Molecular Pathogenesis and Preventive Advances in HPV-Associated

Cervical Carcinogenesis

Qila Sa

West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China

Keywords: Human Papillomavirus (HPV), Cervical Cancer, Prophylactic Vaccines.

Abstract: Cervical cancer poses a significant threat to women's health worldwide, with its pathogenesis being strongly

associated with persistent infection by high-risk human papillomavirus (hrHPV). As the predominant

oncogenic subtypes, HPV16 and HPV18 encode E6 and E7 proteins that disrupt cell cycle control through

p53 degradation and pRb inactivation, drive genomic instability, and establish an immunosuppressive

microenvironment to evade host immune surveillance. Prophylactic HPV vaccines (bivalent, quadrivalent,

and nonavalent), utilizing virus-like particle (VLP) technology, effectively prevent targeted HPV infections

and significantly reduce the incidence of premalignant lesions and invasive carcinomas. However, existing

vaccines demonstrate limited efficacy in already infected individuals and against non-vaccine-targeted HPV

types, while global disparities in vaccine accessibility and suboptimal vaccination coverage in males further

compromise their preventive impact. Future directions should prioritize the development of pan-HPV

spectrum vaccines, optimization of immunization protocols for high-risk populations, and breakthroughs in

therapeutic vaccine design. Concerted efforts to ensure equitable vaccine allocation, implement male

vaccination programs, and establish integrated prevention-screening-treatment frameworks will be crucial for

accelerating the global elimination of cervical cancer. This review explores the evolving landscape of HPV

vaccines, highlighting current challenges and emerging opportunities, aiming to inform evidence-based

strategies for preventing and managing cervical cancer.

1 INTRODUCTION

Cervical cancer remains a leading cause of global

female cancer burden, with the World Health

Organization (WHO) estimating 604,000 incident

cases and 342,000 attributable deaths in 2020 alone.

Notably, this malignancy disproportionately affects

resource-limited settings, where over 85% of both

incident cases and mortality clusters in low- and

middle-income countries (LMICs) (Sung et al.,

2021). Epidemiological evidence establishes cervical

cancer incidence as inversely associated with regional

socioeconomic development gradients, where

structural determinants including healthcare access

inequities, screening program deficiencies, and HPV

vaccine implementation gaps synergistically

contribute to disproportionate disease burden

distribution (Bruni et al., 2016). Cervical cancer is

primarily classified histologically as squamous cell

carcinoma (75%-90%), with adenocarcinoma and

adenosquamous carcinoma occurring less frequently

(Wang et al., 2020). Despite marked improvements in

clinical outcomes through early screening and

surgical interventions, survival rates among patients

with advanced-stage or recurrent cervical cancer

remain suboptimal, underscoring the critical

imperative for elucidating pathogenic mechanisms

and refining prevention strategies.

Persistent infection with high-risk human

papillomavirus (hrHPV) is a critical factor in cervical

carcinogenesis. More than 99% of cervical cancer

cases are associated with hrHPV infection, with

HPV16 and HPV18 accounting for 70% and 12% of

cases respectively, constituting the predominant

oncogenic subtypes (Singh et al., 2023). hrHPV

disrupts host cell cycle regulation through the

encoding of early proteins E6 and E7: E6 induces

ubiquitin-mediated degradation of p53 to suppress

apoptosis, while E7 binds to and inactivates the

retinoblastoma protein (pRb), thereby promoting

aberrant cell proliferation (Moody and Laimins,

2010). The HPV-induced immunosuppressive

microenvironment (PIM) facilitates viral immune

evasion and tumorigenesis by impairing dendritic cell

functionality, recruiting regulatory immune cells, and

430

Sa, Q.

Molecular Pathogenesis and Preventive Advances in HPV-Associated Cervical Carcinogenesis.

DOI: 10.5220/0014494700004933

Paper published under CC license (CC BY-NC-ND 4.0)

In Proceedings of the 1st International Conference on Biomedical Engineering and Food Science (BEFS 2025), pages 430-434

ISBN: 978-989-758-789-4

inducing metabolic reprogramming (Zhou et al.,

2019).

The implementation of HPV vaccination has

revolutionized primary prevention strategies for

cervical cancer. Current prophylactic vaccines—

bivalent, quadrivalent, and nonavalent

formulations—are designed using virus-like particles

(VLPs) to elicit neutralizing antibodies,

demonstrating >90% protective efficacy against

targeted HPV types (Joura et al., 2015). Large-scale

clinical studies have demonstrated that prophylactic

HPV vaccination significantly reduces the incidence

of HPV infections, genital warts, and high-grade

cervical lesions (Garland et al., 2016). However,

existing prophylactic vaccines demonstrate limited

efficacy in individuals with established HPV

infections and against immune escape phenomena

mediated by non-vaccine-targeted HPV types

(Malagón et al., 2012). Thus, the development of

second-generation vaccines covering a broader

spectrum of HPV types and therapeutic vaccines

targeting E6/E7 proteins has become a current

research priority (Hancock, Hellner and Dorrell,

2018). By analyzing epidemiological data,

pathogenic mechanisms, and prevention strategies of

HPV-positive cervical cancer, this review aims to

provide theoretical support for future prevention and

control efforts, while offering a solid foundation for

formulating public health policies.

