Licensed Human Papillomavirus Vaccines Research Articles

Evaluation of HPV infection and presence of licensed HPV vaccine genotypes among genital warts in Foshan, China.

This study aimed to evaluate the prevalence of human papillomavirus (HPV) infection and presence of licensed HPV vaccine genotypes among patients with genital warts in Foshan, China from 2015 to 2022, to provide useful references for the detection, prevention and control of genital warts in Foshan. The present study retrospectively analyzed the HPV detection rates in patients with genital warts. A total of 1,625 patients were seen at the Second People's Hospital of Foshan, Guangdong Province, China, from 2015 to 2022. Samples were collected from various lesions and genotyped for 21 genotypes of HPV by infusion hybridization. The classification principle of HPV genotypes in this study: (1) Based on the relationship between HPV and carcinogenicity; (2) Based on the number of HPV genotypes infected; (3) Based on the HPV genotypes of licensed HPV vaccines. The detection rate of any HPV in patients with genital warts was 80.37% (1,306/1,625). The detection rates of HPV for low-risk infection, co-infection and high-risk infection were 49.48% (804/1,625), 24.92% (405/1,625) and 5.97% (97/1,625), respectively. Single infection was the predominant type (51.94%, 844/1625). HPV-6 and HPV-11 were the predominant types of single infection; HPV-6 and HPV-52 were the predominant types of paired combinations of multiple infection. 82.22% (1,336/1,625) of the cases had an age distribution of ≤ 24, 25-34, and 35-44. The distribution of some HPV genotypes had age specificity, annual specificity and gender specificity. The genotype detection rates of 2v, 4v and 9v showed a decreasing trend with ages (all P < 0.05). The genotype detection rates of 4v and 9v showed a decreasing trend over the 8-year period (both P < 0.05). The genotype detection rates of 4v and 9v in the male group were higher than those in the female group (both P < 0.05). The genotype detection rate of 9v was significantly higher than that of 2v and 4v in the female group (both P < 0.05). Our study demonstrated that low-risk infection and single infection were the main types of HPV infection in patients with genital warts, mainly among young patients. Our study provides epidemiological data for the detection, prevention and control of genital warts in China.

OAE-based data mining and modeling analysis of adverse events associated with three licensed HPV vaccines

PurposeThree licensed human papillomavirus (HPV) vaccines (Cervarix, Gardasil, and Gardasil 9) have been effectively used to prevent infection with oncogenic HPV types; however, many adverse events (AEs) have also been reported following their vaccinations. We assessed AE profiles after receiving the HPV vaccines based on the reported data from Vaccine Adverse Event Reporting System (VAERS). MethodsThe AE data associated with Cervarix, Gardasil, and Gardasil 9 were retrieved from VAERS database respectively. The combinatorial biomedical statistical methods were used to identify the statistically significant AEs. The Gamma-Poisson Shrinker (GPS) model with gender/age stratification was applied to ascertain the serious adverse events (SAEs) related to the three licensed HPV vaccines. The AE profiles were classified and represented by the Ontology of Adverse Events (OAE) for further analysis. ResultsAs of July 31, 2020, VAERS recorded 3,112, 31,606, and 6,872 AE case reports for Cervarix, Gardasil, and Gardasil 9, respectively. Our Frequentist statistical methods identified 135 Cervarix-enriched AEs, 55 Gardasil-enriched AEs, and 17 Gardasil 9-enriched AEs. Based on the OAE hierarchical classification, these AEs were clustered in the AEs related to behavioral and neurological conditions, immune system, nervous system, and reproductive system. Combined with GPS modeling, 46 unique statistically significant SAEs were founded to be associated with at least one of the three vaccines. ConclusionsOur study led to the better understanding of the AEs associated with the licensed HPV vaccines. The hypotheses on the cause and effect relationships between the HPV vaccination and specific AEs deserve further epidemiological investigations as well as clinical trial studies.

Human Papillomavirus Vaccine to End Oropharyngeal Cancer. A Systematic Review and Meta-Analysis.

