Gateway to Typhoid Conjugate Vaccine Introduction in India and Beyond—Programmatic Effectiveness of a Public Sector Typhoid Conjugate Vaccine Campaign in Navi Mumbai

(See the Major Article by Hoffman et al. on pages 138–44.)

Salmonella enterica serovar Typhi (S. Typhi) caused an estimated 9.24 million cases (5.94 M, 14.1 M) of typhoid fever in 2019, resulting in 110 000 deaths (52 800, 191 000) [1]. Over 4.8 million cases and 50 000 deaths are estimated to have occurred in India [1]. Increasing prevalence and severity of antimicrobial resistance (AMR) jeopardize effective typhoid fever control, particularly in South Asia, where resistance to all oral antimicrobials used to treat typhoid fever has been reported [2–6], and where disease incidence is highest. The advent of typhoid conjugate vaccines (TCVs), which promise to provide longer duration of protection than previously licensed typhoid vaccines and are suitable for use in children as young six months of age, represents a major opportunity to accelerate typhoid fever control and to slow the emergence and spread of AMR. The World Health Organization (WHO) recommends use of TCVs in routine immunization and catch-up campaigns for the prevention of typhoid fever in typhoid-endemic countries, particularly those where AMR S. Typhi is present [7]. Two TCVs have been prequalified by the WHO, with several additional vaccine candidates in late-stage clinical development, which bodes well for future vaccine supply security [8]. Five countries have introduced TCV into their national immunization programs (Pakistan, Liberia, Zimbabwe, Nepal, Samoa), and several additional countries are planning national introductions, yet a number of typhoid-endemic countries have not made the decision to introduce the vaccine.

A single dose of TCV has been shown to be safe, immunogenic, and highly efficacious (79%–85%) over 18–36 months in large randomized-controlled field efficacy trials conducted in Malawi, Nepal, and Bangladesh [9–14]. A single dose of TCV has been shown to be highly effective when delivered through vaccination campaigns in response to drug-resistant S. Typhi outbreaks in Pakistan and Zimbabwe [15–17]. In addition, TCV was highly effective (97%) against extensively drug resistant (XDR) S. Typhi in Pakistan [16]. There is enormous potential for TCVs to slow the emergence and spread of drug-resistant S. Typhi through the prevention of infections caused by drug-resistant strains, as well as reductions in antimicrobial use and decreased selection pressure [18].

In this issue of Clinical Infectious Diseases, Dr Seth Ari Sim-Son Hoffman and colleagues [19] share results from an effectiveness evaluation of a pediatric vaccination campaign using a WHO Prequalified TCV, Typbar-TCV® (Vi polysaccharide conjugated to tetanus toxoid, Bharat Biotech India Ltd., Hyderabad, India). This public sector campaign, which targeted children 9 months to 14 years of age, was conducted by the Navi Mumbai Municipal Corporation (NMMC) in Maharashtra, India in 2018. The campaign was intended to be biphasic, and a stepped wedge randomized controlled evaluation was planned [20], but the onset of the coronavirus disease 2019 (COVID-19) pandemic prevented the second stage of the campaign from occurring, leading investigators to evaluate the programmatic effectiveness of the initial campaign against community-level risk of typhoid fever using a test-negative design (TND). These are the first published effectiveness data from a non-outbreak response public sector mass vaccination campaign.

NMMC is divided into 22 urban health posts (UHPs) of roughly equal population size; investigators stratified these based on proportion of residents living in slum areas and randomly assigned equal numbers from each stratum to be included in the initial vaccination campaign or the second one. In total, 320 000 children were age-eligible for vaccination within NMMC, and 160 000 were targeted for the initial campaign, which achieved 71% coverage in the initial vaccination communities. Blood culture surveillance was established in 6 hospitals throughout NMMC, and a continuous community survey was planned to account for healthcare seeking behavior. The survey was halted on account of COVID-related risk to field workers, but blood culture surveillance continued throughout the duration of the 33-month study follow-up period (September 2018 to March 2021). Each S. Typhi blood culture positive case was matched with up to 3 blood culture negative febrile controls based on age and time of enrollment (±28 days). The adjusted odds ratio that a culture-confirmed typhoid case resided in a vaccination community was 0.44 (0.26, 0.75, P = .0003), meaning that the programmatic effectiveness of the campaign was 56% (25%, 74%), which is consistent with 71% coverage of a vaccine that was estimated as 80.2% effective in the same setting in an unpublished analysis [21], assuming no indirect protection. The programmatic effectiveness among older vaccinees (≥5 years) was 63% (30%, 81%, P = .002), and 30% for younger vaccinees (<5 years old), although the latter was not statistically significant (P = .5), as there were only 21 cases within this age group. Programmatic effectiveness stratified by time since vaccination appeared higher within 365 days of the campaign (70%; 36%, 86%, P = .002), but the study was underpowered to measure campaign effectiveness >365 days after vaccination. Investigators also recently published results of a costing study estimating incremental costs associated with this campaign [22].

This study had several limitations stemming from the COVID-19 pandemic, including disruptions to healthcare seeking behavior, as well as inability to track migration and difficulty in ascertaining individual vaccination status due the halted community survey. Despite this, investigators were able to estimate programmatic effectiveness of the campaign, and the results appear consistent with previously published efficacy and effectiveness estimates. This demonstrates the utility of a TND approach in measuring TCV effectiveness under challenging circumstances. TND has been used previously to assess the effectiveness of influenza, rotavirus, and more recently, COVID-19 vaccines [23–26]. Investigators from the Typhoid Vaccine Acceleration Consortium (TyVAC) recently simulated a matched test-negative design using 3 different test-negative definitions and compared results to those generated as part of a “gold standard” individually randomized controlled trial in Malawi, finding high concordance between results (TND effectiveness estimates ranged from 80.3% to 80.5% as compared to 80.4% efficacy from the randomized trial) [10]. This suggests that TND may be appropriate for measuring TCV effectiveness in the context of an observational study, in spite of design-related concerns about possible confounding and low blood culture sensitivity. TND will also be used as part of an ongoing cluster-randomized trial assessing the effectiveness of another WHO Prequalified TCV, TYPHIBEV® (Vi polysaccharide conjugated to a nontoxic variant of diphtheria toxin [CRM₁₉₇] carrier protein, Biological E Ltd, Hyderabad, India) in Vellore, India [27]. Similar approaches could be considered for future post-introduction effectiveness evaluations of TCVs to support country demand and uptake of these products.

Questions remain about optimal programmatic use of TCV, including longer-term efficacy and effectiveness conferred by a single dose and how this might vary by initial age of administration [28], but this vaccine is safe, well tolerated, and highly efficacious for at least 3 years following immunization. Decision makers must weigh the value of these immunization programs against other competing health priorities, often without the benefit of subnational incidence and/or AMR data. However, the risk of typhoid fever is not static and is likely to increase due to water scarcity, climate change, and the increasing prevalence of AMR, which elevates the urgency for widespread TCV introduction. In addition, TCVs can be incorporated into multi-antigen campaigns, particularly in areas where routine immunization coverage declined during the COVID-19 pandemic [29]. This study strengthens the case for widespread deployment of TCVs in India and in other typhoid-endemic countries and paves the way for future evaluations of pipeline vaccines. India is slated to introduce TCV with Gavi support [30], which bodes well for advancing health equity and reducing typhoid-related morbidity and mortality across the sub-continent. In light of the growing body of evidence demonstrating the public health value of TCVs, additional typhoid-endemic countries should follow suit.