Introducing a routine typhoid vaccine (TCV) is a cost-effective solution for many low-income countries

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Introducing a typhoid conjugate vaccine (TCV) into routine child vaccine schedules and conducting a catch-up campaign to vaccinate all children up to age 15 is a cost-effective solution for many low- to middle-income countries severely burdened by typhoid, a new study led by researchers at the Yale School of Public Health finds.

The study is the first comprehensive analysis of the cost-effectiveness of different typhoid vaccination strategies for 54 countries hit hardest by typhoid – primarily located in Asia and sub-Saharan Africa – and where funding from Gavi, an international organization dedicated to vaccine introduction, is available.

The study – published Thursday in Lancet Infectious Diseases – analyzed disease transmission rates, hospitalizations, mortality rates, vaccine-related costs and the financial resources of each country.

Extensive computer modeling and analysis were applied to evaluate four strategies: no vaccination, routine immunization at nine months, or routine immunization at nine months with catch-up campaigns to either age 5 or age 15.

An optimum strategy for a country was considered one that maximized the average net monetary benefit.

“We have provided all of the information for decision-makers to evaluate whether the typhoid conjugate vaccine is a good value,” said Virginia Pitzer, associate professor of epidemiology at the Yale School of Public Health and the study’s senior author.

“Now each country will have the information needed to decide for itself whether or not to apply for Gavi funding to introduce the vaccine.”

Typhoid is a serious and sometimes fatal disease caused by the bacteria Salmonella Typhi.

It impacts over 10 million people a year and is spread through contaminated food and water, usually due to inadequate sanitation and water infrastructures in low- and middle-income countries.

While global incidence of typhoid has declined in recent years, prolonged multi-year outbreaks continue to pose a public health threat.

Climate change, urbanization and increasing drug resistance have contributed to the significant health and economic burden that typhoid places on families and communities.

The typhoid conjugate vaccine, Typbar-TCV, was recently approved by the World Health Organization and is currently recommended as part of an integrated approach to controlling the disease along with improvements in water, sanitation and hygiene.

The conjugate vaccine overcomes many of the limitations of earlier typhoid vaccines: it offers longer-lasting protection, requires fewer doses and is suitable for children as young as 6 months of age, allowing it to be included in routine childhood immunization programs.

“Expanding access to, and coverage of, TCVs can protect children and adolescents from illness, reduce the need for antibiotics, slow emergence of drug-resistant strains, and save lives,” said Dr. Kathleen Neuzil, director of the Center for Vaccine Development and Global Health at the University of Maryland School of Medicine and director of the Typhoid Vaccine Acceleration Consortium (TyVAC).

TyVAC, one of the funders of the study, is a partnership between the Center for Vaccine Development and Global Health at the University of Maryland School of Medicine, the Oxford Vaccine Group at the University of Oxford and PATH, an international nonprofit, that aims to accelerate the introduction of TCVs into low-resource settings.

Individual country reports on the cost-effectiveness and potential benefits of TCV can be found at the Together We Can Take On Typhoid website.

The study was led by Pitzer and Professor A. David Paltiel, co-directors of the Yale School of Public Health’s Modeling Concentration, in close collaboration with a team in the Center for Health Economics and Modelling Infectious Diseases (CHERMID) at the University of Antwerp in Belgium. Other collaborators included experts from the University of Oxford and the University of Maryland School of Medicine.

Uncertainty surrounding the probability of hospitalization, typhoid incidence and mortality rates had the greatest influence on a country’s optimal vaccination strategy, the researchers said. But such unknowns should not deter decision-makers.

“For some countries, substantial uncertainty exists around the optimal vaccination strategy,” said the study’s lead author Joke Bilcke, a postdoctoral researcher and lecturer at CHERMID, part of the Vaccine & Infectious Disease Institute at the University of Antwerp, Belgium.

“Nevertheless, this should not preclude the introduction of TCV. Decisions need to be made in the context of uncertainty, and the strategy of choice in terms of cost-effectiveness should be the one with the highest expected net benefit.”


