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HPV vaccination is an integral component of the World Health Organization's For novel (rather than next-in-class) drugs it was US$ 8 McGovern, B, a, 'Biotech stocks still gaining despite drug price regulation fears', Life Science Investing News website. The E6 protein from the high-risk HPV types represents an attractive target lesions and classified as “high-risk” for their ability to promote cancer. WWW DSEBD ORG IPO Therefore, we like ask your host multiple versions of is looking for for example specific desktop PC, with access your webspace. This is the dispute, claim or. The moment the installed programs and sum up the.

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Licensing of subunit vaccine VLP-based from the L1 protein plus adjuvant has been done already It is interesting to note that for judgment of subunit vaccines in future, the benchmark should be the HPV VLP vaccines The safety of DNA naked is relatively higher. They are stable and lucrative due to ease of production and they have got application in sustaining expression of antigen in the cells at greater level — Additionally the DNA vaccines do not evoke anti-DNA antibodies for which their repeated administration can be done Moreover, DNA vaccines offer several other benefits such as having inherent adjuvant properties that are lacking in a traditional peptide or attenuated-virus vaccines, and they are highly effective in treating HPV infections.

Safety, immunogenicity, and efficacy of this vaccine were evaluated in phase I clinical trial that recruited 18 women who were previously treated for cervical lesions. The intramuscular route into the deltoid muscle was adopted for administration of the vaccine. This was followed by electroporation , Finally, these genotype-specific vaccines are in phase I clinical trials and in demand to resolve HPV infections and neoplasias However, it must be kept in mind that due to shortage of specificity cell type DNA vaccines show low immunogenicity.

The DNA further lacks the capability intrinsic of amplification or nature of spreading to the cells in vivo in the surrounding. Nevertheless, there may be enhancement of potency of DNA vaccines used against cervical cancer induced by HPV by making DNA or the encoded antigen as the target to antigen presenting cells APCs and along with this, modification of the feature of APCs antigen expressing can boost immune response induced by the vaccine Furthermore, it is also interesting to note that on employing as immunotherapeutic interventions stand alone , the DNA-based anticancer vaccines are ineffective which can be explained by the establishment of immunosuppression either systemic or local , — Production of candidate HPV vaccines in plant systems is a promising approach.

These vaccines have been shown to be efficient and immunogenic, even though they are in the early stages of development , One such vaccine is produced in microalgae that have immunomodulatory properties , In one study, a plant codon-optimized version of the HPV L1 major capsid protein coding sequence was synthesized and transformed into tobacco and potato plants, resulting in immunologically functional VLPs.

The ingestion of this material activated anti-VLP immune responses in mice Moreover, the L1 major capsid protein gene of HPV, with or without nuclear localization signals, was integrated into the Nicotiana tabacum cv. Xanthi genome and the proteins were assembled into capsomeres to produce VLPs. Rabbits immunized with small doses of the transgenic plants showed weak anti-HPV L1 immune responses Xanthi was evaluated as candidates for a low-cost subunit vaccine.

Another study revealed that the HPV L1 protein expressed in tobacco chloroplasts induced the self-assembly of VLPs that were highly immunogenic in mice after intraperitoneal injection A circular dsDNA replicon was constructed by cloning a secreted embryonic alkaline phosphatase SEAP reporter gene and promoter into a geminivirus-derived plant expression vector that was co-transfected with vectors expressing L1 and L2 proteins into N.

This pseudovirus was neutralized by antisera against current and candidate HPV vaccines and represents a potential plant-derived vaccine Transplastomic plants have been used for expression of mutated L1 gene of HPV. This results in the sole production of capsomeres that are pentameric in nature , This promising approach has been used to produce HPV therapeutic vaccines.

In another study, a recombinant adenovirus encoding codon-optimized HPV E6 and E7 proteins linked to DCs induced protective immunity against challenge by TC-1 cancer cells in vivo For increasing the efficacy of DC-based vaccines not only antigens, but also novel strategies can also be incorporated into DCs.

For evaluation of the immunogenicity as well as safety of such vaccines DC-based , conduction of a dose escalation trial phase I has been done in cervical cancer stage IIa or Ib patients In case of recurrency of cervical cancer also, phase I clinical trial has been conducted An overview of advanced vaccine technologies available for prevention and control of HPV is depicted in Figure 2.