2 ASSOCIATION OF HPV WITH

CERVICAL CARCINOGENESIS

2.1 Virological Characteristics of HPV

Human papillomavirus (HPV) is a circular double-

stranded DNA virus with more than 200 identified

subtypes. Categorized by oncogenic risk, HPV strains

are stratified into low-risk and high-risk types. Low-

risk HPV (e.g., HPV type 6, HPV type 11) primarily

induces benign proliferative lesions such as genital

warts, whereas high-risk HPV (e.g., HPV type 16,

HPV type 18) is strongly associated with cervical

carcinoma and other anogenital/oropharyngeal

malignancies (Singh et al., 2023). HPV is primarily

transmitted through sexual contact and can also

establish infection via direct skin-to-skin or mucosal

contact. The virus gains entry into cervical basal

epithelial cells through microtraumas, where it exerts

its oncogenic effects. Following cellular entry, HPV

early genes (e.g., E6 and E7) are transcribed,

initiating abnormal cellular proliferation that

progresses to precancerous lesions. Late genes (L1

and L2) mediate viral capsid protein assembly,

facilitating virion production and subsequent

transmission (Moody and Laimins, 2010).

2.2 Association of HPV Infection with

Cervical Carcinogenesis

Epidemiological evidence establishes persistent high-

risk human papillomavirus (hrHPV) infection as a

necessary causal factor for cervical carcinogenesis.

Globally, 99% of cervical cancer cases demonstrate

hrHPV association, with HPV16 and HPV18

accounting for 70% and 12% of cases respectively,

constituting the predominant oncogenic subtypes

(Singh et al., 2023). These genotypes demonstrate

strong etiological associations not only with cervical

squamous cell carcinoma (SCC) but also with

adenocarcinoma (ADC) pathogenesis (Wang et al.,

2020). Notably, although approximately 90% of HPV

infections are cleared by the immune system,

persistent infections (>2 years) may lead to the

progression of cervical intraepithelial neoplasia

(CIN) to invasive carcinoma (Sung et al., 2021).

Chronic HPV persistence drives the accumulation of

oncogenic mutations in host cells, culminating in

malignant transformation.

2.3 Pathogenesis

The oncogenic potential of hrHPV is primarily

mediated by its early oncoproteins E6 and E7. The E6

protein induces ubiquitin-mediated proteasomal

degradation of the tumor suppressor p53, thereby

suppressing apoptosis and fostering cellular survival

with accumulated genomic alterations. Meanwhile,

the E7 protein binds to and inactivates retinoblastoma

protein (pRb), derepressing cyclin E to drive cell

cycle progression, ultimately resulting in genomic

instability and neoplastic transformation (Moody and

Laimins, 2010). Furthermore, HPV infection

facilitates the establishment of a protumorigenic

immunosuppressive microenvironment (PIM).

Mechanistically, viral-mediated downregulation of

major histocompatibility complex (MHC) class I

expression facilitates immune evasion, while

concurrent recruitment of regulatory T cells (Tregs)

and myeloid-derived suppressor cells (MDSCs)

suppresses effector T-cell-mediated antitumor

immunity (Zhou et al., 2019). Emerging evidence has

elucidated that HPV infection induces metabolic

reprogramming in host cells, exemplified by

upregulated glycolytic flux (Warburg effect), which

fosters tumor microenvironment evolution through

Molecular Pathogenesis and Preventive Advances in HPV-Associated Cervical Carcinogenesis

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metabolic crosstalk, ultimately providing

bioenergetic and biosynthetic support for neoplastic

proliferation (WHO, 2020).

3 HPV VACCINATION IN

CERVICAL CANCER

PREVENTION

3.1 Classification and Mechanistic

Basis of Prophylactic HPV

Vaccines

Currently approved HPV vaccines encompass

bivalent, quadrivalent, and nonavalent formulations,

all employing virus-like particle (VLP) technology.

