Figure - available from: Frontiers in Cellular and Infection Microbiology
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Schematic representation of the dsHPV16 genome (gray circles, other HPV subtypes are similar to it), with the ORFs of the virus indicated by colored arcs above the genome. The promoters are indicated by P (P97, P670, PE8) and the pAE and pALs (polyadenylation sites) stages are indicated by short straight lines.
Source publication
Persistent human papillomavirus (HPV) infection is recognized as the main cause of cervical cancer and other malignant cancers. Although early detection and treatment can be achieved by effective HPV screening methods and surgical procedures, the disease load has not been adequately mitigated yet, especially in the underdeveloped areas. Vaccine, be...
Similar publications
The human papillomavirus (HPV) belongs to the Papillomavirus family and is considered a non-enveloped virus. HPV affects individuals by causing both benign and malignant lesions. We aim to define HPV and its important characteristics, explain the relation between HPVs and cervical cancer, review its prevalence among Saudi women and their awareness...
Cervical cancer (CC) is a major health problem among reproductive-age females and comprises a leading cause of cancer-related deaths. Human papillomavirus (HPV) is the major risk factor associated with CC incidence. However, lifestyle is also a critical factor in CC pathogenesis. Despite HPV vaccination introduction, the incidence of CC is increasi...
background
Human papillomavirus (HPV) is one of the most prevalent sexually transmitted viruses in the world, and is associated with many medical conditions cervical cancer being the most common and serious HPV-related diseases.
Therefore, it is highly important to introduce HPV vaccination as a strategy for preventing cervical cancer and other pro...
Human papillomavirus (HPV) plays an essential role in cervical cancer development. Angola has a high cervical cancer incidence rate (36.1 per 100,000); therefore, knowledge of HPV among clinicians is essential for the prevention of cervical cancer and educating at-risk individuals. This study aimed to evaluate knowledge of HPV among healthcare prof...
Background: Cervical cancer (CC) is an important cause of cancer death among Bangladeshi women and human papillomavirus (HPV) is the causative factor for developing CC. HPV vaccination is yet to be implemented as part of national immunization programme in Bangladesh. Method: The objective of this cross-sectional research was to evaluate the underst...
Citations
... Although preventive HPV vaccinations have demonstrated efficacy in preventing new infections, persons who are already infected do not experience the same advantages. As a result, individuals, especially those in disadvantaged groups with restricted access to screening and immunization programs, nevertheless suffer from cervical cancer, genital warts, and other illnesses caused by HPV [4]. Although there have been notable progres- ...
... Although most techniques primarily target the oncogenes E6 and E7, a significant challenge that has to be addressed is the immune evasion mechanisms employed by cells infected with HPV. Hence, it is imperative to specifically focus on targeting supplementary proteins or antigens that are unique to the tumor in order to generate more potent and long-lasting immune reactions [4]. The E2 protein, because of its crucial function in the HPV infection process, has great potential. ...
... The E2 protein is currently under investigation as a potential target for the creation of vaccines due to its significant importance. Nevertheless, due to the significant upregulation of the E2 gene during the initial phase and its subsequent removal following chromosomal integration, a vaccine that specifically targets the E2 protein is more beneficial for treating precancerous conditions rather than cancer itself [4]. ...
The human papillomavirus (HPV) is the predominant viral infection of the reproductive system, leading to a range of diseases in both males and females, including precancerous lesions that have the potential to develop into cancer. Certain HPV infections can cause the development of genital warts, while others can lead to the formation of abnormal cells that have the potential to progress into cancer. Although preventative vaccines are accessible and have shown encouraging outcomes, the worldwide occurrence and death rates of HPV-related malignancies continue to be elevated, especially in low- and middle-income nations. Currently, there is no known remedy for HPV infection, and innovative therapeutic methods such as immunotherapy have emerged as successful tactics for treating and eradicating malignancies caused by the virus. The oncoproteins E6 and E7 have been widely employed in early immunotherapies, such as HPV therapeutic vaccines, with the goal of treating related illnesses and cancers by inducing a strong cellular immune response to eradicate infected cells.Moreover, the E2 protein shows great potential in the advancement of HPV therapeutic vaccines because of its crucial function in controlling viral gene expression and replication. This publication provides an overview of the HPV genome and emphasizes the crucial significance of the E2 protein in the life cycle of HPV. We provide an overview of the present state of E2-targeting techniques and examine their potential for use in cancer therapy.
