A Look at Each Vaccine: Diphtheria, Tetanus and Pertussis Vaccines

Diphtheria, tetanus and pertussis are prevented by a childhood vaccine, called DTaP, and a vaccine for adolescents and adults, called Tdap. A version for adults is also available without the pertussis component, called Td.

The diseases

Diphtheria

What is diphtheria?

The dangers associated with diphtheria come from the toxin released by the bacterium, Corynebacterium diphtheriae. The toxin makes it difficult for children to breathe and swallow, but it also attacks the heart, kidneys and nerves.

Incidence of diphtheria

In the 1920s, diphtheria was a common cause of death in children and adolescents. At its peak, about 150,000 cases of diphtheria occurred in the United States every year. The diphtheria vaccine, first used in the United States in the early 1940s, has virtually eliminated the disease. Now we see fewer than two cases a year.

Outbreaks still occur around the world and typically coincide with a drop in immunization rates.

Tetanus

What is tetanus?

Tetanus is another disease caused by a toxin-releasing bacterium, Clostridium tetani. Unlike most vaccine-preventable diseases, tetanus is not a disease that you catch from someone else. The bacteria live in the soil and usually enter the body following punctures or wounds that are not kept clean or include damaged tissues such as from burns, frostbite, or gangrene. Items likely to be contaminated with the tetanus bacteria include nails or pieces of glass that were lying on the ground.  

Given the playful, adventurous, and oftentimes injury-prone nature of children, it's important to immunize them against tetanus. Hand washing and bathing do little once the bacteria actually get under the skin.

Once under the skin, the bacteria make a toxin that causes muscle spasms. If these spasms affect the throat and jaw (lockjaw), they can interfere with breathing, causing suffocation. The tetanus toxin can also damage the heart.

Because of its presence in the environment and the noninfectious nature of this disease, eradication will not be possible through vaccination. Further, people cannot be protected from this disease because everyone around them has had a vaccine; that is, there is no protection from herd immunity.

Two populations most affected by tetanus

In developed countries tetanus is typically thought of as infecting wounds in adults who have injured themselves; however, in the developing world many infants suffer from neonatal tetanus. Infections in newborns result from poor sanitation either during or after delivery. Efforts to eliminate infant deaths from tetanus are making progress, but work remains to be done.

Pertussis

What is pertussis?

Pertussis (also known as whooping cough) is one of the most contagious diseases around. Caused by a bacterium (Bordetella pertussis), whooping cough makes children cough uncontrollably. The cough is often so hard and so persistent that children can't catch their breath and make a "whooping" sound when they attempt to breathe in against a windpipe severely narrowed by mucus. The cough can be so violent that people with pertussis crack ribs, break blood vessels, or develop hernias. Pneumonia or seizures can also develop. Young infants can also experience bouts of apnea in which they briefly stop breathing.

Pertussis is unusual in that most children catch the disease from adults and not from other children. Because pertussis is often misdiagnosed and underdiagnosed, people do not always realize how common it is. For example, over the last several years, an average of about 23,500 cases of pertussis have been reported annually to the Centers for Disease Control and Prevention, but these likely represent only the tip of the iceberg of what is occurring in the community.

Read a personal story about pertussis»

Why is pertussis sometimes called the “100-day cough?”

Severe coughing spells that come with pertussis are the main reason this illness is sometimes called the “100-day cough.” Imagine having 15 severe coughing spells in a day — coughing spells that cause vomiting and prevent you from sleeping; coughing spells so severe that you get a nosebleed or crack your rib; coughing spells that last for months. This is pertussis.

Five things you should know about pertussis include:

  • Pertussis is highly contagious; in fact, eight of 10 non-immune people will be infected when exposed to someone with the disease.
  • Pertussis is commonly misdiagnosed and under-diagnosed.
  • You can get pertussis more than once, and protection from the vaccine fades over time.
  • Older children and adults commonly transmit pertussis to infants and young children.
  • Pertussis can be particularly severe, even deadly, in infants.
Misdiagnosis, under-diagnosis, and fading immunity

Experts are aware that the actual number of pertussis infections each year is much greater than the number diagnosed. That’s because of:

  • Misdiagnoses: Because pertussis bacteria are only detected at the beginning of the infection, the test may be negative by the time someone seeks medical care.
  • Under-diagnoses: Because many adults who are ill do not go to the doctor, they are never diagnosed with pertussis.
  • Fading immunity: Since there is a vaccine, people expect to be immune, but booster doses are needed to maintain immunity.
Susceptible infants

Although a pertussis infection can interfere with day-to-day life, adults tend to recover. Unfortunately, infants and young children with narrow windpipes are not always as lucky. Coughing episodes caused by pertussis often turn babies blue as they struggle to breathe. Sadly, some of them do not survive.