Figure 2. Advanced vaccine technologies available for prevention and control of HPV. These vaccines are all based on L1 structural proteins and are designed to inhibit HPV infections on first exposure. Gardasil and Cervarix both contain aluminum-based adjuvants and trigger strong protective immune responses. These two vaccines are beneficial in case of recurrent cervical cancer. They are also safe to used However, case reports from the U.

These vaccines do not induce sufficient cross-protection against non-vaccine types of HPV, as cross-protective immunity was shown to decline with the time , To date, only bivalent and quadrivalent vaccines have shown efficacy; but a newer nonavalent vaccine is also under trial to evaluate its anti-HPV potential This vaccine is licensed in many countries and has been shown to be immunogenic and safe and to inhibit infections with other HPV serotypes.

Elevated HPV antibodies have been found in all vaccinated persons, ranging from 9 to 45 years of age. Gardasil is administered in 0. Gardasil is also administered to boys and men 9 to 26 years of age for the control of anal cancers induced by HPV and 18, genital warts condyloma acuminata induced by HPV-6 and 11, dysplastic lesions induced by HPV-6, 11, 16, and 18, and grades 1, 2, and 3 AINs.

Currently, the duration of protection by Gardasil is considered 9 years Food and Drug Administration FDA for administration to females 10—25 years of age and has been approved in Europe and Australia The AS04 adjuvant in the vaccine induced increased expression of phenotypic maturation markers along with production of pro-inflammatory cytokines as well as cytotoxicity against tumor cells that are positive for HPV when interleukin IL dendritic cell DC are exposed to the vaccine The vaccine exerted immunity againsy HPV via a novel mode, i.

The vaccine is well tolerated, highly immunogenic, and capable of generating high titers of neutralizing antibody to HPV and 18 , A phase III double-blind, randomized controlled trial of the Cervarix vaccine showed an efficacy of Cervarix induces high antibody titers in comparison to natural infection. In women, there has been demonstration of an enhanced humoral immune response Currently, the duration of protection generated by Cervarix is estimated to be 9.

One study showed that HPV universal mass vaccination of people in the UK with Cervarix prevented females from developing cervical cancer and protected males from HPV and 18 infections Gardasil 9 Merck and Co. A phase III clinical trial in women aged 16—26 years demonstrated the efficacy of the vaccine in inhibiting HPV infection In another study, the safety and efficacy of the 9vHPV vaccine in males and females of 9—26 years were assessed across seven phase III clinical trials.

Increased use of the Gardasil 9 vaccine offers the hope of reducing neonatal transmission of HPV and decreasing the incidence and morbidity of recurrent respiratory laryngeal pappillomatosis RRP It is important to note that Gardasil-9 has not yet been approved for use in subjects who have received three doses of Gardasil or Cervarix Moreover, Gardasil-9 is expected to be more cost-effective than HPV vaccines currently in use , This requires adjuvantation with a Toll-like receptor 9 agonist, i.

This ultimately results in elimination of tumors that express HPV E7 , There are two GTL formulations, viz. The formulations have been tested in a clinical trial phase I and both are found to be safe and induced E7-specific CTL responses The safety as well as efficacy of the 9-valent vaccine providing protection against HPV types 6, 11, 16, 18, 31, 33, 45, 52, and 58 has been proven recently.

This will help further in reducing the incidences of infection due to HPV along with the cancer related to the virus. Moreover, a herd immunity is generated for providing indirect protection to individuals that are unvaccinated In boys as well as girls in the age group of 9—15 years, geometric mean titer GMT non-inferior is generated by 9-valent vaccine , , The vaccine efficacy is proven also in 16—26 years age group of males Safety of HPV vaccines was studied in both clinical trials before they were licensed and through post-licensure surveillance programmes — Like any other vaccines administered by intramuscular route, the HPV vaccinees may get inflammation pain, erythema, swelling and pruritus at the injection site.

The other side effects include pyrexia, headache, chill, weakness, malaise, myalgia, and joint pain. These HPV vaccine-related adverse effects AEs usually occur from day 1 to day 15 after vaccination and mostly are mild; the vaccines are believed to be well tolerated in girls, boys and young women A systemic review and meta-analysis of 11 studies did not find any evidence of increased demyelinating diseases after HPV vaccination However, at least 10 cases of neurological events were reported worldwide after HPV vaccination — A case-control epidemiological study of the vaccine adverse event reporting system VAERS database was undertaken to evaluate the risk for reported autoimmune adverse events following quadrivalent HPV vaccination Cases with gastroenteritis, rheumatoid artritis, thrombocytopenia, SLE, vasculitis, alopecia, CNS demyelinating conditions, ovarian damage, or irritable bowel syndrome were significantly more likely than control to have received quadrivalent HPV vaccine Safety of HPV vaccines in pregnancy or immediately pre-conceptually has been reviewed The HPV vaccination concerns were not only the maternal safety, but also and more on the teratogenicity and other fetal adverse events AEs following HPV vaccination, including spontaneous miscarriage, preterm birth, congenital malformations, and fetal decease.

