γδ T CELLS MEDIATE PROTECTIVE IMMUNE RESPONSES INDUCED BY EILV/CHIKV, A CHIMERA VACCINE CANDIDATE, AGAINST CHIKUNGUNYA INFECTION

Chikungunya virus (CHIKV) is a re-emerging virus that causes acute chikungunya fever, often accompanied by severe and persistent arthralgia, known as chronic CHIKV infection (CHIKD). Development of safe and effective vaccines against CHIKV infection and disease remains a high priority. Eilat virus, (EILV) a mosquito-specific alphavirus with the inability to replicate in mammalian cells, can provide a novel platform for creating chimeric viruses as vaccine candidates. An EILV/CHIKV chimera that contains the nonstructural proteins of EILV and the structural proteins of CHIKV has previously shown to protect against wild-type (WT) CHIKV challenge in rodents and non-human primates. The mechanism of the vaccine-induced protection remains unknown. γδ T cells react to WT CHIKV infection by controlling CHIKV inflammation and tissue damage and expand quickly in response to EILV/CHIKV vaccination. TCRδ -/- mice, which are deficient of γδ T cells, displayed lower levels of innate immune cytokines at 2 days post vaccination (DPV). EILV/CHIKV-vaccinated TCRδ-/- mice, following CHIKV infection, displayed increased weight loss and viremia at 7 days post-infection (DPI). These mice also had impaired CHIKV-specific CD8+ T cell responses as early as day 8 post vaccination and this impairment persisted until 28 DPV and even day 7 post WT CHIKV challenge. Compared to vaccinated WT group, TCRδ-/- mice had reduced CHIKV-specific IgG responses, including IgG1 and IgG2c responses, 28 DPV TCRδ-/- mice also demonstrated reduced neutralization antibodies against WT CHIKV 28 DPV and reduced B cell memory responses 71 DPV. Type I IFNAR1-/- mice transferred with sera of vaccinated TCRδ-/- mice displayed more weight loss and succumbed to lethal WT CHIKV challenge more quickly compared to those treated with vaccinated WT mice sera. Type I IFNAR1-/- mice transferred with CD8+ T cells of vaccinated TCRδ-/- mice demonstrated reduced protection compared to WT group. To study the safety aspects of the vaccine, a sensitization study performed in guinea pigs, which were exposed to female Ae. albopictus mosquitoes four times in a 2-week interval, demonstrated that EILV/CHIKV did not induce hypersensitive reactions in guinea pigs. Overall, our results suggest EILV/CHIKV is a safe vaccine candidate and induces γδ T cell-mediated protective adaptive immunity against CHIKV infection in animal models.

Name thesis:degree_name

Microbiology and Immunology (Doctoral)

Grantor

The University of Texas Medical Branch at Galveston

Year dc:date.issued

2025

Author dc:creator

• Rodriguez, Leslie 1996-

Advisor dc:contributor.advisor

• Wang, Tian (Tina) (ti1wang@utmb.edu)

Committee members dc:contributor.committeemember

• Adam, Awadalkareem (awadam@utmb.edu)
• Rossi, Shannan L. (slrossi@utmb.edu)
• Weaver, Scott C. (sweaver@utmb.edu)
• Wang, Penghua (pewang@uchc.edu)

Language dc:language.iso

English

Handle dc:identifier.uri

https://hdl.handle.net/2152.3/12731

OAI identifier oai:identifier

oai:utmb-ir.tdl.org:2152.3/12731