The DOMI study highlighted the magnitude of Multi-drug resistance (MDR) to first-line antibiotics, namely, chloramphenicol, ampicillin and co-trimoxazole. Pakistan had a high proportion of resistance, with 65% of its S.　typhi strains isolated being multidrug resistant, followed by Vietnam (22%) and India (7%) [5]. The H58 clade, a dominant, MDR haplotype of S. typhi, circulating in Asia and Africa over the last 25 years is a serious concern [7]. Since 2016, extended drug resistance (XDR) typhoid cases (resistant to fluoroquinolones and third generation cephalosporins in addition to first line antibiotics) have been reported from Pakistan, and this is an impending threat for other countries [8].

Well-engineered water and sanitation systems, effective treatment of cases and carriers, food hygiene measures, and a pragmatic vaccination programme have demonstrated a decrease in burden of typhoid fever [9]. Water, sanitation and hygiene (WASH) interventions carry multiple benefits beyond typhoid prevention. However, their implementation is expensive and takes time, particularly in resource-constrained LMICs.

In the year 2000 and 2008, WHO recommended typhoid vaccination in high-burden countries, including India [10,11]. Further, in 2018, the Strategic advisory group of experts on immunisation (SAGE) upheld its view on programmatic implementation of typhoid vaccines in endemic countries [12], and WHO additionally prequalified one typhoid conjugate vaccine (TCV) which has the Vi polysaccharide conjugated to tetanus toxoid (Vi-TT) [13]. In this article we critically analyze the currently available options for typhoid vaccination in India and the need for the introduction of the vaccine into the National immunization program.

Three WHO prequalified typhoid vaccines are currently available: live attenuated Ty21a, Vi capsular polysaccharide (ViPS) and TCV vaccines.

Both Ty21a and ViPS vaccine have demonstrated efficacies of 50% in large field trials and possess a good safety profile as per Global Advisory Committee for Vaccine Safety (GACVS) (Table I). The need for booster doses and the fact that these vaccines were not licensed for use in younger children, limits the potential for their use in national programs.

TABLE I Comparison Of Ty21a, Vi Polysaccharide and Typhoid Conjugate Vaccines

TCV has a capsular polysaccharide (Vi) covalently linked to a protein conjugate such as recombinant exoprotein of Pseudomonas aeruginosa (rEPA), tetanus toxoid, diphtheria toxoid or cross reactive material 197 (CRM197). Linkage of a protein moiety results in T-cell dependent differentiation of B cells. Thus, TCVs are able to mount a robust immune response in children aged less than 2 years, rendering the vaccine highly immunogenic and suitable for use in this age group [14]. Currently, the Drug Controller General of India has licensed three Vi-conjugated vaccines. The features of Vi vaccines are detailed below:

Higher seroconversion and avidity: Vi-TT demonstrated higher seroconversion rate (100%) when compared to ViPS (88.6%), 28 days following vaccination [15]. In an Indian trial, in individuals aged between 2 and 45 years, Vi-TT had a significantly higher seroconversion rate than ViPS (97.3% vs. 93.1%; P<0.01) at six weeks post-vaccination [17]. A two year follow-up showed antibody titers to be significantly higher in Vi-TT group when compared to ViPS group (74.1% vs. 53.3%; P<0.001) [12]. The avidity of antibodies (Avidity Index >60) following a booster dose was superior in Vi-TT recipients (46%) compared to ViPS (16%) vaccines [12]. Conjugate vaccines not only demonstrate a better seroconversion rate and a longer antibody response when compared to ViPS, but also offer greater avidity (Web Table I).

Higher immunogenicity of TCV in children aged <2 y: A Vi-TT trial in Indian children aged between 6 and 23 months demonstrated a seroconversion rate of 96.8% (95% CI: 92.1-99.1) and 65.1% (95% CI: 56.1-73.4) at 6 weeks and 2 years, respectively after vaccination. Even after 5 years, antibodies persisted in over 70% of Vi-TT vaccinees. Children of both age groups, 6-11 and 11-23 months, showed a robust immune response [12].

Sero-efficacy: The Vi-TT trial also determined the sero-efficacy, which was 85% (95% CI: 80-88%) [18].

Co-administration with EPI vaccines: Co-administration of Vi-TT and measles or measles-mumps-rubella (MMR) vaccines at 9 or 15 months of age showed no interference with antibody response to any antigen [12].

Safety: In 2018, SAGE acknowledged the safety profile of Vi-TT in children, but GACVS reports on post-marketing surveillance will provide more evidence on its safety [12].

Cost-effectiveness analysis of Vi-TT: Vaccination is ‘cost saving’ if cost of the vaccination program is lesser than the costs involved in treatment of cases. On the other hand, vaccination is ‘very cost-effective’ if cost-effectiveness (CE) ratio is less than the per capita gross national income (GNI) and ‘cost-effective’ if less than 3 times the per capita GNI.

