The disease

Typhoid fever is a systemic infection caused by the gram-negative bacterium Salmonella enterica, subspecies enterica, serotype typhi. Paratyphoid fever is an illness clinically similar but usually less severe than typhoid and is caused by S. paratyphi A, B and C.
Following ingestion of contaminated food or water, S. typhi penetrates the intestinal mucosa, replicates and enters the bloodstream. The severity of symptoms varies. Clinical features range from mild fever, diarrhoea, myalgia and headache to severe disseminated disease with multi-organ involvement in 10 to 15% of cases. The case–fatality rate (CFR) is less than 1% with prompt antibiotic therapy, but may be as high as 20% in untreated cases. Typhoid has previously been thought to be a milder disease in children. Recent information, however, indicates that typhoid can cause significant morbidity in children aged one to five years who reside in endemic countries (Sinha et al., 1999).
Unlike other Salmonella species, both S. typhi and S. paratyphi only colonise humans. Most of the more than 2000 other serotypes of Salmonella cause only local infection of the gastro-intestinal tract (gastroenteritis or ‘food poisoning’) and are commonly found in many mammalian hosts.
Transmission is primarily via the oral route following ingestion of food or water contaminated by faeces and occasionally the urine of persons acutely ill with typhoid or those who are chronic carriers. Direct faecal–oral transmission can also occur. In healthy individuals, one million or more organisms may be required to cause illness; however, ingestion of fewer organisms may still result in illness, especially in susceptible individuals. The incubation period varies from one to three weeks, depending on host factors and the size of the infecting dose (Glynn and Bradley, 1992).
The risk of contracting typhoid fever is highest for travellers to areas of high endemicity. In the Indian subcontinent, a region of high incidence of typhoid fever (more than 100 cases per 100,000 people per year (Crump et al., 2004)), the attack rate for travellers has been estimated at 1 to 10 per 100,000 journeys (Mermin et al., 1998; Steinberg et al., 2004; Connor and Schwartz, 2005).
All patients with typhoid and paratyphoid excrete the organisms at some stage during their illness. About 10% of patients with typhoid excrete S. typhi for at least three months following the acute illness, and 2 to 5% become long-term carriers (more than one year). The likelihood of becoming a chronic carrier increases with age, especially in females and those with a biliary tract abnormality.
Typhoid can be successfully treated with antibiotic therapy and general medical support. Strains of S. typhi have become increasingly resistant to antibiotics, particularly in South Asia (Threlfall and Ward, 2001). This has implications for the treatment of typhoid fever as traditional antibiotic therapy (chloramphenicol, co-trimoxazole and amoxycillin) may not be effective. Treatment is usually with fluoroquinolones; third-generation cephalosporins or azithromycin may need to be given in resistant cases.
Following natural infection with typhoid, an immune response develops that may partially protect against reinfection and severity of disease (WHO, 2000).

History and epidemiology of the disease

Typhoid is predominantly a disease of countries with inadequate sanitation and poor standards of personal and food hygiene. The disease is endemic in South Asia and parts of South-East Asia, the Middle East, Central and South America, and Africa. Outbreaks of typhoid have been reported from countries in Eastern Europe (Kyrgyzstan, Tajikistan, Ukraine and Russia). In 2000, the global annual incidence of typhoid fever was estimated to be around 21.7 million cases with 216,510 deaths per year (CFR 1%) (Crump, Luby and Mintz, 2004).
Typhoid is rare in resource-rich countries where standards of sanitation are high. Typhoid and paratyphoid in England and Wales are usually imported diseases associated with foreign travel or contact with somebody who has travelled. Between 1990 and 2004, there were an average of 374 laboratory reports of typhoid and paratyphoid each year in England and Wales, nearly 70% of which reported recent foreign travel (HPA, 2005).
The most frequently reported region of foreign travel for typhoid and paratyphoid A was South Asia; the Mediterranean and the Middle East were the most frequently reported regions for paratyphoid B (HPA, 2004). Occasional outbreaks of indigenous typhoid occur in the UK; the last community outbreak was in 2001 in Newport, Wales and involved five cases (Public Health Laboratory Services, 2001). For the latest epidemiological data on typhoid and paratyphoid please see: https://www.gov.uk/government/publications/enteric-fever-surveillance-2014-to-2015-quarterly-reports
Prevention of typhoid and paratyphoid depends primarily on improving sanitation and water supplies in endemic areas and on scrupulous personal, food and water hygiene. Immunisation may be considered for individuals at risk from typhoid fever. There is no vaccine available to prevent paratyphoid infection.

