Project 2

Jet vaccination with pBI-11 DNA to treat HPV16/18+ ASC-US/LSIL

HPV16 remains the most prevalent oncogenic genotype, responsible for over half of all cervical cancer cases worldwide, and HPV18 contributes another 20%. The licensed preventive HPV vaccines are not effective to treat HPV16/18 infection or disease identified in population-based cervical screening. Nearly half of all persistent HPV16 infections and a quarter of HPV18 progress to high grade cervical intraepithelial neoplasia (CIN2/3), the precursor of cervical cancer, and the risk of HPV persistence increases with age. Currently, there are no treatment options available for persistent HPV16/18 infections that have not yet progressed to high grade cervical intraepithelial neoplasia (<CIN2), other than continued screening until progression, with subsequent surgery for CIN2/3. Patients with persistent cervical HPV16/18 infections have significant potential for transmission and/or the development of disease at other sites, and suffer considerable psychosocial stress associated with having a sexually-transmitted infection that can cause cancer. Therefore, there is a clear unmet medical need for a therapeutic medical intervention to safely eliminate persistent HPV16/18 infections before oncogenic progression. Patients with a persistent HPV16/18 infection are likely to be highly motivated to receive such a therapy and avoid progression requiring an excisional procedure that is associated with significant rates of recurrence and side effects including infection, cervical incompetence and premature birth.

The goal of this proposal is to develop a treatment regimen that safely and effectively elicits immune clearance of persistent cervical HPV16/18 infections, thereby intercepting progression to cervical cancer precursor lesions and cervical cancer. We developed a DNA vaccine, pBI-11, encoding HPV16/18 E6 and E7 proteins that are linked to the danger-associated molecular pattern (DAMP) heat shock protein 70 (HSP70) because it dramatically enhances HPV antigen-specific CD8+ T cell immunity and antitumor potency in mice. However, DNA vaccines alone have shown limited potency in patients because of inefficient delivery. Needle-free delivery of a naked DNA vaccine (ZyCov-D) with a jet device was shown to be safe and effective for prevention of SARS-CoV2 and received licensure in India, demonstrating the utility of these devices in patients for potent delivery of a DNA vaccine. This novel intervention may also prevent other HPV-associated anogenital and oropharyngeal cancers in addition to cervical cancer.

Aim 1: To assess the safety, tolerability and feasibility of repeat intradermal or intramuscular vaccination with pBI-11 DNA via a needle-free jet device in women with HPV16 and/or HPV18+ <CIN2 cervical disease.

Aim 2: To determine the immunogenicity of intradermal or intramuscular jet administration of pBI-11 DNA to women with HPV16/18+ <CIN2 cervical disease.

Aim 3: To examine virologic, cytologic, and pathologic changes at the cervix upon repeat intradermal or intramuscular needle-free jet administration of pBI-11 DNA in women with HPV16 and/or HPV18+ <CIN2 cervical disease.

Investigators