Typhoid fever

What

Typhoid fever is caused by a systemic infection with Salmonella enterica subspecies enterica serovar Typhi. It is transmitted mainly through faecally contaminated food and water.

Who

Typhoid vaccination is recommended for:

• military personnel
• laboratory workers who routinely work with Salmonella Typhi
• travellers aged ≥2 years travelling to typhoid-endemic regions

How

Military personnel are recommended to receive 1 dose of parenteral typhoid vaccine, or 3 or 4 doses of oral typhoid vaccine.

Laboratory workers who routinely work with Salmonella Typhi are recommended to receive 1 dose of parenteral typhoid vaccine, or 3 or 4 doses of oral typhoid vaccine.

Children aged ≥2 years and adults travelling to typhoid-endemic regions are recommended to receive either 1 dose of parenteral typhoid vaccine, or 3 or 4 doses of oral typhoid vaccine, depending on their age.

Children aged ≥2 years and adults who received parenteral typhoid vaccine for their 1st vaccination and have ongoing exposure to Salmonella Typhi are recommended to be revaccinated every 3 years with a dose of parenteral typhoid vaccine.

Children aged ≥6 years and adults who received oral typhoid vaccine for their 1st vaccination and have ongoing exposure to Salmonella Typhi are recommended to be revaccinated with oral typhoid vaccine either:

• 3 years after a 3-dose course, or
• 5 years after a 4-dose course

Why

Typhoid fever is typically a travel-related disease. Most recent typhoid fever cases reported in Australia were acquired overseas.

Typhoid 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 oral live attenuated typhoid vaccine is supplied in a pack of 3 capsules. Each dose (a whole capsule) is the same for both adults and children. The vaccination schedule consists of 1 capsule on days 1, 3 and 5 (and day 7 if following a 4-dose schedule) taken 1 hour before food.

The dose of the parenteral monovalent typhoid vaccine is 0.5 mL (for both adults and children) given by intramuscular injection.

Co-administration with other vaccines

Oral live attenuated vaccine

Children and adults can receive oral typhoid vaccine at the same time as any other live parenteral vaccines. This includes yellow fever vaccine, BCG (bacille Calmette–Guérin) vaccine or MMR (measles-mumps-rubella) vaccine. ^1,4

If the person is also receiving the inactivated oral cholera vaccine, give the 2 vaccines at least 8 hours apart. See Contraindications and precautions.

Children and adults can receive the oral live attenuated typhoid vaccine at the same time as mefloquine or atovaquone/proguanil combination (Malarone). However, other antimalarials, including doxycycline, may interfere with the activity of the live attenuated typhoid vaccine and should not be started within 72 hours of the last dose of oral typhoid vaccine.⁵ See Contraindications and precautions.

Parenteral Vi polysaccharide vaccine

Children and adults can receive parenteral Vi polysaccharide typhoid vaccine at any time before or after, or with, other travel vaccines, such as oral cholera or yellow fever vaccines.

Contraindications

Typhoid vaccines are contraindicated in people who have had:

• anaphylaxis after a previous dose of any typhoid vaccine
• anaphylaxis after any component of a typhoid vaccine

Oral live attenuated vaccine

These groups should not receive the oral live attenuated vaccine:

• children <6 years of age — use the parenteral Vi polysaccharide vaccine instead in children 2–5 years of age
• pregnant women — use the parenteral Vi polysaccharide vaccine instead
• people who are immunocompromised, including people with HIV — use the parenteral Vi polysaccharide vaccine instead
• people who are taking antibiotics — use the parenteral Vi polysaccharide vaccine instead

Precautions

Oral live attenuated vaccine

Gastric acid can destroy the oral live attenuated vaccine strain. Because of this, people must swallow the capsules whole with water, not chew them or open them.

People receiving both oral live attenuated typhoid vaccine and inactivated oral cholera vaccine should have the vaccines at least 8 hours apart. This is because the buffer in the cholera vaccine may affect how the capsules of oral typhoid vaccine move through the gastrointestinal tract.

Some antibiotics and antimalarial agents can inactivate the oral live attenuated typhoid vaccine. Time the vaccination so the person receives the last dose of oral typhoid vaccine at least 3 days before starting antibiotics or antimalarial prophylaxis. However, immune responses and efficacy are not affected by concurrent administration of either mefloquine or atovaquone/proguanil combination (Malarone).

Close contacts, such as household members of immunocompromised people, can receive oral live typhoid vaccine. However, similar to other oral vaccines, precautions should be taken to avoid the theoretical risk of vaccine strain virus transmission to immunocompromised close contacts (see Close contacts of people who are immunocompromised). After receiving live oral typhoid vaccine, care should be taken to ensure strict hand hygiene for both the person who received the vaccine and household members who are immunocompromised.