Typhoid, a serious and sometimes fatal disease caused by the bacterium Salmonella entericaserovar Typhi (S. Typhi), is spread through contaminated food and water and poor sanitation. Although typhoid has been largely eliminated in industrialized countries, it continues to be a substantial public health problem in many low- and middle-income countries.

Globally, there are nearly 12 million cases and more than 128 000 deaths due to typhoid each year [1].

The burden is likely underestimated due to lack of comprehensive surveillance data, poor sensitivity of available diagnostics, and their limited deployment.

Current trends in antibiotic resistance, urbanization, and climate change may increase the risk for typhoid.

While improved water quality, sanitation, and hygiene (WASH) are the major ways to break the typhoid transmission cycle, until these investments are made in all countries, vaccination is an important and effective option to prevent typhoid.

To reduce the burden of S. Typhi, the Bill & Melinda Gates Foundation funded the Typhoid Vaccine Acceleration Consortium (TyVAC) in late 2016.

TyVAC is led by the Center for Vaccine Development and Global Health at the University of Maryland School of Medicine, the Oxford Vaccine Group at the University of Oxford, and PATH.

TyVAC uses a multidisciplinary, iterative approach to accelerate the introduction of typhoid conjugate vaccines (TCVs) into low- and middle-resource countries, particularly those eligible for support from Gavi, the Vaccine Alliance.

TyVAC is working closely with the World Health Organization (WHO), Gavi, and other local and global stakeholders to design and execute a strategy based on prior successful new vaccine introductions. Core activities are customized to address challenges posed by typhoid fever and demonstrate TCV introduction for optimal impact.

TYPHOID VACCINES: CURRENT STATUS

In 2018, typhoid continues to be a public health threat.

Children and adolescents in Asia and sub-Saharan Africa are disproportionately impacted by typhoid, with those living in poor communities at the greatest risk.

In addition to the disease burden, global outbreaks and growing antimicrobial resistance further highlight the need for prevention. In and around Harare, Zimbabwe, for example, an outbreak has been ongoing since October 2017, with 200 new cases reported in the first few weeks of 2018 [2].

In Pakistan, the first large outbreak of third-generation cephalosporin-resistant S. Typhi occurred in 2017, greatly complicating treatment options [3].

Prior to 2017, 2 typhoid vaccines were available: the oral, live attenuated Ty21a vaccine licensed for children aged ≥6 years, and an injectable Vi capsular polysaccharide vaccine licensed for children aged ≥2 years [4].

Only the latter is prequalified by WHO.

These vaccines are underutilized in high-burden countries despite typhoid’s substantial and detrimental impact and WHO recommendation for their use.

It has been difficult to incorporate these vaccines into routine immunization programs in low-resource countries because neither is approved for children aged <2 years or subsidized by Gavi.

ADVANTAGES OF TCVS

New TCVs have the potential to overcome challenges that have impeded the uptake of earlier vaccines. TCVs have longer-lasting protection, require fewer doses, and are suitable from infancy, allowing delivery through routine childhood immunization programs.

Expanded use of TCVs through routine immunization has the potential to reduce the need for antibiotics, slow further emergence of drug-resistant typhoid strains, and save lives.

Typbar-TCV, manufactured by Bharat Biotech International Limited, is safe, well tolerated, and induces a robust and long-lasting response across age groups for longer periods of time than a currently prequalified polysaccharide typhoid vaccine [4].

The high immunogenicity of Typbar-TCV makes it an ideal candidate in typhoid-endemic countries, especially for children aged <2 years, a group particularly vulnerable to typhoid fever.

Researchers at Oxford University conducted the first clinical trial to assess the efficacy of Typbar-TCV using a controlled human infection model.

Results showed that the vaccine halved the total number of typhoid cases and had an efficacy of 87.1% when endpoints of fever >38°C followed by a positive blood culture were used [5].

Interestingly, this estimate was aligned with an analysis of serological evidence of protection in an immunogenicity trial in India [6].

These data were essential supporting evidence for global policy decisions.