For the fetal safety, none of the studies reported a significant increased rate of spontaneous abortion and other fetal outcomes in overall subgroup analyses e. The conclusion was the risk of AEs during pregnancy is unrelated to HPV vaccination before or during pregnancy Currently, there are no HPV therapies available.

Removal of the abnormal tissue by surgical operation is currently the recommended cure for cervical dysplasia. Removal of the affected tissue, e. Thus, development of non-invasive treatment therapies for HPV-induced cancers is needed, and therapeutic HPV vaccines are a promising strategy , One study demonstrated the therapeutic potential of curcumin in high-risk HPV-infected oral cancer cells.

The regulatory activity of the immune system is influenced by either chemotherapy or radiotherapy and in tumor models of mice in combination with vaccination can increase the efficacy of T cell-based immunity against HPV infection The lesions induced by HPV that are of lesser risk and shows infestation with regulatory T cells can be successfully treated by the use of cyclophosphamide at low dose thereby altering the local environment of the immune system.

In recent past, properly planned randomized trial has been introduced in patients with cervical cancer that shows metastasis to compare solely chemotherapy versus chemotherapy combined with a long synthetic peptide of HPV Adoptive cell therapy ACT or antibody based-therapeutic approaches have been proven to be successful for treatment of patients with melanoma , Earlier, it was evident from various sources that effector T cells that are specific to HPV can be obtained with consistency from cervical cancer patients.

By the significance of local microenvironment of HPV-induced lesions, there may be a shift in the local balance of immune effectors through treatment. Ultimately, the main goal is a suppression of regulatory T cells and a generation of an effective effector T cell microenvironment by identifying the combination that is optimum in enhanced trafficking of the immune effector cells and their efficiency at the affected site.

This ultimately provides scope to the immunity induced by vaccination for effective eradication of lesions that are persistent. In this regard, a good example is the use of imiquimod for priming the microenvironment to clear successfully HPV induced-vulvar lesions that are immune-mediated , For eliminating malignancies at an early Stage as well as for palliative treatment of cutaneous Tumors Along With Tumors of lungs and esophagus at late stage , photodynamic therapy PDT is an option already approved by Food and Drug Administration FDA — PDT is another approach used widely to treat various cancers.

Topical administration of PDT is considered to be most appropriate for cervical and vulval intraepithelial lesions Complete remission was observed after 1—4 treatments in This indicates the efficacy and safety of the PDT Hexaminolevulinate-mediated PDT has been found to be safe for treating cervical intraepithelial neoplasia CIN , Immune cell infiltration is a striking feature of photodynamic therapy, and it forms the basis for treatment of neoplasms that are HPV-associated; especially in the case of vulvar intraepithelial neoplasia VIN.

In chronic VIN, there is an alteration of the immunological balance if photodynamic therapy is employed. This leads to clearance of virus as well as lesions For treating cervical intraepithelial neoplasia, the efficacy along with safety and acceptability of cryotherapy is well documented. The cure rate with cryotherapy is very high In low as well as middle income countries, cryotherapy seems to be suitable. But the shortage of refrigerant gas creates hindrance in the application of cryotherapy for treating HPV , It is interesting to note that within a period of 3 months one-fourth of the infection due to high risk HPV hrHPV can be cleared by cryotherapy A few cytotoxic agents, including podophyllin or trichloroacetic acid, have been used topically to remove genital warts , while 5-fluorouracil has been used to a lesser extent because it elicits a strong inflammatory reaction Anti-cancer agents, i.

Some immunomodulators like imiquimod have records of safety and efficacy in treating HPV-caused genital warts Aspergillus, Gliocladium , and Penicillium species produce tricyclic alkaloid gliotoxin and effectively reduce the proliferation of HPV infected cells by inducing Bax, caspase-3, caspase-8, and caspase-9 and suppressing Bcl-2 Cis-retinoic acid is used as adjunctive therapy for treating HPV-induced lesion of the larynx; but due to efficacy issues, the drug had been discontinued in patients suffering from recurrent respiratory papillomatosis RRP At present, the most common drug used in adjuvant therapy of RRP is cidofovir.

