Measles-Rubella Vaccine Immunogenicity at 6 and 9 Months of Age
Condition: Measles; Rubella; Rubella Syndrome, Congenital
MeSH terms: Measles; Rubella; Rubella Syndrome, Congenital
Study type: Interventional
Phase: Phase 4

Summary: 
      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
    

Detailed description: 
      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).
    

Intervention name(s): Measles-rubella (MR) vaccine at 6 and 9 months; Measles-rubella (MR) vaccine at 9 months
Intervention type(s): Biological; Biological
Intervention description(s): Arm A will receive MR vaccine dose at 6 and 9 months of age; Arm A will receive MR vaccine dose at 9 months of age
Other intervention name(s): Arm A; Arm B
Intervention MeSH terms: Vaccines
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Prevention
Keywords: measles; rubella; immunogenicity; congenital rubella syndrome; measles-rubella vaccine