Measles is one of the most contagious diseases for humans. Measles complications such as pneumonia, diarrhea and encephalitis can occur in up to 30% of persons depending on age and predisposing conditions, such as young age, malnutrition and immunocompromising conditions. Mumps is an infectious viral disease transmitted via respiratory droplets, fomites, or personal contact. Some infected individuals develop severe complications such as orchitis, pancreatitis, septic meningitis, and deafness. Rubella is a mild viral infection that typically occurs in children and non-immune young adults. In nonpregnant individuals, rubella is generally a self-limited and benign infection. However, maternal rubella infection, especially during embryogenesis leads to the classic triad of cataracts, congenital heart defects, and sensorineural deafness; however, other defects may be seen including miscarriages, fetal death, or severe birth defects collectively known as Congenital Rubella Syndrome (CRS). Yellow fever (YF) is a mosquito borne viral disease caused by RNA virus belonging to Flavivirus genus of the Flaviviridae family. This virus is transmitted by Aedes aegypti and Haemagogous species mosquitoes, during the rainy season. This disease is endemic in the tropical and subtropical areas in South America and Africa. The current study is designed to compare the safety and immunogenicity of SIBP MMR administered alone with that of GSK MMR vaccine administered alone in the African context and to evaluate the interaction of co-administration of SIBP MMR vaccine with YF vaccine in children 9-11months of age, in terms of immune responses against antigens contained in both vaccines The results of this study is expected to complete the package required for applying for WHO pre-qualification for the SIBP MMR vaccine.

Measles is one of the most contagious diseases for humans. It is caused by a paramyxovirus virus, manifesting as a febrile illness with rash.1 Initial symptoms (prodrome) generally consist of fever, malaise, cough, conjunctivitis, and coryza appear 10-12 days after infection. The characteristic maculopapular rash appears two to four days after onset of the prodrome. Measles complications such as pneumonia, diarrhea and encephalitis can occur in up to 30% of persons depending on age and predisposing conditions, such as young age, malnutrition and immunocompromising conditions. Measles can infect anyone of any age, but most of the burden of disease globally is still among children < 5 years of age. There is no specific antiviral treatment against the measles virus. Measles can be prevented by immunization. The measles vaccine is a live attenuated virus vaccine which is available since 1963; two doses are recommended by WHO to provide protection from disease. Accelerated immunization activities have had a major impact on reducing measles deaths including Kenya. Post introduction of vaccine global measles deaths have decreased by 73% from an estimated 536 000 in 2000 to 142,000 in 2018. During 2000– 2018, measles vaccination prevented an estimated 23.2 million deaths.2All six WHO regions had a measles elimination goals by or before 2020, and surveillance was considered a key element to achieve elimination.3 Mumps is an infectious viral disease transmitted via respiratory droplets, fomites, or personal contact. Symptoms often begin with chilly sensations, headache, loss of appetite, feeling of not being well and fever. Once symptoms appear, a typical mumps infection is characterized by inflammation of the parotid glands. Some infected individuals develop severe complications such as orchitis, pancreatitis, septic meningitis, and deafness. The first mumps vaccine was licensed in 1967. Soon after, the mumps vaccine was included as part of the trivalent measles, mumps, and rubella (MMR) vaccine. Currently, the MMR vaccine is given in two doses as part of a routine immunization schedule in many countries. Although widespread use of the two-dose MMR vaccine largely reduced mumps incidence among school children by the 1990s, there has been a significant increase in the number of mumps outbreaks since. Additionally, vaccine efficacy and safety remain a concern.4 Rubella, or German measles, is a mild viral infection that typically occurs in children and non-immune young adults. The prodromal illness is characterized by low-grade fever, malaise, anorexia, headaches, sore throat, and lymphadenopathy. The exanthem could be the first manifestation in children and consists of short-lived pinpoint pink macules and papules that classically begins on the face and rapidly spreads to involve the trunk and extremities. In nonpregnant individuals, rubella is generally a selflimited and benign infection. However, maternal