Such concentration and dose regimen can be followed both in children as well as adults 65 , — Cidofovir can also be administered through inhalation, and in the near future such inhalation therapy may provide scope further to perform research on the clinical ground The expression of E6 as well as E7, has been reduced by cidofovir. This drug is also involved in the reduction of metastatic characteristics of tumor cells that are positive for HPV Ribavirin and acyclovir have also been used from time to time, but their clinical efficacy is questionable For reduction of the size of precancerous lesions of cervix PLC , an essential oil natural containing drug known as anti-viral 2 AV2 has been introduced.

The drug contains various organic compounds, viz. Due to the anti-viral activity, anti-proliferative nature and capability to generate host immune response, interferons are quiet noteworthy for treatment of HPV For adjuvant therapy against papillomatosis of larynx, interferons are among the earliest agents to be adopted. Similarly, pegylated interferon along with ribavirin is useful for treating disseminated HPV infection In the Chinese herbal medicine system, several plants with anti-HPV activity have been identified.

The Chinese medicine named Paiteling, containing folium, sophora, cnidium, gall, and javanica oil, inhibits HPV by destroying mitochondrial and other membranes to cause necrosis Carrageenan isolated from red algae, is known to bind HPV virions and inhibit post-attachment entry Carrageenan gel as a sexual lubricant has shown efficacy in preventing infection with an HPV pseudovirus Significant activities against HPV are shown by certain Chinese medicines traditional which are used for preventing as well as treating cancer in relation to HPV.

Youdujing is another medicine that is responsible for reversion of the cervical lesion function in patients having a greater risk of infection due to HPV — Inhibition of the risk of infection due to HPV can be done by Paiteling consisting of folium as well as javanica oil as essential components.

Moreover, this medicine also contains gall and cnidium as well as sophora all of which can ultimately cause the specific destruction of the mitochondria as well as other biological membranes ultimately resulting in degeneration of cells along with programmed cell death Treating with fraction of Pinellia extract causes reduction of the expression of mRNA and level of protein of HPV E6 whereas there is increase in the protein level as well as mRNA of p53 in cancer cells of the cervix.

The antitumor effect of the Pinellia extract fraction is thought to be due to the down-regulation of expression of HPV E6 gene and p53 gene upregulation , There is reduction of viral load along with improvement of cytological as well as pathological results in patients with infected cervix by application of Zibai gel Youdujing cream is clinically effective and for condyloma acuminatum it is a popular choice.

The amplification of HPV-DNA is inhibited as is evident by in vitro experiments to reveal the therapeutic efficacy of Youdujing in lesions of the genital tract — It can eradicate HPV from cultured cells. This drug has been used to treat several malignancies with few side effects, even with a transiently increased serum creatinine level.

In a patent application by Sulley and Squiquera , the enzyme is formulated with a vehicle that does not affect its activity and can be applied topically to genital warts for potential approval as a sexual lubricant. A close variant of ranpirnase has been granted with patent, which contained three mutations I11V, D20B, and SR was found non-toxic and well-tolerated in humans For cancer therapies based on RNAi, an ideal model system is the HPV-induced tumors because there is expression of E6 as well as E7 the oncogenes responsible for causing cervical cancer only on tumor cells As far as the RNAi therapy is concerned, any of the non-structural early genes or structural genes late genes of HPV can be targeted Subsequently, apoptosis is induced in cell lines of cervical cancer origin which are positive for HPV — Nine siRNAs designed by Chang et al.

In mice immunocompetent , there is development of tumors small sized when HPV E7 siRNAs are used for pre-treating tissue culture-1 cells of murine origin In Caski cells, there may be suppression of tumors if siRNAs are injected intratumorally However in the clinical setting, the success of RNAi-based therapies is limited It is further interesting to note that the cisplastin sensitivity of cancerous cells is increased when siRNA is used to target oncogenes of HPV as it leads to reactivation of p53 pathway For clearance or suppression of infection due to HPV immunologically in a normal manner, the usefulness of localized immunomodulation has already been proven.

The Aldara cream contains an active agent called imiquimod a Toll like receptor-7 agonist and this cream can be used topically. There is release of interferons type I along with proinflammatory cytokines due to activation of macrophages, dendritic cells along with keratinocytes by imiquimod , Imiquimod enhances immunity by activating a Th1 response Imiquimod causes side effects that include irritation at the site of application.

