Diphtheria

What

Diphtheria is an acute illness caused by the bacterium Corynebacterium diphtheriae. Infection can produce a thick membrane in the pharynx, causing severe respiratory obstruction. The bacteria produce a toxin that can cause life-threatening heart failure and paralysis.

Who

Diphtheria-toxoid vaccine is recommended for:

• routine vaccination in infants, children and adolescents
• routine booster vaccination in adults, including those in special risk groups such as
  • pregnant women
  • laboratory workers
  • travellers to countries where health services are difficult to access
• vaccination of people who have missed doses of diphtheria-containing vaccine

How

Diphtheria-toxoid vaccines are only available in Australia as combination vaccines that include other antigens such as pertussis and tetanus.

Diphtheria-toxoid vaccines are recommended for children at 2, 4, 6 and 18 months, and 4 years of age, and adolescents at 11–13 years of age.

A diphtheria-toxoid vaccine booster is recommended for adults at 50 years of age.

Vaccination is recommended every 10 years for travellers to countries where health services are difficult to access. Travellers to some areas where there is a higher risk of acquiring diphtheria are recommended to be vaccinated every 5 years.

Laboratory workers who may be exposed to toxigenic Corynebacterium diphtheriae in their jobs are recommended to have a serology test for diphtheria antibodies every 10 years. They should receive a booster dose of either dTpa (reduced antigen content diphtheria-tetanus-acellular pertussis) or dT (diphtheria-tetanus) if the diphtheria antitoxin level is <0.1 IU per mL.

Adolescents and adults who have never had a diphtheria-toxoid vaccine are recommended to receive 3 doses of diphtheria-toxoid vaccine with at least 4 weeks between doses, and booster doses at 10 years and 20 years after the primary course.

Why

Diphtheria is rare in Australia but remains endemic in many developing countries. Most Australian cases are imported from overseas. However, an unimmunised person who had never been overseas died from diphtheria myocarditis in Queensland in 2018 and an unimmunised toddler required ICU admission for respiratory diphtheria in 2022.

Diphtheria vaccines available in Australia

The Therapeutic Goods Administration website provides product information for each vaccine.

See also Vaccine information and Variations from product information for more details.

Dose and route

The dose of all diphtheria-toxoid vaccines is 0.5 mL given by intramuscular injection.

Co-administration with other vaccines

Do not mix DTPa- or dTpa-containing vaccines or dT vaccine with any other vaccine in the same syringe, unless specifically registered for use in this way.

Diphtheria-toxoid vaccines can be co-administered with most other vaccines.

Vaxelis can be given at the same time as other scheduled vaccines, including MenB vaccines.

Nimenrix vaccine contains small amounts of tetanus toxoid. If a person needs to receive Nimenrix and a vaccine containing tetanus toxoid, co-administration of these vaccines is preferred. Giving Nimenrix after a vaccine containing tetanus toxoid may interfere with the immune response against some meningococcal serogroups. There is uncertainty about whether this reduced immune response affects clinical protection, and there are no data on the optimal interval between the vaccines. Therefore, Nimenrix should be given as scheduled, even if it is being given shortly after a vaccine containing tetanus toxoid.

Interchangeability of diphtheria vaccines

If possible, complete the vaccination schedule for diphtheria with the same vaccine brand. If this is not possible, use an alternative brand of the same antigen combination following the dose recommendations. See Recommendations.

Contraindications

The only absolute contraindications to diphtheria-toxoid vaccines are:

• anaphylaxis after a previous dose of any diphtheria-toxoid vaccine
• anaphylaxis after any component of a diphtheria-toxoid vaccine

Precautions

People with latex allergy

The product information for Adacel and ADT booster states that the tip cap of the syringe contains latex. Consider using an alternative product in people with an allergy or sensitivity to latex.