... In conclusion, there has been limited research on nucleic acid vaccines in the context of HPV, and their efficacy in animal experiments has been inconsistent. At this time, mRNA vaccines are gaining traction in the context of the epidemic due to their high level of safety and effectiveness [28]. Thus, the various attributes, preventive strategies, and custom-made mRNA vaccines for HPV shall be investigated in this research endeavor. ...
... Nevertheless, an organism that has already acquired the virus cannot be effectively treated with the HPV prophylactic vaccination. Furthermore, several early genes (E1, E2, E4, E5) and late genes (L1, L2) have been lost as a result of the integration of the viral genome into the host genome, rendering preventative vaccinations useless against HPV-related precancerous lesions and malignancies [28]. ...
Cervical cancer (CC) and other malignant malignancies are acknowledged to be primarily caused by persistent human papillomavirus (HPV) infection. Historically, vaccinations against viruses that produce neutralizing antibodies unique to the virus have been an affordable way to manage viral diseases. CC risk is decreased, but not eliminated, by HPV vaccinations. Since vaccinations have been made available globally, almost 90% of HPV infections have been successfully avoided. On the lesions and diseases that are already present, however, no discernible treatment benefit has been shown. As a result, therapeutic vaccines that elicit immune responses mediated by cells are necessary for the treatment of established infections and cancers. mRNA vaccines possess remarkable potential in combating viral diseases and malignancy as a result of their superior industrial production, safety, and efficacy. Furthermore, considering the expeditiousness of production, the mRNA vaccine exhibits promise as a therapeutic approach targeting HPV. Given that the HPV-encoded early proteins, including oncoproteins E6 and E7, are consistently present in HPV-related cancers and pre-cancerous lesions and have crucial functions in the progression and persistence of HPV-related diseases, they serve as ideal targets for therapeutic HPV vaccines. The action mechanism of HPV and HPV-related cancer mRNA vaccines, their recent advancements in clinical trials, and the potential for their therapeutic applications are highlighted in this study, which also offers a quick summary of the present state of mRNA vaccines. Lastly, we highlight a few difficulties with mRNA HPV vaccination clinical practice and provide our thoughts on further advancements in this quickly changing sector. It is expected that mRNA vaccines will soon be produced quickly for clinical HPV prevention and treatment.
Graphical Abstract
... Since proper folding and glycosylation of viral surface antigens are essential for pathogenicity, stability, and immune recognition, it is vital to determine the effectiveness of VLP-based vaccines. Like in the case of vaccines for HPV, despite the excellent protective efficacy and potential to induce neutralizing antibodies against HPV, the approved VLP vaccines for HPV are not appropriate for treating people who are already infected because many early (E1, E2, E4, and E5) and late genes are lost as a result of the viral genome's integration into the host genome [188]. Fig. (5) depicts Virus-Like Particle-Based Anti-HER2 Breast Cancer Vaccine [189]. ...
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analyses the toxicity study of VLPs. It provides a comprehensive review, touching on ongoing clinical trials and significant patents that impact the environment
... (1) The early transcribed region (E region), consisting of 4500 base pairs, encodes eight early proteins (E1, E2, E3, E4, E5, E6, E7) (Su et al. 2010) with functions involved in replication, transcription, posttranslational regulation of viral DNA. (2) The late transcribed region (L region), consisting of 2500 base pairs, encodes 2 capsid proteins, namely, the major capsid protein L1 and the minor capsid protein L2 (Mo et al. 2022), which comprise the viral capsid and are associated with viral proliferation. (3) The nontranscribed region, also known as the long regulatory region (LCR), consists of 1000 base pairs and is located between E6 and L1. ...
In recent years, as cancer immunotherapeutic approaches continue to be intensively investigated, therapeutic cancer vaccine strategies have shown great advantages in targeting and mediating host immune defense responses. Development of therapeutic vaccines targeting specific cancer types is considered an effective and feasible way to facilitate clinical translation of immunotherapy for malignancies in the future, with significant benefits in reducing cancer incidence and mortality. Live vector vaccines, DNA vaccines, peptide vaccines, protein vaccines, and entire cell-based vaccines are examples of therapeutic vaccines. Among them, peptide vaccines, one of the main types of therapeutic vaccines, can be prepared in vitro by chemical synthesis techniques based on the amino acid sequence of a known or predicted segment of an antigenic epitope in the antigenic gene of a pathogen. Studies have shown that peptide vaccines are capable of generating specific cellular immune responses and modulating the tumor microenvironment while having no significant toxic side effects; thus, peptide-based vaccines are expected to be an effective treatment for malignant tumors. Therapeutic human papillomavirus (HPV) peptide vaccines, which are usually based on the HPV oncoproteins E6 and E7 as target antigens, are currently in the clinical research phase and have shown encouraging results. This article reviews the development of peptide vaccines, adjuvant selection and its mechanism of action, ideal target selection and research progress in targeting cervical cancer.
