This study will evaluate the efficacy of a Typhoid conjugate vaccine (Vi-TCV) in Malawi, Africa among children age 9 months through 12 years. Participants will be randomized in a 1:1 ration to receive the study vaccine or the control vaccine (meningococcal group A conjugate vaccine - MCV-A).

This study is a double-blind, individually randomized, controlled, clinical efficacy trial with two vaccine groups: Vi-TCV (Typhoid conjugate) and MCV-A (meningococcal group A conjugate). This study will take place in Blantyre, Malawi, Africa. Participants (up to 30,000) will be randomized in a 1:1 ratio. Children 9 months through 12 years of age in the Blantyre area who meet the inclusion criteria will be eligible for enrollment.

Participants will be unaware of which study vaccine, Vi-TCV or MCV-A, is received. A subset of 600 children will have study visits on days 3, 7, 28 and 180 post-vaccination to assess select solicited events, unsolicited events, and all serious adverse events. Serious Adverse Events (SAEs) in all participants will be monitored through the end of the trial.

For the evaluation of efficacy, passive surveillance will be conducted for up to 36 months to identify cases among vaccinated subjects. Children who meet the protocol-defined specimen collection criteria will have a blood culture collected. Additional information will be collected from any child who has a blood culture obtained. This will include information about the signs and symptoms of the illness and treatment given. Likewise, any child with blood culture-confirmed typhoid fever will have follow-up until the illness resolves. Additional information on the illness, treatment and complications will be recorded. Vaccine efficacy will be evaluated when the pre-specified number of cases is reached after a minimum of two years of follow-up on each participant.

A subset of 600 children (200 in each of three age groups: 9-11 months, 1-5 years, and 6-12 years) will be included in an additional Vaccine Immunogenicity and Reactogenicity Sub-study. More stringent exclusion criteria will apply for this subset. The purpose of this detailed evaluation is to assess the reactogenicity of the vaccine and the immune responses to Vi-TCV. Serum specimens will be collected on day 0 (before vaccination) and on post-vaccination days 28 and 730 from all children included in the sub-study. For the children in the 9-11 month group, Vi-TCV or MCV-A will be administered with measles-containing vaccine, as per Malawi Expanded Programme on Immunization (EPI) schedule. These 9-11-month-old children will have antibody to measles assessed on days 0 and 28. All children in the sub-study will have visits at days 4 and 7 following vaccination for solicitation of local and systemic adverse events. Serious and non-serious adverse events will be assessed at days 28 and 180.

An additional subset of -up to 225 HIV-exposed-but-uninfected and up to 100 HIV-unexposed children ages 9-11 months will be included in an additional HIV-exposed Vaccine Immunogenicity and Reactogenicity Substudy. The purpose of this detailed evaluation is to assess the reactogenicity of the vaccine and the immune responses to one or two doses of Vi-TCV in HIV-exposed children. Up to 225 HIV-exposed children in this substudy will be randomized 1:1:1 to receive either TCV at 9-11 months and TCV at 15 months (Group 1), TCV at 9-11 months only (Group 2), or TCV at 15 months only (Group 3). A separate group of about 100 HIV-unexposed children will serve as controls and receive TCV at 9-11 months and TCV at 15 months (Group 4). Serum specimens will be collected on day 0 (before vaccination) and on 28 days after each vaccination from all children included in the sub-study. For this substudy, Vi-TCV will be administered with measles-rubella-containing vaccine #1 at 9-11 months and/or #2 at 15 months, as per Malawi EPI schedule. These 9-11-month-old children will have antibody to typhoid, measles, and rubella assessed on day 0 and 28 days after each vaccination. All children in the sub-study will be assessed at 7 days after each vaccination for solicitation of local and systemic adverse events. Serious and non-serious adverse events will be assessed up to the last study visit for HIV-exposed substudy participants.

Inclusion Criteria:

• Healthy male or female child between the ages of 9 months and 12 years/364 days at the time of study vaccination.
• A child whose parent or guardian resides primarily within the Ndirande or Zingwangwa study areas at the time of study vaccinations and who intends to be present in the area for the duration of the trial.
• A child whose parent or guardian has voluntarily given informed consent.

Exclusion Criteria:

• History of documented hypersensitivity to any component of the vaccine
• Prior receipt of any typhoid vaccine in the past 3 years
• History of severe allergic reaction with generalized urticarial, angioedema, or anaphylaxis
• Any condition determined by the investigator to be likely to interfere with evaluation of the vaccine or to be a significant potential health risk to the child or make it unlikely that the child would complete the study.

Temporary Exclusion Criteria:

The following will be considered temporary contraindications to enrollment and vaccination. If these apply, the participant will be temporarily excluded for vaccination until 48 hours has passed. A re-assessment will be needed to ensure these temporary exclusion criteria no longer exist.

• Reported fever within 24 hours prior to vaccination
• Use of anti-pyretics within 4 hours prior to vaccination

An additional temporary exclusion criteria will be:

- Receipt of measles vaccine in the one month prior to enrollment, as determined by parental history or vaccination card.

Additional Exclusion Criteria for Safety and Immunogenicity Substudy:

In addition to the exclusion criteria of the efficacy study, participants enrolled in the immunogenicity and reactogenicity substudy may not have, or have had, any:

• Known history of diabetes, tuberculosis, cancer, chronic kidney, heart, or liver disease, progressive neurological disorders, poorly controlled seizures, or terminal illness
• Severe malnutrition as determined by MUAC< 12.5 cm for children younger than 5 years;
• Receipt of any other investigational intervention in the last 6 months or anticipated during the course of the study.
• Receipt of blood products in the last 6 months.
• Known HIV-infection or exposure or other immunosuppressive conditions.
• Receipt of systemic immunosuppressant or systemic corticosteroids.
• Receipt of any measles-containing vaccine for children younger than 1 year of age