Because the most negatively impacted age group is infants, who are too young to get a vaccine, public health officials have recommended two ways to protect them in the interim:

  •  “Borrowed” immunity — Because pregnant women have previously been exposed to pertussis, receipt of a single dose of Tdap vaccine between 27 and 36 weeks’ gestation boosts the level of pertussis antibodies in their blood. The result is that their babies receive a higher level of maternal antibodies against pertussis that can protect them if they are exposed to the bacteria before vaccination. Pregnant women should get the Tdap vaccine as early during this window of 27 to 36 weeks as possible to maximize the quantity of antibodies the baby may have at the time of birth. 
  •  Limited exposure — Family members who will be with the new infant for extended periods of time are also recommended to get a single dose of Tdap vaccine if they have not already had one. This recommendation promotes a technique called cocooning. Cocooning is like wrapping your baby in a blanket of protection — when everyone around them has been protected with a recent dose of the pertussis vaccine, babies are less likely to come into contact with the bacteria and, therefore, less likely to become ill before they develop their own protection from DTaP vaccine.

The vaccines

DTaP, Tdap, and Td Vaccines

The DTaP and Tdap vaccines both protect against three bacterial infections: diphtheria, tetanus and pertussis, whereas the Td vaccine only protects against diphtheria and tetanus. In addition, the vaccines vary in terms of who should receive them and the quantities of vaccine proteins they contain:

  • DTaP: The DTaP vaccine is given to infants and young children in a series of five shots ─ at 2 months, 4 months, 6 months, 15 to 18 months, and again at 4 to 6 years of age.
  • Tdap: The Tdap vaccine is different from the DTaP vaccine because it contains lesser quantities of diphtheria and pertussis proteins. For this reason, Tdap is much less likely than DTaP to cause side effects such as pain, redness and tenderness in adolescents and adults. The Tdap vaccine is recommended for most people 11 years and older who have not previously received it:
    • Adults who are going to be around infants, including those who are 65 and older
    • Those 65 and older who have not had Tdap previously should get a dose in place of their next Td vaccine
    • Pregnant women should get one dose of Tdap vaccine between 27 and 36 weeks’ gestation during each pregnancy. Although anytime during this window is acceptable, the best time to get the vaccine is early during this window.
  • Td: The Td vaccine is the one people commonly think of when they think of getting their tetanus booster. Like Tdap, it contains lesser quantities of diphtheria protein to reduce the occurrence of side effects in adults. Adults should get this vaccine every 10 years with the exception that they replace their next dose of Td with the Tdap vaccine if they have not already had it. 

Diphtheria vaccine

How is the diphtheria vaccine made?

The bacteria that causes diphtheria makes a harmful protein, called a toxin. People who develop an immune response to this toxin are protected against the disease. The diphtheria vaccine is made by taking the diphtheria toxin and inactivating it with a chemical. The inactivated toxin is called a "toxoid." Once injected, the toxoid causes an immune response to the toxin, but, unlike the toxin, it doesn't cause disease.

What are the side effects of the diphtheria vaccine?

The diphtheria vaccine can cause mild side effects such as pain or soreness in the local area of the shot and occasionally a low-grade fever.

Tetanus vaccine

How is the tetanus vaccine made?

The bacteria that causes tetanus makes a harmful protein, called a toxin. The name of the tetanus toxin is tetanospasmin. People who develop an immune response to this toxin are protected against tetanus. The tetanus vaccine is made by taking the tetanus toxin and inactivating it with a chemical. The inactivated toxin is called a "toxoid." Once injected, the toxoid elicits an immune response against the toxin, but, unlike the toxin, it doesn't cause disease.

What are the side effects of the tetanus vaccine?

Like the diphtheria vaccine, the tetanus vaccine can cause mild side effects such as pain or soreness in the local area of the shot and occasionally a low-grade fever.

The tetanus vaccine is also a rare cause of a severe allergic reaction. It is estimated that this allergic reaction could occur in about one of every 1 million children who receive the tetanus vaccine, and could include hives, difficulty breathing or a lower blood pressure. The allergic reaction can be treated with medications.

Pertussis vaccine

How is the pertussis vaccine made?

The bacteria that cause pertussis make several harmful proteins, called toxins. People who develop an immune response to some of these toxins are protected against disease. The pertussis vaccine is made by taking two to five of these toxins and inactivating them with a chemical. The inactivated toxins are called "toxoids." Once injected, the toxoids elicit an immune response against the toxins, but, unlike the toxins, they don't cause disease.

The latest version of the pertussis vaccine was released in the fall of 1996. This vaccine is called the "acellular" pertussis vaccine (or aP) and is purer than the old "whole cell" pertussis vaccine. The "old" pertussis vaccine still contained a killed form of the whole pertussis bacteria. Because individual bacteria are sometimes called cells, the "old" pertussis vaccine was called the "whole-cell" vaccine. On the other hand, the new pertussis vaccine takes advantage of advances in protein chemistry and protein purification. Because the whole killed pertussis bacteria are no longer present, the "new" pertussis vaccine is called the "acellular" vaccine.

What are the side effects of the pertussis vaccine?

The "old" pertussis vaccine, called the "whole cell" vaccine, had a high rate of mild and severe side effects. Mild side effects such as pain and tenderness where the shot was given, fever, fretfulness and drowsiness occurred in as many as one-third to one-half of children who received the vaccine. Severe side effects, such as persistent, inconsolable crying occurred in one of every 100 doses, fever greater than 105 degrees occurred in one of every 330 doses, and seizures with fever occurred in one of every 1,750 doses.