rubella infection, especially during embryogenesis leads to the classic triad of cataracts, congenital heart defects, and sensorineural deafness; however, other defects may be seen including miscarriages, fetal death, or severe birth defects collectively known as Congenital Rubella Syndrome (CRS). Of all the manifestations, deafness in the newborn is the most common finding and could be the only defect observed. Individuals that survive the neonatal period may face severe disabilities (e.g., visual and hearing impairments) and have an increased risk for developmental disorders, including autism. Universal immunization of all susceptible individuals with rubella vaccines is the cornerstone to the prevention of rubella and, more importantly, congenital rubella syndrome. The vaccine is usually administered in combination with measles and mumps (MMR) or measles, mumps, Rubella and varicella (MMRV), with the first dose at ages 12-15 months and the second dose at ages 4-6 years.5 Immunization of all unvaccinated adolescents and adults with at least one dose of rubella vaccine is also recommended. Before the introduction of the rubella vaccine, outbreaks of rubella occurred at variable intervals of 3 to 7 years, with the highest incidence among school children. Steep declines in rubella cases occurred with the routine immunization of young children, and countries with high rates of rubella immunizations no longer see cases of rubella or CRS.6 After the introduction of the live-virus vaccine, outbreaks occurred more commonly among older adolescents and young adults.7,8 The currently used Yellow Fever Vaccine (Stamaril) is a licensed live, attenuated, lyophilized yellow fever vaccine manufactured by Sanofi Pasteur Europe, Lyon, France. A single dose of 0.5 mL contains not less than 1000 IU of yellow fever virus 17D-204 strain. The vaccine is produced in specific pathogen-free chick embryos. YF vaccine is incorporated in the Kenya Expanded Programme for Immunization (KEPI) schedule and is given at 9 months in selected endemic counties. The results of a study R01 (comparison with a prequalified MMR vaccine (Merck Sharp & Dohme or MSD) and R04 (comparison with GlaxoSmithKline’s (GSK’s) MMR vaccine) in China have sufficiently demonstrated the non-inferiority of SIBP MMR with that of licensed vaccine. However, given that these studies were carried out in an Asian population, this study could better support future use in additional jurisdictions such as Africa. The WHO Prequalification supports the specific needs of national immunization programs. Studies R05 and R06 (co-administration with varicella vaccine or with rotavirus vaccine) have also sufficiently demonstrated non-interference when co-administered with these vaccines. Since earlier studies have already assessed the immunogenicity of the vaccine in different age groups and the fact that the vaccine is in wide use in EPI of China supports not conducting any additional studies in other age groups. It is also expected that no additional studies will be required demonstrating non-inferiority between the vaccines produced from old process versus that produced by new process as the change is only in the method of cultivation of the strain virus without any change in excipients or downstream manufacturing process. The current study is designed to demonstrate non-inferiority based on the immune response of SIBP MMR vaccine when compared against an already licensed and WHO prequalified GSK MMR vaccine. In addition, the study will evaluate the interaction of co-administration of SIBP MMR vaccine with a licensed Yellow Fever (YF) vaccine in children 9-11months of age, in terms of immune responses against antigens contained in both vaccines. To study this interaction, the study is designed such that one group of children will concomitantly receive SIBP MMR and YF vaccine whereas the comparator groups will either receive SIBP MMR followed by YF vaccine six weeks later. The study is designed as an observer-blind for Group 1 vs Group 2 until Day 43 and an open label study for Group 3 from Day 1 since the number of vaccinations to be administered, the appearance of the vaccine and their containers are different in the study arms. A blood draw has been planned prior to vaccination on Day 1 and Day 43 after vaccination to measure the immune responses in the study arm as done in many prior clinical trials for licensure of the vaccine. An extended solicitation period has been included to capture solicited systemic reactions as the reaction of fever and rash are most seen in second week following vaccination. The result of this study is expected to complete the package required for applying for WHO pre- qualification for the SIBP MMR vaccine.