A trial of a typhoid conjugate vaccine in children in Malawi
Authors: Priya Venkatesan
Journal: The Lancet Microbe (2021)

Improved sanitation and the introduction of antibiotics have reduced the number of cases and deaths from typhoid fever in high-income countries, but it remains a huge public health problem in many low-income regions, particularly in Africa. An estimated 9 million cases and more than 110 000 deaths occur annually in the world due to typhoid fever, with around 1 million cases and nearly 19 000 deaths occurring in sub-Saharan Africa. Most of the disease burden occurs in children; in 2017, global incident rates were highest in children aged 15 years or younger. The threat of typhoid fever has increased in the past few years in Africa because of the emergence of multidrug-resistant strains of Salmonella enterica subsp enterica serovar Typhi (S Typhi) lineages, some of which are resistant to first-line antibiotics chloramphenicol, ampicillin, and trimethoprim-sulfamethoxazole. Thus, effective typhoid vaccines that can be used in all vulnerable populations including infants and children are vital. In a randomised trial in children in Malawi (sub-Saharan Africa), a single dose of Vi polysaccharide typhoid conjugate vaccine (Vi-TCV) resulted in fewer incident cases of typhoid fever after 18 to 24 months than the control (meningococcal capsular group A conjugate vaccine). In this double-blind trial conducted in two urban townships in Blantyre (Malawi), Priyanka Patel (Malawi-Liverpool Wellcome Trust Clinical Research Programme, Blantyre, Malawi) and co-investigators enrolled 28 130 healthy children aged 9 months to 12 years, and randomly assigned (1:1) 14 069 children to receive one dose of Vi-TCV and 14 061 to receive the control meningococcal vaccine. After 18–24 months of follow-up, blood cultures were obtained from 7314 (94·1%) of 7776 children who presented to a passive surveillance centre. The primary outcome of typhoid fever confirmed by blood culture occurred in 12 children in the Vi-TCV group (46·9 cases per 100 000 person-years) and in 62 children in the control group (243·2 cases per 100 000 person-years). Efficacy of the vaccine at any time after vaccination analysed by intention to treat was 80·7% (95% CI 64·2–89·6); over time, efficacy was estimated to be 84·6% (50·0–94·4) at 12 months after vaccination, decreasing to 78·7% (52·8–91·7) at 24 months after vaccination. Efficacy in the per-protocol analysis was 83·7% (68·1–91·6). The most frequently reported serious adverse events within 6 months after vaccination were in the infections and infestations category, occurring in 34 (<1%) of 14 069 children in the Vi-TCV group and in 55 (<1%) of 14 061 children in the control group. Six children died within 6 months of vaccination, all in the control group; one child died from typhoid 7 months after receiving the control vaccine. The trial results are encouraging and support the use of the typhoid conjugate vaccine in routine vaccination programmes. Seth Berkley (Gavi, the Vaccine Alliance, Geneva, Switzerland) commented “The results of this study are consistent with previous data that confirm the high effectiveness of typhoid conjugate vaccine to prevent typhoid fever, including among young children. This year saw the first vaccine introductions [in routine immunisation programmes] in Liberia and Zimbabwe and we look forward to supporting the typhoid conjugate vaccine rollout in more countries to ensure young children are protected—particularly with the rise of drug resistant typhoid strains.” However the trial findings also highlighted the growing and widespread threat of resistance; of 75 blood samples that were positive for S Typhi, 100% were resistant to first-line drugs including to fluoroquinolones, and four (5·3%) were resistant to ciprofloxacin. Resistance to first-line drugs is also becoming evident for other pathogens. A longitudinal study in northern Uganda showed that 14 patients (6%) of 240 with Plasmodium falciparum infection had evidence of in-vivo artemisinin resistance, the primary drug in the fight against malaria. Parasite clearance half-lives in these patients were prolonged to more than 5 h, particularly those with P falciparum parasites with mutations in the A675V or C469Y allele in the kelch13 gene (Pfkech13). Vaccines are an important and effective tool to reduce the need for widespread use of antimicrobials, but more action also needs to be taken to combat the rapidly increasing threat of antimicrobial resistance, and investment needs to be made into equitable access of adequate sanitation facilities across the globe. For more on the typhoid vaccine trial see N Engl J Med 2021; 385: 1104–15For more on global typhoid incidence and mortality http://www.healthdata.org/results/gbd_summaries/2019/typhoid-fever-level-4-causeFor the arteminisin resistance study see N Engl J Med 2021; 385: 1163–71 For more on the typhoid vaccine trial see N Engl J Med 2021; 385: 1104–15 For more on global typhoid incidence and mortality http://www.healthdata.org/results/gbd_summaries/2019/typhoid-fever-level-4-cause For the arteminisin resistance study see N Engl J Med 2021; 385: 1163–71 Zimbabwe tackles typhoid and cholera through vaccinationIn early November 2021, the Government in Zimbabwe started a so-called mop-up vaccination initiative with the typhoid conjugate vaccine (TCV) to reach children who were not immunised in the TCV vaccination campaign that took place in the country in May. In the 10-day vaccination campaign, more than 4 million children aged 9 months to 15 years received TCV. Full-Text PDF Open AccessThe global burden of typhoid and paratyphoid fevers: a systematic analysis for the Global Burden of Disease Study 2017Despite notable progress, typhoid and paratyphoid fevers remain major causes of disability and death, with billions of people likely to be exposed to the pathogens. Although improvements in water and sanitation remain essential, increased vaccine use (including with typhoid conjugate vaccines that are effective in infants and young children and protective for longer periods) and improved data and surveillance to inform vaccine rollout are likely to drive the greatest improvements in the global burden of the disease. Full-Text PDF Open AccessIncidence of invasive salmonella disease in sub-Saharan Africa: a multicentre population-based surveillance studyTyphoid fever and iNTS disease are major causes of invasive bacterial febrile illness in the sampled locations, most commonly affecting children in both low and high population density settings. The development of iNTS vaccines and the introduction of S Typhi conjugate vaccines should be considered for high-incidence settings, such as those identified in this study. Full-Text PDF Open Access