Diphtheria

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Diphtheria is an acute, bacterial disease caused by toxinproducing strains of Corynebacterium diphtheriae. The name 

of the disease is derived from the Greek diphthera, meaning 

‘leather hide.’ The disease was described in the 5th century 

BCE by Hippocrates, and epidemics were described in the 

6th century AD by Aetius. The bacterium was first observed 

in diphtheritic membranes by Edwin Klebs in 1883 and 

cultivated by Friedrich Löffler in 1884. Beginning in the early 

1900s, prophylaxis was attempted with combinations of toxin 

and antitoxin. Diphtheria toxoid was developed in the early 

1920s but was not widely used until the early 1930s. It was 

incorporated with tetanus toxoid and pertussis vaccine and 

became routinely used in the 1940s. 

Corynebacterium diphtheriae

C. diphtheriae is an aerobic, gram-positive bacillus. 

Toxin production (toxigenicity) occurs only when the 

bacillus is itself infected (lysogenized) by specific viruses 

(corynebacteriophages) carrying the genetic information for 

the toxin (tox gene). Diphtheria toxin causes the local and 

systemic manifestations of diphtheria. 

C. diphtheriae has four biotypes: gravis, intermedius, mitis, 

and belfanti. All biotypes can become toxigenic and cause 

severe disease. All isolates of C. diphtheriae should be tested 

for toxigenicity.

Pathogenesis

Susceptible persons may acquire toxigenic diphtheria bacilli in 

the nasopharynx. The organism produces a toxin that inhibits 

cellular protein synthesis and is responsible for local tissue 

destruction and formation of the pseudomembrane that is 

characteristic of this disease. The toxin produced at the site 

of the membrane is absorbed into the bloodstream and then 

distributed to the tissues of the body. The toxin is responsible 

for major complications such as myocarditis, polyneuropathies, 

and nephritis, and can also cause thrombocytopenia.

Non-toxin-producing C. diphtheriae strains can cause mild to 

severe exudative pharyngitis. Severe cases with pseudomembranes caused by such strains have been reported rarely; 

it is possible that these infections were caused by toxigenic 

strains that were not detected because of inadequate culture 

sampling. Other manifestations of nontoxigenic 

C. diphtheriae infection include cutaneous lesions, endocarditis, bacteremia, and septic arthritis. 

Diphtheria

● Described by Hippocrates in 

5th century BCE

● Epidemics described in 

6th century

● Bacterium first observed in 

1883 and cultivated in 1884

● Diphtheria toxoid developed 

in 1920s

Corynebacterium diphtheria

● Aerobic gram-positive bacillus

● Toxin production occurs 

when bacillus is infected 

by corynebacteriophages 

carrying tox gene 

● Four biotypes: gravis, 

intermedius, mitis, and belfanti

● All isolates should be tested 

for toxigenicity

Diphtheria Pathogenesis

● Toxigenic diphtheria bacilli 

acquired in the nasopharynx

■ Produces a toxin that inhibits 

cellular protein synthesis, 

destroys local tissue, and 

forms a pseudomembrane

■ Responsible for 

major complications, 

including: myocarditis, 

polyneuropathies, nephritis, 

and thrombocytopenia

● Non-toxin-producing 

C. diphtheriae strains cause 

mild to severe exudative 

pharyngitis and sometimes 

lesions, endocarditis, 

bacteremia, and septic arthritis

Anna M. Acosta, MD; Pedro L. Moro, MD, MPH; Susan Hariri, PhD; and Tejpratap S.P. Tiwari, MD
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Clinical Features

The incubation period for diphtheria is 2 to 5 days, with 

a range of 1 to 10 days. Disease can involve almost any 

mucous membrane. In untreated people, organisms can be 

present in discharges and lesions 2 to 6 weeks after infection. 

For clinical purposes, it is convenient to classify diphtheria 

by anatomic site: respiratory (pharyngeal, tonsillar, laryngeal, 

nasal) and non-respiratory (cutaneous and other mucus 

membranes) disease.

Pharyngeal and Tonsillar Diphtheria

The most common sites of diphtheria infection are the 

pharynx and the tonsils. Infection at these sites is usually 

associated with substantial systemic absorption of toxin. 

The onset of pharyngitis is gradual. Early symptoms include 

malaise, sore throat, anorexia, and low-grade fever (less than 

101°F). Within 2 to 3 days, a bluish-white membrane forms and 

extends, varying in size from covering a small patch on the 

tonsils to covering most of the soft palate. Often by the time 

a physician is contacted the membrane is greyish-green or, if 

bleeding has occurred, black. There is a minimal amount of 

mucosal erythema surrounding the membrane. The membrane 

is firmly adherent to the tissue, and forcible attempts to remove 

it cause bleeding. Extensive membrane formation may result in 

respiratory obstruction.

