|Year : 2011 | Volume
| Issue : 4 | Page : 267-271
Typhoid vaccine: A case for inclusion in national program
Pragya Sharma1, Davendra K Taneja2
1 Assistant Professor, Department of Community Medicine, Maulana Azad Medical College, New Delhi, India, and Convener of Immunization Subcommittee, Indian Public Health Association, India
2 Director Professor, Department of Community Medicine, Maulana Azad Medical College, New Delhi, India, and Convener of Immunization Subcommittee, Indian Public Health Association, India
|Date of Web Publication||30-Jan-2012|
C -704 Vikaspuri, New Delhi - 18
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Typhoid has been reported to be a common and significant cause of morbidity in pre-school and school-age children in the endemic countries like India. The incidence of typhoid has been reported to be as high as 27.3 per 1000 person-years in children less than 5 years of age. Serious complications occur in about 10% of cases requiring hospitalization. The mean cost of treatment per episode of blood culture-confirmed typhoid fever has been calculated as INR 3,597 (1996 prices) in an outdoor setting, whereas in case of hospitalization, the cost of illness increases by several folds (INR 18,131). Vi polysaccharide vaccine is safe, efficacious and affordable for use as a cost-effective public health tool to protect children from typhoid and related complications, when given at 2 and 5 years of age as a part of National Immunization Schedule.
Keywords: Burden, Prevention, Typhoid, Vaccine
|How to cite this article:|
Sharma P, Taneja DK. Typhoid vaccine: A case for inclusion in national program. Indian J Public Health 2011;55:267-71
| Introduction|| |
Typhoid fever is a water- and food-borne systemic infection caused by Salmonella More Details enterica serotype Typhi (S. typhi). The disease remains an important public health problem in developing countries including India.
| Burden of Disease|| |
In 2000, it was estimated that over 2.16 million episodes of typhoid occurred worldwide, resulting in 216,000 deaths, and that more than 90% of this morbidity and mortality occurred in Asia. Its real impact is difficult to estimate because the clinical picture is confused with those of many other febrile infections. Additionally, the disease is underestimated because there are no bacteriology laboratories in most areas of developing countries. These factors are believed to result in many cases going undiagnosed. 
Typhoid has been reported to be a common and significant cause of morbidity between 1 and 5 years of age in the endemic areas. Though the most common age affected is between 5 and 12 years, however, in areas of endemicity and in large outbreaks, most cases occur in persons aged between 3 and 19 years.  Hospital-based studies show it to be a disease mainly of school-age group; however, cases have also been reported in infants and neonates as old as 8 days.  Another study has revealed that children under 5 have a three-fold increase in culture-positive typhoid fever compared with 5-19 -year-olds. S typhi bacteraemia accounted for 60% of positive blood cultures, and other Salmonella sp. and non-specified bacteria accounted for 23% and 17%, respectively.  Also, clinically apparent bacteraemia in S. typhi infection in children aged less than 3 years of age has been described in India and other developing countries, , with a case fatality rate of 1-4% depending upon the availability of diagnostic services and effective treatment. 
In a multicentric study conducted in five endemic Asian countries, higher incidences have been reported in India, with the incidence of typhoid fever in pre-school children aged 2-5 years being of the same order of magnitude as that for school-aged children aged 5-15 years. The overall incidence of typhoid has been calculated to be 170.8 cases per 100,000 person-years with as high as 493.5 cases per 100,000 person-years in children aged between 5 and 15 years in India. 
The fact that the disease is underreported and also affects the pre-school children has been established by a community-based study conducted in Delhi by active surveillance of fever cases in the community wherein the incidence rate of typhoid has been reported to be 27.3 per 1000 person-years at age under 5 years. The study also highlights the age-specific incidence of typhoid fever per 1000 person-years as 11.7 for 5-19 years and 1.1 for between 19 and 40 years, thereby emphasizing on a very high incidence in children under 5 years of age. 
The clinical presentation of typhoid fever varies from a mild illness with low-grade fever, malaise, and slight dry cough to a severe clinical picture with multiple complications. Depending on the clinical setting and the quality of available medical care, up to 10% of typhoid patients can develop serious complications like hemorrhages (causing rapid death in some patients), hepatitis, myocarditis, pneumonia, disseminated intravascular coagulation, thrombocytopenia and haemolytic uremic syndrome, and as many as 15% of typhoid fever related mortality may be associated with prolonged persistent fever and diseases. Patients may also experience genitourinary tract manifestations or relapse, and a chronic carrier state may develop in 1-5% of patients depending on age, sex and treatment regimen.  With the emergence of multidrug-resistant strains of S. typhi with reduced susceptibility to fluoroquinolones, the associated complications and cost of their management are further increasing. 