Oropharyngeal cancer (OPC) is currently the most frequent human papillomavirus (HPV)-related malignancy in high-income countries. Oral HPV16 infection is the cause of HPV-related OPC in more than 90% of cases and is primarily (90%) linked to oral sex. This systematic review and meta-analysis aimed at comparing the prevalence of oral vaccine-type HPV infection in individuals vaccinated with HPV vaccines and unvaccinated controls. Three databases (MEDLINE, ScienceDirect, and the Cochrane Library), as well as other sources, were searched by 2 independent reviewers. Controlled studies testing the efficacy or effectiveness of licensed HPV vaccines were included. The primary end point was multiple oral HPV infections in one individual with low-risk and high-risk types. Secondary end point was the number of oral HPV16 infections. Six studies-2 randomized controlled trials and 4 cross-sectional studies-with a total of 15,240 participants were included in a meta-analysis, which showed that vaccinated individuals were 46% (risk ratio, 0.54; 95% confidence interval, 0.32-0.91) less likely to develop oral vaccine-type HPV infection (P = 0.02). A second meta-analysis of 4 studies (1 randomized controlled trial and 3 cross-sectional studies) and 13.285 participants showed 80% (risk ratio, 0.20; 95% confidence interval, 0.09-0.43) less likelihood of oral HPV16 infection (P < 0.0001). This study suggests that HPV vaccines can protect against oral vaccine-type HPV infection including high-risk HPV16 infection, thus reducing the incidence of HPV-related OPC. Vaccination against HPV, especially in males, who are predominantly affected by HPV-related OPC, could result in the prevention of this disease.

Immunogenicity of Alternative Dosing Schedules for HPV Vaccines among Adolescent Girls and Young Women: A Systematic Review and Meta-Analysis.

Alternative dosing schedules for licensed human papilloma virus (HPV) vaccines, particularly single dose and extended intervals between doses (>12 months), are being considered to address vaccine shortages and improve operational flexibility. We searched PUBMED/MEDLINE for publications reporting immunogenicity data following administration of one of the licensed HPV vaccines (2vHPV, 4vHPV, and 9vHPV) to females aged 9–26 years. We conducted non-inferiority analyses comparing alternative to standard schedules using mixed effects meta-regression controlling for baseline HPV status and disaggregated by vaccine, subtype, time point, and age group (9–14 and 15–26 years). Non-inferiority was defined as the lower bound of the 95% confidence interval (CI) for the geometric mean titer (GMT) ratio being greater than 0.5. Our search returned 2464 studies, of which 23 were included in data analyses. When evaluated against standard schedules, although robust immunogenicity was demonstrated across all multi-dose groups, non-inferiority of extended interval dosing was mixed across vaccines, subtypes, and time points. Single dose did not meet the criteria for non-inferiority in any comparisons. Sparse data limited the number of possible comparisons, and further research is warranted.

Abstract LB-200: A cGMP-grade chimeric papillomavirus candidate vaccine (HPV16 RG1-VLP) confers long term cross-protection compared to a nonavalent hpv vaccine in a pre-clinical papillomavirus animal model

