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.
Highlights
The current research and development (R&D) pipeline has further benefited from the availability of various resources, including in vitro systems for the propagation of infectious viruses [52] and preclinical models for testing vaccine efficacy against two major oncogenic subtypes (HPV-16 and -18) [36,53]
Oncogenic human papillomavirus (HPV) is well-known for its ability to evade host immune responses [54,55,56], with three HPV proteins (E5, E6 and E7) interfering with both innate immune pathways and the antigen-processing and -presenting machinery embedded in the major histocompatibility complex (MHC)
Because MHC-TCR interaction is a prerequisite for T-cell activation, preclinical experiments must be done in C57BL/6 (B6) mice only [92]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. DNA vaccines encoding tumor-specific antigens are highly attractive because of their ability to induce potent, cell-mediated immunity Anti-HPV vaccines, at least three major advantages are apparent. HPV epitopes [33], epitopes some of [33], which (e.g.,ofE1, E2 and epitopes) fallepitopes) beyond E6 and E7 [7,34] but can be harnessed for enhancing vaccine efficacy, either indirectly by Viruses 2022, 14, 239 serving as natural immune adjuvants (through cytokine induction) or directly by triggering anamnestic immune responses when these epitopes are added to the vaccine constructs. The current R&D pipeline has further benefited from the availability of various resources, including in vitro systems for the propagation of infectious viruses (e.g., the HPV-18 organotypic cultures) [52] and preclinical models for testing vaccine efficacy against two major oncogenic subtypes (HPV-16 and -18) [36,53]. E6 and E7 (a key measure of authentication), facilitates direct comparison of research data from various laboratories
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