These vaccines utilize self-assembling L1 capsid

proteins to generate structurally authentic viral

mimics, effectively eliciting high-titer neutralizing

antibodies. The bivalent vaccine Cervarix specifically

targets HPV16/18 - the two predominant oncogenic

types. Incorporating the AS04 adjuvant system

(monophosphoryl lipid A + aluminum hydroxide) to

potentiate immunogenicity, pivotal clinical trials

(NCT00128661; PATRICIA) have demonstrated

93% efficacy in preventing HPV16/18-associated

cervical intraepithelial neoplasia grade 2+ (CIN2+)

lesions (Joura et al., 2015). The quadrivalent vaccine

Gardasil targets HPV types 6, 11, 16, and 18,

providing dual protection against both oncogenic

(HPV16/18) and benign pathological manifestations

(HPV6/11-induced genital warts). Population-based

studies demonstrate its implementation has

significantly reduced the incidence of HPV-

associated malignancies (cervical/vaginal/vulvar

cancers) and precursor lesions across vaccinated

cohorts (Garland et al., 2016). The nonavalent

vaccine Gardasil 9 expands coverage to HPV types 6,

11, 16, 18, 31, 33, 45, 52, and 58, collectively

accounting for approximately 90% of global cervical

cancer-associated HPV genotypes. This formulation

elicits robust cross-neutralizing immunity against

targeted types, with phase III trials (NCT00543543)

demonstrating 97% efficacy in reducing high-grade

squamous intraepithelial lesions (HSIL) attributable

to these genotypes (Huh et al., 2017).

3.2 Clinical Efficacy and Safety Profile

of Prophylactic HPV Vaccines

Large-scale clinical trials have demonstrated that

prophylactic HPV vaccination significantly reduces

the incidence of HPV infections and cervical

intraepithelial neoplasia. In a phase III randomized

controlled trial (FUTURE II) enrolling 14,215

women, the nonavalent vaccine demonstrated 96.7%

efficacy (95% CI: 94.2-98.2) against high-grade

squamous intraepithelial lesions (HSIL) associated

with HPV31/33/45/52/58 genotypes (Huh et al.,

2017). Furthermore, long-term follow-up data

indicate that the vaccine's protective efficacy persists

for more than a decade, with no serious adverse

events observed (Phillips et al., 2018). Common

vaccine-associated adverse reactions comprise

injection-site pain (84%) and pyrexia (13%), with the

majority of these reactions being self-limited and

resolving spontaneously within 48-72 hours post-

vaccination (Garland et al., 2016).

3.3 Global HPV Vaccine Voverage

Landscape and Population Health

Implications

As of 2022, 110 countries/territories have integrated

HPV vaccination into their national immunization

schedules under WHO's Expanded Program on

Immunization (EPI) framework, however,

vaccination coverage rates remain under 15% in low-

income countries (WHO, 2020). High-income

countries have demonstrated remarkable success

through national school-based vaccination programs.

A prime example is Australia, where implementation

of the quadrivalent vaccine in 2007 has led to a 92%

reduction in HPV prevalence rates among vaccine-

eligible cohorts (Brotherton Julia M L., 2019).

Nevertheless, persisting challenges such as

inequitable global vaccine allocation, suboptimal

vaccination coverage in males, and the emergence of

non-vaccine-targeted HPV genotypes remain critical

barriers to achieving global cervical cancer

elimination targets.

4 HALLENGES IN

PROPHYLACTIC HPV

VACCINE DEVELOPMENT

4.1 Inherent Limitations of

Prophylactic HPV Vaccines

Although current prophylactic HPV vaccines

demonstrate high efficacy in preventing de novo

infections, their inherent limitations warrant critical

attention. Foremost, these vaccines provide limited

therapeutic benefit for individuals with pre-existing

HPV infections, as they neither clear established viral

BEFS 2025 - International Conference on Biomedical Engineering and Food Science

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reservoirs nor reverse HPV-induced cervical

intraepithelial neoplasia (CIN) or invasive

carcinomas (Malagón et al., 2012). Second, a

principal limitation lies in the predominant

mechanism of current vaccines, which primarily elicit

neutralizing antibodies to prevent de novo viral entry

but fail to modulate the expression of HPV oncogenic

drivers (e.g., E6/E7) integrated into host genomic

DNA, resulting in minimal therapeutic efficacy

against established precursor or invasive

malignancies (Hancock, Hellner and Dorrell, 2018).

Furthermore, prophylactic HPV vaccines lack the

capacity to remodel established protumor genic

immunosuppressive microenvironments (PIM),

thereby compromising their clinical utility in patients

with advanced-stage malignancies (Zhou et al.,

2019).

4.2 Narrow Spectrum Coverage of

Current HPV Vaccines

While the nonavalent HPV vaccine provides

coverage against approximately 90% of cervical

cancer-associated HPV genotypes globally (including

HPV16/18/31/33), the remaining 10% of cases are

attributable to non-vaccine-targeted high-risk

genotypes such as HPV35/39/51, as evidenced by

global HPV genotyping surveillance data (Huh et al.,

2017). Emerging epidemiological surveillance data

reveal an increasing prevalence of non-vaccine-

targeted HPV genotypes in specific geographic

regions, a trend potentially amplified through

vaccine-mediated selective pressure driving type

replacement dynamics (Singh et al., 2023).

