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What is the history of Diphtheria vaccine use in America?
Prior to a vaccine for diphtheria, one of the first treatments of diphtheria was a horse-derived antitoxin developed in the 1890s. This antitoxin was made by injecting the diphtheria toxin into horses to produce an antibody response. Blood was then drawn from the horses and the antitoxin serum was separated and purified for use in humans. The H.K. Mulford Company of Philadelphia was the first U.S. company to develop diphtheria antitoxin for commercial use.
The diphtheria antitoxin, however, only produced short-term immunity, and in certain individuals, the injections resulted in fever, rash, joint pain, and anaphylaxis. This adverse reaction was referred to as “serum sickness” and seen in persons who received multiple doses of antitoxin. In 1913, Dr. Bela Schick introduced the Schick test, a procedure which involved injecting a small amount of diphtheria toxin in a solution into the arm to determine the necessity of the antitoxin. If redness at the injection site occurred, the use of the antitoxin was indicated.
The first vaccine against diphtheria was developed by William Park of the New York City Health Department. Park combined the diphtheria antitoxin with diphtheria toxin and this combination was reportedly capable of triggering an antibody response. The use of this product, however, was questioned in the medical literature at the time due to reports of failure and harm. Serious side effects included serum sickness, anaphylaxis and even death.
In 1923, two independent researchers, Gaston Ramon and Alexander Thomas Glenny, developed a method to inactivate the diphtheria toxin. This product, known as the diphtheria toxoid (DAT), was considered inferior to the toxin-antitoxin (TAT) because it did not produce a strong immune response. Ramon also discovered that the use of formalin could decrease the toxic properties of the diphtheria toxoid while still maintaining its immunogenicity. In 1926, Glenny and his colleagues discovered that adding the diphtheria antigen to alum (aluminum potassium sulphate) would enhance the immune response.
In 1930, government officials reported that while widespread vaccination programs were occurring in some areas, other areas had few programs. However, after 1925, diphtheria morbidity and mortality rates decreased in all U.S. states at the same time. Public health officials reviewing the decline in diphtheria morbidity and mortality reported that:
“The great decline in mortality, the early date at which it was manifested, and the widespread area over which it has been experienced, all go to indicate that it is attributable largely to causes other than specific treatment and immunization. The remarkable reduction in morbidity and mortality since 1927, if viewed as a separate phenomenon, might be attributed in part at least to artificial immunization. That this has been a major factor, however, would seem to be quite improbable, as the recent acceleration of the decline has likewise been experienced over a wide area and, even in many cities in which immunization has been most extensively practised, the reduction has been far greater than can be satisfactorily explained by the numbers of persons immunized. Viewing all the available facts, the conclusion seems inevitable that other factors have played a major role.”
In the mid 1940’s, the diphtheria toxoid was combined with tetanus toxoid to create the tetanus- diphtheria (Td) toxoid vaccine and additionally combined with whole cell pertussis to create the diphtheria-tetanus-pertussis vaccine (DTP). The newly created DTP combination vaccine was then absorbed onto aluminum salts when researchers discovered aluminum’s ability to enhance blood immune responses to both diphtheria and tetanus. Numerous companies held licenses for tetanus toxoid vaccines in the mid 1940’s, however, product licensing was not indicative of product endorsement. Safety, purity, and potency (if tests were available to determine potency) were tested as part of licensing approval, however, product efficacy was not, and not required for product licensing. Companies that held tetanus toxoid vaccine licenses in 1945 included Parke Davis and Co., Sharp and Dohme, Cutter Laboratories, Lederle Laboratories and more.
A diphtheria toxoid improperly manufactured by a Japanese pharmaceutical company in 1948 resulted in the toxoid reversing to toxin. Many children were harmed and killed because of this error. This disaster prompted vaccine manufacturers to put procedures into place to prevent a reoccurrence of this event.
In 1966, the Public Health Service Advisory Committee on Immunization Practices (now the CDC’s Advisory Committee on Immunization Practices) published its first tetanus, diphtheria and pertussis vaccine recommendations and guidance for tetanus disease prevention pertaining to wound management. In this report, the Advisory Committee on Immunization Practices (ACIP) formally recommended that all infants receive three doses of diphtheria, tetanus, and pertussis vaccine (DTP) beginning between two and three months of age at intervals of four to six weeks. Additional booster doses were recommended at one year of age and between the age of three and six years, preferably prior to school entry.
School children and adults not previously vaccinated with DTP were recommended to receive two doses of tetanus-diphtheria (Td) vaccine at four to six weeks intervals with a booster dose one year later, and routine booster doses every 10 years. The Td vaccine was recommended for use among schoolchildren and adults instead of the DTP vaccine. This recommendation was made due to the significant increase in adverse reactions that occurred with age following full doses of the diphtheria toxoid found in the DTP vaccine.
In September of 1984, ACIP published its first adult vaccination guidelines. In this publication, adults not previously vaccinated with diphtheria toxoid vaccine were recommended to receive two doses of Td vaccine at least four weeks apart, followed by a booster dose one year later and routine booster doses every 10 years. In the case of wound management, Td vaccine was recommended if a person had not received a Td vaccine within five years. Persons previously vaccinated with the DTP primary series were recommended to receive the first booster dose of Td vaccine between the age of 14 and 16.
The FDA approved the first acellular pertussis combination vaccine (DTaP) for use in the United States in 1991, however, between 1991 and 1996, the whole cell diphtheria, tetanus, and pertussis (DPT) vaccine continued to be recommended for the first three primary doses at two, four, and six months of age. The DTaP vaccine was only approved for use in children between the ages of 15 months and six years after completion of three primary doses of DPT.