While some patients may recover at this point without 

treatment, others may develop severe disease. The patient 

may appear quite toxic, but the fever is usually not high. 

Patients with severe disease may develop marked edema 

of the submandibular areas and the anterior neck along 

with lymphadenopathy, giving a characteristic “bull neck” 

appearance. If enough toxin is absorbed, the patient can 

develop severe prostration, pallor, rapid pulse, stupor, and 

coma. Death can occur within 6 to 10 days. 

Laryngeal Diphtheria 

Laryngeal diphtheria can be either an extension of the 

pharyngeal form or can involve only this site. Symptoms include 

fever, hoarseness, and a barking cough. The membrane can lead 

to airway obstruction, coma, and death.

Anterior Nasal Diphtheria

The onset of anterior nasal diphtheria looks much like the 

common cold and is usually characterized by a mucopurulent 

nasal discharge that may become blood-tinged. A white 

membrane usually forms on the nasal septum. The disease 

is usually fairly mild because of apparent poor systemic 

absorption of toxin from this location, and it can be terminated 

rapidly by diphtheria antitoxin and antibiotic therapy.

Diphtheria Clinical Features

● Incubation period 2 to 5 days 

(range, 1 to 10 days)

● May involve any mucous 

membrane

● Classified based on site 

of disease

■ Respiratory (pharyngeal, 

tonsillar, laryngeal, nasal)

■ Non-respiratory (cutaneous 

and other mucus 

membranes)

● Most common sites of 

infection are the pharynx 

and tonsils
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Cutaneous Diphtheria

Skin infections may be manifested by a scaling rash or by 

ulcers with clearly demarcated edges and an overlying 

membrane, but any chronic skin lesion may harbor 

C. diphtheriae along with other organisms. Cutaneous 

diphtheria is quite common in the tropics and is probably 

responsible for the high levels of natural immunity found in 

these populations. Infection with toxigenic strains appears to 

result less frequently in systemic complications with cutaneous 

compared to other forms of diphtheria. C. diphtheriae isolated 

from cutaneous cases in the United States typically has 

been nontoxigenic, although recently a number of imported 

toxigenic cutaneous cases have been identified. 

Other

Other rare sites of involvement include the mucous membranes 

of the conjunctiva and vulvovaginal area, as well as the external 

auditory canal.

Complications

Most complications of diphtheria, including death, are 

caused by effects of the toxin. The severity of the disease 

and complications are generally related to the extent of 

local disease. The toxin, when absorbed, affects organs and 

tissues distant from the site of invasion. The most frequent 

complications of diphtheria are myocarditis and neuritis.

Myocarditis may present as abnormal cardiac rhythms and can 

occur early in the course of the illness or weeks later. Myocarditis 

can lead to heart failure and, if it occurs early, it is often fatal. 

Neuritis most often affects motor nerves and usually resolves 

completely. Paralysis of the soft palate is most frequent 

during the third week of illness. Paralysis of eye muscles, 

limbs, and the diaphragm can occur after the fifth week. 

Secondary pneumonia and respiratory failure may result from 

diaphragmatic paralysis.

Other complications include otitis media and respiratory 

insufficiency due to airway obstruction, especially in infants.

The estimated overall case fatality ratio for diphtheria is 

5% to 10%.

Laboratory Testing

Diagnosis of respiratory diphtheria is usually made based 

on clinical presentation because it is imperative to begin 

presumptive therapy quickly. Non-respiratory diphtheria, such 

as cutaneous diphtheria, may not be clinically suspected and 

therefore diagnosis is typically based on the laboratory finding.

Diphtheria Complications

● Most complications attributable 

to toxin

● Severity generally related to 

extent of local disease

● Most frequent complications 

are myocarditis and neuritis

● Death occurs in 5%-10% 
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Confirmatory testing for diphtheria includes culture to identify 

the bacterial species and the Elek test to confirm diphtheria 

toxin production. Capacity for diphtheria culture may be 

available at public health or commercial laboratories. CDC’s 

Pertussis and Diphtheria Laboratory routinely performs culture 

to confirm C. diphtheriae and is currently the only laboratory in 

the United States that tests for toxin production. It is critical to 

take a swab of the affected area, especially any ulcerations or 

pseudomembranes. The organism can be cultured on common 

laboratory media; culture on a selective medium containing 

tellurite allows for distinguishing C. diphtheriae and C. ulcerans 

from other Corynebacterium species that normally inhabit the 

nasopharynx and skin (e.g., diphtheroids). However, further 

biochemical tests are required to fully identify an isolate as 

C. diphtheriae. If C. diphtheriae or C. ulcerans are isolated, they 

must be tested for toxin production. 