Mild discomfort or pain at the injection site is common after receiving diphtheria-toxoid vaccine. This can last for a few days. Uncommon general adverse events after receiving dT vaccine include:

• headache
• lethargy
• malaise
• myalgia
• fever

Very rare adverse events after receiving dT vaccine include:

• anaphylaxis
• urticaria
• peripheral neuropathy

Brachial neuritis may occur after receiving diphtheria-toxoid vaccine. This is inflammation of a nerve in the arm, causing weakness or numbness. The excess risk is approximately 0.5–1 in 100,000 doses in adults. ^5,6

Specific adverse events after receiving a combination vaccine containing both diphtheria and pertussis antigens are extensive limb swelling, febrile convulsions and hypotonic-hyporesponsive episodes. See Pertussis for more details.

Combination vaccines containing both diphtheria and pertussis antigens are safe and well tolerated in adults when given as a booster dose.^3,7-9 See Pertussis.

Adverse reactions to a single dose of dTpa vaccine are similar whether a person receives the vaccine shortly after, or at a longer interval after, a previous dT vaccine.^10-13 See also Pertussis.

Local and systemic adverse reactions are more common after hexavalent vaccines than after monovalent vaccines. There is little to no difference in the rates of adverse events after hexavalent vaccines compared with other combination vaccines including other hexavalent vaccines.^14-16

Diphtheria is an acute illness caused by toxigenic strains of Corynebacterium diphtheriae. The bacterium is gram-positive, non-spore-forming and non-capsulate.¹

The bacteria produce an exotoxin that acts locally on the mucous membranes of the respiratory tract or, less commonly, on damaged skin. It produces an adherent pseudomembrane. Systemically, the toxin acts on cells of the myocardium, nervous system and adrenals.

The incubation period is 2–5 days. The disease is communicable for up to 4 weeks, but carriers may shed organisms for longer.¹⁷ Diphtheria spreads by:

• aerosol transmission
• direct contact with skin lesions
• direct contact with articles soiled by infected people

Diphtheria infection may lead to two different clinical outcomes: respiratory disease or cutaneous (skin) disease. Almost any mucous membrane can be involved, with pharyngeal diphtheria historically the most common form of the disease in unimmunised people. Pharyngeal diphtheria is characterised by an inflammatory exudate that forms a greyish or green membrane in the upper respiratory tract. This can cause acute severe respiratory obstruction.

Life-threatening complications from diphtheria include myocarditis and neuritis (usually affecting motor nerves). The case-fatality rate in the past 3 decades has been up to 16%.¹⁸

Diphtheria antitoxin neutralises unbound toxin. It was first used in the 1890s. Antibiotics and antitoxin are the main treatments for diphtheria, but may not always be successful.

Active immunisation with diphtheria-toxoid vaccines is the only effective way to protect against diphtheria.^1,17

In the early 1900s, diphtheria caused more deaths in Australia than any other infectious disease.¹⁹ Since the implementation of vaccination programs in the 1940s, the incidence of diphtheria has declined in Australia, and globally. Although diphtheria remains rare in Australia, there were 45 cases reported between 2011 and 2019. Of the total cases (46) reported between 1999 and 2019, 38 (0.008 per 100,000 population per year) were cutaneous diphtheria and 8 (0.002 per 100,000 population per year) were respiratory diphtheria.²⁰ 

Cutaneous and respiratory diphtheria occur mostly among adults in Australia with no cases of respiratory diphtheria reported in children <15 years of age between 1999 and 2019. During this period, there were 2 deaths reported in unvaccinated adults, both acquiring diphtheria in Australia.20 In 2022, the first contemporary case of respiratory diphtheria was reported in an unvaccinated toddler, followed by a 6-year-old child who was a close contact.²¹

Almost all recent cases in the United Kingdom and the United States have been associated with imported infections.²² Likewise, in Australia between 1999 and 2019, the majority of cases were acquired overseas, predominantly from the Western Pacific Region.²⁰

 

Diphtheria toxoid is available in Australia only in combination with tetanus toxoid. Vaccines may also include other antigens, such as pertussis, inactivated poliovirus, hepatitis B and Haemophilus influenzae type b.

The acronym DTPa, using capital letters, signifies a child formulation of diphtheria, tetanus and acellular pertussis–containing vaccine.

