Use of Typhoid Conjugate Vaccine Among Children in Typhoid-Endemic Countries

The typhoid conjugate vaccine (TCV) for protection against typhoid fever was found to be associated with long-term safety and immunogenicity among children in Malawi, according to study findings published in The Lancet Global Health.

Researchers conducted a substudy, nested within a double-blind, parallel design, randomized-controlled phase 3 trial (ClinicalTrials.gov Identifier: NCT03299426), to evaluate the safety, reactogenicity, and immunogenicity of TCV among children in Malawi.

Eligible patients were aged between 9 months and 12 years with no known immunosuppression or chronic health conditions, including HIV infection or severe malnutrition. Patients (N=631) were randomly assigned 1:1to receive TCV or an intramuscular injection of the meningococcal serogroup A conjugate vaccine (control participants). Patients also were stratified into 3 groups based on age, including those aged between 9 and 11 months, 1 and 5 years, and 6 and 12 years.

Serum samples, collected from patients prior to vaccination and at day 28 and between days 730 and 1035 following vaccination, were used to measure anti-Vi antibodies via enzyme-linked immunosorbent assay (ELISA). Safety outcomes were the occurrence of solicited and unsolicited adverse events within 7 and 28 days of vaccination, respectively.

A total of 320 patients were assigned to the TCV group and 311 were assigned to the control group, of whom 305 and 297, respectively, were vaccinated. Of patients in the TCV and control groups, the median age was 3.0 and 3.0 years, 44% and 51% were girls, and 7% and 8% had a concentration of 7.4 ELISA units (EU)/mL or higher of detectable anti-Vi antibody titers at baseline, respectively.

Between baseline and day 28 after vaccination receipt, anti-Vi immunoglobulin G (IgG) geometric mean titers (GMTs) increased by more than 500 times among patients in the TCV group. No changes in anti-Vi IgG GMTs were noted among patients in the control group. Further analysis showed that the mean concentration of anti-Vi IgG GMTs decreased to 48.0 EU/mL (95% CI, 39.9-57.8) among patients in the TCV group between days 730 and 1035 following vaccination.

At day 28, seroconversion was observed among 99% of patients in the TCV group and less than 1% of those in the control group. The researchers noted that the rate of 28-day seroconversion was similar among patients in the TCV group after stratification by age.

Between days 730 and 1035, seroconversion occurred among 219 patients in the TCV group vs 9 patients in the control group. Compared with baseline, the mean concentration of anti-Vi IgG GMTs between days 730 and 1035 for patients in the TCV group was 22.9 times higher among those aged 6 to 12 years, 8.9 times higher among those aged 1 to 5 years, and 6.2 times higher among those aged 9 to 11 months.

Mild or moderate pain at the injection site occurred among 7 and 2 patients in the TCV and control groups, respectively. Analysis at days 0, 3, and 7 following vaccination showed a similar rate of systemic adverse events (AEs) among patients in the TCV vs control groups. The most common AEs included fever, irritability, and malaise. However, a higher percentage of unsolicited AEs was reported among patients in the TCV vs control groups (24% vs 17%).

Limitations included that the safety and immunogenicity of TCV was not assessed among uninfected children with prior exposure to HIV infection.

“Based on previous TCV studies,” the researchers noted, “seroprotection likely persists for at least 5 years.”

We discussed these study findings with coauthor Matthew B. Laurens, MD, MPH. Dr Laurens is a professor of pediatrics and medicine at the University of Maryland, College Park.

What inferences can you draw regarding the effect of a booster dose on the longevity of seroprotection against TCV?

Dr Laurens: As this study only evaluated a single-dose TCV strategy, we can’t really say if a booster dose will be needed. Results of this study and other TCV clinical trials in children from Africa and Southeast Asia have documented immunogenicity from single-dose TCV endures for around 3 years. Additional studies are ongoing and will help to determine if a booster dose is needed. Clearly, a single dose of TCV is quite effective against typhoid fever, as several large, randomized clinical trials in children in multiple countries have documented.  

What is the rationale for the current routine use of the meningococcal serogroup A conjugate vaccine (MCV-A) and its preference over TCV in African countries?

Dr Laurens: MCV-A is a routine vaccine that children who live in the “meningitis belt” commonly receive during early childhood to protect against meningococcal serogroup A disease.

We conducted a clinical trial in Burkina Faso, West Africa, to determine if TCV could be safely coadministered with the MCV-A vaccine, and to determine if TCV interferes with the immune response to MCV-A. Results demonstrated no safety concerns among younger children who received both vaccines at their 15-month vaccination visit, and TCV did not interfere with immune responses to MCV-A. This study provides evidence to support adding TCV to routine vaccination visits where MCV-A is already given, which allows for consolidation of vaccination visits, reduces delivery costs, and protects children at a younger age before they are at high risk for typhoid fever.

In Bangladesh, TCV effectiveness was 85% among children aged between 9 months to 15 years and vaccine-conferred protection was consistent across different age strata, including those younger than 2 years. Are there any instances in which seroprotection provided by TCV may differ when administered across different ethnicities/subgroups of children?

Dr Laurens: TCVs have now been tested in children living in many countries in Southeast Asia and sub-Saharan Africa, areas where disease burden is greatest. The protective efficacy against disease measured in all of these clinical trials has consistently been around 80%, confirming that the TCV protects children regardless of geographic location or ethnicity.

Can you elaborate on any monitoring parameters that clinicians should be aware of and counsel their patients when administering TCV?

Dr Laurens: Similar to other vaccines routinely given to younger children, TCVs can cause minor AEs such as fever, fussiness, and injection site pain, all of which are short-lived and without any lasting effect. Essentially, all children can receive the TCV, except in very rare circumstances in which a child has a severe allergy to a component of the vaccine.

Are there any patient-specific risk factors that might necessitate the administration of MCV-A over TCV?

Dr Laurens: TCV and MCV-A can be coadministered among children. We used MCV-A as a control vaccine in this study, both to provide benefit to the included study patients and to permit comparison of the immune and safety effects between TCV and a control vaccine.