CE of Vi-TT (priced at US$ 1 per dose) was analyzed in Delhi and Kolkata from a healthcare payer perspective under the following strategies: (i) Routine immunisation (RI) with TCV (9 months); (ii) RI + catch up vaccination (9 months–5 years); (iii) RI + catch up vaccination (9 months–15 years); (iv) RI + catch up vaccination (9 months–25 years); and (v) RI + catch up vaccination (all ages more than 9 months). In Delhi, compared to no vaccination, both RI with TCV (strategy1) and RI + catch up at all ages (strategy 5) were ‘cost saving’ strategies with a probability >99%. In Kolkata, compared with no vaccination, RI with TCV (strategy 1) was ‘very cost effective’ with >75% probability. On imputing the current market price of Vi-TT at a unit price of 1800 INR in the analysis, it was found that none of the above strategies were ‘cost effective’ at Kolkata. However, at Delhi, RI with TCV (strategy 1) was still ‘cost effective’ at the same unit price of the vaccine, and this may be due to higher costs incurred in treatment of cases [19].

Typhoid-endemic LMICs are classified based on annual incidence, as low (10-50 cases/100,000 population), moderate (50-200 cases/100,000 population), and high (>200 cases/100,000 population). Considering the annual incidence of typhoid, CE of Vi-TT in LMICs was analyzed using two strategies: (i) RI in infants through EPI, and (ii) RI through EPI + one time catch-up campaign in school-aged children (5-14 years). Results showed that RI of infants through EPI (strategy 1) would be ‘cost effective’, if annual incidence is >50/100,000 population, and the second strategy of RI + one time catch up would be ‘cost effective’, if annual incidence of typhoid is >130/100,000 population [20]. These analyses thereby show that use of typhoid vaccines is indeed ‘cost effective’, provided vaccine delivery is strategically planned as per the geographic heterogeneity of disease distribution across different age groups.

In South-East Asia, considering the significant burden of typhoid, clinicians perceive undifferentiated acute febrile illness as suspected typhoid fever, and treat it empirically with antibiotics. It is estimated that, for every case of blood culture confirmed typhoid fever, three to 25 febrile patients without typhoid illness receive antibiotics, which could have been potentially avoided. This over-treatment with antibiotics can result in antimicrobial resistance (AMR) towards commonly used antibiotics, thereby compelling the use of higher antibiotics. Routine CEA involving vaccines, while considering the costs of illness from both societal as well as health care payer’s perspective, leaves out potential benefits of avoiding overtreatment with antibiotics. Thus, using TCV to reduce typhoid burden can eventually bring down the prescription rates of antibiotics attributed for treating suspected typhoid fever cases [21], and potentially prevent emergence of antibiotic resistance.

In 2018, SAGE recommended a single dose of Vi-TT for children aged less than 2 years, either, along with initial dose of measles vaccine at 9-12 months of age or with the second dose of measles vaccine at 15-18 months. For children aged more than 2 years, SAGE continued its prior recommendation of either ViPS or Ty21a according to the country’s immunization policy: although, Vi-TT likely offers longer duration of protection when compared to ViPS or Ty21a and hence, can be potentially considered for use in older children as well [13]. Further, in 2018, the Indian Academy of Pediatrics recommended a single dose of TCV for children from 6 months onwards, without any subsequent booster dose [22].

Following WHO’s prequalification of Vi-TT in 2018, the GAVI Alliance agreed to provide a support of US$ 85 million towards introduction of TCV in 2019 in developing countries [23]. Following this, the manufacturer of Vi-TT vaccine has stated its willingness to reduce the price of Vi-TT from US$ 26 (1800 INR) per dose to US$ 1.5 (100 INR) per dose for GAVI eligible countries [24]. This significant cost reduction of Vi-TT will be an important factor to be considered by policymakers in India.

Country-level data in the Indian context on burden of typhoid fever among children is likely to be available from an ongoing Surveillance for enteric fever in India (SEFI) by 2020 [25]. In addition, the Typhoid Vaccine Acceleration Consortium (TyVAC) has begun a trial to study the effectiveness of TCV among children in Bangladesh, Malawi and Nepal [26]. The Navi Mumbai municipality has begun a campaign of TCV immunization in two rounds in July 2018, and vaccine effectiveness will be evaluated by a consortium including the Indian Council of Medical Research [27]. Thus, data on typhoid disease burden and effectiveness of TCVs are awaited, which will serve as strong evidence to aid the government to consider typhoid vaccine.

Typhoid burden is associated with considerable heterogeneity in distribution, and hence the decision on vaccination and its strategies for delivery should be based on local epidemiology. Vi-TT, with its unique advantage of being amenable for use in children, aged less than two years through routine immunization can decrease disease burden. With antimicrobial resistance looming large in Asia, this is a crucial time for India to consider introduction of typhoid vaccine into the national immunization programme at the earliest.

Contributors: JJ, MS: conceptualized the article; MS, KNS: reviewed the literature, drafted and revised the manuscript under the overall support and supervision of JJ and GK. All authors approved the manuscript for publication.

Funding: None; Competing interest: None stated.

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