Safety and immunogenicity following co-administration of Yellow fever vaccine with Tick-borne encephalitis or Japanese encephalitis vaccines: Results from an open label, non-randomized clinical trial

Abstract

Background Flavivirus infections pose a significant global health burden underscoring the need for the development of safe and effective vaccination strategies. Available flavivirus vaccines are from time to time concomitantly delivered to individuals. Co-administration of different vaccines saves time and visits to health care units and vaccine clinics. It serves to provide protection against multiple pathogens in a shorter time-span; e.g., for individuals travelling to different endemic areas. However, safety and immunogenicity-related responses have not been appropriately evaluated upon concomitant delivery of these vaccines. Therefore, we performed an open label, non-randomized clinical trial studying the safety and immunogenicity following concomitant delivery of the yellow fever virus (YFV) vaccine with tick-borne encephalitis virus (TBEV) and Japanese encephalitis virus (JE) virus vaccines. Methods and findings Following screening, healthy study participants were enrolled into different cohorts receiving either TBEV and YFV vaccines, JEV and YFV vaccines, or in control groups receiving only the TBEV, JEV, or YFV vaccine. Concomitant delivery was given in the same or different upper arms for comparison in the co-vaccination cohorts. Adverse effects were recorded throughout the study period and blood samples were taken before and at multiple time-points following vaccination to evaluate immunological responses to the vaccines. Adverse events were predominantly mild in the study groups. Four serious adverse events (SAE) were reported, none of them deemed related to vaccination. The development of neutralizing antibodies (nAbs) against TBEV, JEV, or YFV was not affected by the concomitant vaccination strategy. Concomitant vaccination in the same or different upper arms did not significantly affect safety or immunogenicity-related outcomes. Exploratory studies on immunological effects were additionally performed and included studies of lymphocyte activation, correlates associated with germinal center activation, and plasmablast expansion. Conclusions Inactivated TBEV or JEV vaccines can be co-administered with the live attenuated YFV vaccine without an increased risk of adverse events and without reduced development of nAbs to the respective viruses. The vaccines can be delivered in the same upper arm without negative outcome. In a broader perspective, the results add valuable information for simultaneous administration of live and inactivated flavivirus vaccines in general. Trial registration Eudra CT 2017-002137-32.

Tick-Borne Encephalitis Vaccine: Recommendations of the Advisory Committee on Immunization Practices, United States, 2023

“…Data are limited on co-administration of TBE vaccine with other vaccines. One open label, nonrandomized clinical trial investigated concomitant administration of TBE vaccine and yellow fever vaccine (Stamaril) among adults aged 18-55 years (264). Among persons who received TBE and yellow fever vaccines concomitantly (n = 38), TBE vaccine alone (n = 19) or yellow fever vaccine alone (n = 20), no significant differences were identified between groups in TBE neutralizing antibody titers at 30 days after dose 3 of TBE vaccine, or in final yellow fever neutralizing antibody titers (taken at day 210 in the concomitant group and day 60 in the yellow fever vaccine alone group).…”

“…Data are limited on co-administration of TBE vaccine with other vaccines or drugs. One clinical trial in which the first dose of TBE vaccine was administered concomitantly with yellow fever vaccine indicated no interference with the immune response to TBE vaccine or yellow fever vaccine (264). If TBE vaccine and other vaccines are administered concomitantly, they should be administered with separate syringes and at different anatomic sites (271).…”

A reporter virus particle seroneutralization assay for tick-borne encephalitis virus overcomes ELISA limitations

“…However locally acquired cases of DENV have been described in recent years in different European countries, including France in 2022 (11) and in Italy in 2023 (12). Vaccines against JEV and YFV are administered prior to travelling to endemic areas, and simultaneous administration of multiple vaccines is not uncommon (13, 14).…”