The new "acellular" pertussis vaccine, the one that has been in use in the United States since 1996, has much lower rates of both mild and severe side effects. Mild side effects such as pain and tenderness at the injection site occur in about one-third of children, most often after the fourth or fifth dose. More severe reactions occur in about one of every 10,000 children. Severe reactions can include fever of 105 degrees or higher, fever-associated seizures, inconsolable crying, or hypotonic-hyporesponsive syndrome, a condition in which a child can become listless and lethargic with poor muscle tone for several hours. (see "Are vaccines safe?" page).

Unfortunately, recent data suggests that the tradeoff for increased safety was decreased vaccine effectiveness. Children who received the “acellular” version of pertussis vaccine become susceptible more quickly than those who received the “whole-cell” version. However, it is unlikely that we would return to using the older version; instead, additional booster doses may be recommended until a newer version of the vaccine that is both safe and more effective can be developed.

Other questions you might have

Should babies who cry uncontrollably after DTaP vaccine receive additional doses?

Babies who experience uncontrollable crying after the DTaP vaccine are considered to have a “precaution” to getting future doses of the vaccine, meaning that they can still receive future doses of the DTaP vaccine; however, the relative risks and benefits should be discussed with the child’s doctor before the vaccination is given.

Because pertussis, in particular, is circulating in many parts of the country and young infants are most susceptible to complications from the disease, the relative benefits of the vaccine may still outweigh the risks. Previous experience has shown that in most cases, infants who experience inconsolable crying after the first dose of DTaP do not experience the same reaction after subsequent doses.

Should teenagers and adults get the pertussis vaccine?

Pertussis is common in teenagers and adults. Therefore, a vaccine to prevent pertussis in teenagers and adults is of great benefit. However, the old “whole cell” pertussis vaccine and the "acellular" pertussis vaccine for young children (part of the DTaP combination vaccine) had a high rate of side effects when given to people older than 7 years of age. A newer "acellular" pertussis-containing vaccine is available for older children and adults (part of the Tdap vaccine).

Because adolescents and adults can transmit this disease to infants who are too young to have received their series of the DTaP vaccine, it is imperative that adults around the baby are immune. The phenomenon in public health is called “cocooning” because the immunized adolescents and adults essentially provide a barrier around the baby to keep pertussis infections at bay. Parents, grandparents and childcare providers should all be immunized before the baby is born. (Also see vaccine considerations for new and expectant moms.)

How can I protect my newborn from pertussis?

Pertussis can be a dangerous disease for a new baby. Because of their small airways and the amount of mucus caused by infection with pertussis, babies have trouble breathing, often turning blue during their coughing spells. Every year in the U.S. about 20 children die from pertussis, most are young babies who have not been fully immunized.

There are several things that you can do to help protect your baby from pertussis. Babies get a vaccine to protect them from pertussis when they are 2 months, 4 months, and 6 months of age. They get an additional dose at 15 to 18 months. However, babies are most susceptible during their first few months of life either because they have not gotten the vaccine yet or because the dose they received did not fully protect them. During this time, you can protect your baby by making sure that all of the adults (or siblings) who will be around the baby are protected - this is what public health personnel call the "cocooning" method.

There is a vaccine available for adolescents and adults called Tdap. The "p" means that it contains a pertussis component. Pregnant women should receive the Tdap vaccine between 27 and 36 weeks’ gestation during each pregnancy. Although any time during this window is acceptable, public health officials recommend getting the vaccine as early as possible during this window. If you are past 36 weeks in your pregnancy, be sure to ask for the Tdap vaccine before being discharged from the hospital. Your spouse, the baby's grandparents and any other adults who will commonly be around the baby should also get the vaccine in advance of your delivery if they have not had a dose previously.

Additionally, you can encourage hand washing before people touch the baby, and if anyone has a cough, try to limit the baby's exposure to this person. Unfortunately, people are not only contagious in the first few weeks of the severe coughing stage, but also in the one- to two-week period leading up to cough onset. During this period, symptoms may resemble cold-like respiratory symptoms (e.g., runny nose, sneezing, occasional cough).

Read more about ways to protect your baby before vaccinations.

If I had whooping cough as a child, do I still need to get the vaccine before being around an infant?

Protection after a pertussis infection is not life-long. Because infants are at increased risk of suffering complications and death from pertussis infections, adults and teens who will be around them, including childcare providers, should have a single dose of the Tdap vaccine.

If I had the DTP vaccine as a child, do I need the booster vaccine for pertussis?

Yes. Adults who have not previously gotten the Tdap vaccine should receive a single dose. Some people are recommended to get the vaccine as soon as possible, including healthcare workers and people who will be in contact with infants. Pregnant women should get the Tdap vaccine between 27 and 36 weeks’ gestation during each pregnancy because pertussis can be fatal to young infants. Although any time during this window is fine, public health personnel suggest earlier rather than later during the window for maximum protection for the baby.

Read about a mom who lost her 3-week-old baby when they both got pertussis»

The Tdap vaccine is also recommended for all adolescents 11 or 12 years old.