The typhoid vaccination

Worldwide, three types of typhoid vaccine are available: a polysaccharide vaccine; an oral, live, attenuated vaccine; and a whole-cell inactivated vaccine.

Vi polysaccharide vaccine

One of the typhoid vaccines available in the UK is composed of purified Vi capsular polysaccharide from S. typhi. Each 0.5ml dose contains 25μg of antigen. A four-fold rise in antibody against Vi antigen has been detected seven days following primary immunisation with Vi vaccine. Maximum antibody response is achieved one month following vaccination and persists for about three years (Keitel et al., 1994; Tacket et al., 1998).
The efficacy of the Vi vaccine was evaluated in field trials in Nepal (Acharya et al., 1987) and in Eastern Transvaal, South Africa (Klugman et al., 1987; Klugman et al., 1996). In the Nepalese study, vaccine efficacy at 20 months against culture-positive typhoid was 75% (95% CI = 49 to 87%) in adults and children aged five to 44 years. The South African study found the cumulative three-year efficacy of vaccine against culture-positive typhoid to be 55% (95% CI = 30 to 71%) in children aged six to 15 years.
Protective antibody titres to Vi antigen fall over time. Re-vaccination is necessary when continuing protection is required. Additional doses of Vi vaccine do not boost serum antibody levels; re-vaccination returns antibody levels to those achieved after the primary immunisation (Keitel et al., 1994).
Non-conjugated polysaccharide vaccines are poorly immunogenic in infants and young children. There is little definitive data on the efficacy of Vi vaccine in children aged less than 18 months (Cadoz, 1998).
Furthermore, in 2008, the lower age limit for Typhim Vi was increased from 18 months to two years.
Protection by vaccination may be less if a large number of infective organisms are ingested. Because of the limited protection offered by the vaccine, the importance of scrupulous attention to personal, food and water hygiene must still be emphasised for those travelling to endemic areas.

Oral typhoid vaccine (Ty21a)

Oral typhoid vaccine contains a live, attenuated strain of S. typhi (Ty21a) in an enteric-coated capsule. A three-dose regimen gives a cumulative three-year efficacy of about 50 to 60% (Engels et al., 1998). The vaccine is indicated for persons from six years of age.

Whole-cell typhoid vaccine

The injectable, killed, whole-cell typhoid vaccine contains heat-inactivated, phenol-preserved S. typhi organisms. A two-dose regimen gives a cumulative three-year efficacy of about 70%, and provides protection for up to five years (Engels et al., 1998). This vaccine is highly reactogenic and is no longer used in the UK.

Storage

Both Vi polysaccharide and oral typhoid (Ty21a) vaccines should be stored in the original packaging at +2°C to +8°C and protected from light. All vaccines are sensitive to some extent to heat and cold. Heat speeds up the decline in potency of most vaccines, thus reducing their shelf life. Effectiveness cannot be guaranteed for vaccines unless they have been stored at the correct temperature. If Vi vaccines have been frozen they should not be used as this can reduce their potency and increase local reactions. If a blister containing Ty21a vaccine capsules is not intact, it should not be used.

Presentation

Vi vaccines are supplied in pre-filled syringes, each containing a single dose of 0.5ml. Vaccines are available as a single antigen product or combined with hepatitis A vaccine.
Ty21a vaccines are supplied in blister packs containing three capsules.

Dosage and schedule

Vi vaccine

A single dose of 0.5ml of Vi vaccine is recommended for adults and children over the age of two years.

Ty21a vaccine

The first Ty21a capsule is taken on day 0, the second capsule on day 2 and the third on day 4. The vaccine is recommended for children over the age of six years and adults. Reinforcing doses of three capsules should be given as recommended.
Dosage of injectable monovalent typhoid vaccines
Dosage of injectable monovalent typhoid vaccines
Vaccine productAgesDoseVolume
Typhim ViTwo years and older25μg0.5ml
TypherixTwo years and older25μg0.5ml
Dosage of oral monovalent typhoid vaccine
Dosage of oral monovalent typhoid vaccine
Vaccine productAgesDose
VivotifSix years and olderThree capsules on days 0, 2 and 4
Dosage of combined typhoid and hepatitis A vaccines*
Dosage of combined typhoid and hepatitis A vaccines*
Vaccine productAgesDose typhoidDose HAV†Volume
Hepatyrix15 years and older25μg1440 ELISA units1ml
ViATIM16 years and older25μg160 antigen units1ml
 * For booster doses of either typhoid or HAV, single antigen vaccines can be used  HAV – hepatitis A vaccine

