This is an open-label, randomized, 2-arm clinical trial in healthy infants in Bangladesh. The primary purpose of the study is to assess the immunogenicity of measles-rubella (MR) vaccine when delivered at 6 months. In addition, the study will establish the equality of MR vaccine seroconversion administered at 9 months following administration of an earlier MR vaccine dose at 6 months of age compared to MR vaccine dose administered at 9 months without previous MR vaccination. This study will also provide additional data on safety and tolerance of MR vaccine given at 6 months, and impact of maternal antibodies on immunogenicity of MR vaccine at 6 months.

• Primary objectives:

  1. To assess immunogenicity of MR vaccine at 6 months of age
  2. To assess immunogenicity of MR vaccine at 9 months of age among children without prior measles and rubella vaccination, compared with MR vaccine immunogenicity among those who had a prior MR vaccination at 6 months of age

• Secondary objectives

  1. To assess the frequency of adverse reactions following administration of MR vaccine at 6 months
  2. To compare the immunogenicity of the MR vaccine first dose administered at 6 months vs at 9 months.
  3. To assess the proportion of mothers with undetectable, detectable and protective levels of measles and rubella antibodies
  4. To determine the extent of variation in measles antibodies in women of child bearing age in a population with a long standing measles vaccination program
  5. To determine the extent of variation in rubella antibodies in women of child bearing age in a population where rubella vaccine have been recently introduced
  6. To determine if variation in antibody levels in infants at 6 months is predominately explained by variation in starting antibody levels in the mother in this population
  7. To estimate the half-life of decay of measles and rubella antibodies in infants

In countries with low levels of circulating measles virus, and lower risk for measles infection, measles containing vaccine first dose (MCV1) is recommended at 12 months of age. In countries with high risk for measles, MCV1 is recommended at 9 months. In the past decade, many countries have been experiencing measles outbreaks with a high proportion of cases among infants < 9 months of age, below the recommended age of routine MCV1.

Recent publications suggest that this may be due to the fact that the majority of infants now are born to mothers with vaccine induced immunity to measles, and who lose maternal antibodies much earlier, by age of 4-6 months. For example, in a measles outbreak in Malawi in 2010, 14% (17,858) of the estimated 134,000 cases occurred in children 0-8 months. In 2013, in a measles outbreak in Sri Lanka approximately 34% of measles cases were in children 6-12 months of age. Furthermore, in 2013 Jordan experienced a large measles outbreak with high proportion of young infants affected (6-9 months). WHO measles outbreak response guidelines recommend vaccinating children as young as 6 months during outbreaks. As an example, in response to a measles outbreak, Sri Lanka and Jordan conducted outbreak response immunization (ORI) that included infants 6 months of age despite the limited evidence on immunogenicity of MR vaccine at that age.

Some researchers suggest that routine MCV should be given before age of 9 months based on published data showing that infants born to mothers with vaccine induced measles immunity are born with lower concentration of maternal measles antibodies (MMA) and lose protection against measles infection at an earlier age. Measles vaccine immunogenicity depends on several factors, including presence of maternal measles antibodies (i.e., passively acquired measles antibodies may neutralize vaccine virus before a complete immune response develops resulting in primary vaccine failure.), maturity of immune system of the vaccine recipient, and strain of the measles vaccine used. So any decisions to alter the age of MCV1 dose should balance the potential risk of primary vaccine failure against the risk of measles infection and measles related complications, including death. Immunogenicity of measles vaccine given at 6 months is well studied; however, data on immunogenicity of combined MR vaccine administered at 6 months and its impact on MR vaccine effectiveness given at 9 months, is limited.

Because the number of infants born to mothers with vaccine induced immunity has been steadily increasing and most countries will be using MR vaccine routinely in the Expanded Program of Immunization (EPI), it is timely to conduct a study to assess immunogenicity of MR vaccine given at 6 months and its impact on a subsequent 9 month MR dose. The first dose of MCV given at 6 months is frequently referred to as MCV-0, indicating that two subsequent doses are needed to attain population seroprotection levels necessary to stop endemic transmission of the measles virus.

