Therapeutic DNA Vaccines against HPV-Related Malignancies: Promising Leads from Clinical Trials

Abstract

In 2014 and 2021, two nucleic-acid vaccine candidates named MAV E2 and VGX-3100 completed phase III clinical trials in Mexico and U.S., respectively, for patients with human papillomavirus (HPV)-related, high-grade squamous intraepithelial lesions (HSIL). These well-tolerated but still unlicensed vaccines encode distinct HPV antigens (E2 versus E6+E7) to elicit cell-mediated immune responses; their clinical efficacy, as measured by HSIL regression or cure, was modest when compared with placebo or surgery (conization), but both proved highly effective in clearing HPV infection, which should help further optimize strategies for enhancing vaccine immunogenicity, toward an ultimate goal of preventing malignancies in millions of patients who are living with persistent, oncogenic HPV infection but are not expected to benefit from current, prophylactic vaccines. The major roadblocks to a highly efficacious and practical product remain challenging and can be classified into five categories: (i) getting the vaccines into the right cells for efficient expression and presentation of HPV antigens (fusion proteins or epitopes); (ii) having adequate coverage of oncogenic HPV types, beyond the current focus on HPV-16 and -18; (iii) directing immune protection to various epithelial niches, especially anogenital mucosa and upper aerodigestive tract where HPV-transformed cells wreak havoc; (iv) establishing the time window and vaccination regimen, including dosage, interval and even combination therapy, for achieving maximum efficacy; and (v) validating therapeutic efficacy in patients with poor prognosis because of advanced, recurrent or non-resectable malignancies. Overall, the room for improvements is still large enough that continuing efforts for research and development will very likely extend into the next decade.

Keywords: DNA vaccine; HPV; cervical cancer; epitope; squamous intraepithelial lesions.

Figure 1

Strategies for screening and filtering current literature for a focused review. Given the large numbers of clinical trials and related literature, as already captured by two major public databases, our goal here is to summarize the current status of research and development toward therapeutic, anti-HPV DNA vaccines, with a focus on insights and expectations, as well as questions about potential consensus, remaining gaps and future directions for refinements or improvements. CTL, cytotoxic T-lymphocyte; MOA, mechanism of action.

Figure 2

Premises and advantages of DNA-based, therapeutic anti-HPV vaccines. Unlike prophylactic HPV vaccines that induce HPV-specific antibodies to neutralize invading viruses, therapeutic DNA vaccines against HPV-induced malignancies must induce cytotoxic T-lymphocytes (CTLs) to eliminate HPV-infected or -transformed cells in patients with chronic/persistent infections [23,24]. Several critical components are color-coded. APCs, antigen-presenting cells; HLA-I, human leukocyte antigen class I (class I heavy chain); β2m, β2 microglobulin (class I light chain).

Figure 3

Milestones in the R&D paths of two promising vaccine candidates (MVA E2 and VGX-3100) that have completed phase III clinical trials in patients with HPV-related pre-cancerous conditions (mostly high-grade squamous intraepithelial lesions). The results from key developmental stages are readily available in peer-reviewed publications [79,80,83,93,94,95,97,98,100] or online resources [84,99]. The lead authors of two highly cited studies (more than 250 citations each) are underlined.