If antibiotic therapy was started prior to specimen collection 

from a suspected diphtheria case, and culture was negative 

for C. diphtheriae, two sources of evidence can help support 

presumptive diagnosis: 

1. a positive polymerase chain reaction (PCR) test for 

diphtheria tox gene; 

2. isolation of C. diphtheriae from cultures of specimens 

from close contacts.

Medical Management 

Diphtheria Antitoxin

Diphtheria antitoxin, produced in horses, has been used 

for treatment of respiratory diphtheria in the United States 

since the 1890s. It typically is not administered in cases of 

non-respiratory diphtheria and it is not indicated for prophylaxis 

of diphtheria patient contacts. Diphtheria antitoxin is available 

only from CDC, through an Investigational New Drug (IND) 

protocol. Diphtheria antitoxin does not neutralize toxin that is 

already fixed to tissues, but it will neutralize circulating toxin 

and prevent progression of disease. 

After a provisional clinical diagnosis of respiratory diphtheria is 

made, appropriate specimens should be obtained for culture 

and the patient placed in isolation. Persons with suspected 

diphtheria should be promptly given diphtheria antitoxin and 

antibiotics in adequate dosage, without waiting for laboratory 

confirmation. Respiratory support and airway maintenance 

should also be provided as needed. Consultation on the use of 

and access to diphtheria antitoxin is available through the duty 

officer at CDC’s Emergency Operations Center at 770-488-7100.

Antibiotics

In addition to diphtheria antitoxin, patients with respiratory 

diphtheria should also be treated with antibiotics. The disease 

is usually no longer contagious 48 hours after antibiotics have 
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been given. Elimination of the organism should be documented 

by two consecutive negative cultures taken 24 hours apart, with 

the first specimen collected 24 hours after therapy is completed. 

Preventive Measures

Diphtheria disease might not confer immunity. Unvaccinated 

or incompletely vaccinated persons recovering from diphtheria 

should begin or complete active immunization with diphtheria 

toxoid during convalescence. 

Vaccination history of close contacts of diphtheria patients 

should also be assessed: if vaccination history is incomplete 

or unknown, the contact should receive a dose of diphtheria 

toxoid-containing vaccine immediately, and the vaccination 

series should be completed according recommendations from 

the Advisory Committee on Immunization Practices (ACIP). If 

the contact is up-to-date according to ACIP recommendations 

but the last dose was more than 5 years ago, a diphtheria 

toxoid-containing vaccine should be immediately administered. 

In addition, close contacts should receive a single intramuscular 

dose of benzathine penicillin G or a 7- to 10-day course of 

oral erythromycin. Benzathine penicillin G should be given to 

contacts for whom surveillance cannot be maintained for 7 

to 10 days. Contacts should be closely monitored and begin 

diphtheria antitoxin treatment at the first signs of illness.

Epidemiology

Occurrence

Diphtheria occurs worldwide, particularly in countries with 

suboptimal vaccination coverage. Diphtheria is rare in 

industrialized countries, including the United States. Because it 

is a rare disease, seasonal and geographic distribution patterns 

are no longer observed. 

Reservoir

Humans are the reservoir for C. diphtheriae. 

Transmission 

Transmission is most often person-to-person through 

respiratory droplets. Transmission may also occur from 

exposure to infected skin lesions or articles soiled with 

discharges from these lesions. 

Temporal Pattern

In temperate areas, diphtheria most frequently occurs during 

winter and spring. 

Diphtheria Epidemiology

● Reservoir

■ Human

● Transmission

■ Person-to-person through 

respiratory droplets

■ Exposure to infected skin 

lesions and fomites

● Temporal pattern

■ Winter and spring in 

temperate climates

● Communicability

■ As long as virulent bacilli 

are present in discharge 

and lesions
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Communicability

Transmission may occur as long as virulent bacilli are present 

in discharges and lesions. Effective antibiotic therapy promptly 

terminates shedding. 

Secular Trends in the United States

During the 1920s, 100,000 to 200,000 cases of diphtheria 

(140 to 150 cases per 100,000 population) and 13,000 to 

15,000 deaths were reported each year. After diphtheria 

toxoid-containing vaccines became available in the 1940s, 

the number of cases gradually declined to about 19,000 

in 1945 (15 cases per 100,000 population). A more rapid 

decrease began with implementation of a universal 

childhood vaccination program which included diphtheria 

toxoid-containing vaccines beginning in the late 1940s. 

From 1996 through 2018, 14 cases of diphtheria were reported 

in the United States, an average of less than 1 per year. One 

fatal case occurred in a 63-year-old male returning to the 

United States from a country with endemic diphtheria disease. 

Within the United States, coverage with diphtheria toxoid 

childhood vaccines (DTaP) has been consistently high. Among 

children born during 2016–2017, 93.3% had received at least 

3 doses of DTaP vaccine by age 24 months, and 80.6% had 

received at least 4 doses of DTaP vaccine by age 24 months.