Relative risks and benefits

Do the benefits of the diphtheria vaccine outweigh its risks?

Diphtheria is an extremely rare cause of disease in the United States. Over the past 20 years there have been only about 15 cases of diphtheria and fewer than five deaths. The last death from diphtheria in the United States was in 2003. Most cases of diphtheria are imported; in fact, there have been no cases in U.S. residents since 1999. On the other hand, the diphtheria vaccine has no serious side effects. So although the risk of disease and death from diphtheria is very small, the risk of severe adverse reactions or death from the diphtheria vaccine is zero. In addition, drops in immunization rates in other parts of the world have taught us how quickly outbreaks of diphtheria can return. For these reasons, the benefits of the diphtheria vaccine outweigh its risks.

Do the benefits of the tetanus vaccine outweigh its risks?

Although tetanus bacteria are everywhere, tetanus is an uncommon cause of disease in the United States. But it’s probably not as rare as you may think. Between 2006 and 2016, an average of 28 cases of tetanus was reported each year in the United States with three or four deaths. On the other hand, although the tetanus vaccine can be a very rare cause of a short-lived allergic reaction called "anaphylaxis," the tetanus vaccine does not cause death. Therefore, the benefits of the tetanus vaccine outweigh its risks. In addition, because most of the disease and death from tetanus occur in the elderly, it is important to get booster immunizations every 10 years.

Do the benefits of the pertussis vaccine outweigh its risks?

This question is best answered by taking a look at the side effects of the old pertussis vaccine. The old pertussis vaccine had a high rate of severe side effects such as persistent inconsolable crying, fever higher than 105 degrees, and seizures with fever. Due to negative publicity surrounding this vaccine, the use of the pertussis vaccine decreased in many areas of the world. For example, in Japan, children stopped receiving the pertussis vaccine by 1975. In the three years before the vaccine was discontinued, there were 400 cases and 10 deaths from pertussis. In the three years after the pertussis vaccine was discontinued, there were 13,000 cases and 113 deaths from pertussis. It should be noted that although the side effects of the old pertussis vaccine were high, no child ever died from pertussis vaccine.

The Japanese Ministry of Health, realizing how costly its error had been, soon reinstituted the use of pertussis vaccine. The children of Japan proved that the benefits of the old pertussis vaccine clearly outweighed the risks. The new "acellular" pertussis vaccine has a much lower risk of severe side effects than the old "whole cell" vaccine.

Pertussis is quite common in the United States. An average of about 23,500 cases of pertussis were reported to the CDC each year between 2007 and 2016, and more than 30 people died from the disease in the U.S. However, because of underdiagnosis and misdiagnosis, the number of cases is likely to be a vast underestimate of that which actually occurred. Sadly, most of the deaths from pertussis occur in young infants who struggle to breathe against a narrowed windpipe, leading them to turn blue or stop breathing for a short time. Because the pertussis vaccine does not cause death, the benefits of the pertussis vaccine clearly outweigh its risks.

Diseases risks

Diphtheria

  • Damage to heart, kidneys and nerves
  • Can be fatal

Tetanus

  • Severe muscle spasms
  • If muscles in throat and neck spasm, it may lead to suffocation and death
  • Heart damage

Pertussis

  • Uncontrollable coughing for weeks or months
  • Severe coughing attacks can crack ribs, break blood vessels, or cause hernias.
  • Pneumonia or seizures
  • Bouts of apnea (young infants)
  • Can be fatal

Vaccine risks

  • Pain, redness and swelling at the injection site
  • Mild fever
  • Fussiness, fatigue, lack of appetite
  • Nausea, vomiting, diarrhea, stomach ache
  • Extensive swelling of the limb where the shot was given (about 3 in 100 people)
  • Severe reactions (about 1 in 10,000 people):
    • Fever of 105 degrees or higher
    • Fever-associated seizures
    • Inconsolable crying
    • Hypotonic-hyporesponsive syndrome, a condition in which a child can become listless and lethargic with poor muscle tone for several hours

References

  • Plotkin SA, Orenstein W, Offit PA and Edwards KM. Diphtheria Toxoid in Vaccines, 7th Edition. 2018, 261-275.
  • Plotkin SA, Orenstein W, Offit PA and Edwards KM. Tetanus Toxoid in Vaccines, 7th Edition. 2018, 1052-1079.
  • Plotkin SA, Orenstein W, Offit PA and Edwards KM. Pertussis Vaccines in Vaccines, 7th Edition. 2018, 711-761.

Specific topic references

Pertussis vaccine and neurologic complications

Top KA, Brna P, Ye L, Smith B. Risk of seizures after immunization in children with epilepsy: a risk interval analysis. BMC Pediatr 2018;18:134.
The authors analyzed the risk of seizures after immunization in children with epilepsy less than 7 years of age. Nearly half of the immunization visits that occurred after epilepsy diagnosis were characterized by receipt of DTaP. The risk of seizures was not increased 0-14 days after any vaccine. The authors concluded that children with epilepsy do not appear to be at increased risk of seizures following immunization. These findings suggest that immunization is safe in children with epilepsy.