... In addition, these HPVs are divided into high-and lowrisk types based on their carcinogenic potential. Of which, at least 14 are classified as high-risk HPV types, such as HPV16, 18,31,33,35,39,45,51, 52, 56, 58, 59, 66 and 68. It is worth noting that almost all high-risk HPV types belong to the α genus, including α-5 (HPV51), α-6 (HPV56, 66), α-7 (HPV18, 39,45,59,68), and α-9 (HPV16, 31,33,35,52,58). ...
... Viral antigen peptides are presented at the cell surface through human leukocyte antigen (HLA) and are recognized by CD8 + cytotoxic T lymphocytes (CTLs) [15][16][17]. Therefore, E6 or E7 molecules are considered ideal targets for HPV therapeutic vaccines, inducing cell-mediated immunity by stimulating CTLs in immune response strategies or eliciting humoral immunity by activating B lymphocytes to produce specific antibodies [18,19]. ...
... The protocol for HPV genotyping has been described in detail in our previous studies [7,20]. Briefly, the kit uses a set of biotinylated amplimers and multiplex HPV genotyping methods with bead-based Luminex suspension array technology, which is able to simultaneously identify 14 high-risk HPV types including 16,18,31,33,35,39,45,51,52,56,58,59,66, 68 and β-globin gene (internal control). ...
Background
Alpha-papillomavirus 9 (α-9) is a member of the human papillomavirus (HPV) α genus, causing 75% invasive cervical cancers worldwide. The purpose of this study was to provide data for effective treatment of HPV-induced cervical lesions in Taizhou by analysing the genetic variation and antigenic epitopes of α-9 HPV E6 and E7.
Methods
Cervical exfoliated cells were collected for HPV genotyping. Positive samples of the α-9 HPV single type were selected for E6 and E7 gene sequencing. The obtained nucleotide sequences were translated into amino acid sequences (protein primary structure) using MEGA X, and positive selection sites of the amino acid sequences were evaluated using PAML. The secondary and tertiary structures of the E6 and E7 proteins were predicted using PSIPred, SWISS-MODEL, and PyMol. Potential T/B-cell epitopes were predicted by Industrial Engineering Database (IEDB).
Results
From 2012 to 2023, α-9 HPV accounted for 75.0% (7815/10423) of high-risk HPV-positive samples in Taizhou, both alone and in combination with other types. Among these, single-type-positive samples of α-9 HPV were selected, and the entire E6 and E7 genes were sequenced, including 298 HPV16, 149 HPV31, 185 HPV33, 123 HPV35, 325 HPV52, and 199 HPV58 samples. Compared with reference sequences, 34, 12, 10, 2, 17, and 17 nonsynonymous nucleotide mutations were detected in HPV16, 31, 33, 35, 52, and 58, respectively. Among all nonsynonymous nucleotide mutations, 19 positive selection sites were selected, which may have evolutionary significance in rendering α-9 HPV adaptive to its environment. Immunoinformatics predicted 57 potential linear and 59 conformational B-cell epitopes, many of which are also predicted as CTL epitopes.
Conclusion
The present study provides almost comprehensive data on the genetic variations, phylogenetics, positive selection sites, and antigenic epitopes of α-9 HPV E6 and E7 in Taizhou, China, which will be helpful for local HPV therapeutic vaccine development.
... Although a variety of therapeutic HPV vaccines are already under active development, such as VGX3100, a DNA vaccine targeting the HPV16 E6/E7 fusion protein, there is currently no successful vaccine on the market to eliminate established HPV infections [5]. Relying on traditional laboratory strategies, vaccine development is generally a time-consuming and costly endeavor [22]. ...