Green tea leaves contain an extract known as polyphenon E sinecatechins that causes immunomodulatory stimulation of the clearance of the virus Substances used in the cancer immunotherapy include non-specific immune stimulators, cytokines, monoclonal antibodies and adoptive or engineered autologous immune cells, mainly T cells. The same strategies canbe applied for treatment of HPV-induced cancers. Bacillus Calmette-Guerin BCG given via catheter into bladder with tumor mass in several cycles over several months reduces the otherwise high recurence and progression rates of bladder cancer by causing stimulation of effective immune response against cancer cells American Cancer Society.

Cytokines such as interferons enhance immune system aganst cancers. Therapeutic antibodies, nakedly or conjugated loaded with radioisotope, toxin, or drug, kill directly the cancer cells. Some antibodies recognizes molecule which is highly expressed on cancer cells such that the cells are better seen by the effector immune system for antibody-dependent cell-mediated cytotoxicity ADCC or complement-mediated cell lysis.

Anitbody binding to cell surface receptor can also cause inhibition of downstream cell signaling and prevent cancer cell shading of decoy to increase effectiveness of the host immune system. Monoclonal antibodies in the form of bispecific T cell engager BITE bind to cancer cell and effector T cell simultaneously and bring them into vinicity for increasing the effector cell effectiveness.

Antibodies to immune checkpoint molecules on effector T cells such as programmed cell death-1 PD1 and cytotoxic lymphocyte antigen-4 CTLA-4 restores the effector T cell activity which is suppressed by ligands highly expressed on the cancer cells leading consequently to not only cancer cell death, but also death of regulatory T cells in the tumor environment. These options canbe adopted for treatment of HPV-mediated cancers. Two monoclonal antibodies against the L1 protein of HPV have been produced for diagnostic and therapeutic purposes Cimetidine has been found to be useful for papillomas of conjunctiva in case of ocular surface infection due to HPV.

It augments the immune system by inhibition of T suppressor cell function and enhances delayed-type hypersensitivity DTH One interesting immunomodulator is dinitrochlorobenzene DNCB which may cause induction of DTH response; thereby causing regression of tumor. It has got direct application and is useful in case of surgical failure There is reduction in the rate of recurrence of HPV-induced tumors by use of radiation therapy.

Additionally chemotherapy eye drops are found to be efficacious in clinical various trials It is also interesting to find that there is effective inhibition of the growth of tumors expressing HPV E6 as well as E7 by cetuximab when grafting is done in severe combined immunodeficient SCID mice An overview on various therapeutic approaches available for treatment of HPV is depicted in Figure 3.

Moreover, the mind of researchers will be more innovative to combine therapeutic vaccines against HPV with radiation and chemotherapy for designing better control measures along with adopting advanced therapeutic approaches to counter HPV infections and the associated cancerous conditions. The advanced information on HPV vaccines and therapeutics presented in this review compilation along with carrying out more researches in futuristic prospects in the right directions would pave way to design and develop suitable prophylactic and therapeutic vaccines, drugs and treatment modalities delivering clinical outcomes in an improved manner and to combat HPV and its cancerous conditions effectively at global level.

This review highlights the advances in designing prophylactic and therapeutic vaccines as well as treatment regimens against human papilloma virus HPV to encourage the development of effective vaccines and therapies against this important disease. For prevention of HPV infection, the use of topical microbicides has been explored widely. For instance, like the use of carrageenan to prevent genital infection due to HPV, several patent applications for formulations are pending which comprise several natural components, such as Aloe vera , turmeric, Citrullus colocynthis , hard sea salt, myrrh, and garlic to treat HPV.

More clinical trials are needed to be conducted to explore the utility of topical microbicides. Studies through mathematical modeling have predicted that vaccination can maintain the antibody levels especially against HPV and 18 at a much higher level than the level reached due to natural infection for a period of minimum two decades after vaccination.

So it can eliminate the requirement of booster dose for a long period. Derivation of the consensus sequence for E6 and E7 genes, followed by codon optimization of these genes and their use as immunogen will pave the way for effective prophylactics. Three commercially available prophylactic vaccines show sufficient efficacy; however, attempts to develop next-generation vaccines that are inexpensive, effective, stable, and that show broad cross-neutralizing immunity are in progress.

Recombinant vaccine immunogens based on transgenic plants are an attractive and potentially affordable alternative to vaccines by injection. For example, edible plants can be grown locally and distributed easily without special training or equipment. There are studies to evaluate alternative approaches to deliver current vaccine in a safer and affordable way.