Lateef TM, Johann-Liang R, Kaulas H, Hasan R, Williams K, et al. Seizures, encephalopathy, and vaccines: experience in the National Vaccine Injury Compensation Program. J Pediatr 2015;166:576-581 
The authors described the demographic and clinical characteristics of children younger than 2 years of age for whom claims were filed with the National Vaccine Injury Compensation Program (VICP) alleging seizure disorder or encephalopathy or both during a one-year period. In 80 percent of these claims, a pertussis-containing vaccine was implicated, and four times more often related to the whole-cell pertussis vaccine. Seizure disorder was the primary condition for which compensation was sought and less than half of the claimants were known to have been febrile at the time of presentation. A significant number of children with alleged vaccine injury had pre-existing neurologic or neurodevelopmental abnormalities. Among those developing chronic epilepsy, many had clinical features suggesting that the epilepsy had a genetic basis.

Daley MF, Yih WK, Glanz JM, Hambidge SJ, Narwaney KJ, et al. Safety of diphtheria, tetanus, acellular pertussis and inactivated poliovirus (DTaP-IPV) vaccine. Vaccine 2014;32:3019-3024.
The authors examined the risk of serious, but uncommon, adverse events after receipt of DTaP-IPV in more than 200,000 children 4-6 years of age during a four-year period via the Vaccine Safety Datalink project. Receipt of DTaP-IPV did not significantly increase the risk of meningitis/encephalitis, seizures, stroke, Guillain-Barré syndrome, Stevens-Johnson syndrome, anaphylaxis, serious allergic reactions, or serious local reactions.

Sun Y, Christensen J, Hviid A, Li J, Vedsted P, et al. Risk of febrile seizures and epilepsy after vaccination with diphtheria, tetanus, acellular pertussis, inactivated poliovirus, and Haemophilus influenzae type b. JAMA 2012;307(8):823-831.
The authors evaluated the risk of febrile seizures and epilepsy in more than 300,000 children who received DTaP-IPV-Hib at ages 3, 5, and 12 months in Denmark during a six-year period. DTaP-IPV-Hib vaccination was not associated with an increased risk of febrile seizures in children within seven days following receipt of vaccine compared with those children beyond seven days of vaccination. Sub-analyses indicated an increased risk of febrile seizures on the day of the first two vaccinations, although absolute risk was small. DTaP-IPV-Hib vaccination was not associated with an increased risk of epilepsy.

Huang WT, Gargiullo PM, Broder KR, Weintraub ES, Iskander JK, et al. Lack of association between acellular pertussis vaccine and seizures in early childhood. Pediatrics 2010;126(2):e263-e269.
The authors investigated the incidence of seizures following receipt of DTaP during a 10-year period in more than 430,000 children aged 6 weeks to 23 months. They found no significant increase in the risk of seizures following receipt of DTaP.

Yih WK, Nordin JD, Kulldorff M, Lewis E, Lieu TA, et al. An assessment of the safety of adolescent and adult tetanus-diphtheria-acellular pertussis (Tdap) vaccine, using active surveillance for adverse events in the Vaccine Safety Datalink. Vaccine 2009;27:4257-4262.
The safety of Tdap was monitored weekly among subjects aged 10-64 years during 2005-2008 with specific attention to encephalopathy-encephalitis-meningitis, paralytic syndromes, seizures, cranial nerve disorders, and Guillain-Barré syndrome (GBS).  No evidence of an association between Tdap and any of these adverse events was found during a three-year-surveillance period that included more than 660,000 Tdap doses. GBS and cranial nerve sub-analyses found no statistically significant temporal clustering within 42 days after vaccination.

Ray P, Hayward J, Michelson D, Lewis E, Schwalbe J, et al. Encephalopathy after whole-cell pertussis or measles vaccination: lack of evidence for a causal association in a retrospective case-control study. Pediatr Infect Dis J 2006;25:768-773.
The authors investigated the possible relationship between whole-cell pertussis (DTP) or measles (MMR) vaccination and encephalopathy, encephalitis, and Reye syndrome by evaluating 15 years of health records from four health maintenance organizations in the United States, which encompassed nearly 2.2 million children. DTP and MMR vaccines were not associated with an increased risk of encephalopathy, encephalitis, or Reye syndrome after vaccination. Additionally, a clinically distinctive pertussis vaccine-induced encephalopathy was not detected, which was consistent with other studies.

Le Saux N, Barrowman NJ, Moore DL, Whiting S, Scheifele D, et al. Decrease in hospital admissions for febrile seizures and reports of hypotonic-hyporesponsive episodes presenting to hospital emergency departments since switching to acellular pertussis vaccine in Canada: a report from IMPACT. Pediatrics 2003;112:e348-e353.
The authors compared the incidence of hospital admissions for febrile seizures and hypotonic-hyposresponsive episodes (HHEs) presenting to hospital emergency departments before and after transition from DTP to DTaP in Canada. Hospital admissions secondary to pertussis vaccine-related febrile seizures and HHEs associated with pertussis vaccine decreased by 79 percent and 60-67 percent %, respectively.

