Typhoid conjugate vaccines for preventing typhoid fever (enteric fever)

- Rationale Typhoid fever is a major cause of enteric disease‐related morbidity and mortality. Vaccination reduces disease burden and prevents outbreaks, but policies and programmes should be informed by the most recent evidence as newer vaccines become available. Objectives To assess the benefits and harms of typhoid conjugate vaccines (TCVs) compared to no vaccine, placebo, typhoid‐inactive agents (vaccines for another disease) or other typhoid vaccines for preventing morbidity and mortality associated with typhoid fever in adults and children. Search methods In April 2024, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, Global Index Medicus, United States Advisory Committee on Immunization Practices and the World Health Organization vaccine repository for randomised controlled trials (RCTs), with no restrictions. We also searched clinical trial registries for ongoing trials (www.clinicaltrials.gov and the WHO International Clinical Trials Registry Platform), grey literature, bibliographic citations of reviews and key articles for additional studies. We contacted study authors for information about ongoing studies. Eligibility criteria We included RCTs and cluster‐RCTs of children and adults living in typhoid‐endemic areas or travelling to typhoid‐endemic areas. We included studies comparing TCVs to controls (i.e. no vaccine, placebo or vaccines for another disease), non‐conjugated typhoid vaccines or other TCVs. Outcomes Outcomes included acute typhoid fever, defined by laboratory‐confirmed isolation of Salmonella typhi , all‐cause mortality, adverse events (AEs) and serious adverse events (SAEs). Risk of bias Review authors independently assessed risk of bias for all outcomes, using the Cochrane RoB 2 tools. We resolved disagreements through discussion or adjudication. We assessed the intention‐to‐treat effect and used the overall RoB judgement to assess the certainty of evidence for each outcome. Synthesis methods Three review authors independently screened titles and abstracts for eligible studies, followed by full‐text assessment. Disagreements were resolved through discussion or adjudication by a fourth author. Four authors independently extracted characteristics of included studies and outcome data using a piloted, standardised data extraction form. We synthesised results for each outcome where possible, using the Mantel‐Haenszel statistical method and random‐effects analysis model. Where meta‐analysis was not possible due to the nature of the data, we planned to synthesise results based on direction of effect. We used GRADE to assess the certainty of evidence for each outcome, assessing risk of bias, inconsistency, indirectness, imprecision and other bias. Included studies We included 19 trials (17 RCTs and two cluster‐RCTs). The 19 trials enrolled 395,650 participants, with ages ranging from six weeks to 60 years. Vaccines were delivered as a single dose in 14 studies; two doses, ranging from four to 24 weeks apart, in six studies; and three doses, four weeks apart, in one study. Comparators included: no vaccine, placebo and other vaccines. Seven studies compared TCV with non‐conjugated typhoid vaccines. Six studies compared one TCV to another TCV. Synthesis of results TCV compared to control may result in a large reduction in acute typhoid fever (risk ratio (RR) 0.20, 95% confidence interval (CI) 0.12 to 0.32; I 2 = 70%; 6 studies, 101,896 participants; low‐certainty evidence) and probably results in little to no difference in all‐cause mortality (RR 0.80, 95% CI 0.35 to 1.85; I 2 = 52%; 4 studies, 100,337 participants; moderate‐certainty evidence). TCV results in little to no difference in AEs when compared to control (RR 0.91, 95% CI 0.76 to 1.09; I 2 = 0%; 3 studies, 29,465 participants; high‐certainty evidence) and a slight reduction in SAEs compared to control (RR 0.82, 95% CI 0.71 to 0.95; I 2 = 0%; 6 studies, 89,625 participants; high‐certainty evidence). TCV compared to non‐conjugated typhoid vaccines may result in little to no difference in acute typhoid fever (RR 0.90, 95% CI 0.48 to 1.69; 1 study, 78 participants; low‐certainty evidence). There were no deaths in the included studies. When compared to non‐conjugated typhoid vaccines, TCV likely results in little to no difference in AEs (RR 1.00, 95% CI 0.77 to 1.31; I 2 = 0%; 3 studies, 244 participants; moderate‐certainty evidence) and likely results in a slight reduction in SAEs (RR 0.30, 95% CI 0.05 to 1.88; I 2 = 0%; 2 studies, 732 participants; moderate‐certainty evidence). For TCV compared to another TCV, none of the studies reported on acute typhoid fever. Vi tetanus toxoid vaccine (Vi‐TT) may result in little to no difference in all‐cause mortality compared to a different TCV (RR 5.19, 95% CI 0.54 to 49.80; I 2 = 0%; 2 studies, 2422 participants; low‐certainty evidence). Vi‐TT likely results in little to no difference in AEs compared to another TCV (RR 1.18, 95% CI 0.92 to 1.51; I 2 = 39%; 4 studies, 2916 participants; moderate‐certainty evidence) and may result in little to no difference in SAEs (RR 2.48, 95% CI 0.74 to 8.36; I 2 = 0%; 3 studies, 2866 participants; low‐certainty evidence). The certainty of evidence was consistently reduced due to imprecision, indirectness and bias. Authors' conclusions This review highlights that TCVs, compared to controls, are effective in preventing typhoid fever, and may confer protection for up to four years. TCVs compared to non‐conjugated typhoid vaccines may result in little to no difference in acute typhoid fever