The acronym dTpa signifies a formulation that contains substantially less diphtheria toxoid and pertussis antigens than the child formulation. Adolescents and adults usually receive reduced antigen dTpa vaccine because they generally respond better to diphtheria toxoid and require lower doses to establish or maintain immunity.

Immunogenicity

Diphtheria vaccination stimulates the production of antibodies, also known as ‘antitoxin’, which protect against diphtheria toxin.

The vaccine antigen is prepared by treating a cell-free toxin preparation with formaldehyde. This converts it into diphtheria toxoid, which is safe.

Diphtheria toxoid is usually adsorbed onto an adjuvant to increase its immunogenicity. Adjuvants are either aluminium phosphate or aluminium hydroxide.

The circulating levels of antitoxin required for protection from diphtheria are well described:

• Levels of <0.01 IU per mL are poorly protective.
• Levels of 0.01–0.1 IU per mL are usually protective.
• Levels of >0.1 IU per mL are associated with more certain and prolonged protection.²³

Studies have shown that, 1 month after the 3-dose primary vaccination series of DTPa-hepB-IPV-Hib vaccines, 97.4–100% (Infanrix hexa) and 99.8% (Vaxelis) of infants had diphtheria antitoxin levels of ≥0.1 IU per mL. After a 4th dose in the 2nd year of life, 96.8–100% (Infanrix hexa) and 98.6%-100% (Vaxelis) of infants had antibody levels of ≥0.1 IU per mL for both diphtheria and tetanus.^24-26

A study of adults with unknown vaccination history showed that, after 3 doses of either a dT or a dTpa vaccine, 99% of adults had protective antibody levels.³

Duration of immunity

Complete immunisation induces protective levels of antitoxin that last throughout childhood. But, by middle age, at least 50% of people who have not been vaccinated since childhood have levels <0.1 IU per mL.^27-29 This has been confirmed in Australia by a national serosurvey.² The clinical significance of these antibody levels with regard to protective immunity is uncertain.

A single low dose of diphtheria toxoid in a previously immunised adult induces protective levels of antitoxin within 6 weeks.³⁰

Transport according to National Vaccine Storage Guidelines: Strive for 5.³¹ Store at +2°C to +8°C. Do not freeze. Protect from light.

Infanrix hexa vaccine must be reconstituted. Add the entire contents of the syringe to the vial and shake until the pellet completely dissolves. Use the reconstituted vaccine as soon as practicable. If it must be stored, hold at room temperature for no more than 8 hours.

Diphtheria is a notifiable disease in all states and territories in Australia.

Confirmed or suspected diphtheria is of considerable public health importance. It should be notified immediately to state or territory public health authorities. Contacts usually need vaccination (either primary or booster, depending on their vaccination status) and appropriate prophylactic antibiotics.³²

State and territory public health authorities can advise on and coordinate:

• public health management of diphtheria, including management of cases of diphtheria and their contacts
• access to diphtheria antitoxin
• dosage of diphtheria antitoxin
• special arrangements if hypersensitivity is suspected

Routine vaccination in children and adults

Infanrix

The product information for Infanrix states that this vaccine is for:

• primary immunisation of infants aged between 2 months and 12 months
• booster dose in children aged 15 months to 6 years who have previously been vaccinated against diphtheria, tetanus and pertussis

The Australian Technical Advisory Group on Immunisation (ATAGI) recommends that Infanrix may also be used for catch-up of the primary schedule or as a booster in children <10 years of age. ATAGI also recommends that the primary schedule can start at 6 weeks of age.

Infanrix hexa

The product information for Infanrix hexa states that this vaccine is for:

• primary immunisation of infants from the age of 6 weeks
• booster dose in children 18 months of age if they need boosting for all antigens

ATAGI recommends that Infanrix hexa may also be used for catch-up of the primary schedule or as a booster in children <10 years of age.

Vaxelis

The product information for Vaxelis states that this vaccine is for:

• primary immunisation of infants from the age of 6 weeks
• a booster dose at least 6 months after the last priming dose

ATAGI recommends that Vaxelis may also be used for catch-up of the primary schedule or as a booster in children <10 years of age.