Barlow WE, Davis RL, Glasser JW, Rhodes PH, Thompson RS, et al. The risk of seizures after receipt of whole-cell pertussis or measles, mumps and rubella vaccines. N Engl J Med 2001;345:656-661.
The authors investigated the relationship between DTP and MMR and the risk of a first seizure, subsequent seizures and neurodevelopmental disability in children. During the three-year period, more than 340,000 DTP vaccines and more than 130,000 MMR vaccines were administered. Receipt of DTP vaccine was associated with an increased risk of febrile seizures only on the day of vaccination (six to nine febrile seizures per 100,000 children vaccinated). Receipt of MMR vaccine was associated with an increased risk of febrile seizures eight to 14 days after vaccination (25-34 febrile seizures per 100,000 children vaccinated). DTP and MMR were not associated with an increased risk of non-febrile seizures. Children with febrile seizures after vaccination were not found to be at a higher risk for subsequent seizures or neurodevelopmental disabilities as compared with their unvaccinated counterparts. The authors concluded that the increased risk of febrile seizures secondary to DTP and MMR do not appear to be associated with any long-term, adverse consequences.

Goodwin J, Nash M, Gold M, Heath TC, Burgess MA. Vaccination of children following a previous hypotonic-hyporesponsive episode. J Paediatr Child Health 1999;35:549-552.
Hypotonic-hyporesponsive episodes (HHE) were once considered a contraindication to pertussis vaccination in Australia. In this study, the authors evaluated the safety of further vaccination in children who had experienced an HHE (95 percent  experienced with whole-cell pertussis and 80 percent after the first dose). Researchers found no HHE or serious reactions after subsequent DTaP, DTP, or DT. The authors concluded that previously healthy children who experience HHE reactions can safely continue standard vaccination schedules.

Vermeer-de Bondi PE, Labadie J, Rumke HC. Rate of recurrent collapse after vaccination with whole cell pertussis vaccine: follow up study. BMJ 1998;316:902-903.
The authors conducted a follow-up study of 84 children in the Netherlands with reported collapse after their first whole cell pertussis vaccination (DTP) to determine the rate of recurrence in those who received subsequent doses of DTP. None of the children had recurrent collapse, and other adverse events were only minor.

Greco D, Salmaso S, Mastrantonio P, Giuliano M, Tozzi A, et al. A controlled trial of two acellular vaccines and one whole cell vaccine against pertussis. N Engl J Med 1996;334:341-348.
The authors compared the efficacy and safety of two acellular pertussis vaccines with whole-cell pertussis and DT alone in more than 14,000 children within six to 28 weeks of life. DTwP was found to have a significantly higher rate of local and systemic reactions, including local swelling and tenderness, irritability, fever, persistent crying for ≥ 3 hours, and hypotonic/hyporesponsive episodes with those receiving DTaP. Events following receipt of DTaP were similar to the control group that received DT alone. Seizures were either infrequent or did not occur in the vaccine groups.

Gustafsson L, Hallander HO, Olin P, Reizenstein E, Storsaeter J. A controlled trial of a two-component acellular, a five-component acellular, and a whole-cell pertussis vaccine. N Engl J Med 1996;334:349-356.
The authors compared the efficacy and safety of a two-component acellular pertussis vaccine, a five-component acellular pertussis vaccine, a whole-cell pertussis and DT alone in more than 9,000 children within the first six months of life. DTP was found to have a significantly higher rate of local and systemic reactions, including protracted crying, cyanosis, fever, and local reactions compared with both DTaP vaccines and DT. DTaP rates of these events were similar to the control group who received DT alone. Seizures occurred infrequently in the 48 hours after any vaccine receipt, and rates were similar among all groups.

Rosenthal S, Chen R, Hadler S. The safety of acellular pertussis vaccine vs whole-cell pertussis vaccine. Arch Pediatr Adolesc Med 1996;150:457-460.
In December 1991, the FDA licensed the first diphtheria, tetanus toxoid, and acellular pertussis vaccine (DTaP) for use in children aged 15 months to 7 years. In this study, the authors analyzed post-marketing surveillance data submitted to the Vaccine Adverse Event Reporting System (VAERS) between late 1990 and late 1993 to determine whether serious but uncommon adverse events are less frequent after DTaP as compared with whole-cell pertussis (DTP) vaccine receipt. An estimated 27 million DTP doses (with or without Haemophilus influenzae type b vaccine) and 5 million DTaP doses were administered during this period. DTaP was associated with significantly fewer total adverse event reports, as well as significantly fewer reports of subcategory adverse events (fever, seizures or hospitalization), compared with DTP.

Gale JL, Thapa PB, Wassilak SGF, Bobo JK, Mendelman PM, et al. Risk of serious acute neurological illness after immunization with diphtheria-tetanus-pertussis vaccine. JAMA 1994;271:37-41.
The authors prospectively identified children between mid-1987 and mid-1988 in Washington and Oregon states to evaluate the association between receipt of whole-cell pertussis vaccine and serious acute neurological illness within seven days of vaccination. Among an estimated 368,000 DTP vaccines administered, no increased risk of serious acute neurological illness including complex febrile seizures, afebrile seizures, infantile spasms, or acute encephalitis/encephalopathy was detected.

