Tag Archives: acellular

A Brief History of Pertussis Vaccines

Previously, I wrote about the dangers of attempting to protect an infant by cocooning (vaccinating all of his adult contacts against whooping cough), demonstrating how doing so actually increases the risk to the infant rather than decreasing it. I discussed how I’ve never been a fan of influenza or HPV vaccination, but how, due to research published primarily in the last couple years, I’ve come to feel similarly about pertussis vaccination.

Whooping cough deaths and cases dropped dramatically prior to introduction of the vaccine. They continued to drop after the introduction of the vaccine, decreasing by about 99% between the mid-1940s and 1970. Vaccination rates fell in concert with rising concerns about the safety of the DTP vaccine in the 1970s-1990s. However, vaccination rates have steadily risen since then and are now at an all-time high. Nevertheless, since the 1980s, the incidence has steadily increased in spite of simultaneously increasing rates of pertussis vaccination.

As I was reading studies and articles about the many possible explanations for this paradoxical increase, I came across what was to me a fascinating and detailed (and apparently award-winning) article authored by Dr. Geier, a former researcher at the National Institutes of Health (NIH) and advisor to the Centers for Disease Control and Prevention (CDC), about the history of pertussis vaccines. After reading it, I’m amazed at how much disinformation abounds on the internet about this topic! You may not be as fascinated by the topic as am I—in which case, you can skip this one and wait for my next blog post—but I found it so interesting that I summarized the article and filled in the few blanks from a few other sources. So without further ado, I present to you a brief history of pertussis vaccination.

 

And So It Starts

In 1906, researchers Bordet and Gengou developed a technique to grow B. pertussis in a laboratory, which paved the way for the creation of a pertussis vaccine. The first whole cell pertussis (wP) vaccine was produced by Bordet and Gengou in 1912 and by 1914, there were six U.S. manufacturers of pertussis vaccines. Pertussis vaccines sans formal testing were used sporadically between 1914 and 1925. The first clinical trials of wP vaccines were published in 1925 and 1933, with the 1933 study reporting serious adverse effects for the first time in its listing of two deaths that occurred within 48 hours of vaccination. The first modern wP vaccine, which was combined with diphtheria and tetanus toxoids, was created in 1942 by Dr. Pearl Kendrick. Because the wP vaccine does not inactivate endotoxin or pertussis toxin, it may be associated with some or all the side effects of pertussis infection from fever to seizures, shock, and death. Evidence of the dangerous side effects of the wP vaccine as compared to the aP vaccine were reported as early as the 1930s and considered conclusive by the 1950s, with the first deaths reported in 1933 and the first published reports of irreversible brain damage appearing in 1947 and 1948. By 1948, there were a dozen manufacturers of DPT. The “mouse toxicity test,” which essentially determined the toxicity of the vaccine by seeing how many mice died from it, was introduced to ensure licensure of safer vaccines; however, researchers concluded in 1963 that there was no correlation between mouse safety and human safety. From the late 1940s to the early 1960s, physicians continued to use wP vaccines because they had no other choice on the market and because manufacturers hid the presence of endotoxin in the vaccine and its associated risk. Vaccine manufacturers began a successful lobbying campaign of pediatric societies and state legislators in the 1940s, ultimately resulting in legislation requiring DTP vaccination prior to school entry in most states by the mid-1960s. However, with such widespread vaccination came the first published reports of irreversible brain damage and deaths resulting from the vaccine, with these reports being published almost every year from the early 1950s through the early 2000s, with additional published reports coming out of other countries. This causal relationship was deemed definite by a report from the National Institutes of Health (NIH) in 1963. Criticism of the wP vaccine due to its high rate of adverse effects, cited at 93% in a 1984 study, increased through the 1970s and peaked in the 1980s.

 

A Better Option?