Parenteral Vi polysaccharide vaccine

The parenteral Vi polysaccharide vaccine is not routinely recommended for pregnant or breastfeeding women. Vaccination with typhoid Vi polysaccharide vaccine during pregnancy has not been directly evaluated, although it is unlikely to result in adverse effects. Pregnant or breastfeeding women can receive the vaccine if travelling to endemic countries where water quality and sanitation are poor and the high potential benefit outweighs the minimal risks.³

See Vaccination for women who are planning pregnancy, pregnant or breastfeeding for more details.

Typhoid vaccines, both oral and parenteral, are associated with very few serious adverse events. When adverse events do occur, they tend to be mild and transient.⁶

Oral live attenuated vaccine

The following adverse events have occasionally been reported after receiving the oral live attenuated vaccine:⁶

• abdominal discomfort
• diarrhoea
• nausea
• vomiting
• rashes

Parenteral Vi polysaccharide vaccine

Adverse events after receiving the parenteral Vi polysaccharide vaccine are common and include: ⁶

• local adverse events such as erythema, swelling and pain at the injection site, which occur in 10–20% of vaccine recipients
• systemic adverse events, such as fever (3% of recipients), malaise and nausea

Typhoid fever is caused by a systemic infection with Salmonella enterica subspecies enterica serovar Typhi (Salmonella Typhi). Paratyphoid fever, caused by infection with Salmonella enterica serovar Paratyphi A or B, is similar to typhoid fever.⁷ The 2 diseases are often indistinguishable.

Typhoid and paratyphoid fever are collectively known as enteric fever. Their geographic distributions largely overlap. No vaccine specifically targets paratyphoid fever, but some evidence suggests that the oral live attenuated typhoid vaccine cross-protects against Salmonella Paratyphi B.^8-10

Pathogenesis

Typhoid fever has a usual incubation period of 7–14 days. This ranges from 3 to 60 days.¹¹

Humans are the sole reservoir of Salmonella Typhi. It is shed in the faeces of people who are acutely ill and people who are chronic asymptomatic carriers of the organism.

Transmission

Transmission usually occurs by ingesting faecally contaminated food or water.

In countries where human waste is not disposed of appropriately, typhoid fever is most commonly transmitted through contaminated water supplies. In contrast, in countries with better sanitation practices, typhoid fever is more commonly transmitted through contaminated food.¹

Symptoms of typhoid fever

Clinical presentations can be quite variable, but typical symptoms are:¹¹

• low-grade fever
• dull frontal headache
• malaise
• myalgia
• anorexia
• dry cough

As the disease progresses, common symptoms include:¹¹

• increased fever
• constipation (more typically diarrhoea in young children)
• abdominal tenderness
• relative bradycardia
• splenomegaly

Complications of typhoid fever

Complications occur in 10–15% of patients. Patients who have been ill for more than 2 weeks tend to develop complications. Important complications include:¹¹

• gastrointestinal bleeding
• intestinal perforation
• typhoid encephalopathy

Relapse occurs in up to 10% of patients, usually 2–3 weeks after the initial fever resolves.

Up to 5% of patients with typhoid fever develop chronic asymptomatic biliary carriage of Salmonella Typhi, even after treatment. A chronic carrier is someone who continuously sheds the organism for at least 1 year. Carriers are an important reservoir in endemic areas. They are of public health significance — for example, if they work in the food industry.¹¹

Typhoid fever in Australia

Fewer than 150 cases of typhoid fever are typically reported in Australia each year. Most cases are in people who have travelled to regions with endemic disease.^12,13 In 2014, 119 cases of typhoid fever were notified in Australia, and 92% of these cases were acquired overseas.¹³

In developed countries, typhoid fever is mainly a travel-related disease. People have a considerably greater risk if they are travelling to the Indian subcontinent than to other regions.^13-15

People who travel to endemic regions to visit friends and relatives appear to be at considerably greater risk of acquiring typhoid fever than other travellers.^14,15 This group includes immigrants who travel to their former homelands.

Typhoid fever in developing countries

Most typhoid fever cases occur in developing countries, where endemic disease is influenced by:

• poor sanitation
• poor food hygiene
• untreated drinking water

In these countries, typhoid fever has moderate to high incidence, and high mortality.¹⁴

Geographic regions with high incidence (>100 cases per 100,000 population per year) include:

• the Indian subcontinent
• most Southeast Asian countries
• several South Pacific nations, including Papua New Guinea

Estimates of incidence from African countries are limited.