Abstract Background: The National Cancer Institute (NCI) PREVENT Cancer Program (PREVENT) is a peer-reviewed R&amp;D pipeline with the core emphasis on preclinical development and clinical translation of novel cancer preventive interventions. One of the latest PREVENT-supported projects include cGMP production and IND enabling studies of a broad spectrum experimental human papillomavirus (HPV) vaccine- HPV16 RG1-VLP. This monovalent chimeric virus-like particle (VLP) displays 360 copies of the highly conserved epitope RG1 (aa 17-36 of minor capsid protein HPV16 L2) in the DE loop of HPV16L1 VLP backbone, and is capable of eliciting broadly neutralizing antibodies that target several clinically relevant HPV genotypes. RG-1 induced cross-neutralizing titers are typically lower than anti-L1 antibodies generated by currently licensed HPV vaccines. Hence, durability of protection has been cited as a cause of concern. Here, using engineering-run cGMP grade HPV16-RG1VLPs formulated with alhdyrogel®, the durability of protection 6 month post-vaccination of HPV16 RG1-VLPs against Gardasil-9®, a licensed HPV vaccine was evaluated using an established papillomavirus disease model. Methods: New Zealand white rabbits (n=15 per treatment group) were administered three intra-muscular vaccinations of HPV16-RG1 (80 µg), human doses of Gardasil-9®, or no vaccine (adjuvant only). Following vaccination, in vivo protection was assessed against 8 high-risk oncogenic HPVs utilizing methods from an established cottontail rabbit papillomavirus (CRPV) disease model. Within each treatment group, 5 rabbits were challenged two weeks post-final vaccination (at peak serum ELISA titer), while another 5 were challenged six months post-final vaccination to assess durability of protection. The remainder 5 rabbits will be challenged one year post final vaccination. Results: During the peak-titer period, rabbits vaccinated with monovalent HPV16-RG1VLP were protected from disease development, which was comparable to the protection afforded by Gardasil-9®. Six months after final vaccination, despite lower serum titers, HPV16-RG1VLP immunized rabbits were still protected from disease development with vaccine efficacy comparable to that of Gardasil-9®. And, in some instances, HPV16-RG1VLP vaccine demonstrated a superior cross-protection. Conclusions: Even as a monovalent formulation, HPV16 RG1 VLP vaccination was able to provide comparable protection against a number of high-risk oncogenic HPV types, including types not covered by Gardasil-9®, even after six months post-vaccination. As a monovalent VLP, HPV16 RG1 VLP holds promise as a broad-spectrum preventative vaccine candidate that could potentially provide broader protection at lower production costs. Studies evaluating protection one-year-post vaccination is currently in progress. Citation Format: Jiafen Hu, Karla Balogh, Ken Matsui, Huimin Tan, Pola Olczak, George Buchman, Brian Howard, Jonathan White, Michelle Kennedy, Shizuko Sei, Elizabeth Glaze, Sarah Brendle, Christina Schellenbacher, Reinhard Kirnbauer, Richard Roden, Robert Shoemaker, Neil Christensen, Joshua Weiyuan Wang. A cGMP-grade chimeric papillomavirus candidate vaccine (HPV16 RG1-VLP) confers long term cross-protection compared to a nonavalent hpv vaccine in a pre-clinical papillomavirus animal model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-200.

Effect of Human Papillomavirus Vaccine to Interrupt Recurrence of Vulvar and Anal Neoplasia (VIVA)

Human papillomavirus (HPV), particularly HPV type 16, causes most anal and vulvar high-grade squamous intraepithelial lesions (HSIL), which are precursors to cancer. After initial treatment of HSIL, more than 30% of patients will have disease recurrence, with even higher recurrence among HIV-positive individuals and men who have sex with men. Recurrences can be debilitating and lead to significant morbidity and medical expense. Observational studies suggest a possible therapeutic benefit of the licensed HPV vaccines in reducing recurrent lesions in previously infected persons. To test whether the licensed prophylactic HPV vaccine (Gardasil-9) can reduce the risk of HSIL recurrence by 50% in previously unvaccinated individuals recently treated for anal or vulvar HSIL. This is a trial protocol for a randomized, double-blind, placebo-controlled, proof-of-concept clinical trial. Eligible participants are aged 27 to 69 at study start and have not received prior HPV vaccination, have had anal or vulvar HSIL diagnosed on or after January 1, 2014, and have no evidence of HSIL recurrence at screening. Persons infected with HIV are eligible for the study provided they are receiving antiretroviral therapy. Target enrollment is 345 individuals. The primary outcome is time to histopathologically confirmed recurrence of HSIL. Differences in the risk for recurrence of HSIL will be evaluated using Cox proportional hazard models. Additional analyses include (1) frequency of HSIL recurrence; (2) role of HPV antibodies in deterring recurrence; (3) role of HPV persistence in recurrence, as measured by HPV genotype or HPV-16 variant lineage determined using swab samples collected at months 0, 18, and 36; and (4) incidence of adverse events. The study will be conducted at the University of Washington Virology Research Clinic from 2017 through 2022. Participants will be followed up for up to 36 months in the clinic, and up to 42 months by telephone. Management of persistent or rapidly recurring anogenital HSIL remains challenging. Results from this study will provide evidence on whether incorporating the nonavalent HPV vaccine into routine care can decrease recurrence of anal and vulvar HSIL. ClinicalTrials.gov identifier: NCT03051516.

