byJohn Gever, Contributing Writer, MedPage Today
In a major trial conducted in the African nation of Malawi, a new vaccine against typhoid fever in young children was highly effective, researchers said.
An intention-to-treat analysis showed 80.7% efficacy (95% CI 64.2%-89.6%), with fewer adverse events than were seen with a standard meningococcal A (MenA) vaccine used as a control, according to Melita A. Gordon, MD, of the Malawi-Liverpool-Wellcome Program in Liverpool, England, and colleagues.
Some 28,000 children, ages 9 months to 12 years, participated in the trial, assigned in roughly equal numbers to the MenA product or to the Vi-TCV typhoid vaccine (a conjugated product combining tetanus toxoid with aSalmonella entericaTyphi polysaccharide), the group reported in theNew England Journal of Medicine.
Typhoid vaccines have been around for years (two are currently approved in the U.S., although one hasreportedly been discontinued), yet the disease remains commonplace in Africa and South Asia. Ti-TCV has recently become available but clinical testing is still ongoing, with multiple trials organized in diverse epidemiologic settings, Gordon and colleagues explained, including Nepal and Bangladesh as well as Malawi. Only the latter was reported in the current study.
The typhoid vaccine was administered as a single 0.5-mL dose, containing 25 g ofS.Typhi polysaccharide. Both it and the MenA vaccine were given along with routine measles-rubella vaccination in participants ages 9-11 months. Randomization was by blocks of six to 12 children. Those administering the vaccines along with trial staff, child participants, and their parents were blinded to the assignments.
Among the 14,069 children assigned to Ti-TCV, 12 developed typhoid infection versus 62 of those randomized to MenA during 18 months or more of passive surveillance. Infection rates per 100,000 person-years were 46.9 for Ti-TCV and 243.2 for MenA.
Gordon and colleagues also performed a per-protocol analysis, including only those children who actually received the proper vaccine and otherwise adhered to the protocol for follow-up. This included about 95% of those randomized to MenA and more than 99% of those assigned to the typhoid vaccine — a testament, perhaps, to the feasibility of vaccine administration in the study population. In this analysis, vaccine efficacy came out at 83.7% (95% CI 68.1%-91.6%).
Some 130 serious adverse events were recorded in the first 6 months after vaccination, including six deaths. All the fatalities and a majority of the other serious events occurred in the MenA group. In all, 52 in the Ti-TCV group and 78 assigned to MenA had serious events. The most common were infections and infestations (34 and 55, respectively), followed by respiratory infections (16 and 21), gastroenteritis (11 and 8), malaria, and other infections.
An important subgroup in the sample was children infected with HIV (n=196). The researchers did not examine vaccine effectiveness in these children — for unknown reasons, culture-confirmed typhoid illness is extremely rare in HIV-infected individuals — but no excess of serious adverse events considered to be related to vaccination was seen in the subgroup.
Surveillance is continuing for children in the study, and Gordon and colleagues are conducting a substudy to evaluate a second dose for HIV-infected children.
One disturbing finding from the study was that all of the infections that developed in study participants were resistant to first-line agents for suspected bloodstream infection, the researchers said. Moreover, they wrote, it is particularly worrisome that fourS.Typhi strains among participants enrolled in this trial showed reduced susceptibility to fluoroquinolones.
This speaks to the growing prevalence of multidrug-resistant organisms in Malawi, as seen in several Asian countries, Gordon and colleagues wrote, and it adds urgency and relevance to efforts to introduce a safe and efficacious Vi-TCV vaccine across the African continent and globally.
John Geverwas Managing Editor from 2014 to 2021; he is now a regular contributor.
The study was supported by the Bill and Melinda Gates Foundation. The Malawi-Liverpool-Wellcome Program is funded by the Wellcome Trust. Bharat Biotech International supplied the vaccine but had no other involvement in the trial.
Source Reference:Patel PD, et al Safety and Efficacy of a Typhoid Conjugate Vaccine in Malawian Children N Engl J Med 2021; DOI: 10.1056/NEJMoa2035916.