Blumberg DA, Lewis K, Mink CM, Christenson PD, Chatfield P, et al. Severe reactions associated with diphtheria-tetanus-pertussis vaccine: detailed study of children with seizures, hypotonic-hyporesponsive episodes, high fevers and persistent crying. Pediatrics 1993;91:1158-1165.
The authors prospectively evaluated children in Los Angeles, California, between 1986 and 1990 to determine causes and risk factors for severe DTP reactions within 48 hours of vaccine receipt. Children with seizures had a high rate of personal and family histories of seizures, and 90 percent  had documented fevers. Persistent crying was associated with painful local reactions. Neither lymphocytosis nor hypoglycemia occurred. No biologically active pertussis toxin was found in the acute sera of children experiencing possible severe DTP reactions. As acellular pertussis vaccines have less endotoxin, which is thought to lead to febrile seizures, the authors concluded that use of acellular vaccines should lead to a reduction in DTP-related seizures due to a decrease in febrile events. Acellular pertussis vaccines also have lower local and systemic reaction rates compared with the whole cell vaccine utilized in this study; therefore, persistent crying may also be reduced.

Griffin MR, Ray WA, Mortimer EA, Fenchel GM, Schaffner W. Risk of seizures and encephalopathy after immunization with the diphtheria-tetanus-pertussis vaccine. JAMA 1990;263:1641-1645.
The authors evaluated the risk of seizures and other neurological events, including encephalopathy, following DTP immunization in Denmark in more than 38,000 children who received about 107,000 DTP immunizations in the first three years of life. The authors found no increased risk of febrile or afebrile seizures in the 0- to three-day window following immunization when compared with 30 or more days after vaccine receipt. Two cases of encephalitis were reported, but onset occurred more than two weeks after vaccine receipt.

Griffith AH. Permanent brain damage and pertussis vaccination: is the end of the saga in sight? Vaccine 1989;7:199-210.
The author provides an overview of the pertussis vaccine and controversies surrounding its possible link to permanent brain damage.  Reports of permanent brain damage thought secondary to receipt of the pertussis vaccine were published in the 1950s through 1970s. Most notably, a case series suggesting permanent brain damage secondary to pertussis vaccination out of the National Hospital for Sick Children by Kulenkampff and colleagues was the subject of a United Kingdom television documentary in 1974 that resulted in a significant decline in vaccination rates and a consequent resurgence of pertussis in England. Repercussions from this documentary in the UK included the establishment of expert panels and sponsored research teams by the Department of Health and Social Security to examine existing clinical data and to carry out prospective studies including the North West Thames study (see Pollock, et al, Lancet 1983 data reported below) and the National Childhood Encephalopathy Study (NCES).

The NCES evaluated reported cases of defined serious neurological disorders arising in children between 2 and 36 months of age admitted to the hospital between mid-1976 and mid-1979 in the UK. These researchers estimated the attributable risk of neurological damage after pertussis immunization to be 1 in 310,000-330,000 injections, but the report was limited by certain structural biases and incomplete information; furthermore, these results could not be reproduced in subsequent studies.

The Kulenkampff and NCES data were reexamined in the High Court of Justice, London, in the wake of neurologic damage claims brought to the court. Regarding the Kulenkampff data, more than half of the cases either could not be linked to pertussis vaccination (e.g., DT given instead of DTP), had normal outcomes, or were found to have alternative causes. Reexamination of the NCES data showed

  1. No previously normal child suffered permanent brain damage with an onset within 48 hours of vaccination
  2. No evidence supported the notion that previously neurologically abnormal children had a greater risk than normal children of suffering an event within a short period following vaccination
  3. Of the 12 previously normal cases of “serious neurological disorder” with onset within the first 48 hours, 10 were cases of febrile convulsions and those with prolonged convulsions were normal at follow-up
  4. If the cases of Reye’s syndrome and of viral origin were excluded— given that they are not caused by DTP — no cases of permanent brain damage or death were linked to the vaccine
  5. The figure of 1 in 310,000 or 330,000 given as the attributable risk of permanent brain damage following DTP vaccine could not be supported
  6. Evidence supports that on rare occasions, DTP causes febrile convulsions

Livengood JR, Mullen JR, White JW, Brink EW, Orenstein WA. Family history of convulsions and use of pertussis vaccine. J Pediatr 1989;115:527-531.
The authors evaluated data from the CDC Monitoring System for Adverse Events Following Immunization during the period of 1979 to 1986 to determine the risk of neurologic events after vaccination with DTP in patients with a family history of convulsions compared with those without a family history. Children with a family history of seizures had an increased risk of neurologic events, primarily febrile convulsions, after DTP receipt, but this increase in risk may reflect a nonspecific familial tendency for convulsions rather than a specific vaccine effect as well as selection bias. Given the rare occurrence of neurologic events after DTP vaccination, the generally benign outcome of febrile convulsions that accounted for more than 75 percent  of the events, and the risk pertussis caused by not vaccinating people with a family history of convulsions, the authors concluded that a history of convulsions in a close relative should not be a contraindication to the pertussis vaccination. Rather, prevention of post-vaccination fever may be warranted in these children.