Coverage with the adolescent and adult diphtheria toxoid 

vaccines (Tdap or Td) is variable: Tdap coverage among 

adolescents age 13 through 17 years reached 90.2% in 2019.

Diphtheria Toxoid-containing Vaccines

Diphtheria toxoid is produced by growing toxigenic 

C. diphtheriae in liquid medium. 

Diphtheria toxoid is combined with tetanus toxoid as 

diphtheria and tetanus toxoid (DT) vaccine or tetanus and 

diphtheria toxoid (Td [Tenivac and Tdvax]) vaccine. Diphtheria 

toxoid is also combined with both tetanus toxoid and acellular 

pertussis vaccine as DTaP (Infanrix and Daptacel) or Tdap 

(Boostrix and Adacel) vaccines. Td contains reduced amounts 

of diphtheria toxoid compared with DT. DTaP and Tdap 

contain the same pertussis components, but Tdap contains a 

reduced quantity of some pertussis antigens and diphtheria 

toxoid. Boostrix contains a reduced quantity of tetanus toxoid 

compared to Infanrix. 

Children younger than age 7 years should receive DTaP 

vaccine or DT vaccine (in instances where the pertussis vaccine 

component is contraindicated or where the physician decides 

that pertussis vaccine is not to be administered). Persons age 

Diphtheria Secular Trends 

in the United States

● 100,000-200,000 cases and 

13,000-15,000 deaths 

reported annually during 

1920s before vaccine

● Cases gradually declined after 

vaccines introduced in 1940s; 

cases rapidly declined after 

universal vaccination program 

introduction in late 1940s

● From 1996 to 2018, 14 cases 

and 1 death reported in the 

United States

Diphtheria

Toxoid-containing Vaccines

● DT

● DTaP (Daptacel and Infanrix)

● Td (Tdvax and Tenivac)

● Tdap (Adacel and Boostrix)

● DTaP-HepB-IPV (Pediarix)

● DTaP-IPV/Hib (Pentacel)

● DTaP-IPV (Kinrix and Quadracel)

● DTaP-IPV-Hib-HepB (Vaxelis)
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7 years or older should receive the Td vaccine or Tdap vaccine, 

even if they have not completed a series of DTaP or DT (Tdap 

would be off-label for children age 7 through 9 years but is still 

recommended by ACIP). Tdap (Boostrix) is approved for persons 

age 10 years or older; Tdap (Adacel) is approved for persons age 

10 through 64 years. DTP vaccines are combined diphtheria and 

tetanus toxoids and whole cell pertussis vaccine, but none are 

currently licensed in the United States.

There are five combination vaccines that contain DTaP vaccine. 

DTaP-HepB-IPV (Pediarix) is licensed for the first 3 doses of 

the DTaP series among children age 6 weeks through 6 years. 

DTaP-IPV/Hib (Pentacel) is licensed for the first 4 doses of the 

component vaccines among children age 6 weeks through 

4 years. DTaP-IPV (Kinrix) is licensed only for the fifth dose of 

DTaP and fourth dose of IPV among children age 4 through 6 

years. DTaP-IPV (Quadracel) is licensed only for the fifth dose 

of DTaP and fourth or fifth dose of IPV among children age 4 

through 6 years. DTaP-IPV-Hib-HepB (Vaxelis) is licensed for use 

in children age 6 weeks through 4 years.

Characteristics 

Diphtheria toxoid-containing vaccines are administered 

by intramuscular injection. Each dose of diphtheria toxoidcontaining vaccines contains aluminum as an adjuvant but no 

preservative. DTaP-HepB-IPV (Pediarix), DTaP-IPV/Hib (Pentacel), 

DTaP-IPV-Hib-HepB (Vaxelis), DTaP-IPV (Kinrix), and DTaP-IPV 

(Quadracel) contain neomycin and polymyxin B as antibiotics. 

DTaP-IPV-Hib-HepB (Vaxelis) contains streptomycin as an 

antibiotic. DTaP-HepB-IPV (Pediarix) and DTaP-IPV-Hib-HepB 

(Vaxelis) vaccines contain yeast protein. Presentations of some 

diphtheria toxoid-containing vaccines contain latex rubber.

Vaccination Schedule and Use

DTaP (Infanrix and Daptacel)

DTaP (diphtheria, tetanus toxoids, and acellular pertussis 

vaccine) is recommended for children age 6 weeks through 

6 years. The routine schedule is a primary series of 3 doses at 

age 2, 4, and 6 months, a booster dose between age 15 through 

18 months, and another booster dose between age 4 through 

6 years (total of 5 doses). The first 3 doses should be given at 

4- to 8-week intervals (minimum of 4 weeks). Dose 4 should 

follow dose 3 by no less than 6 months and should not be 

administered before age 12 months. 