Successful and sustainable vaccine introduction requires supporting evidence, government backing, financing, WHO prequalification, country readiness/willingness, political will, and local endorsement.

Within a few short months in 2017, Typbar-TCV was recommended by WHO’s Strategic Advisory Group of Experts (SAGE) on Immunization, supported by Gavi, and prequalified by WHO.

In October, SAGE recommended a single-dose TCV for infants and children aged >6 months in typhoid-endemic countries; introduction prioritized in countries with the highest burden of disease or a high burden of antimicrobial-resistant S. Typhi; a catch-up vaccination strategy, when feasible, for children up to age 15 years, depending on local epidemiology; and typhoid vaccination in response to confirmed outbreaks of typhoid fever and considered in humanitarian emergencies [78].

In November, Gavi announced $85 million to support the introduction of TCVs [9].

This funding opens the way for low-income, high-burden, Gavi-eligible countries to affordably introduce safe and effective typhoid vaccines.

Country applications will be accepted in the second half of 2018 for introductions in 2019 and 2020.

In December, WHO prequalified the first TCV, that is, Typbar-TCV [1011].

Prequalification means the TCV has the WHO stamp of approval and can be purchased by countries through United Nations procurement agencies, including WHO, the United Nations Children’s Fund, and Gavi.

While Typbar-TCV is the first prequalified TCV, many more TCVs are in development [unpublished data]. The availability of additional TCVs will ensure global supply and a competitive marketplace.

Multiple delivery strategies may be used to operationalize the WHO recommendations. Considerations and challenges for a delivery strategy include risk-based vs universal coverage under routine immunization, catch-up, and use in endemic areas and/or during outbreaks.

It is challenging to target high-risk individuals because the risk may be based on the setting or population and may vary over time.

In addition, it can be hard to identify high-risk individuals in advance due to population expansion and movement.

Incorporating TCV into the routine immunization schedule allows protection for all children prior to exposure to typhoid, which is being increasingly recognized in young children [812].

There are challenges related to routine immunization, such as vaccine supply, vaccine cost, and the increasing number of vaccines administered at 9 to 15 months.

WHO SAGE called for further studies to understand tolerability and immunogenicity of Typbar-TCV coadministered with other Expanded Programme on Immunization–recommended vaccines (the Expanded Program on Immunization is a World Health Organization program to expand immunization programs and make vaccines more accessible).

Understanding the duration of immunity through ongoing studies is critical to inform strategies.

Vaccine introduction and the associated policy-making processes are complex, often fragmented, and involve many groups across government.

Lessons learned from new vaccine adoption and introduction are that global action drives country decisions through WHO recommendations and affordable vaccines, support from Gavi for vaccine introduction is extremely important, and processes used by countries that successfully introduce new vaccines are largely similar [1314].

Introduction requires a commitment by the country’s national immunization program to determine the feasibility and acceptability of introduction to generate robust financial support for a sustainable program.

Demonstration of the impact of new vaccines in different endemic populations is critical. Prior to the TyVAC project, there were no field efficacy studies for Typbar-TCV, and challenge studies may not predict field effectiveness.

As a major component of TyVAC, we are implementing vaccine evaluations of Typbar-TCV to provide data to support the introduction of the vaccine in those regions suffering a substantial burden of disease.

Our proposed studies have been designed to be complementary to each other and to other efforts (Table 1) [unpublished data]. In addition to efficacy of culture-confirmed typhoid fever, other outcomes include safety, immunogenicity, costs, and effects on other important public health outcomes such as antibiotic usage.

We will conduct individually randomized, controlled trials in Nepal and Malawi among children beginning at age 9 months, with a 1:1 randomization of TCV or the control vaccine, a serogroup A meningococcal conjugate vaccine.

In Bangladesh, we will conduct a controlled cluster randomized trial.

In this design, rather than randomizing individuals to TCV or the live, attenuated Japanese encephalitis control vaccine, we will randomly allocate groups (or clusters) of individuals to treatment arms [15].