Baraff LJ, Shields WD, Beckwith L, Strome G, Marcy SM, et al. Infants and children with convulsions and hypotonic-hyporesponsive episodes following diphtheria-tetanus-pertussis immunization: follow up evaluation. Pediatrics 1988;81(6):789-794.
In a previous prospective study (Cody, et al Pediatrics 1981), the authors found that minor reactions (e.g., local redness, swelling, fever, etc.) were more common following DTP immunization than DT. Among more than 15,000 DTP injections, nine children developed seizures and nine developed hypotonic-hyporesponsive episodes though no sequelae were detected following these possible temporal reactions. The authors completed a follow-up evaluation six to seven years later in 16 of these children to determine if any had evidence of neurologic impairment too subtle to have been detected at the time of their initial evaluation.  All 16 children were considered to be normal by their parents and — as determined by their school performance — had no evidence of serious neurologic damage.

Shields WD, Nielsen C, Buch D Jacobsen V, Christenson P, et al. Relationship of pertussis immunization to the onset of neurologic disorders: a retrospective epidemiologic study. J Pediatr 1988;113:801-805.
The authors examined the temporal relationship between onset of neurologic disorders and the time of pertussis vaccine in children immunized with either DTP or monovalent pertussis at different ages. They found no relationship between the age of onset of epilepsy and scheduled age of administration of pertussis vaccine; however, a relationship existed between scheduled age of administration and first febrile seizure, which occurred more commonly with the third dose in the series between 10-15 months of age. No relationship between pertussis immunization and the occurrence of central nervous system infections was noted.

Walker AM, Jick H, Perera DR, Knauss TA, Thompson RS. Neurologic events following diphtheria-tetanus-pertussis immunization. Pediatrics 1988;81(3):345-349.
The authors assessed the frequency of serious neurologic events following administration of 106,000 DTP immunizations in children between 1977 and 1983. They found no cases of acute unexplained encephalopathy temporally associated with vaccination. The onset of one serious seizure disorder occurred within three days of immunization, with 1.13 cases expected on the basis of chance alone.  The incidence of recorded febrile seizures in the immediate post-immunization period was 3.7 times that in the period 30 days or more after immunization.

Bellman MH, Ross EM, Miller DL. Infantile spasms and pertussis immunisation. Lancet 1983;321(8332):1031-1034.
The authors investigated the possible role of pertussis immunization and other factors in the etiology of infantile spasms reported to the National Childhood Encephalopathy Study between 1976 and 1979 in England, Scotland and Wales. No significant association was found between infantile spasms and pertussis immunization in the 28 days following vaccination.  

Corsellis JA, Janota I, Marshall AK. Immunization against whooping cough: a neuropathological review. Neuropathol Appl Neurobiol 1983;9(4):261-270.
The authors examined published data on childhood deaths which were thought to be due to receipt of the pertussis vaccine and identified an additional 29 children in England and Wales whose deaths between 1960 and 1980 had been reported as occurring in relation to DTP and had post-mortem examinations. Deaths occurred within three weeks or up to 12 years after DTP receipt. Upon autopsy, various cerebral abnormalities were found; however, none of the cases in this study or in previous published reports had demonstrated a recurring pattern of inflammatory or other damage that could be accepted as a specific reaction to pertussis immunization. Reactive changes that were occasionally found appear to be indistinguishable from those seen in other infantile encephalopathies.

Pollock TM and J Morris. A 7-year survey of disorders attributed to vaccination in North West Thames Region. Lancet 1983;1(8327):753-757.
The authors examined the relationship between pertussis and other vaccines and neurological problems over a seven-year period. All children reported to have serious or unusual vaccine reactions, regardless of severity, had records investigated and were physically examined by an area health authority medical officer four weeks after the original report; and all children, except for those with mild symptoms, had a developmental examination six months after the report. In a group of hundreds of thousands of children and more than 400,000 DTP immunizations, 20 reports of convulsions within three weeks of DTP were reported and three-quarters of the reports were febrile seizures within 48 hours of immunization; all children were developmentally normal on follow-up. Twelve neurological disorders were reported to have occurred within eight weeks of DTP receipt; 11 of which had either infantile spasms, infectious etiology, or epilepsy, none of which were linked to DTP. The authors concluded that their study does not support the claim that DTP produces a syndrome characterized by a previously healthy child who presents with continuous screaming, collapse, convulsion and arrested mental development.

Melchior JC. Infantile spasms and early immunization against whooping cough: Danish survey from 1970 to 1975. Arch Dis Child 1977;52:134-137.
The authors examined the relationship between immunization and the onset of infantile spasms over a six-year period in Denmark after a change in its immunization program. Previously, DTP vaccine had been administered at 5, 6, and 15 months of age, but was changed in 1970 to monovalent pertussis vaccine at 5 weeks, 9 weeks, and 10 months of age. The authors found no differences in the age at onset of infantile spasms between immunized and non-immunized children; half of all cases in each group began before 5 months of age despite children immunized before 1970 not receiving the first dose until 5 months of age.

Reviewed by Paul A. Offit, MD on January 22, 2019

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