For example, microneedle deliveries of lyophilized HPV pseudovirions are thermostable and have been tested in a murine model. Also, acceptance of HPV vaccines has been hindered by many factors associated with place of residence, culture, and economics. Administration of these vaccines has been virtually non-existent in developing countries, mainly because of their extremely high costs and the technical challenges of vaccination, which require multiple doses over a 6-month period Also, refrigeration is needed during shipping and storage, introducing logistical difficulties in areas that lack adequate infrastructure.

Therefore, second-generation HPV vaccines are needed to reduce the costs of vaccine production and increase immunization schedule feasibility. This well-conserved linear neutralizing HPV epitope, which is located at the amino terminus of the L2 protein, may be exposed while the virus is on the basement membrane during infection. Attempts are being made to formulate more stable VLPs for immunization, and in fact, VLPs which are subjected to a disassembly and reassembly process have been found to be more stable, and the patent has been granted to the technology.

Another alternative antigen for use in HPV vaccines is the pentameric subunit or capsomere of the L1 protein that has essential neutralizing epitopes to induce an immune response to protect against HPV. Recombinant capsomeres expressed in E. Therefore, this approach will require further optimization for increased antibody titers.

However, the pentamers can be lyophilized for greater thermostability, suggesting the potential for formulations that can be shipped and stored without refrigeration Thus, use of capsomeres is an attractive and affordable option for developing second-generation HPV vaccines On the other hand, production of combined preventive-therapeutic antigens, focusing on fusions of L2 with E7, or both E6 and E7, is in the early stages, and their therapeutic effectiveness has not been demonstrated.

However, these therapeutic vaccines have shown some promise in some early clinical trials. Curcumin has also shown the potential to prevent HPV-associated oral cancers by selectively inhibiting E6 oncogene-mediated p53 degradation. Apart from vaccination, several therapeutic approaches are also becoming popular nowadays to counter HPV, and if given in conjugation with vaccines, the disease may be combated in a better way.

Among some treatment strategies, a photodynamic therapy which uses 5-aminolevulinic acid has been tested against HPV-6, 11, 16, and 18 and a higher clearance rate Topical application of few cytotoxic compounds including podophyllin, arsenic trioxide, carboplatin or trichloroacetic acid also has been suggested to remove genital warts. Interferons and immunomodulators like imiquimod also have been tested for their efficacy in removing genital warts and found useful.

Antivirals like cidofovir, ribavirin, and acyclovir have been tested against HPV, but cidofovir has been used widely, and since it can be administered through inhalation, additional benefits are present for using it in clinical applications. Ranpirnase RNase enzyme cleaves dsRNAs, and in the form of a topically applicable ointment, it has proved effective in treating anal warts. The treatment modules encompassing the use of antisense RNA are still in infancy but have shown some promise in therapeutic efficacy.

For HPV vaccines, pre-adolescent girls are the primary target but evaluation of the cost effectiveness of vaccination of other groups needs to be done. For certain candidate vaccines entering phase III trial, a viable vaccine prophylactic against a few types of HPV may become available in a less period of five years. For complementing conventional therapy designing of the therapeutic vaccines under investigation are done mostly. However, the extent of benefit or the cost at which such benefits can be offered to the women are not yet clear.

Clearing of the earliest stage of infection due to HPV by therapeutic vaccines is possible but is less developed. Certainly such vaccines hold promises to reduce the suffering as well as cost of treatment associated with disease of the cervix. For precancerous lesions, it is, however, crucial to continue the process of development of accurate screening as well as treatment plans and programs as there is forward movement of the process of vaccine development. No one can deny the fact that vaccination against HPV has proven to be a landmark in the history of prevention of cancer.

The incidence of HPV-induced cervical cancer will reduce drastically if adolescent girls are immunized, and this must be the priority not only in the industrialized world, but also in developing nations where it is sometimes impossible to detect the precancerous lesions at an early stage. It is however unfortunate that even in the developed nations of the Western world, the screening to detect cervical HPV-induced cancer is not performed on a regular basis. In this context, implementation of immunization of girls in every nation universally is of immense benefit.

To succeed in such aspect of prevention of HPV infection especially in women, convincing the parents as well as their daughters is a top priority. Similarly, vaccination in homosexual males is of utmost relevance concerning prevention of HPV in the community. But to assess the sexual orientation in every male is somewhat difficult for which universal male vaccination is essential. With the usage of efficient vaccination and application of potent therapeutics, the effective elimination of the disease is expected and in fact combinations of several therapies have helped people in getting rid of this ailment.