Human papillomavirus type 16 (HPV16) infection is responsible for more than 50% of global cervical cancer cases. The development of a vaccine based on cytotoxic T-lymphocyte (CTL) epitopes is a promising strategy for eliminating pre-existing HPV infections and treating patients with cervical cancer. In this study, an immunoinformatics approach was used to predict HLA-I-restricted CTL epitopes in HPV16 E5, E6, and E7 proteins, and a set of conserved CTL epitopes co-restricted by human/murine MHCs was screened and characterized, with the set containing three E5, four E6, and four E7 epitopes. Subsequently, the immunogenicity of the epitope combination was assessed in mice, and the anti-tumor effects of the multi-epitope peptide vaccine E5E6E7pep11 and the recombinant protein vaccine CTB-Epi11E567 were evaluated in the TC-1 mouse tumor model. The results demonstrated that mixed epitope peptides could induce antigen-specific IFN-γ secretion in mice. Prophylactic immunization with E5E6E7pep11 and CTB-Epi11E567 was found to provide 100% protection against tumor growth in mice. Moreover, both types of the multi-epitope vaccine significantly inhibited tumor growth and prolonged mouse survival. In conclusion, in this study, a multi-epitope vaccine targeting HPV16 E5, E6, and E7 proteins was successfully designed and evaluated, demonstrating potential immunogenicity and anti-tumor effects and providing a promising strategy for immunotherapy against HPV-associated tumors.
... While prophylactic HPV vaccines effectively prevent new infections if administered prior to exposure, they lack strong therapeutic efficacy against established lesions and HPV-associated malignancies [5][6][7]. Therefore, the development of therapeutic HPV vaccines has become a major focus, with the goal of clearing infections through robust activation of cellular immunity against infected cells expressing the viral oncoproteins [8]. ...
... Considering the significant global burden of HPV infections, it is crucial to focus on increasing the potency of therapeutic HPV vaccines [8]. Studies have shown that a recombinant protein alone may not be sufficient to generate a strong T cell response especially cytotoxic T cells without the presence of appropriate adjuvants. ...
... Therefore, in a vaccinated person, the HPV antibody levels persist longer and are more stable (Artemchuk et al., 2019). However, even after vaccination, these high antibody levels do not persist at this level forever, but the titers slowly decrease and there is also some notable individual variation (Mo et al., 2022). One cannot exclude the possibility that in people with allergies, the effectiveness and the duration of the effect of HPV vaccines may also be different, because of these differences related to antibody response to natural HPV infections. ...
Human papillomavirus (HPV) infections are common, transmitted by sexual and nonsexual routes. The present case-control setting was designed to examine potential cofactors associated with either persistently low or high HPV-antibody levels. The study subjects were from the Finnish HPV Family cohort of 329 baseline pregnant, non-HPV-vaccinated women, who were sampled for genital and oral HPV-DNA and HPV serology at baseline, and at 12, 24, and 36 months. Antibodies to the L1 major capsid protein of HPV 6, 11, 16, 18, and 45 were analyzed by multiplex HPV serology and HPV genotyping was performed. This study included 59 women, 23 women with persistently low (<200 median fluorescence intensity [MFI]) and 36 women with persistently high and always positive (>200 MFI) levels of these antibodies for all five HPV genotypes. Potential HPV-associated covariates were derived from detailed questionnaires. Only cofactors other than detected HPV genotype significantly impact on the levels of natural HPV antibodies. A higher number of past sexual partners or a history of diagnosed genital warts were significant covariates of high HPV antibody levels (p = 0.023 and p = 0.043, respectively). Of interest, women with a history of allergies presented with low levels of HPV antibodies (p = 0.03), potentially exposing these women to an increased risk of future HPV-related diseases that merit closer surveillance.
... [1][2][3] Prophylactic HPV vaccines were therefore developed to prevent these infections and their associated complications. The most widely used of all four commercially available HPV vaccines is Made of L1 capsid proteins resembling those found on the surface of HPV types 6,11,16,18,31,33,45,52, and 58, this noninfectious vaccine is considered safe and effective, with clinical trials reporting an efficacy of more than 90% at preventing HPV-related diseases. 5 However, this vaccine is not perfect for multiple reasons. ...
... Besides the requirement for three doses, the vaccine manufacturing remains costly, which may be prohibitive to low-income countries. 6 In addition, Gardasil®-9 cannot provide complete protection against all 14 high-risk HPV subtypes, as it only targets 9 of them. 6 Furthermore, the vaccine should be administered before HPV exposure implying that it cannot treat existing infections or established cervical cancer. ...
... 6 In addition, Gardasil®-9 cannot provide complete protection against all 14 high-risk HPV subtypes, as it only targets 9 of them. 6 Furthermore, the vaccine should be administered before HPV exposure implying that it cannot treat existing infections or established cervical cancer. 6 It is therefore recommended for children and young adults before becoming sexually active. ...