The first aP vaccine was created in the 1920s and it was obvious from at least the 1930s that it was associated with fewer adverse events than the wP vaccine. Lederle Laboratories patented a new aP vaccine in 1937, which was shown clinically to be 94% protective against disease, making it significantly more effective than the wP vaccine, and was used widely in the 1940s. However, new federal laws were passed which would require expensive and labor-intensive efficacy testing of aP vaccines, and so Lederle ceased production of its more expensive but more effective and less reactogenic aP vaccine in 1948 and began producing a wP vaccine instead. Another aP vaccine was produced in 1954 but never licensed or marketed in the U.S. due to the higher cost of production and increased clinical trial requirements. Eli Lilly Company created an aP vaccine and named it Tri-Solgen. Tri-Solgen was associated with significantly fewer adverse reactions compared to wP vaccines and was sold widely from 1962-1977, at one point capturing up to 65% of the U.S. market for pertussis vaccines. Merck Sharp & Dohme produced another aP vaccine in 1960 which was found to be both safer and more effective than the wP vaccines, but ceased production by 1963 due to the cost. The following year, 1964, Merck also removed all wP vaccines from the market citing a fear of lawsuits due to damages caused by its wP vaccine because they had a safer and more effective aP product that didn’t sell. Many other aP vaccines were produced but never marketed due to their cost and to similar concerns about legal liability due to having a safer and more effective product (the aP vaccine) but continuing to sell the more dangerous and less effective product (the wP vaccine). Due to these concerns, the market severely contracted and only four manufacturers were still producing DTP vaccines by the 1970s. Lilly ceased production of all biologic products in 1975 and sold the rights to its high quality aP vaccine Tri-Solgen to Wyeth. However, the yield was low and when Wyeth reformulated it to increase its yield, the government required new safety and efficacy trials. Wyeth determined the cost, both financial and legally, wasn’t worth it and ceased production of Tri-Solgen; specifically, Wyeth’s concerns were the same as Merck’s had been—that the studies would show the aP Tri-Solgen to be safer and more effective than Wyeth’s wP vaccine, making them legally liable for continuing to market an inferior product. Hence, the only aP vaccine on the market became unavailable after 1977. By 1984, Wyeth also completely stopped production of pertussis vaccines, again due to concerns of legal liability from its failure to produce its safer product. The end result was that only two pertussis vaccine manufacturers remained in the U.S., and both produced only the wP vaccine.

 

Trouble in Paradise

In 1975, two babies in Japan died from DPT vaccination, and these were two of 37 SIDS deaths linked to vaccination; in response, the Japanese government initially banned the DTP vaccine, but later in the year resumed vaccination in children over age 2. The following year, 1976, the government sent Dr. Sato to the NIH to study aP vaccine production. His aP vaccine was tested between 1978 and 1981 and found to be nearly 100% effective and significantly less reactogenic, and so the Japanese government mandated switching to aP vaccination in 1981. During this period, infant deaths plummeted, bringing Japan from a high 17th place in world comparison of infant mortality rates to 1st place with the lowest infant mortality rate in the world. (Coincidentally, when they reintroduced vaccinations in children as young as 3 months of age in 1988, their SIDS rate quadrupled.)

Also in the 1970s, rising awareness of vaccine adverse effects led to a reduction in the pertussis vaccine compliance rate. Pertussis is an epidemic disease–i.e., there are periodic outbreaks every 3.3 years with low disease rates in the interepidemic periods–but the interepidemic period that correlated to the lowest pertussis vaccine compliance rates was an unusually long interepidemic period with the lowest whooping cough incidence on record. In the 1970s, the U.K. determined that the benefits of continued use of wP vaccination outweighed its risks, while Sweden determined the opposite, pointing out that no one had died from pertussis since 1970 and that the causal relationship between wP vaccines and encephalopathies was too great to ignore, and banned the wP vaccine. Most studies of efficacy look only at the ability of the vaccine to produce an antibody response—termed by some “research efficacy.” However, because the presence of antibodies does not necessarily correlate to immunity, a study of actual disease rates may be used to determine the ability of the vaccine to prevent disease—termed by some “clinical efficacy.” The wP vaccines were determined to be 45-48% clinically effective while the Japanese aP vaccines when tested in Sweden were found to be 55-69% clinically effective. Even when the Swedish scientists compared a two-dose regimen of aP vaccines to a five-dose regimen of wP vaccines, the aP vaccines were found to be more effective.

In the 1970s and 1980s in the U.S., several factors contributed to consideration of abandoning wP vaccination, including: the relative absence of whooping cough in the population; improvements in medical treatment of whooping cough; the serious adverse effects of the wP vaccine, which led to health clinics requiring parents to sign an informed consent prior to receiving a wP vaccine; several SIDS deaths in 1979 which the CDC deemed to be caused by a particular lot of the wP vaccine, causing the FDA to order a recall of the defective lot, followed by a reversal of the recall and efforts by manufacturers to prevent future recalls (e.g., Wyeth began spreading lots out across the country rather than sending an entire lot to one area so that adverse effects of any one lot would not be noticed as quickly in the future); and numerous lawsuits beginning in 1981 which were ironically successful because it was argued that the manufacturers had known how to produce a safer aP product but chose not to. (Unsuccessful lawsuits had been filed previously.) In 1982, a television program about the adverse effects of DPT vaccination raised parental awareness so much that attorneys trying the cases were flooded with hundreds of requests for representation. The vaccine manufacturers attempted to stop the cases by harassing the expert witnesses, leading at least one to file a suit against them. Nevertheless, by 1985, 219 such lawsuits had been filed. Pressure from parents and especially from a group formed in 1982 called Dissatisfied Parents Together led the American Academy of Pediatrics (AAP) to conduct over 8 months of hearings to develop recommendations for the creation of a federal compensation program for vaccine-injured children. Due to the AAP’s recommendations and to the large-scale civil litigation against vaccine manufacturers, Congress introduced the National Compensation Act in 1983, which sought to limit liability for vaccine injuries. One manufacturer agreed to settle out of court for $26 million and then cite its case as an example of why the act was needed. In 1986, the U.S. Congress passed the National Vaccine Injury Act, which established, among other things, the National Vaccine Injury Compensation Program (NVICP) and essentially ended litigation against vaccine manufacturers. However, with the threat of litigation gone, manufacturers were no longer under pressure to produce a safer aP vaccine. Foreseeing that this would happen, the Congress also stipulated in the Act that the IOM hold hearings and make recommendations for improving vaccines in general and the pertussis vaccine specifically.