Dose 4 of both brands of DTaP is recommended to be administered at age 15 through 18 months (15 through 20 months 

for Daptacel). Dose 4 may be given as early as age 12 months 

if at least 6 months have elapsed since dose 3 and, in the 

Diphtheria Toxoid-containing 

Vaccine Characteristics

● Administered by intramuscular 

injection

● Contains aluminum as 

an adjuvant

Diphtheria Toxoid-containing 

Vaccination Schedule

● DTaP

■ 3-dose primary series at age 

2, 4, and 6 months 

■ Primary series interval of 

4- to 8-weeks and minimum 

interval 4 weeks

■ Boosters at age 15 through 

18 months and age 4 through 

6 years

■ Minimum interval for dose 4 

is 6 months from dose 3 and 

minimum age is 12 months

■ If dose 4 is given on or after 

4th birthday, the 5th dose is 

optional

■ DT is used in place of 

DTaP if child has a valid 

contraindication to 

pertussis vaccine
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opinion of the vaccine provider, the child is unlikely to return 

for an additional visit between age 15 through 18 months. 

Children who received 4 doses before their fourth birthday 

should receive a fifth dose of DTaP before entering school. The 

fifth dose is not necessary (but may be given) if dose 4 in the 

series was given on or after the fourth birthday. Administering 

the fifth dose increases antibody levels and may decrease the 

risk of school-age children transmitting the disease to younger 

siblings who are not fully vaccinated. 

If a child has a valid contraindication to pertussis vaccine, DT 

should be used to complete the vaccination series. If the child 

was younger than age 12 months when the first dose of DT 

was administered (as DTP, DTaP, or DT), the child should receive 

a total of 4 DT doses. If the child was age 12 months or older 

at the time the first dose of DT was administered, 3 doses 

(with dose 3 administered 6 through 12 months after dose 2) 

will complete the primary DT series. If dose 4 of DTP, DTaP, or 

DT is administered before the fourth birthday, a fifth dose is 

recommended at age 4 through 6 years.

DTaP-HepB-IPV (Pediarix)

DTaP-HepB-IPV vaccine is approved for use as a 3-dose series 

for children age 6 weeks through 6 years. It is administered 

to infants at age 2, 4, and 6 months. The minimum intervals 

for DTaP-HepB-IPV vaccine are determined by the DTaP 

component. The 3 doses must be separated by at least 4 weeks 

between doses. Because the minimum age for the first dose 

of DTaP-HepB-IPV vaccine is 6 weeks, this vaccine cannot be 

used for the birth dose of hepatitis B (HepB) vaccine. The final 

dose of DTaP-HepB-IPV vaccine should be administered at 

age 24 weeks or older, the minimum age for completion of 

the hepatitis B vaccine series. When DTaP-HepB-IPV vaccine is 

used to provide 3 doses at age 2, 4, and 6 months (based on 

the DTaP and IPV schedules), this will result in a 4-dose HepB 

vaccine series, which is acceptable. 

DTaP-IPV/Hib (Pentacel)

DTaP-IPV/Hib vaccine is approved for use as a 4-dose series 

for children age 6 weeks through 4 years. It is administered to 

infants at age 2, 4, 6, and 15 through 18 months. The minimum 

intervals for DTaP-IPV/Hib vaccine are determined by the 

DTaP component. The first 3 doses must be separated by at 

least 4 weeks between doses. Dose 4 must be separated from 

dose 3 by at least 6 months, and should not be administered 

before age 12 months. When DTaP-IPV/Hib vaccine is used 

to provide 4 doses at age 2, 4, 6, and between 15 through 18 

months (based on the DTaP and Hib schedules), an additional 

booster dose with IPV-stand alone or DTaP-IPV vaccine should 

be administered at age 4 through 6 years. This will result in a 

5-dose IPV vaccine series, which is acceptable. 
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DTaP-IPV-Hib-HepB (Vaxelis)

DTaP-IPV-Hib-HepB is approved for use as a 3-dose series 

for children age 6 weeks through 4 years. It is administered 

to infants at age 2, 4, and 6 months. The minimum intervals 

for DTaP-IPV-Hib-HepB vaccine are determined by the DTaP 

component. The 3 doses must be separated by at least 4 weeks 

between doses. Because the minimum age for the first dose of 

DTaP-IPV-Hib-HepB vaccine is 6 weeks, this vaccine cannot be 

used for the birth dose of hepatitis B (HepB) vaccine. The final 

dose of DTaP-IPV-Hib-HepB vaccine should be administered at 

age 24 weeks or older, the minimum age for completion of the 

hepatitis B vaccine series. When DTaP-IPV-Hib-HepB vaccine is 

used to provide 3 doses at age 2, 4, and 6 months (based on 

the DTaP and IPV schedules), this will result in a 4-dose HepB 

vaccine series, which is acceptable. 