Administration

Vi vaccines are routinely given intramuscularly into the upper arm or anterolateral thigh. Intradermal injection may cause a severe local reaction and should be avoided. Vaccines should be given by deep subcutaneous injection to individuals with a bleeding disorder. Vaccines must not be given intravenously. Ty21a vaccine capsules are taken orally.
An optimal immune response may not be achieved unless the immunisation schedule of three vaccine capsules is completed. Injectable vaccines should be given at separate sites, preferably in different limbs. If given in the same limb, they should be given at least 2.5cm apart (American Academy of Pediatrics, 2003). The site at which each vaccine was given should be noted in the individual’s records.

Disposal

Equipment used for vaccination, including used vials or ampoules, should be disposed of at the end of a session by sealing in a proper, puncture-resistant ‘sharps’ box (UN-approved, BS 7320).

Recommendations for use of the vaccine

Typhoid vaccine is indicated for active immunisation against typhoid fever and is recommended for:
  •  
    travellers visiting typhoid-endemic areas whose planned activities put them at higher risk (please check the country information pages www.Nathnac.org and www.travax.nhs.uk)
  •  
    travellers to endemic areas (see above) with frequent and/or prolonged exposure to conditions where sanitation and food hygiene are likely to be poor
  •  
    laboratory personnel who may handle S. typhi in the course of their work.
Further information on vaccine use in travellers can be found in Health information for overseas travel (Department of Health, 2001).

Primary immunisation

The immunisation schedule of Vi vaccine consists of a single dose; for Ty21a vaccine, a three-dose course.

Vi vaccine

Children aged from two years and adults
A single dose of Vi vaccine is recommended for children and adults.

Ty21a vaccine

Children aged from six years and adults
One capsule on day 0, the second capsule on day 2 and the third on day 4. Capsules should be taken about one hour before a meal with a cold or lukewarm drink (temperature not to exceed 37°C). The vaccine capsule should not be chewed, and should be swallowed as soon as possible after placing in the mouth. An optimal immune response may not be achieved unless the immunisation schedule of three vaccine capsules is completed. Protection commences about seven to ten days after completion of the third dose.
Not all recipients of typhoid vaccines will be protected against typhoid fever, and travellers should be advised to take all necessary precautions to avoid contact with or ingestion of potentially contaminated food or water.
The CDC and WHO advise that most widely used oral live vaccines can be given simultaneously and at any time before or after oral and parenteral live vaccines. However, there is a lack of evidence around the efficacy of live typhoid vaccines given within four weeks of other live vaccines.

Reinforcing immunisation

Vi vaccine

A single dose of Vi vaccine should be administered at three-year intervals in adults and children over two years of age who remain at risk from typhoid fever.
Individuals who have received other non-Vi typhoid vaccines may receive reinforcing doses of Vi vaccine at three-year intervals.

Ty21a

In the case of travel from a non-endemic area to an area where typhoid is endemic, a booster consisting of three doses is recommended every three years (Fraser et al., 2007).

Children under two years of age

Young children may show a sub-optimal response to polysaccharide antigen vaccines. Children between the ages of 12 months and two years should be immunised if the risk of typhoid fever is considered high. Immunisation is not recommended for children under one year of age. When children are too young to benefit fully from typhoid vaccination, scrupulous attention to personal, food and water hygiene measures should be exercised by the caregiver.

Contraindications

There are very few individuals who cannot receive typhoid vaccine. When there is doubt, appropriate advice should be sought from a travel health specialist. Severe reactions to a previous dose of non-Vi typhoid vaccine do not contraindicate the subsequent use of a Vi-containing vaccine. Most severe reactions to typhoid vaccines will have been associated with the inactivated whole-cell vaccine. Typhoid Vi vaccine should not be given to those who have had:
  •  
    a confirmed anaphylaxis to a Vi antigen-containing vaccine.
Ty21a vaccine should not be given to those who are:
  •  
    immunosuppressed (see Chapter 6 for more detail), or those who have had:
  •  
    confirmed anaphylaxis to any component of the Ty21a vaccine or enteric-coated capsule, including gelatin.

