Project 1

Thermostable RG-1 VLPs, A Candidate Broadly Protective HPV Vaccine for the Prevention of Cervical Cancer Globally

HPV is a necessary cause of 10% of all cancers of women globally, including 99% of cervical cancers. Rates of cervical cancer vary markedly by geographic region and level of economic development, with >85% occurring in developing countries. Global estimates of HPV vaccination delivery and cervical screening by region and income level show virtually none in many poorer populations. There are 13 mucosal high-risk (hr) HPV types plus 11 possibly carcinogenic types. Licensed HPV vaccines all target HPV16 and HPV18, and one (Gardasil®9) also targets the next five most common types in cervical cancer. Since none target all cancer-associated HPVs, screening is maintained even in vaccinated women, adding to medical costs. Further, the stringent cold-chain and ≥two dose requirements for HPV vaccines are a serious impediment to delivery in developing countries. Our overall goal is to develop an affordable HPV vaccine that durably extends the breadth of protection to all cancer- associated HPV types, needs only to be administered once, and is stable at ambient temperature. Here we address this goal with two innovations: 1) displaying an L2-based protective epitope (RG1, that is conserved for HPVs) in a unique position on the surface of HPV16 L1 virus-like particles (VLPs), producing a single antigen, broadly protective HPV vaccine technology, RG1-VLP, and 2) the RG1-VLP vaccine is formulated by freeze drying in a glassy organic matrix surrounded by single atomic layer deposits of Al2O3. This atomic layer deposition (ALD) technology confers heat stability, protects against degradation during delivery, and provides slow waves antigen release that potentially allows for a single dose regimen.

Aim 1: To perform a dose escalation phase I trial of the safety and immunogenicity of RG1-VLP absorbed to alum in healthy female volunteers.

Aim 2: To analyze the levels of protection against intravaginal HPV challenge conferred by passive transfer of serum of patients vaccinated with either RG1-VLP or Gardasil®9 in mice with fully humanized Fc receptors or none.

Aim 3: Develop an ALD coated RG1-VLP vaccine, study its in vitro temperature stability, and in murine models test its one dose immunogenicity and protective efficacy and breadth of coverage in comparison to standard regimen Gardasil®9 vaccination.

Investigators