Adjuvant-enhanced CD4 T Cell Responses are Critical to Durable Vaccine Immunity

• Adjuvants can prolong the protection afforded by protein-based vaccines and impact adaptive immune responses
• Enhanced CD4 T cell responses, helper and effector, correlate with duration of protection
• Durable protection from ma-EBOV is associated with Tfh frequency, Th1 antibody titers, and effector CD4 T cellsProtein-based vaccines are extremely safe, but they sometimes require the addition of adjuvants to enhance immunogenicity. In this study, we compared the impact of multiple adjuvants on immunogenicity, focusing on the duration of vaccine-mediated protection in mice. We then looked at how each adjuvant impacted the immune response in order to identify correlates of that long lasting immunity. The most effective adjuvant/vaccine combinations elicited multifunctional CD4 T cell responses and a Th1-skewed antibody response. By transferring antigen-experienced CD4 T cells and serum into naïve animals, we demonstrated that both CD4 T cells and serum were critical for durable vaccine-mediated protection.

Protein-based vaccines offer a safer alternative to live-attenuated or inactivated vaccines but have limited immunogenicity. The identification of adjuvants that augment immunogenicity, specifically in a manner that is durable and antigen-specific, is therefore critical for advanced development. In this study, we use the filovirus virus-like particle (VLP) as a model protein-based vaccine in order to evaluate the impact of four candidate vaccine adjuvants on enhancing long term protection from Ebola virus challenge. Adjuvants tested include poly-ICLC (Hiltonol), MPLA, CpG 2395, and alhydrogel. We compared and contrasted antibody responses, neutralizing antibody responses, effector T cell responses, and T follicular helper (Tfh) cell frequencies with each adjuvant's impact on durable protection. We demonstrate that in this system, the most effective adjuvant elicits a Th1-skewed antibody response and strong CD4 T cell responses, including an increase in Tfh frequency. Using immune-deficient animals and adoptive transfer of serum and cells from vaccinated animals into naïve animals, we further demonstrate that serum and CD4 T cells play a critical role in conferring protection within effective vaccination regimens. These studies inform on the requirements of long term immune protection, which can potentially be used to guide screening of clinical-grade adjuvants for vaccine clinical development.