| Cost of Illness|| |
To introduce a vaccine to the health service system, not only the burden of disease but also the economic consequences need to be explored to determine priority. Therefore, knowledge of treatment cost for typhoid fever and cost of vaccination is important in planning for inclusion of a new vaccine in the existing immunization program. A prospective surveillance carried out in an urban slum in Delhi, India, estimates the mean cost (both direct and indirect) per episode of blood culture-confirmed typhoid fever as INR 3,597 (US$ 1 = INR 35.5 in 1996 prices) in an outdoor setting.  In case of hospitalization, the cost of illness increased by several folds (INR 18,131). The total private and non-patient ex-ante costs, i.e. expected annual losses for each individual, were higher for children aged 2-5 years (INR 154) than for those aged 5-19 years (INR 32), 0-2 year(s) (INR 25), and 19-40 years (INR 2).  Similar findings have also been reported in a study conducted in Kolkata where the incidence-based cost-of-illness analysis has been done from the providers' perspective. In this study, the average cost of hospitalized child patient was US$ 115.36. This was much higher than that of the adult patients (US$ 72.71) (in 2004 prices).  Also, with clinical or in-vitro increase in antibiotic resistance, the costs of illness are likely to increase substantially because of increased hospitalizations. , It has also been shown that typhoid fever has a very high social and economic impact because of the hospitalization of patients with acute disease and the complications, and loss of income of the sufferers/caretakers attributable to the duration of the clinical illness. 
| Typhoid Vaccines|| |
The use of vaccines for prevention of typhoid would not only reduce the risk of typhoid fever, but also restrict antibiotic use and thereby also limit the development of antibiotic resistance.  There are two internationally licensed vaccines against typhoid.
Vi polysaccharide vaccine
A Vi capsular polysaccharide vaccine contains extracted cell surface Vi polysaccharide of Salmonella enterica serovar Typhi, S. typhi Ty2 strain in a sterile solution. It is an injectable vaccine recommended for intramuscular use. It is produced by several internationally recognized vaccine manufacturers, is easily available and being used by private sector. The Vi polysaccharide is a T-cell independent antigen and, therefore is poorly immunogenic in children aged less than 2 years.
The other one is the Ty21a live attenuated vaccine formulated for oral administration. Protection from Ty21a vaccine is based on different surface antigens, including O and H antigens; it lacks Vi antigen and protection is therefore independent of Vi expression by the bacteria. The Ty21a vaccine is available in a lyophilized form in enteric-coated capsules and requires strict cold chain maintenance. Three doses of Ty21a are administered on an every other day schedule. A large experience attests to the safety, practicality and effectiveness of these vaccines as public health tools in other parts of the world.  Depending on the endemicity, reimmunization is recommended periodically. However, Ty21a, being a live attenuated vaccine, is not recommended for use in immunosuppressed individuals. 
Immunogenicity and efficacy of Typhoid vaccines
Ty21 oral vaccine
Indeed, one of the drawbacks of the Ty21a vaccine is the requirement for multiple doses for optimal immunogenicity. The resulting cumulative 3-year efficacy after three doses of Ty21a has been reported in the meta-analyses as 51% (95% CI: 35-63%). , Herd immunity has been demonstrated during field trials of this vaccine, with an adequate safety profile. 
Vi polysaccharide injectable vaccine
It has been proven by various researches that a single dose of Vi polysaccharide vaccine confers 71-80% of immunity. ,, The single-dose Vi polysaccharide injectable vaccine provides about 70% protection against blood culture confirmed typhoid fever.  More recently, a cluster randomized effectiveness trial of Vi typhoid vaccine in India showed 80% protection in children who were vaccinated between 2 and 5 years of age.  A community-based study conducted in Kolkata, India, has demonstrated 61% effectiveness of Vi polysaccharide vaccine in the general population, with significant protection shown in all age groups, especially among children aged 2-5 years (80% PE). 
More importantly, even among the unvaccinated individuals, the protection has been reported as 44%, thus demonstrating significant herd effect with the use of Vi polysaccharide vaccine. 
Thus, Vi vaccine has been deemed a better candidate for widespread immunization campaigns as it is a single-dose vaccine. As typhoid fever is common in pre-school children in India and since children younger than 5-6 years cannot swallow the capsules, injectable Vi polysaccharide vaccine that can be given at 2 years of age is the vaccine of choice. Further, the Vi polysaccharide can be co administered with other routine childhood vaccines. It is affordable in non-industrialized nations because the technology is in the public domain and has been transferred to local producers.
WHO recommends that in routine immunization, the use of the available typhoid vaccines should be considered in children over 2 years of age in areas where typhoid fever is endemic. Either Vi or Ty21a vaccine should be used. 