Consequently, the development of next-generation

pan-genotypic HPV vaccines and the engineering of

multivalent vaccine platforms capable of inducing

cross-neutralizing immunity represent an imperative

trajectory for advancing prophylactic HPV

vaccination strategies (Hancock, Hellner and Dorrell,

2018).

4.3 Impact of Host Immunogenetic

Heterogeneity on Vaccine-Induced

Adaptive Immunity

The immunogenicity of prophylactic HPV vaccines

exhibits marked interindividual variation attributable

to host immunogenetic determinants.

Immunocompromised populations, particularly

individuals with HIV/AIDS (PLWH), demonstrate

significantly attenuated neutralizing antibody

seroconversion rates (Phillips et al., 2018). scents

exhibiting significantly higher geometric mean titers

(GMTs) of neutralizing antibodies and prolonged

serological protection following immunization. In

contrast, adult females demonstrate age-dependent

waning of humoral immunity, necessitating

supplemental booster immunization or regimen

modifications to ensure sustained vaccine

effectiveness (Brotherton Julia M L., 2019). These

immunobiological disparities underscore the

imperative for developing demographically tailored

vaccination protocols aligned with WHO's age-

stratified immunization guidelines.

4.4 Male HPV Vaccination: An

Underrecognized Pillar of Herd

Immunity

Current global HPV vaccination strategies

predominantly prioritize female immunization, while

male vaccination coverage remains suboptimal

(Bruni et al., 2016). Notably, vaccinating males—

who serve as principal HPV transmission vectors—

provides dual preventive benefits: reducing their

susceptibility to HPV-associated malignancies

(penile, oropharyngeal, and anal carcinomas) and

establishing population-level herd immunity effects

that significantly reduce heterosexual transmission to

female populations (WHO, 2020). Evidence from

Australia and other countries demonstrates that

enhancing male HPV vaccination coverage

accelerates the reduction in HPV transmission rates.

However, this progress necessitates targeted public

health education to rectify the prevalent

misconception that HPV exclusively affects females

(Brotherton Julia M L., 2019).

4.5 Therapeutic HPV Vaccine

Development Challenges

Therapeutic HPV vaccine development for infected

individuals remains in experimental stages.

Candidate platforms—including E6/E7-targeting

DNA vaccines, viral-vectored vaccines, and dendritic

cell-based vaccines—are designed to prime antigen-

specific cellular immunity against infected cells, yet

demonstrate suboptimal clinical outcomes in phase

II/III trials (Hancock, Hellner and Dorrell, 2018). Key

challenges stem from HPV oncoproteins'

immunoevasive properties and the multifaceted

complexity of tumor microenvironments,

exemplified by the suboptimal immunogenicity of

E6/E7 antigens coupled with regulatory T cell (Treg)-

mediated immunosuppression (Zhou et al., 2019).

Therapeutic vaccine efficacy enhancement requires

combinatorial immunotherapy approaches targeting

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multiple antigens alongside synergistic integration

with immune checkpoint inhibitors.

5 CONCLUSION

The broad implementation of HPV vaccination has

precipitated a marked decline in cervical cancer

incidence globally, representing a landmark

achievement in oncology prevention. Nevertheless,

critical barriers persist—including restricted

therapeutic efficacy in established infections, non-

pan-genotypic coverage, interindividual

heterogeneity in immunogenicity, and inadequate

male immunization rates—which collectively

constitute multifactorial obstacles to achieving full

cervical cancer eradication (WHO, 2020). Future

research priorities should center on three strategic

axes: (1) developing pan-genotypic HPV vaccines

with extended valency to broaden protective

coverage, while harnessing cross-neutralizing

immunity to address type replacement dynamics; (2)

optimizing vaccine delivery platforms and

immunization regimens to enhance immunogenicity

in immune-vulnerable populations; (3) accelerating

translational pipelines for therapeutic vaccines,

synergizing them with existing screening protocols

and surgical interventions to establish integrated

prevention frameworks (Hancock, Hellner and

Dorrell, 2018). Policymaking necessitates

multinational collaborations to implement tiered

pricing mechanisms and equitable allocation

frameworks, prioritizing vaccination coverage

expansion in low-resource settings (Bruni et al.,

2016). Concurrently, scaling up health literacy

initiatives is critical to counteract vaccine hesitancy

rooted in misinformation, while codifying gender-

inclusive vaccination policies. The synergistic

integration of tripartite prevention-screening-

treatment paradigms, augmented by technological

innovation and coordinated public health action,

provides a viable pathway toward achieving WHO's

cervical cancer elimination threshold (WHO, 2020).

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