To improve the accuracy of interpretation of study results blood samples of mothers of enrolled infants will be tested for measles and rubella antibodies. This will also enable us to determine the proportion of mothers with undetectable, detectable and protective levels of antibodies, and to assess the relationship between the level of antibodies in mothers and their infants' maternal antibodies.

This study will be conducted in a single site in rural Bangladesh at Matlab. Matlab is a major rural field site for icddr,b, where for the past 50 years continuous health and demographic information was collected on >200,000 population.

From 2007 to 2010, icddr,b, the Ministry of Health (MOH) in collaboration with other international organizations conducted several randomized vaccine effectiveness studies.

This study will be an open-label, randomized, 2-arm clinical trial. 620 children will be enrolled and randomized at 6 months of age to one of two study arms. The primary objectives of this study are to assess the immunogenicity of MR vaccine at 6 months, and assess equality of MR vaccine seroconversion administered at 9 months following administration of an earlier MR vaccine dose at 6 months of age compared with MR vaccine dose administered at 9 months only without previous MR vaccination. The study will enroll generally healthy 6 month old infants living in Matlab and who have never received an MR vaccine dose and have no history of measles or rubella. Participants will be followed to 11 months of age.

Infants in this study will be randomly assigned to one of two arms. Infants in Study Arm A will receive MR vaccine at 6 months of age (at enrolment) and at 9 months. Infants in Study arm B will receive MR vaccine only at 9 months.

Blood specimens will be collected from all infants at 6, 9 and 11 months of age. The 6 month sample is a pre-vaccination sample and mainly will be used to determine maternal antibody levels. For arm A, the sample collected at 9 months before the second MR dose will be used to assess antibody levels after the first MR dose at 6 months of age. For study Arm B, the 9 month sample will be used to assess measles and rubella antibody decay rate. The sample collected at 11 months will be used to assess immune response to either a two dose or a one dose schedule (arms A and B, respectively).

Age is based on the age of the infant.

Inclusion Criteria: INFANTS:

• Healthy infants at 6 months (180 days, +/- 7 days) of age
• A parent or guardian that consents for participation in the full length of the study
• A parent or guardian that is able to understand and comply with planned study procedures

Inclusion criteria: MOTHERS:

• Mothers of infants that meet inclusion criteria.
• ≥18 years of age
• Mothers who consent to participate in the full length of the study

Exclusion Criteria: INFANTS:

• Family that is unable to participate in the full length of the study
• A diagnosis or suspicion of immunodeficiency disorder either in the infant or mother
• A diagnosis or suspicion of bleeding disorder that would contraindicate parenteral administration of MR vaccine or collection of blood by venipuncture
• Acute infection or illness at the time of enrollment (6 months) that would require infant's admission to a hospital
• Receipt of any measles or rubella containing vaccine prior to enrolment (i.e., before age 6 months) outside of study based upon documentation or parental recall
• Known history of laboratory confirmed measles or rubella infection
• A diagnosis of rubella infection in mother during pregnancy
• A diagnosis of congenital rubella syndrome in infant
• Known allergy/sensitivity or reaction to measles-rubella containing vaccine or contents of measles-rubella containing vaccine
• Persons with a history of an anaphylactic reaction to any components of the vaccine
• Infants from premature births (<37 weeks of gestation)

Exclusion criteria: MOTHERS:

• Refuses to give blood samples. (If the mother agrees for her child to participate in the study, but refuses to give a blood samples herself or blood samples cannot be obtained, the child will still be enrolled.)
• A diagnosis or suspicion of immunodeficiency disorder
• A diagnosis or suspicion of bleeding disorder that would contraindicate collection of blood by venipuncture

Temporary exclusion: INFANTS:

• Acute febrile illness (≥38°C) at the time of enrollment
• Family will be requested to bring back the child 1-2 days later or when child feels better.

Group A and group B, each had 2 participants without laboratory results and were removed from the analysis.

Infants were assessed 0-30 minutes following immunization at the clinic, and parents were queried for adverse events at each subsequent study visit, up to 5 months in total duration. Arm A also received a safety monitoring visit at home 48 hours after immunization following the 6-month visit.

Only infants were assessed for adverse events. Additional exclusions are based on patient flow (eg. loss to follow-up, withdrawal of consent).

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