DTaP-IPV (Kinrix) 

DTaP-IPV (Kinrix) vaccine is approved only for dose 5 of DTaP 

vaccine and dose 4 of IPV vaccine in children age 4 through 

6 years whose previous DTaP vaccine doses have been with 

Infanrix and/or Pediarix for dose 1, 2, and 3 and Infanrix for 

dose 4. However, if DTaP-IPV (Kinrix) vaccine is administered to 

children who received another brand of DTaP vaccine for prior 

DTaP vaccine doses, or if administered as dose 1, 2, 3, or 4 of the 

DTaP vaccine series or dose 1, 2, or 3 of the IPV vaccine series, 

the dose of DTaP-IPV (Kinrix) does not need to be repeated.

DTaP-IPV (Quadracel)

DTaP-IPV (Quadracel) vaccine is approved only for dose 5 of 

DTaP vaccine and dose 4 or 5 of IPV vaccine in children age 4 

through 6 years who have received 4 doses of Pentacel and/or 

Daptacel vaccine. However, if DTaP-IPV (Quadracel) vaccine is 

administered to children who received another brand of DTaP 

vaccine for prior DTaP vaccines doses, or if administered as 

dose 1, 2, 3, or 4 of the DTaP vaccine series or dose 1, 2, or 3 of 

the IPV series, the dose of DTaP-IPV (Quadracel) does not need 

to be repeated.

Tdap (Boostrix and Adacel) and Td (Tenivac and Tdvax)

Both Tdap vaccines are approved by the FDA for a booster 

dose for persons who have completed the recommended 

childhood DTP/DTaP vaccination series. Boostrix is approved 

for persons age 10 years or older. Adacel is approved for a 

single dose in persons age 10 through 64 years. A second dose 

of Adacel is also licensed for administration 8 or more years 

after the first Tdap dose and for use for tetanus prophylaxis 

when indicated for wound management if at least 5 years 

have elapsed since the previous receipt of any tetanus toxoidcontaining vaccine. Both Td vaccines are approved for use in 

persons age 7 years or older.

Diphtheria Toxoid-containing 

Vaccination Schedule

● Tdap

■ 1 dose at age 11 through 18 

for adolescents who have 

completed DTaP series

■ Booster dose of Td or Tdap 

every 10 years for all persons
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A single Tdap dose is recommended for adolescents age 11 

through 18 years who have completed the recommended 

childhood DTP/DTaP vaccination series, preferably at age 11 

through 12 years. Adults age 19 years or older who have not 

previously received Tdap should receive a single dose of Tdap. 

To reduce the burden of pertussis in infants, a dose of Tdap 

has been recommended during each pregnancy since 2012, 

although this practice is an off-label use.

All adolescents and adults should have received a primary 

series of at least 3 documented doses of tetanus and diphtheria 

toxoids-containing vaccine (i.e., DTaP, DTP, DT, or Td) during their 

lifetime. A person without such documentation should receive a 

series of 3 doses of tetanus- and diphtheria-containing vaccine. 

One of these doses, preferably the first, should be Tdap. The 

remaining 2 doses should be either Td or Tdap. 

For persons age 7 to 9 years who receive a dose of Tdap as 

part of the catch-up series, an adolescent Tdap dose should 

be administered at age 11 through 12 years. If a Tdap dose is 

administered at age 10 years or older, the Tdap dose may count 

as the adolescent Tdap dose. Either brand of Tdap may be used.

Adults age 19 years or older who previously have not received 

Tdap should receive a single dose of Tdap to protect against 

pertussis and reduce the likelihood of transmission. For adults 

age 19 through 64 years, either brand of Tdap may be used. 

Adults age 65 years or older should be vaccinated with Boostrix, 

if feasible. However, either vaccine administered to a person age 

65 years or older is immunogenic and would provide protection. 

A dose of either vaccine would be considered valid. 

Adolescents and adults who have not previously received 

Tdap, and have or anticipate having close contact with an 

infant younger than age 12 months (e.g., parents, siblings, 

grandparents, child care providers, and health care personnel) 

should receive a single dose of Tdap to protect against pertussis. 

Ideally, these persons should receive Tdap at least 2 weeks 

before beginning close contact with the infant.

Health care personnel should receive a single dose of Tdap 

as soon as feasible if they have not previously received Tdap, 

regardless of the time since their most recent Td vaccination. 

When Tdap is indicated (e.g., routine vaccination, catch-up 

vaccination, or pregnancy), it can be administered regardless 

of the interval since the last tetanus- or diphtheria-toxoidcontaining vaccine. After receipt of Tdap, persons should 

continue to receive a dose of Td or Tdap for routine booster 

immunization against tetanus and diphtheria every 10 years 

unless needed sooner for tetanus prophylaxis as part of 

wound management.