Infanrix IPV

The product information for Infanrix IPV states that this vaccine is for:

• use in a 3-dose primary schedule for immunisation of infants from the age of 6 weeks
• a single booster dose in children ≤6 years of age who have previously been vaccinated against diphtheria, tetanus, pertussis and poliomyelitis

ATAGI recommends that Infanrix IPV may also be used for catch-up of the primary schedule or as a booster in children <10 years of age.

Quadracel

The product information for Quadracel states that this vaccine is for:

• use in a 3-dose primary schedule from the age of 2 months to 12 months
• booster dose in children from 15 months to 6 years of age who have previously been vaccinated against diphtheria, tetanus, pertussis and poliomyelitis

ATAGI recommends that Quadracel may also be used for catch-up of the primary schedule or as a booster in children aged <10 years. ATAGI also recommends that the primary schedule can start at 6 weeks of age.

Tripacel

The product information for Tripacel states that this vaccine is for:

• use in a 3-dose primary schedule from the age of 2 months to 12 months
• booster dose in children from 15 months to 8 years of age who have previously been vaccinated against diphtheria, tetanus and pertussis

ATAGI recommends that Tripacel may also be used for catch-up of the primary schedule or as a booster in children aged <10 years. ATAGI also recommends that the primary schedule can start at 6 weeks of age.

Adacel and Boostrix

The product information for Adacel (reduced antigen content dTpa) states that this vaccine is for use in people aged ≥10 years for booster doses only.

The product information for Boostrix (reduced antigen content dTpa) states this vaccine is for use in people aged ≥4 years for booster doses only.

ATAGI recommends that, when an adolescent or adult receives a 3-dose primary course of diphtheria/tetanus toxoids:

• dTpa should replace the 1st dose of dT
• the 2nd and 3rd doses should be dT

If dT is not available, dTpa can be used for all 3 primary doses.

The product information for Adacel and Boostrix states that there is no recommendation about the frequency of vaccination against pertussis in adults. ATAGI recommends that adults in contact with infants and/or at increased risk from pertussis should have received the vaccine within the past 10 years.

Adacel Polio, Boostrix and Boostrix-IPV

The product information for Adacel Polio, Boostrix and Boostrix-IPV states that vaccine is for use in people aged ≥4 years for booster doses only.

ATAGI recommends that Adacel Polio, Boostrix and Boostrix-IPV should not be used in people aged <10 years, except in certain circumstances.

ADT Booster

The product information for ADT Booster states that this vaccine is for use as a booster dose only in:

• children aged ≥5 years
• adults who have previously received at least 3 doses of diphtheria and tetanus vaccines

ATAGI recommends that, where a dT vaccine is required, ADT Booster can be used for any dose. This includes for primary immunisation against diphtheria and tetanus for any person ≥10 years of age.

Vaccination during pregnancy

The product information for Adacel states that vaccinating pregnant women is not recommended unless there is a definite risk of acquiring pertussis.

The product information for Boostrix states that the vaccine may be considered during the 3rd trimester of pregnancy when the possible advantages outweigh the possible risks for the fetus.

The product information for Adacel and Boostrix states that there is no recommendation about vaccination against pertussis in subsequent pregnancies.

ATAGI recommends that pregnant women receive a dose of pertussis-containing vaccine with each pregnancy, from 20 weeks gestation, or if indicated earlier, at any time in the pregnancy.

Vaccination after tetanus-containing vaccines

The product information for Adacel, Boostrix and Boostrix-IPV states that people should not receive a dTpa-containing vaccine within 5 years of a tetanus-containing vaccine.

ATAGI recommends that, if the person needs protection against pertussis, they can receive a dTpa-containing vaccine at least 4 weeks after a dT-containing vaccine.

