APL-10456; An Adjuvanted Rhinovirus Clinical Vaccine Candidate Which Generates Cross-species Humoral and Th1-polarized Cellular Immunity

Abstract Rationale: Rhinoviruses (RV) are the most common respiratory pathogen responsible for exacerbations of COPD and asthma. The antigenic diversity of the ∼180 circulating RV subtypes has thus far been a barrier to the development of an effective cross-protective vaccine. Our aim is to develop a vaccine, that will overcome this historic limitation. In a set of preclinical studies we evaluate the effect of including a Th1-polarising adjuvant in a broadly protective RV candidate vaccine formulation. Methods: The immune response to vaccination with adjuvanted or non-adjuvanted APL-10456, a vaccine based upon the VP0 sequence from an RV-C strain and to subsequent heterotypic RV infection was characterised in a mouse model. Results: Vaccination with adjuvanted APL-10456 evoked a high titer, IgG2c-dominant, humoral response. Lower titers and IgG1 dominance were observed following vaccination with non-adjuvanted APL-10456. Importantly, antibodies generated by adjuvanted APL-10456 bound both VP0 and whole virions from heterotypic RV-subtypes. Splenocytes from mice immunized with adjuvanted APL-10456 stimulated with peptide pools corresponding to full-length VP0 from 19 different heterotypic isolates secreted IFN-γ, but not IL-5. Conversely, splenocytes from mice immunized with non-adjuvanted APL-10456 secreted IL-5, but not IFN-γ, following stimulation, indicating the important role of the adjuvant in skewing the immune response towards a Th1 pathway. Following challenge with heterotypic RV-A01 virus, analysis of BAL samples taken from vaccinated mice showed that neutrophilia was reduced in favour of a stronger lymphocyte response. Infection after vaccination was also associated with rapid expansion of RV-A, -B and -C reactive antigen-specific T-cells in respiratory tissues, together with enhanced production of neutralizing antibodies to the heterotypic infecting virus. The overall impact of vaccination was accelerated virus clearance from the lungs after infection. Conclusions: Adjuvanted APL-10456 generates a robust immune response, offering protection from heterotypic RV infection. This protection is likely mediated by generation of cross-strain humoral and cellular immunity, polarized towards Th1 by the selected adjuvant. These data support the progression of APL-10456 into clinical development to establish if a similar response is generated in humans and to determine if the raised antibodies neutralize exemplars from RV-A, -B and -C species.