Antigen-specific T cell responses following single and co-administration of tick-borne encephalitis, Japanese encephalitis, and yellow fever virus vaccines: Results from an open-label, non-randomized clinical trial-cohort
Authors: Wullimann David , Sandberg John Tyler , Akber Mira , Löfling Marie , Gredmark-Russ Sara , Michaëlsson Jakob , Buggert Marcus , Blom Kim , Ljunggren Hans-Gustaf 
Published: November 2024

Background

Flavivirus infections pose a significant global health burden, highlighting the need for safe and effective vaccination strategies. Co-administration of different vaccines, including licensed flavivirus vaccines, is commonly practiced providing protection against multiple pathogens while also saving time and reducing visits to healthcare units. However, how co-administration of different flavivirus vaccinesde factoaffects immunogenicity, particularly with respect to T cell responses, is only partially understood.

Methods and findings

Antigen-specific T cell responses were assessed in study participants enrolled in a previously conducted open-label, non-randomized clinical trial. In the trial, vaccines against tick-borne encephalitis virus (TBEV), Japanese encephalitis virus (JEV), or yellow fever virus (YFV) were administered either individually or concomitantly in different combinations in healthy study participants. Peripheral blood samples were collected before vaccination and at multiple time points afterward. To analyze antigen-specific CD4+ and CD8+ T cell responses, PBMCs were stimulated with overlapping peptide pools from TBEV, JEV, YFV, and Zika virus (ZIKV) envelope (E), capsid (C), and non- structural protein 5 (NS5) viral antigens. A flow cytometry-based activation-induced marker (AIM) assay was used to quantify antigen-specific T cell responses. The results revealed remarkably similar frequencies of CD4+ and CD8+ T cell responses, regardless of whether vaccines were administered individually or concomitantly. In addition, administering the vaccines in the same or different upper arms did not markedly affect T cell responses. Finally, no significant cross-reactivity was observed between TBEV, JEV, and YFV vaccines, nor with related ZIKV-specific antigens.

Conclusions

TBEV or JEV vaccines can be co-administered with the live attenuated YFV vaccine without any markedly altered antigen-specific CD4+ and CD8+ T cell responses to the respective flaviviruses. Additionally, the vaccines can be delivered in the same or different upper arms without any significant influence on the T cell response. From a broader perspective, these results provide valuable insights into the outcome of immune responses following simultaneous administration of different vaccines for different but related pathogens.

Author summary

Why was this study done?

The World Health Organization recently declared a global initiative to control arboviral diseases. Many of these are caused by pathogenic flaviviruses, most transmitted by mosquitos and other arthropod vectors such as ticks.

Vaccination is a key intervention for diseases caused by flaviviruses.

Co-administration of different vaccines, including currently licensed flavivirus vaccines, is commonly practiced.

Co-administration of vaccines saves time and reduces the number of visits to healthcare facilities and vaccine clinics.

Cellular immune responses have not been thoroughly evaluated upon co- administration of currently licensed flavivirus vaccines, including yellow fever virus (YFV), tick-borne encephalitis virus (TBEV), and Japanese encephalitis virus (JEV) vaccines.

What did the researchers find?

The magnitude and specificity of CD4+ and CD8+ T cell responses to virus- specific antigens remained largely unchanged by the concomitant delivery of the studied flavivirus vaccines.

Concomitant delivery of vaccines in the same or different upper arms of the study participants had minimal impact on CD4+ and CD8+ T cell responses.

The studied vaccines maintained distinct CD4+ and CD8+ T cell reactivity across their respective viral antigens without generating any significantly detectable cross-reactivity to each other or ZIKV-antigens.

What do these findings mean?

Along with recently published data from the present study cohort, co- administration of three commonly used current licensed flavivirus vaccines is feasible without increasing the risk of adverse events or significantly affecting the development of either neutralizing antibodies (nAbs) or T cell responses against the respective viral antigens.