Use of Tdap 

● 1 dose Tdap during each 

pregnancy (off-label use)

● 1 dose Tdap for the 

following with no previous 

documentation of Tdap: adults, 

adolescents and adults who 

have or anticipate having close 

contact with an infant younger 

than age 12 months, and health 

care personnel

● 3 doses of tetanus- and 

diphtheria-containing vaccine 

(1 dose should be Tdap) for 

adolescents and adults 

without documentation of 

a primary series
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Immunogenicity and Vaccine Efficacy

After a primary series of 3 properly spaced doses of diphtheria 

toxoid-containing vaccines in infants and a booster dose at age 

15 through 18 months or 3 properly spaced doses in adults, a 

protective level of antitoxin (defined as greater than 0.1 IU of 

antitoxin/mL) is reached in more than 95% of vaccine recipients. 

Diphtheria toxoid-containing vaccine has been estimated to 

have an efficacy of 97%. 

Contraindications and Precautions 

to Vaccination

As with other vaccines, a history of a severe allergic reaction 

(anaphylaxis) to a vaccine component or following a prior 

dose is a contraindication to further doses. Moderate or severe 

acute illness (with or without fever) in a patient is considered a 

precaution to vaccination, although persons with minor illness 

may be vaccinated. 

Contraindications to combination vaccines that contain DTaP 

include the contraindications to the individual component 

vaccines (e.g., IPV, hepatitis B, Hib), but specific ingredients 

might differ. DTaP-HepB-IPV (Pediarix) and DTaP-IPV-HibHepB (Vaxelis) vaccines contain yeast. Presentations of some 

diphtheria toxoid-containing vaccines contain latex rubber. 

DTaP-HepB-IPV (Pediarix), DTaP-IPV/Hib (Pentacel), DTaP-IPVHib-HepB (Vaxelis), DTaP-IPV (Kinrix), and DTaP-IPV (Quadracel) 

contain neomycin and polymyxin B. DTaP-IPV-Hib-HepB (Vaxelis) 

contains streptomycin.

Encephalopathy not attributable to another identifiable cause 

occurring within 7 days after vaccination with DTaP, DTP, or Tdap 

is a contraindication for DTaP and Tdap vaccination.

A progressive or unstable neurological disorder, uncontrolled 

seizures, or progressive encephalopathy is a precaution for DTaP 

and Tdap vaccination. For persons with a known or suspected 

neurologic condition, vaccination with DTaP or Tdap should 

be delayed until the condition has been evaluated, treatment 

initiated, and the condition stabilized. These conditions 

include the presence of an evolving neurologic disorder 

(e.g., uncontrolled epilepsy, infantile spasms, and progressive 

encephalopathy); a history of seizures that has not been 

evaluated; or a neurologic event that occurs between doses 

of vaccine. A family history of seizures or other neurologic 

diseases, or stable or resolved neurologic conditions (e.g., 

controlled idiopathic epilepsy, cerebral palsy, developmental 

delay), are neither contraindications nor precautions to DTaP or 

Tdap vaccination. 

Diphtheria Toxoid-containing 

Vaccine Efficacy

● More than 95% of recipients 

develop protective antibody 

levels after 3 doses and booster 

(infants) or 3 doses (adults).

Diphtheria and Tetanus Toxoidscontaining Vaccine Contraindications 

and Precautions

● Contraindication

■ Severe allergic reaction 

to vaccine component or 

following a prior dose

■ Encephalopathy not 

attributable to another 

identifiable cause within 7 

days after vaccination*

● Precaution

■ Moderate or severe acute 

illness

■ Progressive or unstable 

neurological disorder*

■ Uncontrolled seizures*

■ Progressive encephalopathy*

■ Guillain-Barré syndrome 

within 6 weeks after a 

previous dose of tetanus 

toxoid-containing vaccine**

■ History of Arthus-type 

hypersensitivity reactions 

after a previous dose of 

diphtheria toxoid- or tetanus 

toxoid-containing vaccine**

*DTaP and Tdap

**DTaP, DT, Tdap, Td
108

Diphtheria

 7

Guillain-Barré syndrome within 6 weeks after a previous dose of 

tetanus toxoid-containing vaccine is a precaution for DTaP, Tdap, 

DT, and Td vaccination.

A history of Arthus-type hypersensitivity reactions after a 

previous dose of diphtheria toxoid-containing or tetanus 

toxoid-containing vaccine is a precaution for DTaP, Tdap, DT, 

and Td vaccination; vaccination should be deferred until 

at least 10 years have elapsed since the last tetanus toxoidcontaining vaccine.

