations governing the manufacture of vaccine and the techniques employed by the companies.  Active virus was isolated from a number of vaccine lots.  As a result, new requirements were introduced for safety testing along with a filtration step.  With these relatively modest changes, the problem was solved, and no untoward reactions for the inactivated vaccine have since been observed.

Fortunately, Cutter produced the smallest amount of vaccine of any of the manufacturers, and the products of the other companies proved to be safe.  Nonetheless, 260 cases of poliomyelitis were identified as being due to the Cutter vaccine.  Of these, 94 were in vaccinees, 126 were in family contacts and 40 were in community contacts.  Of the 260 cases, 192 were paralytic; there were no deaths.  Surprisingly, the "Cutter incident" did not shake public confidence in the vaccine, and when vaccination was resumed, it was well accepted.  The outcome might have been very different if the product of just one other manufacturer had proved to be unsafe.

Live Attenuated Vaccines

The idea of attenuated vaccines as opposed to killed vaccines appealed to many investigators, because it was presumed that an active infection most nearly reproduced the natural situation and could be expected to give longer-lasting immunity and greater resistance of the bowel to reinfection.

It was demonstrated in Enders' laboratory that the polioviruses lost virulence for the central nervous system upon passage in non-nervous tissues.

An important point at issue was the genetic stability of the vaccine strains - would they revert to virulence after multiplying in the human host? Unfortunately, few in vitro markers of virulence, such as growth at higher temperature, were available, and these were not particularly precise.  The most definitive test for neurovirulence was considered to be inoculation of monkeys intracerebrally or directly into the spinal cord.  Although expensive and requiring expert interpretation, the monkey test was adopted as the definitive one for neurovirulence by the regulatory agencies.

Field trials of increasingly large size were conducted with the various candidate strains in different parts of the world.  It was difficult to conduct large-scale trials in the United States because the Salk vaccine had been licensed and was being used widely; therefore, only a few trials were done there.  Originally, the different types were fed separately, because some degree of interference occurred among them.  However, it was later found that by adjusting the amounts, virus interference could be overcome to a large extent, and a trivalent vaccine became possible.

The Simian Virus 40 (SV40) Episode

In 1960, Sweet and Hilleman described the isolation from cultures of rhesus monkey kidney cells of a virus that caused a typical vacuolation in cells from cynomolgus monkeys.  The virus, simian virus 40 (SV40) was found to cause an inapparent infection of rhesus monkeys in nature.  It remained latent in the kidney cells until activated in tissue culture and could be detected only by testing cultures of cells from a susceptible species.  It was found to be a contaminant of many lots of both inactivated and live vaccines.  SV40's inactivation curve with formaldehyde was such that some active virus might survive an exposure that was fully adequate to inactivate poliovirus.  Once the presence of the contaminating virus was recognized, proper measures were taken to assure its exclusion from the vaccine.  However, this finding did cause a great deal of concern, sing SV40 was a DNA virus of the papova virus family and had been show to cause cancer in several species of animals and to transform cells in culture.  Evidence was presented that some persons who received contaminated poliovirus vaccines orally or parenterally developed antibodies to SV40 and, occasionally, virus was isolated from the feces of recipients of oral polio vaccine (OPV).  There were similar findings in volunteer subjects who had received SV40 by the respiratory route.  Recent evidence indicates that in some populations, antibodies to SV40 are present in sera collected before poliovirus vaccines had been available, suggesting that the antibodies were evoked by natural infection with related viruses.  Two epidemiological approaches have been taken in the assessment of whether or not SV40-contaminated vaccine causes any deleterious effects in recipients.  Fraumeni, Ederer and Miller compared the causes of mortality, particularly from cancer, of populations that had presumably received SV40-contaminated vaccine with those that had not.  No differences of any kind were found. (For a partial review of the literature on SV40, click here.)  In addition, prospective surveillance of a cohort of approximately 1077 infants who received contaminated OPV in the first days of life and 150 who received killed polio vaccine (KPV) intramuscularly, containing SV40 has revealed no excessive incidence of cancer or mortality due to any other cause during an observation period of 17-19 years.  These findings, although not absolute proof of the benignity of SV40 in humans, are reassuring, and it seems highly unlikely that SV40 is carcinogenic or otherwise pathogenic for humans.  (Note: Unfortunately these sanguine remarks are arguable.)  However, this experience has clearly demonstrated one of the problems associated with the use of primary cell cultures for the production of vaccines and biologicals for use in humans. 