Contraindications

The product information for all vaccines except ADT Booster states that these vaccines are contraindicated in children with either:

• encephalopathy of unknown aetiology, or
• neurologic complications occurring within 7 days after a vaccine dose

ATAGI recommends that the only contraindications are:

• anaphylaxis after a previous dose of any diphtheria-toxoid vaccine
• anaphylaxis after any component of a diphtheria-toxoid vaccine

1. Tiwari TS, Wharton M. Diphtheria toxoid. In: Plotkin SA, Orenstein WA, Offit PA, Edwards KM, eds. Plotkin's vaccines. 7th ed. Philadelphia, PA: Elsevier; 2018.
2. Gidding HF, Backhouse JL, Burgess MA, Gilbert GL. Immunity to diphtheria and tetanus in Australia: a national serosurvey. Medical Journal of Australia 2005;183:301-4.
3. Theeten H, Rümke H, Hoppener FJ, et al. Primary vaccination of adults with reduced antigen-content diphtheria-tetanus-acellular pertussis or dTpa-inactivated poliovirus vaccines compared to diphtheria-tetanus-toxoid vaccines. Current Medical Research and Opinion 2007;23:2729-39.
4. Centers for Disease Control and Prevention (CDC). Updated recommendations for use of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine (Tdap) in pregnant women – Advisory Committee on Immunization Practices (ACIP), 2012. MMWR. Morbidity and Mortality Weekly Report 2013;62:131-5.
5. Hamati-Haddad A, Fenichel GM. Brachial neuritis following routine childhood immunization for diphtheria, tetanus, and pertussis (DTP): report of two cases and review of the literature. Pediatrics 1997;99:602-3.
6. Institute of Medicine. Stratton KR, Howe CJ, Johnston RB, Jr., eds. Adverse events associated with childhood vaccines: evidence bearing on causality. Washington, DC: National Academy Press; 1994.
7. Blatter M, Friedland LR, Weston WM, Li P, Howe B. Immunogenicity and safety of a tetanus toxoid, reduced diphtheria toxoid and three-component acellular pertussis vaccine in adults 19–64 years of age. Vaccine 2009;27:765-72.
8. Turnbull FM, Heath TC, Jalaludin BB, Burgess MA, Ramalho AC. A randomized trial of two acellular pertussis vaccines (dTpa and pa) and a licensed diphtheria-tetanus vaccine (Td) in adults. Vaccine 2000;19:628-36.
9. Pichichero ME, Rennels MB, Edwards KM, et al. Combined tetanus, diphtheria, and 5-component pertussis vaccine for use in adolescents and adults. [erratum appears in JAMA. 2005 Dec 28;294(24):3092]. JAMA 2005;293:3003-11.
10. David ST, Hemsley C, Pasquali PE, et al. Enhanced surveillance for vaccine-associated adverse events: dTap catch-up of high school students in Yukon. Canada Communicable Disease Report 2005;31:117-26.
11. Tremblay M, Grenier JL, De Serres G, et al. Adverse events after vaccination with dTap in high school students who have previously been vaccinated with d₂T₅. Canada Communicable Disease Report 2006;32:25-8.
12. Halperin SA, Sweet L, Baxendale D, et al. How soon after a prior tetanus-diphtheria vaccination can one give adult formulation tetanus-diphtheria-acellular pertussis vaccine? Pediatric Infectious Disease Journal 2006;25:195-200.
13. Talbot EA, Brown KH, Kirkland KB, et al. The safety of immunizing with tetanus-diphtheria-acellular pertussis vaccine (Tdap) less than 2 years following previous tetanus vaccination: experience during a mass vaccination campaign of healthcare personnel during a respiratory illness outbreak. Vaccine 2010;28:8001-7.
14. Oliver SE, Moro P, Blain AE. Haemophilus influenzae type b. In: Hall E, Wodi AP, Hamborsky J, Morelli V, Schillie S, eds. Epidemiology and prevention of vaccine-preventable diseases. 14th ed. Washington, DC: Public Health Foundation; 2021. https://www.cdc.gov/vaccines/pubs/pinkbook/downloads/hib.pdf
