Multi-drug resistant Salmonella typhi: why should African countries move quickly toward adopting typhoid conjugate vaccine

Introduction

Typhoid fever remains a significant public health burden resulting in high morbidity and mortality among millions of individuals in resource-constrained settings.¹ Typhoid fever is caused by the bacterium Salmonella Typhi and is spread mainly through the ingestion of contaminated food or water. While the disease has been largely eliminated in higher-income countries with modern sanitary facilities and safe drinking water, it still persists as a significant public health issue in many low- and middle-income countries (LMICs) worldwide.^2,3 This public health threat is further compounded by the emergent multi-drug resistant strains (H58 Salmonella). These multi-drug resistant strains have been on the rise especially in sub-Saharan Africa (SSA) and leads to prolonged illness and severe complications.⁴

S. Typhi has reportedly been cultured from patients in 42 of 57 African countries until 2018. However, this could result from limited diagnostic capacities and underreporting in the remaining 15 countries.⁵ Many studies in Africa have reported an incidence rate that is similar to or even higher than that reported in South/Southeast Asia.^5,6 A 2019 comprehensive review estimated the African incidence of typhoid fever from previous results and presented an initial pooled estimate of 112.1/100,000 person-years, with a 95% confidence interval (CI) of 46.7–203.5.⁷ This high incidence may likely be compounded by the impact of climate change in some countries in Southern parts of Africa.⁸ With such a huge impact of the disease on households, and health care systems, more innovative preventive efforts are required to curb the spread of the disease. Introduction of Typhoid conjugate vaccine (TCV) offers a new hope in addressing the enduring problem of typhoid fever as well as the evolving problem of multi-drug resistance in affected regions.

Typhoid fever; current treatment options, development of multi-drug resistance, and economic impact of the disease

Antibiotics have offered the most effective way to treat typhoid fever since 1940’s. Chloramphenicol, co-trimoxazole and ampicillin were the first recommended antibiotic treatment options for typhoid fever.⁹ Even though the antibiotics were highly effective during inception, the bacterium has evolved quite quickly, rendering most of them ineffective. Multi-drug resistant (MDR) typhoid, (resistance to chloramphenicol, ampicillin, and co-trimoxazole) first appeared in the 1970’s and has since spread globally.⁹ In the last decade, several regions in Africa have reported typhoid outbreaks, and these have been closely linked with MDR phenotypes, H58.S.⁹ This strain has been isolated in many parts of the world including SSA. Owing to the rapid rise of MDR strains, fluoroquinolones, azithromycin and third-generation cephalosporins were eventually recommended as second line and third line treatment options respectively. However, since 2016, extensive drug resistant strains (resistant to chloramphenicol, ampicillin, co-trimoxazole, streptomycin, fluoroquinolones, and third-generation cephalosporins) have been reported in Pakistan.¹⁰ This renders azithromycin as the only effective oral treatment option for typhoid. The emergence of these extensively drug resistant strains with a high potential to spread to other regions poses significant concerns to treatment of typhoid as treatment options are limited. Furthermore, most African countries have limited diagnostic capacity leading to increase in empiric treatment of infections, and eventually overuse of antibiotics.¹¹ This will likely worsen the development of resistant strains and render all available treatment options ineffective.

Intravenous antibiotics required in advanced, severe typhoid disease are more expensive and less readily accessible in most health care centers/facilities.¹² In most developing countries, these antibiotics are mostly found in referral hospitals. This poses a significant economic burden on households as they must travel long distance to access care. Drug resistant cases leads to prolonged hospitalization, high case fatality and morbidity leading to increased pressure on health care systems.¹²

Typhoid conjugate vaccine: A new hope for Africa

Increase in MDR and emergence of extensively resistant strains highlight the need for urgent escalation of preventive efforts such as adoption of Typhoid Conjugate Vaccine (TCV) and improvement in Water, Sanitation and Hygiene (WASH) facilities. However, the former offers a better option in most African countries where hope for improving water supply systems and hygiene practices has greatly staggered for a century. Approximately, 418 million people still lack even a basic level of drinking water service, 779 million lack basic sanitation services (including 208 million who still practice open defecation) and 839 million still lack basic hygiene services.¹³ With such threatening figures on inequitable access to safe drinking water and sanitation facilities, perhaps two more decades would elapse to alleviate the challenge. The problem is more likely to be compounded by the effects of Climate change, which further leads to disruption of WASH facilities. The cases of water borne diseases are likely to be on the increase, and typhoid is not an exception.

The TCV is highly effective and efficacious. The vaccine was prequalified for use for control of typhoid fever by WHO in 2018. The Vaccine is administered in a single dose and approved for children six months of age and older. Large Phase 3 efficacy studies conducted in Bangladesh, Malawi, and Nepal show that Typbar TCV is safe and highly effective, preventing 85%, 84%, and 79% of typhoid cases in vaccinated children, respectively.¹⁴ A recent phase 3 trial report from Malawi has also demonstrated the longer durability of protection, with little decrease in efficacy for up to 48 months. An age stratified analysis from the same study also demonstrated that the vaccine is efficacious in all age groups, including children <2 years old.⁴

Despite being highly efficacious and prequalified by the WHO nearly four years ago, Most African countries haven’t adopted the TCV into their routine immunization programs.

Policy outcomes and implications

Even though improving WASH facilities offers a longer term and most effective option for controlling typhoid fever, most African countries are far from achieving that. Adopting the TCV is not only the most effective approach, but also a cost-effective immediate solution for Africa. TCV can be administered as reactive campaign or as part of national preventive efforts. Studies have demonstrated reactive vaccination to be cost-effective if delays in vaccine deployment are minimal; otherwise, introduction of preventive routine immunisation with a catch-up campaign is the preferred strategy.¹⁵ Countries such as Zimbabwe, Liberia, and Malawi in partnership with international organizations have moved and adopted TCV into a routine immunization program. TCV has also shown to have a major role not only in reducing the burden of typhoid but also preventing the spread of drug-resistant typhoid strains. A recent modelling analysis projected that TCV introduction with catch-up campaigns could drastically reduce the number of drug-resistant typhoid cases and deaths.¹⁶ This analysis further predicts that two-thirds of cases and deaths due to fluoroquinolone resistant- and MDR typhoid could be averted through TCV introduction and the proportion of typhoid cases that are drug resistant could decrease by more than 16% in Gavi, the Vaccine Alliance-eligible countries over ten years. With the weakening pipeline in development of new antibiotics, TCV offers a new hope to most developing countries in Africa.

Furthermore, studies done in Malawi indicate that typhoid can be economically catastrophic for families, despite accessible free medical care.¹⁷ The disease is also costly for government healthcare provision. With the high economic burden of the disease on family and increased pressure on health care systems, studies have demonstrated that introduction of routine immunization with TCV along with a catch-up campaign in children aged less than 15 years could be a cost-effective solution to combat the burden of typhoid fever, especially in countries with high typhoid incidence receiving Gavi support.

Actionable recommendations

Conclusions

The burden of typhoid fever is worsened by growing concerns about drug resistance. In view of the MDR typhoid in Africa highlighted in this article, it is imperative that countries adopt and adapt global policies for contextually appropriate use of TCV. Countries need to identify typhoid research priorities and set up typhoid national action plans (NAP) to oversee all collaborative efforts against MDR typhoid strains. The NAPs should outline a comprehensive prevention approach that should involve multiple stakeholders from the designing stage up to implementation.