For all these reasons, it is necessary for the public health authorities to remain proactive and at the same time innovative methods will also be required for financing introduction of HPV vaccine and advancing the development of potent therapeutics. All the authors substantially contributed to the conception, design, analysis, and interpretation of data, checking and approving the final version of the manuscript, and agree to be accountable for its contents.

RK designed table. KK designed the figures. This compilation is a review article written, analyzed and designed by its authors and required no substantial funding to be stated. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Hospital transmission of HPV, especially to surgical staff, has been documented. HPV infection is limited to the basal cells of stratified epithelium , the only tissue in which they replicate. It is believed that involved antibodies play a major neutralizing role while the virions still reside on the basement membrane and cell surfaces.

HPV lesions are thought to arise from the proliferation of infected basal keratinocytes. Infection typically occurs when basal cells in the host are exposed to the infectious virus through a disturbed epithelial barrier as would occur during sexual intercourse or after minor skin abrasions. HPV infections have not been shown to be cytolytic ; rather, viral particles are released as a result of degeneration of desquamating cells.

HPV can survive for many months and at low temperatures without a host; therefore, an individual with plantar warts can spread the virus by walking barefoot. A sophisticated transcriptional cascade then occurs as the host keratinocyte begins to divide and become increasingly differentiated in the upper layers of the epithelium.

The phylogeny of the various strains of HPV generally reflects the migration patterns of Homo sapiens and suggests that HPV may have diversified along with the human population. Studies suggest that HPV evolved along five major branches that reflect the ethnicity of human hosts, and diversified along with the human population.

Thus, viral genome integration into host DNA genome increases E6 and E7 expression to promote cellular proliferation and the chance of malignancy. The degree to which E6 and E7 are expressed is correlated with the type of cervical lesion that can ultimately develop. E6 in association with host E6-associated protein, which has ubiquitin ligase activity, acts to ubiquitinate p53, leading to its proteosomal degradation.

E7 in oncogenic HPVs acts as the primary transforming protein. E7 competes for retinoblastoma protein pRb binding, freeing the transcription factor E2F to transactivate its targets, thus pushing the cell cycle forward. All HPV can induce transient proliferation, but only strains 16 and 18 can immortalize cell lines in vitro.

It has also been shown that HPV 16 and 18 cannot immortalize primary rat cells alone; there needs to be activation of the ras oncogene. Once an HPV virion invades a cell, an active infection occurs, and the virus can be transmitted. Several months to years may elapse before squamous intraepithelial lesions SIL develop and can be clinically detected. The time from active infection to clinically detectable disease may make it difficult for epidemiologists to establish which partner was the source of infection.

Most HPV infections are cleared up by most people without medical action or consequences. The table provides data for high-risk types i. Clearing an infection does not always create immunity if there is a new or continuing source of infection. Hernandez' study of 25 couples reports "A number of instances indicated apparent reinfection [from partner] after viral clearance. Over types of HPV have been identified, and they are designated by numbers.

Low-risk types cause warts and high-risk types can cause lesions or cancer. Guidelines from the American Cancer Society recommend different screening strategies for cervical cancer based on a woman's age, screening history, risk factors and choice of tests. Women aged 30—65 should preferably be tested every 5 years with both the HPV test and the Pap test.

In other age groups, a Pap test alone can suffice unless they have been diagnosed with atypical squamous cells of undetermined significance ASC-US. These tests can detect HPV infections before cell abnormalities are evident. However, the tests are approved by the FDA for only two indications: for follow-up testing of women who seem to have abnormal Pap test results and for cervical cancer screening in combination with a Pap test among women over age The diagnosis of oropharyngeal cancer occurs by biopsy of exfoliated cells or tissues.

Because HPV type 16 is the most common type found in oropharyngeal cancer, p16 immunohistochemistry is one test option used to determine if HPV is present, [] which can help determine course of treatment since tumors that are negative for p16 have better outcomes. There is not a wide range of tests available even though HPV is common; most studies of HPV used tools and custom analysis not available to the general public.

Others believe that reducing HPV infection in more men and women, even when it has no symptoms, is important herd immunity to prevent more cancers rather than just treating them. Studies have tested for and found HPV in men, including high-risk types i. In one study researchers sampled subjects' urethra, scrotum and penis. Studies like this led Giuliano to recommend sampling the glans, shaft and crease between them, along with the scrotum, since sampling the urethra or anus added very little to the diagnosis.