The Vi polysaccharide vaccine has been effective and efficacious in the clinical trials. In a retrospective study conducted in China, during the second year following vaccination, vaccine efficacy has been reported as 85% (95% CI: 49% - 96%) and 100% (95% CI: 17% - 100%) in two different sites. A suggestive protection (51% PE) during the third year has also been reported which is nearly identical to the level observed in the third year of an earlier trial in South Africa. , In a meta-analysis, the cumulative efficacy at 3 years for polysaccharide Vi vaccine has been reported as 55% (95% CI: 30% - 70%).  These results confirm that this vaccine protects for 2-3 years, and hence revaccination is required after 3 years.
Role in preventing outbreaks
Vi antigen vaccine is also effective in preventing outbreaks of typhoid fever as demonstrated in a trial conducted in China, wherein it was proven that in students who had been immunized before the outbreak of typhoid, receipt of Vi vaccine was associated with 73% protection. Indirect protection by herd immunity was observed among the non-vaccinated individuals who lived in the clusters where the Vi vaccine was introduced (44% PE). 
Side effects and Adverse Events Following Immunization
The vaccine has been found to be safe by various researches. The safety of re-vaccination with Vi polysaccharide vaccine has also been demonstrated.  Adverse reactions following immunization have been reported to be predominately minor and transient in nature, such as injection site pain, erythema and induration; these local reactions almost always resolve within 48 hours of vaccination. Anaphylaxis, allergic reactions and urticaria have been reported very rarely. 
In a community-based study on side effects post vaccination with Vi polysaccharide, only 2.73% of children were reported to have temperature of at least 37.5°C, 1.22% had an area of swelling of at least 2.5 cm in diameter and 0.38% children reported an area of erythema of at least 2.5 cm in diameter. The reactions lasted as long as 48 hours, but none of the children required hospitalization. ,
There are no specific contraindications to the use of this vaccine other than the established previous hypersensitivity reaction to vaccine components. HIV positivity is not a contraindication for the Vi polysaccharide, but induction of protective antibodies is directly correlated to the levels of CD4 positive T cells. Precaution should be taken for the patients having bleeding disorders and thrombocytopenia to prevent the bleeding at the injection site. Vaccination should be postponed for patients having acute febrile illness. ,
Storage temperature and shelf life
The vaccine is recommended to be stored at 2°C-8°C and freezing should be avoided. Proper maintenance of cold chain during storage and transportation is required. Thus, the same vaccine cold chain system as for other vaccines can be used for storing and transportation of the vaccine vial.
Feasibility and economic implications on public health delivery system
The Vi polysaccharide vaccine for mass vaccinations has been found to be safe, acceptable, and logistically feasible as demonstrated in Vietnam, Pakistan, and Indonesia. ,,
In India, National Capital Territory (NCT) of Delhi has also successfully included this vaccine as a part of Universal Immunization Programme (UIP) since November 2004. The vaccine is available in five-dose vials, each vial costing about 90 INR, thereby with a direct cost implication of approximately INR 18 per dose. Under UIP in Delhi, one dose is being given to any child presenting between 2 and 5 years of age to the public health system . There is no extra cost for transportation, storage and capacity building of the vaccinators due to utilization of the existing cold chain system and manpower for vaccination.
Cost-effectiveness of vaccine
Incidence of disease in children 5-15 years of age has been reported to be 5/1000, with 10% complications.  Minimum cost of treatment of an uncomplicated case in an outdoor setting for typhoid fever is INR 3,597 and the cost of indoor care in complicated typhoid is INR 18,131. 
Effectiveness of typhoid vaccine in terms of cost saved
5 (number of cases per 1000 population) × 0.7 (PE of Vaccine) = 3.5/1000 individuals protected. Therefore, the cost saved per 1000 population would be 3597 × 3.5 i.e. approximately INR 12,589.50 for uncomplicated cases. Similarly, 0.5 ×18,131 (hospitalization of complicated cases) = INR 9065.50. Therefore, the cost saved over a population base of 1000 is about INR 21,655, while the cost of vaccine is about INR 18,000 for immunizing 1000 children. Vaccination will also save indirect costs like loss of work days of parents and average 2 weeks of absence from school in case of school-age children.
Prevalence in slums has been reported to be as high as 27.3/1000 for children under 5 years of age.  Thus, the annual cost for treating cases in children less than 5 years of age per 1000 population in high endemic areas like slums may be as high as INR 149,134.53 (INR 3,597 per case treated in outdoor  × 27.3 + 2.73 (10% complications) × INR 18,131  ).
| Conclusions and Recommendations|| |
The current epidemiological evidence of typhoid fever in India, and the safety, efficacy and affordable cost of vaccine point to the need for inclusion of typhoid vaccine in the National Immunization Schedule. As the disease is common in pre-school and school-age children, and one dose provides protection for 3 years, it is recommended that first dose be given at 2 years of age, followed by the second dose at 5 years of age. This may be given along with second booster of DPT to make it operationally easy. Further studies need to be carried out to assess the duration of protection following the second dose, and thus determine the timing of further dose(s).
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