In many regions, particularly the Indian subcontinent, strains that are partially or completely resistant to many antibiotics (including ciprofloxacin) are detected with increasing frequency.¹⁶

No prospective clinical trials have studied the oral or the parenteral vaccine in travellers to endemic regions. Many travellers do not have any naturally acquired immunity, so typhoid vaccine may not protect as well as has been documented in some clinical trials.^1,11 However, circumstantial and epidemiological evidence suggests that the vaccines do protect travellers to endemic regions,^1,14,17-20 and that travellers need revaccination every 3 years to prolong protection.²¹

Oral live attenuated vaccines

The attenuated non-pathogenic Salmonella Typhi strain Ty21a was derived by chemically attenuating a wild-type strain.

The Salmonella Typhi strain Ty21a cannot be detected in faeces more than 3 days after receiving the vaccine.

The vaccine stimulates: ¹

• serum IgG
• vigorous secretory intestinal IgA
• cell-mediated immune responses

Clinical trials have been done in several countries with endemic typhoid fever, including Chile, Egypt and Indonesia. The trials used different formulations of the vaccine and a variety of schedules. They revealed varying levels of protection against typhoid fever.^1,11

A large clinical trial in more than 200,000 school children compared the efficacy of 2, 3 and 4 doses of enteric-coated oral typhoid vaccine.² The study showed that 4 doses of the oral typhoid vaccine (administered every other day over 7 days) resulted in a significantly lower typhoid fever incidence than 3 doses.

Parenteral Vi polysaccharide vaccines

Parenteral Vi polysaccharide vaccines are produced by:¹

• fermenting the Ty2 strain
• inactivating it with formaldehyde
• extracting the polysaccharide from the supernatant using a detergent

After vaccination, 85–95% of adults and children >2 years of age quickly develop anti-Vi antibodies. The vaccines have been used in clinical trials in endemic regions, including China, Nepal and South Africa. They showed moderate protection against typhoid fever.^1,11

Epidemiological studies used enteric fever surveillance records to estimate the vaccine effectiveness of typhoid Vi polysaccharide vaccines.²⁰ Vaccine effectiveness was estimated at 65% over 3 years in travellers to typhoid-endemic regions, which was consistent with previous efficacy trials.

Studies have shown herd protection of unvaccinated people living in areas with moderate coverage of parenteral vaccine.^22,23

Transport according to National vaccine storage guidelines: Strive for 5.²⁴ Store at +2°C to +8°C. Do not freeze. Protect from light.

For oral typhoid vaccine, the person to be vaccinated is responsible for the vaccine after they buy it.

Carefully explain:

• how to transport the vaccine from pharmacy to home
• how to store it at home in the refrigerator

Typhoid fever is a notifiable disease in all states and territories in Australia.

The Communicable Diseases Network Australia national guidelines for typhoid and paratyphoid fevers²⁵ have details about the management of typhoid fever cases and contacts.

State and territory public health authorities can provide further advice about the public health management of typhoid fever.

Vivotif 4-dose schedule

The Australian product information for Vivotif Oral live attenuated vaccine does not mention using a 4-dose course of the vaccine for either primary or repeat vaccination. This vaccine is registered for use in a 4-dose schedule in other countries, including Canada and the United States.

The Australian Technical Advisory Group on Immunisation (ATAGI) recommends that children and adults can consider receiving a 4-dose course to increase protection against typhoid fever.

Vivotif in pregnancy

The product information for Vivotif Oral live attenuated vaccine does not include pregnancy among the listed contraindications.

ATAGI recommends that pregnancy is a contraindication to the oral live attenuated typhoid vaccine.

Booster doses of Vivotif

The product information for Vivotif Oral live attenuated vaccine recommends a booster every 3 years.

For people at ongoing risk of typhoid fever, ATAGI also recommends revaccination with a 3- or 4-dose course of the oral live attenuated vaccine 3 years after a 3-dose course, or 5 years after a 4-dose course.

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2. Ferreccio C, Levine MM, Rodriguez H, Contreras R, Chilean Typhoid Committee. Comparative efficacy of two, three, or four doses of TY21a live oral typhoid vaccine in enteric-coated capsules: a field trial in an endemic area. Journal of Infectious Diseases 1989;159:766-9.
3. Therapeutic Goods Administration (TGA). Australian Product Information – Typhim VI, Salmonella Typhi VI Polysaccharide.2023. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2013-PI-01312-1
4. World Health Organization (WHO). Typhoid vaccines: WHO position paper. Weekly Epidemiological Record 2008;83:49-59.
5. Therapeutic Goods Administration (TGA). Australian Product Information – APX Doxycycline (Doxycycline Hyclate (Hydrochloride)) Tablets.2023. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2020-PI-01672-1
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7. Maskey AP, Day JN, Phung QT, et al. Salmonella enterica serovar Paratyphi A and S. enterica serovar Typhi cause indistinguishable clinical syndromes in Kathmandu, Nepal. Clinical Infectious Diseases 2006;42:1247-53.
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