A novel Th17-enhancing adjuvant and conserved antigen for protection against viral/bacterial co-infection

About This Grant

We will develop a novel vaccine with broad efficacy against nontypeable Haemophilus influenzae (NTHi) strains following influenza A virus (IAV) infection. NTHi is one of the most common pathogens that cause secondary bacterial pneumonia following IAV infection. Although vaccines are available for IAV, they confer very limited protection against viral and bacterial co-infection, and effective vaccines against NTHi remain needed. NTHi vaccines under development focus on antibody responses that target bacterial surface proteins and lipooligosaccharide antigens, which are hindered by genetic and antigenic diversity of NTHi strains and there is no universally approved vaccine against NTHi. CD4+ T-helper 17 (Th17) cells are increasingly being recognized as key mediators of protection against respiratory pathogen infections by production of IL-17A. A preceding IAV infection decreases anti-bacterial Th17 responses, whereas established NTHi-specific Th17 memory cells can overcome Th17 inhibition and convey cross-protection against IAV/NTHi co-infection. Adjuvants have been proven to enhance immune response strength and breadth, resulting in improved vaccine efficacy. Therefore, focusing on Th17 cells and incorporation of Th17 adjuvants in vaccine strategies would be effective in broadly protecting against co-infection. We have previously identified a conserved protein (protein 0259) from H. influenzae, that when administered as a vaccine, induces a cross-reactive, protective Th17 response against diverse NTHi strains alone and/or following IAV infection. Our preliminary data indicate that an FDA-approved histone deacetylase inhibitor (HDACi), Romidepsin (RMD), acts as a novel adjuvant that augments Th17 responses to vaccine and enhances protection against IAV/NTHi co-infection. These results provide evidence that a vaccine candidate consisting of protein 0259 with the adjuvant RMD can be developed into a novel mucosal Th17-based vaccine for clinical use. In this phase I STTR, we will perform proof of concept, preclinical studies with the following aims: Aim 1. Establish the optimum antigen/adjuvant vaccine dosage regimen to elicit potent anti-NTHi immune responses and evaluate its protective efficacy. We will produce and purify Th17-inducing antigen to formulate a protein vaccine candidate consisting of this conserved bacterial antigen (protein 0259) with a novel adjuvant (RMD) that induces strong anti-NTHi Th17 responses and will protect against IAV/NTHi co-infection. Vaccine dosage regimens that we have previously found efficacious in mouse models will be compared to other administration strategies, including routes of administration, the volume, and the dose. Successful immunization will be determined by detection of strong antigen-specific Th17 responses. We will use the identified optimal vaccination regimen to protect against co- infection in vivo, in comparison to our earlier immunization regimen. Aim 2. Conduct vaccine toxicological assessments in mice. We will conduct toxicity studies of our novel Th17-inducing vaccine (protein 0259 plus RMD), designed to provide pivotal safety data prior to human clinical trials. The aim will employ murine models, chosen for their relevance to human immune responses, to thoroughly evaluate potential systemic and local toxicity associated with multiple dosages of the vaccine. These studies are crucial for ensuring the safety and efficacy of the vaccine, which represents a significant advancement in treatment/prevention of bacterial pneumonia.