Measles-mumps-rubella vaccine at 6 months of age, immunology, and childhood morbidity in a high-income setting: study protocol for a randomized controlled trial

Abstract

Background Measles is a highly contagious and serious infection. Before the introduction of vaccination, measles caused yearly epidemics putting vulnerable children at risk of brain damage and death. Despite safe and cost-effective vaccines, measles remains a leading cause of death in children globally. Due to insufficient vaccine coverage and low levels of in utero transferred antibodies from vaccinated mothers, outbreaks of measles in Denmark and other high-income countries are observed at increasing frequency. The current vaccine was introduced in Denmark in 1987 as a one-shot measles-mumps-rubella vaccine at 15 months, a timing chosen to avoid inhibition of the infant’s immune response by maternal antibodies. One generation later, the MMR vaccinated mothers have lower antibody levels compared to the naturally infected, and their infants are already susceptible at 6 months of age or earlier, thus increasing the risk of epidemics. Methods The Danish MMR trial is a double-blind randomized clinical trial recruiting between March 2019 and December 2021 with last patient last visit in February 2022. Altogether N = 6500 infants aged 6 months will be randomly assigned to intramuscular vaccination with routine MMR (M-M-R VaxPro) or placebo (solvent only). According to the Danish Childhood vaccination program, all infants will receive a routine MMR vaccination at 15 months of age. At randomization, 1 month later, and 1 month after routine MMR vaccination at 15 months of age, a blood sample is drawn from app. 10% (N = 600) of the population. Additionally, hair, saliva, and urine are sampled at randomization. The co-primary study outcomes are immunogenicity 1 month after MMR vaccination at 6 months of age assessed as plaque-reduction neutralization test, and incidence of infectious disease hospitalizations from randomization to 12 months of age. Six weeks post randomization, all participants are interviewed regarding adverse events. Trial registration The trial is registered in the EU Clinical Trials Registry. EudraCT registration number: 2016-001901-18. Registered on 14 February 2017.

Epidemiological Features of Infectious Diseases in Children and Adolescents: A Population-Based Observational Study in Shandong Province, China, 2013–2017

“…Previous studies have demonstrated that infants aged 0–8 months were too young for routine immunization. The immunity in newborns was temporary and began to wane at 6 months of life, which made infants the most susceptible to rubella [ 42 , 43 ]. Another study found that women of childbearing age had lower levels of rubella antibodies, increasing the risk of congenital rubella syndrome in newborns to some extent [ 44 , 45 ].…”

Genetics and measles, mumps and rubella vaccine response in childhood and adolescence—A systematic review

“…This review is written by members of the 6 months MMR study at The Danish National University Hospital, Rigshospitalet. 72 The study is funded by the hospital and the innovation fund Denmark. All authors attest that they meet the ICMJE criteria for authorship.…”

Measles, mumps, and rubella vaccine at age 6 months and hospitalisation for infection before age 12 months: randomised controlled trial

“…The trial protocol is available elsewhere. 32 33 In Denmark, the measles vaccine is routinely given in combination with mumps and rubella at ages 15 months and 4 years. 34 Recruited infants were randomly allocated 1:1 either to intramuscular vaccination with the live attenuated M-M-R VaxPro vaccine containing measles virus (Edmonston strain, standard titre), mumps virus (Jeryl Lynn strain), and rubella virus (Wistar RA 27/3 strain) 35 or to intramuscular vaccination with placebo (solvent only) at age 5-7 months.…”