KPV Versus OPV

When the live (OPV) vaccine became available, this prompted a comparison with the KPV already in use. The principal points raised were the following:

1.  KPV had been used widely for approximately 6 years and had proved to be safe and effective.

2.  OPV was less expensive and much simpler to administer.  Thus, it was more suitable for mass campaigns and programs directed at difficult-to-reach populations than the KPV, which had to be administered by injection, with a required four-dose schedule.

3.  The principal disadvantage of OPV was its relative lability, compared with KPV, at temperatures above freezing.  There was also concern that it would not be effective in the presence of an enterovirus infection.

4.  Early evidence indicated that whereas both vaccines gave satisfactory protection against paralytic disease, the active infection of the bowel that occurred with OPV, on the one hand, resulted in resistance to reinfection more similar to that of natural infection.  KPV, on the other hand, seemed to produce little resistance to intestinal infection. Thus, OPV could be expected to be more effective than KPV in interrupting the spread of the virus within the community.  A side benefit of OPV was thought to be spread of the vaccine virus from vaccinees to susceptible contacts, thus amplifying its effect.

5.  In spite of the evidence from the 1954 field trial of the effectiveness of KPV, there was some concern that in the interval from 1955, when KPV was licensed, to 1961, when OPV became available, that outbreaks of paralytic disease were still occurring.  Thus, some questions were raised about the true effectiveness of KPV as produced and used in the United States, and, indeed, Berkovich, Pickering and Kibrick presented evidence that the 1959 epidemic of polio in Boston was likely due to the use of vaccine of low potency.

In 1962, recommendations of the Public Health Service for the use of poliomyelitis vaccine for the 1962 poliomyelitis season were issued by they Surgeon General of the United States Public Health Service, Luther Terry.  The relative advantages of OPV and inactivated polio vaccine (IPV) were enumerated, but neither vaccine was recommended to the exclusion of the other.  However, OPV was soon being given almost exclusively in the United States.  By 1964, the Committee on the Control of Infectious Disease of the American Academy of Pediatrics expressed a clear preference for OPV. To quote, "...evaluation of the virtues and limitations of killed and live poliovaccines reveals a clearcut superiority of the OPV from the point of view of ease of administration, immunogenic effect, protective capacity, and potential for the eradication of poliomyelitis."

As indicated previously, the U.S.S.R. had determined at an earlier time to use OPV exclusively, and most of the countries in the world did the same.  However, Sweden, Finland and Holland chose to administer only KPV and thus provided an interesting population for comparison of the effectiveness of KPV and OPV.  In the early years of OPV use, monotypic vaccines were used in sequence -1,3 and 2 at 6-week or 2 month intervals followed by 6 months later a dose of trivalent vaccine.  Later, the trivalent was found to e adequate, and a simplified regimen of three doses of trivalent at 2-month intervals beginning at 2 months of age, simultaneously with the first inoculation of DPT, was adopted in the United States.  A fourth dose of trivalent oral poliovirus vaccine (TOPV) approximately 1 year later completed the series, and a fifth dose was administered on entry to school.

OPV-Associated Disease

From the data of the WHO study and that gathered in the United States by they Centers for Disease Control, rough estimates of the risk of paralysis to vaccinees and contacts can be made.  Based on the number of doses of vaccine distributed, the risk to recipients and contacts is well below one case per 1 million doses.  However, when one examines the risk from the first dose compared with that of subsequent doses, the rise is considerably higher from the first dose (one case per 500,000 doses administered for recipients and contacts) than from subsequent doses (one case per 13 million doses).  Thus, OPV does pose a small risk to recipients of the vaccine and their nonimmune intimate contacts, most of whom are adults.

It (the previous discussion) has also raised the question as to whether or not OPV induces as effective and long-lasting intestinal immunity as is generally believed.