 

Safety Wins

As previously stated, the causal link between DPT and neurological sequelae was deemed definite by the NIH in 1963. However, after receiving several generous donations from vaccine manufacturers and being staffed and/or headed by former and current employees of vaccine manufacturers, the AAP and the Pediatric Neurology Society “mysteriously” reported in 1992 that there was no such link. This was followed by several heavily manufacturer-funded researchers publishing articles that also attempted to deny the link. Backing up a few years, we’ll examine what the government saw. In 1985, the Institute of Medicine (IOM) published a report stating, among other things, that in spite of its initially higher costs, the aP vaccine saves on overall medical costs as compared to the wP vaccine, and the United States would save millions of dollars if the wP vaccine was replaced by the aP vaccine due to the high rate of adverse reactions; it advised that the highest priority should be given to making the switch. However, this recommendation was put on the back shelf and when another IOM committee convened in 1990, only five years later, they were surprised to learn that data presented in the meeting came from their own archives. Nevertheless, the evidence against the wP vaccine was so overwhelming that, regardless of the opinions of those bought by the manufacturers, the IOM determined that the causal link between wP vaccination and encephalitis was definite. The IOM convened a third time in 1993 to again discuss the DTP vaccine and determined that it definitely causes permanent brain damage. Even the AAP failed to argue the point, instead merely notifying its members of the IOM’s position. In 1992, the FDA approved the use of aP for the boosters given at 18 months and 6 years of age. In 1996, the FDA approved the use of aP for the entire schedule. Finally, by the beginning of 2001, the wP vaccine had been removed from the U.S. market, though American manufacturers continue to produce the cheaper (in every sense of the word) wP vaccines for sale in the third world.

 

“The development and acceptance of acellular pertussis vaccine in the United States demonstrates that scientific evidence alone is not always enough to change harmful medical practices. Given the powerful resistance to change demonstrated by the pharmaceutical industry, it took years of litigation, consumer advocacy, international scientific development, and congressional action to create a new norm for childhood immunization. It would seem that open discussion of vaccine problems in the scientific and medical communities, along with policies that preclude those with a conflict of interest from determining vaccine policy, might help to prevent similar difficulties in the future in the rapidly expanding vaccination field.” (Geier & Geier, 2002, p. 284]

 

 

References

Centers for Disease Control and Prevention (1997). “Vaccination: Use of acellular pertussis vaccines among infants and young children recommendations of the Advisory Committee on Immunization Practices (ACIP).” Morbidity and Mortality Weekly Report, 46(RR-7):1-25. Retrieved from <http://www.cdc.gov/mmwr/preview/mmwrhtml/00048610.htm >.

Fine, P.E.M., & Clarkson, J.A. (1982). “The recurrence of whooping cough: Possible implications for assessment of vaccine efficacy.” The Lancet, 319(8273):666-669. doi: 10.1016/S0140-6736(82)92214-0.

Geier, D., & Geier, M. (2002). “The true story of pertussis vaccination: A sordid legacy?” Journal of the History of Medicine, 57:249-284. Retrieved from <http://www.researchgate.net/publication/11177062_The_true_story_of_pertussis_vaccination_A_sordid_legacy >.

Hieb, L. (2015). “How vaccine hysteria could spark totalitarian nightmare.” WND. Retrieved from <http://www.wnd.com/2015/02/how-vaccine-hysteria-could-spark-totalitarian-nightmare/ >.

Howson, C.P., Howe, C.J., Fineberg, H.V., eds. (1991). “B pertussis and rubella vaccines: A brief chronology.” In Adverse Effects of Pertussis and Rubella Vaccines: A Report of the Committee to Review the Adverse Consequences of Pertussis and Rubella Vaccines. Institute of Medicine Committee to Review the Adverse Consequences of Pertussis and Rubella Vaccines. Retrieved from <http://www.ncbi.nlm.nih.gov/books/NBK234365/ >.