PF-1 The HPV serology standardization initiative: Development of critical assay reagents

Introduction: Human Papillomavirus (HPV) has been linked to numerous cancers including cervical, oropharyngeal, and additional anogenital cancers, and is believed to be associated with approximately 5% of cancers world-wide. Current licensed vaccines have shown great promise in being able to reduce persistent infection and HPV-linked cancers, and are based on the use of virus-like particles (VLPs) which are comprised of type-specific HPV L1-expressing empty capsids. While commendable strides have been made within the HPV research community to focus on understanding how the HPV vaccines work and eradicating this cancer-causing virus, there is still a lack of assay standards, reference reagents and testing guidelines for HPV serology assays. Our laboratory is leading an international HPV Serology standardization initiative to develop a series of standards, multiplex immunoassays, and procedures in order to harmonize evaluation of antibody responses to currently available vaccines in the context of HPV vaccine trials. To reduce costs associated with serology testing, we investigated performance of alternative transfection reagents typically used in critical reagent production. Discussion: Currently licensed HPV vaccines are based on HPV L1 virus-like particles. HPV VLPs are used extensively in HPV research and as critical reagents in the assessment of HPV-induced immune responses. There are a variety of available methods to create HPV VLPs for use in the research setting; however, transfection methods are expensive and time-consuming. Our team is currently producing HPV VLPs for the 9 HPV types included in the currently administered vaccines to be used as assay reference reagents by the serology scientific community to aid in standardization and harmonization of HPV serology testing in vaccine trials. With the aim of reducing costs and saving time in VLP production while maintaining robust HPV particle assembly, we have investigated different transfection approaches in a mammalian-based HPV L1L2 VLP production system. Aspects of consideration include transfection reagents and efficiency, cell viability, materials, and method optimization in the context of final VLP output via HEK293TT transfection with pHPVL1L2. The VLPs are subsequently confirmed by electron microscopy and dynamic light scattering as well as epitope confirmation assays. Results demonstrate that cost-efficient reagents such as PEI and Transporter5 are as efficient as Lipofectamine in producing particles. Similarly, adaptation of various transfection methods and use of large-scale production techniques lead to faster production time with similar output. Conclusions: The development of HPV L1-based standardized reagents and immunoassays allow research laboratories to better evaluate and compare the vaccine-induced immune response across clinical trials. VLPs, the cornerstone of the current vaccine, are used to develop immunoassays and standards by which researchers can gauge the immune response. By reducing costs and time to produce VLPs, it becomes more feasible to create large production sets of VLPs in less time and with less financial burden for immune monitoring laboratories. Funded by NCI Contract No. HHSN261200800001E.

Burden of Human Papillomavirus (HPV)-Related Cancers Attributable to HPVs 6/11/16/18/31/33/45/52 and 58.

BackgroundMany countries, mainly high- and upper-middle income, have implemented human papillomavirus (HPV) vaccination programs, with 47 million women receiving the full course of vaccine (three doses) in 2014. To evaluate the potential impact of HPV vaccines in the reduction of HPV-related disease, we aimed to estimate the HPV type distribution and burden of anogenital and head and neck cancers attributable to HPV types (HPVs 16/18/31/33/45/52/58/6/11) included in currently licensed HPV vaccines.MethodsIn all, 18 247 formalin-fixed paraffin-embedded specimens were retrieved from 50 countries. HPV DNA detection and typing were performed with the SPF-10 PCR/DEIA/LiPA25 system. With the exception of cervical cancer, HPV DNA-positive samples were additionally subjected to HPV E6*I mRNA detection and/or p16INK4a immunohistochemistry. For cervical cancer, estimates were based on HPV DNA, whereas for other sites, estimates were based on HPV DNA, E6*I mRNA, and p16INK4a biomarkers.ResultsThe addition of HPVs 31/33/45/52/58 to HPVs 16/18/6/11 in the nonavalent HPV vaccine could prevent almost 90% of cervical cancer cases worldwide. For other sites, the nonavalent HPV vaccine could prevent 22.8% of vulvar, 24.5% of penile, 60.7% of vaginal, 79.0% of anal cancers, 21.3% of oropharyngeal, 4.0% of oral cavity, and 2.7% of laryngeal cancer cases.ConclusionsOur estimations suggest a potential impact of the nonavalent HPV vaccine in reducing around 90% of cervical cancer cases and a global reduction of 50% of all the cases at HPV-related cancer sites.

