Immunogenicity and Safety of Co-Administered Live Attenuated Japanese Encephalitis SA 14-14-2 Vaccine and Measles-Rubella Vaccine Compared with Measles-Rubella Vaccine Alone in Infants 8 Months of Age, China

Background: Measles is one of the most contagious diseases ever known and is an important cause of death and disability among young children worldwide.  Rubella is generally a mild disease in children and adults, but rubella virus infection during pregnancy, especially during the first trimester, can result in miscarriage, fetal death, stillbirth, or infants with a constellation of congenital malformations known as congenital rubella syndrome.  A growing number of countries are adopting the use of the combined measles-rubella vaccine (MR) to prevent both diseases.  In China, measles-rubella vaccine and live, attenuated SA-14-14-2 Japanese encephalitis vaccine (LJEV) are recommended for simultaneous administration at age 8 months, which is the earliest recommended age globally.  Evidence is limited whether co-administering MR and LJEV at 8 months of age will impact immunogenicity of MR antigens. Methods: We conducted a prospective, two-arm randomized trial between August 2015 and June 2016 in two provinces in China to determine whether at 8 months of age, seroconversion to measles antibody and rubella antibody 6 weeks after co-administration of MR and LJEV was non-inferior to seroconversion 6 weeks after administration of MR without LJEV.  Measles immunoglobulin G (IgG) and rubella IgG antibody levels were determined using an enzyme-linked immunosorbent assay on blood samples collected before vaccination and six weeks (42-48 days) post-vaccination.  For non-inferiority tests, we calculated a two-sided, 90% (Farrington-Manning) confidence bound of the difference in antibody levels between persons who received MR LJEV and those who received MR alone.  Solicited and unsolicited adverse events following immunization (AEFI) were recorded for all infants who completed the study. Findings:  Of 1,093 enrolled infants, 507 in the MR LJEV group and 506 in the MR-only group completed the study. Before vaccination, 1.2% in MR LJEV group and 0.2% in the MR-only group were seropositive for measles antibody (p=0.13); 1.6% in MR LJEV group and 0.4% in the MR-only group were seropositive for rubella antibody (p=0.11). Six weeks after vaccination, measles antibody seroconversion rates were 97.8% in the MR LJEV group compared to 98.6% in the MR-only group (non-inferior; p<0.0001). Six weeks after vaccination, rubella antibody seroconversion rates were 94.3% in the MR LJEV group compared to 93.5% in the MR-only group (non-inferior; p<0.0001).  Mild local reactions included redness, swelling and pain; systemic reactions included fever, diarrhea and vomiting. There were no serious non-fatal or fatal AEFIs. Interpretation: The high seroconversion rates, non-inferiority, and safety of co-administered LJEV and MR found in this randomized trial provide support for the co-administration of these live attenuated vaccines in infants, a finding of importance to the global priorities of measles elimination and expansion of JE vaccination in endemic countries. Funding: Centers for Disease Control and Prevention, US Department of Health and Human Services. 2014-2015 Research Program Seven, China-US Collaborative Program on Emerging and Reemerging Infectious Diseases. Conflict of Interests: The authors declare that they have no competing interests. Ethical Approval Statement: This study was approved by the Ethical Review Committee of Chinese Center for Disease Control and Prevention (approval number: 201518); US CDC was designated as a non-engaged collaborator for Institutional Review Board purposes. Parents or legal guardians of participating infants signed an informed consent prior to study enrollment and allocation to study group.