and AEs, and likely result in a slight reduction in SAEs. Vi‐TT compared to another TCV may result in little to no difference in all‐cause mortality or SAEs, and likely results in little to no difference in AEs. Funding NG, TL and TK were partly supported by, and the Cochrane Infectious Diseases Group (CIDG) editorial base is funded by, the Research, Evidence and Development Initiative (READ‐It), funded by UK aid for the benefit of low‐ and middle‐income countries (project number 300342‐104). The views expressed in this review do not necessarily reflect the official policies of the UK government. Registration Protocol available via doi.org/10.1002/14651858.CD015746 Plain language summary Do typhoid conjugate vaccines prevent acute typhoid fever and are they safe? Key messages Compared to a control (no vaccine, placebo ('dummy') or vaccine for another disease), typhoid conjugate vaccines (TCVs) may result in a large decrease in acute typhoid fever cases. We are uncertain whether TCVs, compared to other typhoid vaccines, decrease acute typhoid cases. There may be little to no difference in death from any cause, and unwanted effects, when TCVs are compared to a control, a non‐conjugated typhoid vaccine or a different TCV. There is a slight decrease in serious unwanted effects when TCV is compared to a control, but may be little to no difference when compared to other TCVs. More robust research in typhoid‐endemic countries (countries where typhoid occurs regularly) in this area is needed. What are TCVs? Typhoid conjugate vaccines (TCVs) are designed to protect against typhoid fever, sometimes known as enteric fever, caused by the bacteria Salmonella typhi ( S typhi ). The bacteria have an outer layer of sugar molecules (called the Vi polysaccharide). To help the body make a strong immune response, the Vi polysaccharide is attached to a protein. This helps the immune system recognise and fight S typhi more effectively. The TCVs assessed include Vi tetanus toxoid (Vi‐TT), Vi diphtheria toxoid (Vi‐DT), Vi‐CRM 197 and Vi‐rEPA. Why are TCVs important? Typhoid fever causes sickness and death in people in low‐ and middle‐income countries (LMICs) ‐ mostly sub‐Saharan Africa, South‐ and Southeast Asia. It is passed from person‐to‐person through faecal‐oral transmission (germs spread through contact with human faeces). People with typhoid may have a high fever, body aches, headache, nausea and vomiting, poor appetite and, later, stomach ache. Typhoid should be diagnosed with a laboratory test but is often diagnosed based on symptoms. It can be treated with antibiotics, but there is growing antibiotic resistance. Vaccination, together with interventions like access to clean water, handwashing and improved hygiene, helps to prevent typhoid fever. The World Health Organization (WHO) recommends typhoid vaccination in routine immunisation programmes for children in high‐risk areas. Unlike other typhoid vaccines, TCVs can be given to children under two years old. What did we want to find out? We wanted to find out how well typhoid conjugate vaccines prevent acute typhoid fever and death from any cause, and how safe they are. What did we do? We searched for studies that compared TCVs to a control (no vaccine, a placebo or a vaccine for another disease), other typhoid vaccines and other TCVs. We summarised the results and rated our confidence in the evidence. What did we find? We found 19 studies with 395,650 participants and included 394,790 in our analysis. Participants were aged between six weeks and 60 years. The smallest study included 75 participants and the largest 326,794. The studies were conducted mostly in LMICs with most in Asia. Main results Compared to no vaccine, placebo or vaccine for another disease , TCV vaccination may result in a large decrease in typhoid fever and probably results in little to no difference in deaths from any cause. TCV vaccination results in little to no difference in unwanted effects and in a slight decrease in serious unwanted effects. TCV vaccination compared to control likely results in a longer duration of protection, with one study showing lower rates of acute typhoid fever for up to four years. Compared to non‐conjugated typhoid vaccines , TCVs may result in little to no difference in acute typhoid fever and likely result in little to no difference in unwanted effects. There is a slight decrease in serious unwanted effects when TCV is used instead of non‐conjugate typhoid vaccines. None of the studies reported deaths for this comparison. Compared to other TCVs , no studies reported on typhoid fever. There is little to no difference in deaths from any cause when comparing one TCV (Vi‐TT) to another. Vaccination with Vi‐TT likely results in little to no difference in unwanted effects and may result in little to no difference in serious unwanted effects compared to another TCV. Our confidence in some of the evidence was decreased because it was not always precise, did not always fully apply to our question and there were potential biases. What are the limitations of the evidence? Death was not always reported and, when it was, the number was low. This may have led to fewer deaths being reported than occurred. No studies compared the effectiveness of one TCV to another in preventing typhoid fever. Unwanted effects are not defined identically by study authors. We reported these as a combined outcome instead of as specific effects like nausea or rash, which may limit the use of these results by healthcare practitioners. How up‐to‐date is this evidence? The review is current to 19 April 2024.