Our primary reason for using this design is to determine if the vaccine can prevent typhoid by protecting the vaccinated individuals and also by reducing transmission of typhoid to those in the community who have not been vaccinated (ie, indirect protection).

The groundwork for the TyVAC sites has been provided by the Strategic Typhoid Alliance across Africa and Asia [16], which was conducted at the 3 trial sites.

The large populations under surveillance for blood culture–confirmed typhoid fever in the 3 countries informed our study design and sample sizes.

In Malawi and Nepal, passive surveillance for febrile illness will be conducted at community-based health clinics and local hospital for all vaccinated children. In Bangladesh, the surveillance will cover all vaccinated children and unvaccinated cluster residents.

Table 1.

Summary of Typhoid Vaccine Acceleration Consortium Impact Studies

SiteNepal (Kathmandu)Malawi (Blantyre)Bangladesh (Dhaka)
Trial designIndividually randomized, controlled trialIndividually randomized, controlled trialCluster randomized, controlled trial
Investigational vaccineSingle-dose Vi-TCV
Licensed trade name: Typbar-TCV, Bharat-Biotech
Comparator (control) vaccineSerogroup A meningococcal conjugate vaccineSerogroup A meningococcal conjugate vaccineLive attenuated Japanese encephalitis
Sample size targets20 00028 00043 350 within 150 clusters
Participant age9 months to <16 years9 months through <13 years9 months to <16 years
Start dateNovember 2017February 2018March 2018
Primary outcomeDetermine efficacy and rate reduction of Vi-TCV in preventing blood culture–confirmed symptomatic infection by Salmonella enterica serovar Typhi
Study duration, months303630
Safety follow-up• Immediate reactions
• SAEs
• AEs 7 days post-vaccination
• Immediate reactions and SAEs in all participants
• Subset: local and systemic solicited and unsolicited reactions for 7 days post-vaccination
• Subset: all AEs for 28 days post-vaccination
• Immediate reactions
• SAEs
• AEs 7 days post-vaccination
Immunogenicity data (subset)Anti-Vi antibodies on day 0, 1 month (day 28), day 545, and day 730Anti-Vi antibodies on day 0, 1 month (day 28), and day 730Anti-Vi antibodies on day 0, 1 month (day 28), and day 730
Co-administration with other vaccines (measles-rubella)Not applicableMeasles and rubella antibody response in 200 children aged 9–11 monthsNot applicable
SurveillancePassive surveillance for febrile illness in vaccinated children at community-based health clinics and local hospitalPassive surveillance for febrile illness in vaccinated children at community-based health clinics and local hospitalPassive surveillance for febrile illness in all cluster residents at community-based health clinics and local hospital
Follow-up duration2-year follow-up post-vaccination for each participantMinimum of 2 years follow-up post-vaccination for each participant or until the number of verified cases is reached2-year follow-up post vaccination for each participant

Abbreviation: AE, adverse event; SAE, serious adverse event; Vi-TCV, Vi polysaccharide-tetanus toxoid conjugate vaccine.

From the publication of pivotal typhoid research to local and national efforts against typhoid outbreaks, 2017 and 2018 have been exciting years for efforts to take on typhoid.

The rise of drug-resistant typhoid combined with global trends of urbanization and climate change, which can increase risk factors for the spread of typhoid, have raised the urgency of prevention.

Thanks to the hard work of many global partners, we are raising awareness of the burden of typhoid and accelerating access to TCVs.

This year, we continue to work with countries to help them decide if, when, and how to introduce TCVs along with WASH interventions as part of a comprehensive approach to typhoid prevention and control.

Additional information on TyVAC and the initiative to take on typhoid is available on our website [17].

More information: Joke Bilcke et al. Cost-effectiveness of routine and campaign use of typhoid Vi-conjugate vaccine in Gavi-eligible countries: a modelling study, The Lancet Infectious Diseases (2019). DOI: 10.1016/S1473-3099(18)30804-1

Journal information: Lancet Infectious Diseases
Provided by Yale University

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