Precautions

Minor illnesses without fever or systemic upset are not valid reasons to postpone immunisation. If an individual is acutely unwell, immunisation should be postponed until they have fully recovered. This is to avoid confusing the differential diagnosis of any acute illness by wrongly attributing any sign or symptoms to the adverse effects of the vaccine.
In the event of a gastrointestinal illness, vaccination with the Ty21a vaccine should be postponed until after recovery. Ty21a vaccine should not be commenced within three days of completing any antibacterial agents, and similarly, antibacterial therapy should not commence within three days after the last dose of vaccine.
If malaria prophylaxis is also required, the fixed combination of atovaquone and proguanil can be given concomitantly with Ty21a. Doses of mefloquine and Ty21a should be separated by at least 12 hours. For other anti-malarials, there should be an interval of at least three days between the last dose of Ty21a and the first dose of malaria prophylaxis.

Pregnancy and breast-feeding

No data are available on the safety of Vi polysaccharide and Ty21a typhoid vaccines in pregnancy or during lactation. There is no evidence of risk from vaccinating pregnant women or those who are breast-feeding with inactivated viral or bacterial vaccines or toxoids (Plotkin and Orenstein, 2004). It is not known if Ty21a vaccine can cause fetal harm when administered to pregnant women or affect reproductive ability. If the risk of typhoid is high, vaccination should be considered.

Immunosuppression and HIV infection

Vi vaccine does not contain live organisms and may be given to HIV-positive individuals and those considered immunosuppressed, in the absence of contraindications.
Immunosuppressed individuals may have a sub-optimal immune response to Vi vaccine. The importance of scrupulous attention to personal, food and water hygiene must be emphasised for immunosuppressed persons travelling to endemic areas.
Ty21a vaccine should be avoided in immunosuppressed and HIV-infected individuals.
Further guidance is provided by the Royal College of Paediatrics and Child Health (www.rcpch.ac.uk), the British HIV Association (BHIVA) immunisation guidelines for HIV-infected adults (BHIVA, 2008; http://www.bhiva.org/Immunization2008.aspx) and the Children’s HIV Association of UK and Ireland (CHIVA) immunisation guidelines (www.bhiva.org/chiva).

Adverse reactions

Based on pooled estimates from clinical trials and post-marketing surveillance data, local reactions (pain, swelling, erythema and induration at injection site) are the most commonly reported symptoms following Vi vaccine (Engels et al., 1998; Tacket et al., 1986; Begier et al., 2004). These symptoms are usually mild and transient. Systemic reactions following the vaccine are infrequent. Fever occurs in about 1% of vaccine recipients. Headache, nausea, diarrhoea and abdominal pain have been reported but are uncommon.
There have been rare reports of anaphylaxis following administration of Vi vaccine (Begier et al., 2004).
Following Ty21a vaccine, the most commonly reported adverse events are gastro-intestinal symptoms, fever, influenza-like symptoms and headache. All severe reactions should be reported to the Commission on Human Medicines using the Yellow Card scheme.

Management of cases, carriers, contacts and outbreaks

The local health protection unit (HPU) should be informed immediately whenever a patient is suspected of having typhoid fever. Reporting should not wait until there is laboratory confirmation. Early identification of the source of infection is vital in containing this disease. Reports should contain a travel history, including country of travel.
Cases, carriers and their close contacts in the following groups may pose an increased risk of spreading infection and may be considered for exclusion from work or school (Working Party of the PHLS Salmonella Committee, 1995):
  •  
    food handlers
  •  
    staff of healthcare facilities
  •  
    children aged less than five years of age who attend nurseries or other similar groups
  •  
    older children or adults who cannot maintain good standards of personal hygiene.
Advice on exclusion from work or school must be sought from the local HPU.
Both cases and carriers of S. typhi should be advised to be scrupulous in their hygiene practices. Carriers should be referred for specialist clinical management.
Typhoid vaccine is not recommended for close contacts of either cases or carriers, or during an outbreak of typhoid fever in the UK.

