These are times both for celebration and consternation within the typhoid community. The World Health Organization (WHO) recently prequalified a typhoid conjugate vaccine that promises increased effectiveness against young children and a longer duration of protection than previous vaccines. The Navi Mumbai Municipal Corporation is the first government body scheduled to implement the vaccine into their immunization program later this year. Gavi opened an $85 million funding window to support introduction of typhoid conjugate vaccine into immunization programs in high risk countries. We are on the verge of deploying a powerful new tool against typhoid!
We celebrate these successes, but at the same time we are concerned. In the absence of antibiotic treatment, typhoid can kill healthy people. Leland Stanford Junior, the namesake of Stanford University, my current employer, died from typhoid fever. When chloramphenicol was first introduced to treat typhoid fever in 1948, the case fatality proportion dropped dramatically from more than 30% of hospitalized patients dying to fewer than 2%. Yet, within two years, the first strains of Salmonella Typhi (S. Typhi) that were resistant to chloramphenicol were identified. Over the ensuing decades, clinicians have progressively chosen new, more expensive antibiotics to treat typhoid and just as quickly S. Typhi has developed resistance. Current strains that are widely circulating are resistant to ampicillin, chloramphenicol, trimethoprim sulfamethoxazole and fluoroquinolones. Only azithromycin and third-generation cephalosporins are effective against the majority of strains, but resistance to these drugs is becoming increasingly common. Nowhere is this more troubling than in the ongoing outbreak of ceftriaxone resistant S. Typhi in and around Hyderabad, Pakistan. In the last two years >800 cases of ceftriaxone resistant S.Typhi have been identified and the geographic spread of the outbreak continues to expand.
The pipeline for new antibiotics offer little hope for a midterm solution. Because the financial returns on new antibiotics are lower than investing in other drugs, pharmaceutical companies have not invested in antibiotic development for decades. The imminent loss of effective antibiotic treatment means that deploying an effective vaccine in high-risk communities is a critical priority.
Nevertheless, current vaccines will not protect populations against Salmonella Paratyphi nor against other waterborne diseases. The typhoidal salmonellas have been largely eliminated in high income countries through civil engineering investments that have separated the human fecal stream from drinking water and the food supply. The communities at highest risk of typhoid and paratyphoid are the communities that are most difficult to reach with expensive infrastructure. Poor, marginalized communities have little political influence in the deployment of the substantial funds required to develop effective infrastructure. Although we have known how to construct effective civil engineering infrastructure for 150 years, the cost of constructing and the complexity of maintaining these systems has precluded their expansion into the communities at highest risk for typhoid. This negligence creates an efficient environment for the emergence of highly drug resistant strains.
Investments in research to develop robust engineering solutions that provide clean drinking water, that separate human fecal waste from the environment and that are fit for purpose in impoverished communities with a high incidence of typhoid are important areas for research. Breakthroughs here hold the potential for reducing the burden of typhoid without exerting any selective pressure towards increasing drug resistance. As chair of the Coalition against Typhoid steering committee, I look forward to working across sectors to support these important efforts.
Photo Credit: Sabin Vaccine Institute/Thoko Chikondi