15. Vesikari T, Becker T, Vertruyen AF, et al. A phase III randomized, double-blind, clinical trial of an investigational hexavalent vaccine given at two, three, four and twelve months. Pediatric Infectious Disease Journal 2017;36:209-15.
16. Silfverdal SA, Icardi G, Vesikari T, et al. A phase III randomized, double-blind, clinical trial of an investigational hexavalent vaccine given at 2, 4, and 11–12 months. Vaccine 2016;34:3810-6.
17. Centers for Disease Control and Prevention (CDC). Diphtheria. In: Hamborsky J, Kroger A, Wolfe C, eds. Epidemiology and prevention of vaccine-preventable diseases. 13th ed. Washington, DC: Public Health Foundation; 2015. https://www.cdc.gov/vaccines/pubs/pinkbook/index.html
18. Vitek CR, Wharton M. Diphtheria toxoid. In: Plotkin SA, Orenstein WA, Offit PA, eds. Vaccines. 5th ed. Philadelphia, PA: Saunders Elsevier; 2008.
19. Gidding HF, Burgess MA, Kempe AE. A short history of vaccination in Australia. [erratum appears in Med J Aust 2001 Mar 5;174(5):260]. Medical Journal of Australia 2001;174:37-40.
20. Winkler NE, Dey A, Quinn HE, et al. Australian vaccine preventable disease epidemiological review series: diphtheria 1999–2019. Communicable Diseases Intelligence (2018) 2022;46 (doi:10.33321/cdi.2022.46.42).
21. Beard F, Macartney K, Winkler N. Diphtheria is back in Australia, here’s why – and how vaccines can prevent its spread. The Conversation [online]. 5 July 2022. https://theconversation.com/diphtheria-is-back-in-australia-heres-why-and-how-vaccines-can-prevent-its-spread-186348
22. Gidding HF, Burgess MA, Gilbert GL. Diphtheria in Australia, recent trends and future prevention strategies. Communicable Diseases Intelligence 2000;24:165-7.
23. Sutter RW, Hardy IR, Kozlova IA, et al. Immunogenicity of tetanus-diphtheria toxoids (Td) among Ukrainian adults: implications for diphtheria control in the Newly Independent States of the former Soviet Union. Journal of Infectious Diseases 2000;181 Suppl 1:S197-202.
24. Tichmann-Schumann I, Soemantri P, Behre U, et al. Immunogenicity and reactogenicity of four doses of diphtheria-tetanus-three-component acellular pertussis-hepatitis B-inactivated polio virus-Haemophilus influenzae type b vaccine coadministered with 7-valent pneumococcal conjugate vaccine. Pediatric Infectious Disease Journal 2005;24:70-7.
25. Tregnaghi M, Zambrano B, Santos-Lima E. Antibody persistence after a primary series of a new DTaP-IPV-Hep B-PRP-T combined vaccine or separate DTaP-IPV//PRP-T and hepatitis B vaccines at 2, 4, and 6 months of age and the effect of a subsequent DTaP-IPV//PRP-T booster vaccination at 18 months of age in healthy Argentinean infants. Pediatric Infectious Disease Journal 2012;31:e24-30.
26. Maxx Pharma Pty Ltd. Australian product information: Vaxelis. 2022. https://www.ebs.tga.gov.au
27. Hasselhorn HM, Nübling M, Tiller FW, Hofmann F. Factors influencing immunity against diphtheria in adults. Vaccine 1998;16:70-5.
28. Maple PA, Jones CS, Wall EC, et al. Immunity to diphtheria and tetanus in England and Wales. Vaccine 2000;19:167-73.
29. McQuillan GM, Kruszon-Moran D, Deforest A, Chu SY, Wharton M. Serologic immunity to diphtheria and tetanus in the United States. Annals of Internal Medicine 2002;136:660-6.
30. Marlovits S, Stocker R, Efstratiou A, et al. Effect on diphtheria immunity of combined tetanus and diphtheria booster vaccination in adults. European Journal of Clinical Microbiology and Infectious Diseases 2000;19:506-13.
31. National vaccine storage guidelines: Strive for 5. 3rd ed. Canberra: Australian Government Department of Health and Ageing; 2019. https://www.health.gov.au/resources/publications/national-vaccine-storage-guidelines-strive-for-5
32. Bonnet JM, Begg NT. Control of diphtheria: guidance for consultants in communicable disease control. Communicable Disease and Public Health 1999;2:242-9.