Targeting CD137 Enhances Vaccine-Elicited Anti–Respiratory Syncytial Virus CD8+ T Cell Responses in Aged Mice

Abstract

Respiratory syncytial virus (RSV) causes significant morbidity and mortality in children and the elderly. There are no vaccines for RSV in use. Due to immunosenescence, the immunologic requirements for a successful RSV vaccine in the elderly might differ from a RSV vaccine for young children. Using an aged mouse model of RSV pathogenesis, we found that aged mice had impaired antigen-specific CD8+ T cell responses and delayed RSV clearance compared to young mice. In order to study vaccine-elicited RSV-specific CD8+ T cells in aged mice, we used a peptide vaccine approach. TriVax is a co-mixture of a peptide representing immunodominant RSV CD8+ T cell epitope M282–90, a Toll-like receptor agonist (polyI:C), and a costimulatory anti-CD40 antibody. TriVax vaccination generated robust, polyfunctional, and protective CD8+ T cell responses in young BALB/c mice but not in 18 month old (aged) BALB/c mice. We hypothesized that treatment of aged mice with agonistic anti (α)-CD137 (41BB) monoclonal antibody will partially restore T cell responses and TriVax efficacy in aged mice. We immunized 18-month old BALB/c mice twice with TriVax + α-41BB mAb or TriVax + isotype control Ab. Co-administration of α-41BB mAb with TriVax enhanced RSV-specific CD8+ T cell responses and TriVax efficacy in challenge experiments. Triggering the 41BB costimulatory pathway may be a strategy for enhancing T cell responses to vaccines in the elderly.

Additive protection induced by mixed virus-like particles presenting respiratory syncytial virus fusion or attachment glycoproteins

“…Here, we used RSV strain A2-line19F as the challenge strain because this strain exhibits not only higher viral loads in mice but also airway mucus expression (Lee et al, 2014; Lee et al, 2012; Moore et al, 2009). Mice were unvaccinated (naïve), or vaccinated with VLP M1 (no RSV antigen), VLP F, VLP G, or mixed VLP F + VLP G then boosted 3 weeks later.…”

“…ICS was performed to enumerate cytokine-producing cells as described previously (Lee et al, 2014; Lee et al, 2012). Lung lymphocytes were stimulated in vitro with 50 ng/ml phorbol 12-myristate 13-acetate (PMA) (Sigma-Aldrich, St. Louise, MO), 500 ng/ml ionomycin (Sigma Aldrich, St. Louise, MO), and 0.5 μl Golgi Plug (BD Biosciences, Franklin Lakes, NJ).…”

CD8 T-Cell Response to Respiratory Syncytial Virus Infection

“…Induction of robust CD8 T-cell responses following vaccination may be more difficult in elderly populations given the correlation of immunosenescence with age [116,117]. In agreement, TriVax immunization does not induce a sufficient memory CD8 T-cell response to mediate accelerated viral clearance in aged mice [118]. However, addition of further costimulation through activation of CD137 on CD8 T cells during TriVax immunization accelerated viral clearance following RSV challenge in aged mice.…”

Antiviral Monoclonal Antibodies: Can They Be More Than Simple Neutralizing Agents?

“…Combining antiviral mAbs with immunostimulatory agents can also be considered. Agonistic mAbs targeting T-cell costimulatory receptors such as CD40, OX40, GITR, and CD137 (reviewed in [65]) currently tested in the clinic may serve such a purpose, as the engagement of such costimulatory receptors is already known to enhance antiviral cellular immunity in different infection settings [66][67][68][69]. Alternatively, agonists of Toll-like receptors (TLRs) could be used, as, on one hand, activation of TLRs is essential for the development of many natural antiviral responses and, on the other hand, TLR7/8 and -9 agonists have already been shown to cooperate to enhance the anti-HIV-1 Env humoral response in rhesus macaques [70].…”