Worldwide prevalence of cervical cancer decreased significantly with the use of human papilloma virus (HPV)‐targeted prophylactic vaccines. However, these multivalent antiviral vaccines are inert against established tumors, which leave patients with surgical ablative options possibly resulting in long‐term reproductive complications and morbidity. In an attempt to bypass this unmet medical need, we designed a new E7 protein‐based vaccine formulation using Accum™, a technology platform designed to promote endosome‐to‐cytosol escape as a means to enhance protein accumulation in target cells. Prophylactic vaccination of immunocompetent mice using the Accum‐E7 vaccine (aE7) leads to complete protection from cervical cancer despite multiple challenges conducted with ascending C3.43 cellular doses (0.5‐, 1.0‐, and 2.0 × 10 ⁶ cells). Moreover, the humoral response induced by aE7 was higher in magnitude compared with naked E7 protein vaccination and displayed potent inhibitory effects on C3.43 proliferation in vitro. When administered therapeutically to animals with pre‐established C3.43 or Tal3 tumors, the vaccine‐induced response synergized with multiple immune checkpoint blockers (anti‐PD‐1, anti‐CTLA4, and anti‐CD47) to effectively control tumor growth. Mechanistically, the observed therapeutic effect requires cross‐presenting dendritic cells as well as CD8 T cells predominantly, with a non‐negligible role played by both CD4 ⁺ and CD19 ⁺ lymphocytes. good laboratory practice (GLP) studies revealed that aE7 is immunogenic and well tolerated by immunocompetent mice with no observed adverse effects despite the use of a fourfold exceeding dose. In a nutshell, aE7 represents an ideal vaccine candidate for further clinical development as it uses a single engineered protein capable of exhibiting both prophylactic and therapeutic activity.
... Once the virus integrates into the host genome, many early (E1, E2, E3, and E4) and late genes (L1 and L2) are lost, making preventive vaccination ineffective against HPV-related cancer such as NSCLC [64]. Moreover, considering that vaccines against HPV are available since 2006 (Gardasil ® 4, a quadrivalent vaccine available in 2006, Cervarix™, a bivalent vaccine, in 2007, and Gardasil ® 9, a nonavalent vaccine, in 2014 [65]), this may explain why a certain age-group of patients, already infected by high-risk HPV and at risk to develop HPV-related NSCLC, may not benefit from the positive effects of the vaccination campaign, in our opinion. Furthermore, the vaccination adhesion rate is not the same around the world due to the lack of government founding or political support. ...
... Available therapeutic vaccines against HPV are designed to target E6/7 oncoproteins and aim to boost cellular immunity and improve body's response to cancer treatments [65]. ...
... The main therapeutic vaccines are based on the following: live vectors (bacterial and viral), peptides, proteins, liposomes, nuclei acids (DNA and mRNA), and whole cells (dendritic cells or tumor cells). At present, though not yet available for clinical use, these vaccines are being rigorously tested in clinical trials for the treatment of cervical cancer, demonstrating safety and good tolerance levels [65]. ...
Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Notably, the incidence of lung cancer among never-smokers, predominantly women, has been rising in recent years. Among the various implicated risk factors, human papilloma virus (HPV) may play a role in the development of NSCLC in a certain subset of patients. The prevalence of high-risk HPV-DNA within human neoplastic lung cells varies across the world; however, the carcinogenetic role of HPV in NSCLC has not been completely understood. Bloodstream could be one of the routes of transmission from infected sites to the lungs, along with oral (through unprotected oral sex) and airborne transmission. Previous studies reported an elevated risk of NSCLC in patients with prior HPV-related tumors, such as cervical, laryngeal, or oropharyngeal cancer, with better prognosis for HPV-positive lung cancers compared to negative forms. On the other hand, 16% of NSCLC patients present circulating HPV-DNA in peripheral blood along with miRNAs expression. Typically, these patients have a poorly differentiated NSCLC, often diagnosed at an advanced stage. However, HPV-positive lung cancers seem to have a better response to target therapies (EGFR) and immune checkpoint inhibitors and show an increased sensitivity to platinum-based treatments. This review summarizes the current evidence regarding the role of HPV in NSCLC development, especially among patients with a history of HPV-related cancers. It also examines the diagnostic and prognostic significance of HPV, investigating new future perspectives to enhance cancer screening, diagnostic protocols, and the development of more targeted therapies tailored to specific cohorts of NSCLC patients with confirmed HPV infection.