In 1995, the American Academy of Pediatrics (AAP) and ACIP published a harmonized childhood vaccine schedule and decreased the recommended age of the adolescent booster dose of tetanus-diphtheria (Td) vaccine from 14-16 years, to age 11-12 years. ACIP stated that lowering the recommended age of the Td booster dose to 11-12 years of age would encourage a routine preadolescent healthcare visit where health care practitioners could administer additional vaccines such as a second MMR dose, recommended in 1989 following a resurgence in measles cases related to MMR vaccine failure, and the hepatitis B vaccine, in children not previously vaccinated.
In 1997, ACIP updated its diphtheria, tetanus, and acellular pertussis vaccine (DTaP) recommendation, and recommended that all children receive five doses of DTaP vaccine, at two, four, six, 15-18 months and four to six years of age, in lieu of the highly reactive whole cell DPT vaccine.
In 2005, the FDA approved two tetanus, diphtheria and acellular pertussis vaccines (Tdap), targeting adolescents and adults. Boostrix vaccine received initial approval for use in persons between 10 and 18 years of age, and Adacel received approval for use in individuals aged 11 through 64 years. Following FDA approval, ACIP promptly recommended that all 11-12-year old receive a dose of Tdap vaccine. This recommendation was made in response to the high number of pertussis cases and outbreaks occurring among adolescents due to the waning of vaccine acquired pertussis immunity.
ACIP also recommended that all 11 to 18-year-old adolescents receive a dose of Tdap, including those already vaccinated with the previously recommended booster dose of tetanus-diphtheria (Td) vaccine at age 11-12. While a five-year interval between Tdap and Td vaccine administration was recommended due to the increased risk of both local and systemic reactions, ACIP stated that vaccination at an interval of less than five years was still acceptable. Additionally, ACIP encouraged health care practitioners to administer the newly approved Tdap vaccine at the same time as the newly licensed meningococcal conjugate vaccine (MCV4). This recommendation was made even though no safety or immunogenicity data existed to support the administration of both vaccines simultaneously.
In 2006, ACIP recommended that all adults between the ages of 19 and 65 years receive a dose of Tdap vaccine. The Tdap vaccine was recommended as a one-time dose in lieu of the Td vaccine and administered if more than 10 years had passed since administration of Td vaccine. ACIP, however, reported that the Tdap vaccine could be administered at an earlier interval, to protect a person against pertussis. In their report, they also admitted that pre-licensing clinical trials of Adacel vaccine, the only Tdap vaccine FDA approved at the time for use in adults between 19 and 64 years of age, had purposely excluded all persons previously vaccinated with any vaccine containing tetanus or diphtheria toxoid and/or pertussis vaccine within the preceding five years, and that it was not known if vaccinating at an earlier interval than 10 years was actually safe.
ACIP also acknowledged that adult safety studies of Adacel vaccine were not enough to be able to detect rare adverse events that might occur following vaccination. Tdap vaccine was also recommended for all women of childbearing age, and vaccination was encouraged prior to pregnancy or immediately postpartum. Additionally, all health care providers with direct patient contact were also recommended to receive Tdap vaccine if at least 2 years had passed since a previous dose of Td vaccine had been administered.
In October of 2012, ACIP recommended that all pregnant women receive a Tdap vaccine during each pregnancy, between 27 and 36 weeks gestation. At the time of this recommendation, ACIP acknowledged that “a theoretical risk exists for severe local reactions” in pregnant women vaccinated frequently due to multiple pregnancies spaced closely together, but reported that current tetanus toxoid containing vaccines contained less tetanus toxin than previously recommended tetanus toxoid vaccines and stated that “the potential benefit of preventing pertussis morbidity and mortality in infants outweighs the theoretical concerns of possible severe adverse events.”
In this recommendation, ACIP also acknowledged that no studies had ever examined the safety of administering Tdap vaccine to pregnant women during subsequent pregnancies, but reported that going forward, they planned to monitor both the Vaccine Adverse Events Reporting System (VAERS) and the Vaccine Safety Datalink (VSD) to assess for adverse events, maternal adverse pregnancy outcomes and birth outcomes.
The CDC currently recommends that all children receive five doses of diphtheria, tetanus, and acellular pertussis vaccine (DTaP) at two, four, six, 15-18 months, and four to six years, with an adolescent booster dose of tetanus, diphtheria, and acellular pertussis vaccine (Tdap) at age 11-12. Adults not previous vaccinated with Tdap are recommended to receive one dose of the vaccine, and then continue to receive booster doses of tetanus-diphtheria (Td) vaccine or Tdap vaccine every 10 years. All pregnant women are recommended to receive a Tdap vaccine between 27- and 36-weeks’ gestation, during each pregnancy, regardless of any previous Tdap vaccination.
In 2017, the CDC reported that 94 percent of all 19 to 35-month-old children had received at least three doses of the diphtheria toxoid containing DTaP vaccine and 83 percent had received at least four DTaP vaccine doses. Also in 2017, the CDC reported that 88.5 percent of all adolescents had received a booster dose of Tdap vaccine.
IMPORTANT NOTE: NVIC encourages you to become fully informed about Diphtheria and the Diphtheria vaccine by reading all sections in the Table of Contents, which contain many links and resources such as the manufacturer product information inserts, and to speak with one or more trusted health care professionals before making a vaccination decision for yourself or your child. This information is for educational purposes only and is not intended as medical advice.