Supplies

Vi-containing vaccines

These vaccines are available from
  •  
    Sanofi Pasteur MSD
     
    (Tel: 01628 785 291)
     
    (Fax: 01628 671 722)
     
    Customer care direct line: 01628 733 737.
These vaccines are available from

Ty21a vaccine

This vaccine is available from

References

Acharya IL, Lowe CU, Thapa R (1987) Prevention of typhoid fever in Nepal with the Vi capsular polysaccharide of Salmonella typhi. A preliminary report. N Engl J Med 317: 1101–4. [PubMed]
American Academy of Pediatrics (2003) Active immunization. In: Pickering LK (ed.) Red Book: 2003 Report of the Committee on Infectious Diseases, 26th edition. Elk Grove Village, IL: American Academy of Pediatrics, p 33.
Begier EM, Burwen DR, Haber P, Ball R (2004) Post-marketing safety surveillance for typhoid fever vaccines from the Vaccine Adverse Event Reporting System, July 1990 through June 2002. Clin Infect Dis 38: 771–9. [PubMed]
British HIV Association (2008) British HIV Association guidelines for immunization of HIV-infected adults 2008. HIV Med 9(10): 795–848. http://www.bhiva.org/Immunization2008.aspx. Accessed December 2013.
Cadoz M (1998) Potential and limitations of polysaccharide vaccines in infancy. Vaccine 16: 1391–5. [PubMed]
Connor BA, Schwartz E (2005) Typhoid and paratyphoid fever in travellers. Lancet Infect Dis 5: 623–8. [PubMed]
Crump JA, Luby SP, Mintz ED (2004) The global burden of typhoid fever. Bull World Health Organ 82: 346–53. [PubMed]
Department of Health (2001) Health information for overseas travel. London: The Stationery Office.
Engels EA, Falagas ME, Lau J, Bennish ML (1998) Typhoid fever vaccines: a metaanalysis of studies on efficacy and toxicity. BMJ 316: 110–15. [PubMed]
Fraser A, Goldberg E, Acosta CJ (2007) Vaccines for preventing typhoid fever. Cochrane Database Syst Rev. Jul 18;(3):CD001261.
Glynn JR, Bradley DJ (1992) The relationship between infecting dose and severity of disease in reported outbreaks of Salmonella infections. Epidemiol Infect 109: 371–88. [PubMed]
Health Protection Agency (2004) Illness in England, Wales, and Northern Ireland associated with foreign travel. London: HPA.
HPA (2005) Laboratory reports of cases of typhoid and paratyphoid, England and Wales: 1990 to 2004. CDR Wkly 10 February 2005. www.hpa.org.uk/cdr/pages/enteric.htm#lab_typh
Keitel WA, Bond NL, Zahradnik JM (1994) Clinical and serological responses following primary and booster immunization with Salmonella typhi Vi capsular polysaccharide vaccines. Vaccine 12: 195–9. [PubMed]
Klugman KP, Gilbertson IT, Koornhof HJ (1987) Protective effect of Vi capsular polysaccharide vaccine against typhoid fever. Lancet ii: 1165–9.
Klugman KP, Koornhof HJ, Robbins JB, Le Cam NN (1996) Immunogenicity, efficacy and serological correlate of protection of Salmonella typhi Vi capsular polysaccharide vaccine three years after immunization. Vaccine 14: 435–8. [PubMed]
Mermin JH, Townes JM, Gerber M (1998) Typhoid fever in the United States, 1985–1994. Changing risks of international travel and increasing antimicrobial resistance. Arch Intern Med 158: 633–8. [PubMed]
Plotkin SA, Orenstein WA (eds) (2004) Vaccines. 4th edition. Philadelphia: WB Saunders Company p 109–11.
Public Health Laboratory Services (2001) Typhoid in Newport, Wales – update. Commun Dis Rep CDR Wkly 11:1.
Sinha A, Sazawal S, Kumar R (1999) Typhoid fever in children aged less than 5 years. Lancet 354: 734–7. [PubMed]
Steinberg EB, Bishop R, Haber P (2004) Typhoid fever in travellers: who should be targeted for prevention? Clin Infect Dis 39: 186–91. [PubMed]
Tacket CO, Ferreccio C, Robbins JB (1986) Safety and immunogenicity of two Salmonella typhi Vi capsular polysaccharide vaccine candidates. J Infect Dis 154: 342–5. [PubMed]
Tacket CO, Levine MM, Robbins JB (1998) Persistence of Vi antibody titers three years after vaccination with Vi polysaccharide against typhoid fever. Vaccine 6: 307–8.
Threlfall EJ, Ward LR (2001) Decreased susceptibility to ciprofloxacin in Salmonella enterica serotype typhi, United Kingdom. Emerg Infect Dis 7: 448–50. [PubMed]
Working Party of the PHLS Salmonella Committee (1995) The prevention of human transmission of gastrointestinal infections, infestations, and bacterial infestations. Commun Dis Rep CDR Rev 5:1–16.
World Health Organization (2000) Typhoid vaccines. WHO position paper. Wkly Epidemiol Rec 75: 257–64. [PubMed]
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