In one study the subjects were asked not to wash their genitals for 12 hours before sampling, including the urethra as well as the scrotum and the penis. One small study used wet cytobrushes, rather than wet the skin. It's unclear whether the emery paper collected the virions or simply loosened them for the swab to collect. Studies have found self-collection with emery paper and Dacron swabs as effective as collection done by a clinician, and sometimes more so, since patients were more willing than a clinician to scrape vigorously.

Several studies used cytobrushes to sample fingertips and under fingernails, without wetting the area or the brush. Other studies analyzed urine, semen, and blood and found varying amounts of HPV, [] but there is not a publicly available test for those yet. Although it is possible to test for HPV DNA in other kinds of infections, [] there are no FDA-approved tests for general screening in the United States [] or tests approved by the Canadian government, [] since the testing is inconclusive and considered medically unnecessary.

Genital warts are the only visible sign of low-risk genital HPV and can be identified with a visual check. These visible growths, however, are the result of non-carcinogenic HPV types. Five percent acetic acid vinegar is used to identify both warts and squamous intraepithelial neoplasia SIL lesions with limited success [ citation needed ] by causing abnormal tissue to appear white, but most doctors have found this technique helpful only in moist areas, such as the female genital tract.

Research into testing for HPV by antibody presence has been done. The approach is looking for an immune response in blood, which would contain antibodies for HPV if the patient is HPV positive. The HPV vaccines can prevent the most common types of infection. Cervical cancer screening , such as with the Papanicolaou test pap or looking at the cervix after using acetic acid , can detect early cancer or abnormal cells that may develop into cancer.

This allows for early treatment which results in better outcomes. Three vaccines are available to prevent infection by some HPV types: Gardasil , Gardasil 9 and Cervarix ; all three protect against initial infection with HPV types 16 and 18, which cause most of the HPV-associated cancer cases.

Gardasil is a recombinant quadrivalent vaccine, whereas Cervarix is bivalent, and is prepared from virus-like particles VLP of the L1 capsid protein. The vaccines provide little benefit to women already infected with HPV types 16 and The World Health Organization position paper on HPV vaccination clearly outlines appropriate, cost-effective strategies for using HPV vaccine in public sector programs.

There is high-certainty evidence that HPV vaccines protect against precancerous cervical lesions in young women, particularly those vaccinated aged 15 to The CDC recommends the vaccines be delivered in two shots at an interval of least 6 months for those aged 11—12, and three doses for those 13 and older. The vaccine does not have any therapeutic effect on existing HPV infections or cervical lesions.

Following studies suggesting that the vaccine is more effective in younger girls [] than in older teenagers, the United Kingdom, Switzerland, Mexico, the Netherlands and Quebec began offering the vaccine in a two-dose schedule for girls aged under 15 in Cervical cancer screening recommendations have not changed for females who receive HPV vaccine.

It remains a recommendation that women continue cervical screening, such as Pap smear testing, even after receiving the vaccine, since it does not prevent all types of cervical cancer. Both men and women are carriers of HPV. Duration of both vaccines' efficacy has been observed since they were first developed, and is expected to be longlasting. The Centers for Disease Control and Prevention says that male " condom use may reduce the risk for genital human papillomavirus HPV infection" but provides a lesser degree of protection compared with other sexual transmitted diseases "because HPV also may be transmitted by exposure to areas e.

The virus is unusually hardy, and is immune to most common disinfectants. It is the first virus ever shown to be resistant to inactivation by glutaraldehyde , which is among the most common strong disinfectants used in hospitals.

There is currently no specific treatment for HPV infection. Follow up care is usually recommended and practiced by many health clinics. In addition to the normal methods of phone calls and mail, text messaging and email can improve the number of people who return for care.

Like many diseases, HPV disproportionately affects low-income and resource-poor countries. Other factors that impact the global spread of disease are sexual behaviors including age of sexual debut, number of sexual partners, and ease of access to barrier contraception, all of which vary globally.

HPV is estimated to be the most common sexually transmitted infection in the United States. One study found that, during —, at any given time , This was higher than previous estimates; The prevalence for high-risk and low-risk types is roughly similar over time. Human papillomavirus is not included among the diseases that are typically reportable to the CDC as of On average cases of HPV-associated cancers were diagnosed per year in Ireland during the period to Genital warts are the second most common STI in Ireland.

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