Vaccine Safety

DTaP vaccine may cause local reactions, such as pain, redness, 

or swelling. Local reactions have been reported in 20% to 

40% of children after each of the first 3 doses. Local reactions 

appear to be more frequent after the fourth and/or fifth doses. 

Mild systemic reactions such as drowsiness, fretfulness, and 

low-grade fever may also occur. Temperature of 101°F or higher 

is reported in 3% to 5% of DTaP recipients. These reactions are 

self-limited and can be managed with symptomatic treatment 

with acetaminophen or ibuprofen. 

Moderate or severe systemic reactions (such as fever of 105°F 

or higher, febrile seizures, persistent crying lasting 3 hours or 

longer, and hypotonic-hyporesponsive episodes) have been 

reported after administration of DTaP, but occur less frequently 

than among children who received whole-cell DTP. Rates of 

moderate or severe systemic reactions vary by symptom and 

vaccine but generally occur in fewer than 1 in 10,000 doses. 

Exaggerated local (Arthus-type) reactions are rarely reported but 

may occur following receipt of a vaccine containing diphtheria 

or tetanus toxoids. 

The most common adverse reaction following vaccination with 

both brands of Tdap is a local reaction, such as pain (66% to 

75%), redness (25%), or swelling (21%) at the site of injection. 

Temperature of 100.4°F or higher was reported by 1.4% to 5% of 

Tdap recipients and 1.1% to 5% of Td recipients. Tdap recipients 

also reported a variety of nonspecific systemic events, such as 

headache, fatigue and gastrointestinal symptoms.

The Institute of Medicine reported in 2011 that the evidence 

was inadequate to accept or reject a causal relation between 

receipt of diphtheria toxoid and tetanus toxoid-containing 

vaccine and encephalitis, encephalopathy, infantile spasms, 

seizures, ataxia, autism, acute disseminated encephalomyelitis, 

transverse myelitis, optic neuritis, onset of multiple sclerosis 

in adults, relapse of multiple sclerosis in adults, relapse of 

multiple sclerosis in children, Guillain-Barré syndrome, chronic 

inflammatory disseminated polyneuropathy, opsoclonus 

myoclonus syndrome, or Bell’s palsy. 

Diphtheria Toxoid-containing 

Vaccine Safety

DTaP

● Pain, redness, or swelling

■ 20%-40%

■ More frequent after dose 

4 or 5

● Temperature of 101°F

■ 3%-5%

● Moderate or severe systemic 

reactions

■ Fewer than 1 in 10,000 doses

● Arthus-type reactions are rare

Tdap, Td

● Pain, redness, or swelling

■ 21%-75%

● Temperature of 100.4°F 

or higher

■ 1.1%-5%
Diphtheria

109

7

The most frequently reported adverse events after DTaP in the 

Vaccine Adverse Effect Reporting System (VAERS) and Vaccine 

Safety Datalink (VSD), two post-licensure surveillance systems, 

were consistent with observations from pre-licensure studies 

of these vaccines. When VAERS DTaP reports for each vaccine 

brand were compared individually with reports for all other 

inactivated vaccines in the VAERS database, no concerning 

patterns of adverse events were observed. 

Routine VAERS surveillance for and VSD studies on adverse 

events following receipt of Tdap vaccines in persons aged 10 

through 64 years have provided reassuring data consistent 

with the prelicensure clinical trial safety data and have not 

demonstrated any associations between Tdap and the following 

rare adverse events: encephalopathy-encephalitis-meningitis, 

paralytic syndromes, seizures, cranial nerve disorders, and 

Guillain-Barré syndrome.

Vaccine Storage and Handling

DTaP, Td, and Tdap vaccines should be maintained at refrigerator 

temperature between 2°C and 8°C (36°F and 46°F). Manufacturer 

package inserts contain additional information. For complete 

information on best practices and recommendations, please 

refer to CDC’s Vaccine Storage and Handling Toolkit, www.cdc.

gov/vaccines/hcp/admin/storage/toolkit/storage-handlingtoolkit.pdf. 

Surveillance and Reporting of 

Diphtheria Disease

In January 2019, the Council of State and Territorial 

Epidemiologists modified its diphtheria case definition. This 

modification specifies that toxigenic diphtheria infections from 

any anatomic site (such as skin), not only respiratory infections, 

should be reported. In addition, confirmed case classification 

requires verification of toxin production by the C. diphtheriae

isolate. For information on guidance for state and local health 

department staff who are involved in surveillance activities for 

vaccine-preventable diseases, please consult the Manual for the 

Surveillance of Vaccine-Preventable Diseases, www.cdc.gov/

vaccines/pubs/surv-manual/chapters.html.

Acknowledgements

The editors would like to acknowledge Susan Hariri, Fiona 

Havers, and Jennifer Liang for their contributions to this chapter.
110

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NOTES