Characterization of an Escherichia coli-derived human papillomavirus type 16 and 18 bivalent vaccine.

Human papillomavirus (HPV) types 16 and 18 account for approximately 70% of cervical cancer worldwide. Neutralizing HPV prophylactic vaccines offer significant benefit, as they block HPV infection and prevent subsequent disease. However, the three licensed HPV vaccines that cover these two genotypes were produced in eukaryotic cells, which is expensive, particularly for low-income countries where HPV is highest. Here, we report a new HPV16 and -18 bivalent candidate vaccine produced from Escherichia coli. We used two strategies of N-terminal truncation of HPV L1 proteins and soluble non-fusion expression to generate HPV16 and HPV18 L1-only virus-like particles (VLPs) in a scalable process. Through comprehensive characterization of the bivalent candidate vaccine, we confirm lot consistency in a pilot scale-up of 30L, 100L and 500L. Using cryo-EM 3D reconstruction, we found that HPV16 and -18VLPs present in a T=7 icosahedral arrangement, similar in shape and size to that of the native virions. This HPV16/18 bivalent vaccine shares comparable immunogenicity with the licensed vaccines. Overall, we show that the production of a HPV16/18 bivalent vaccine from an E. coli expression system is robust and scalable, with potentially good accessibility worldwide as a population-based immunization strategy.

Chimeric L2-Based Virus-Like Particle (VLP) Vaccines Targeting Cutaneous Human Papillomaviruses (HPV)

Common cutaneous human papillomavirus (HPV) types induce skin warts, whereas species beta HPV are implicated, together with UV-radiation, in the development of non-melanoma skin cancer (NMSC) in immunosuppressed patients. Licensed HPV vaccines contain virus-like particles (VLP) self-assembled from L1 major capsid proteins that provide type-restricted protection against mucosal HPV infections causing cervical and other ano-genital and oro-pharyngeal carcinomas and warts (condylomas), but do not target heterologous HPV. Experimental papillomavirus vaccines have been designed based on L2 minor capsid proteins that contain type-common neutralization epitopes, to broaden protection to heterologous mucosal and cutaneous HPV types. Repetitive display of the HPV16 L2 cross-neutralization epitope RG1 (amino acids (aa) 17–36) on the surface of HPV16 L1 VLP has greatly enhanced immunogenicity of the L2 peptide. To more directly target cutaneous HPV, L1 fusion proteins were designed that incorporate the RG1 homolog of beta HPV17, the beta HPV5 L2 peptide aa53-72, or the common cutaneous HPV4 RG1 homolog, inserted into DE surface loops of HPV1, 5, 16 or 18 L1 VLP scaffolds. Baculovirus expressed chimeric proteins self-assembled into VLP and VLP-raised NZW rabbit immune sera were evaluated by ELISA and L1- and L2-based pseudovirion (PsV) neutralizing assays, including 12 novel beta PsV types. Chimeric VLP displaying the HPV17 RG1 epitope, but not the HPV5L2 aa53-72 epitope, induced cross-neutralizing humoral immune responses to beta HPV. In vivo cross-protection was evaluated by passive serum transfer in a murine PsV challenge model. Immune sera to HPV16L1-17RG1 VLP (cross-) protected against beta HPV5/20/24/38/96/16 (but not type 76), while antisera to HPV5L1-17RG1 VLP cross-protected against HPV20/24/96 only, and sera to HPV1L1-4RG1 VLP cross-protected against HPV4 challenge. In conclusion, RG1-based VLP are promising next generation vaccine candidates to target cutaneous HPV infections.

Safety and immunogenicity of a quadrivalent human papillomavirus vaccine in HIV-infected and HIV-negative adolescents and young adults

Human papillomavirus (HPV) infection is highly prevalent and can lead to cancer; the development of safe and efficacious vaccines for HPV is a major public health concern. The two licensed HPV vaccines contain recombinant virus-like particles of HPV 16 and 18; one of such vaccines also protects against HPV types 6 and 11 which cause genital warts. We determined safety and immunogenicity of quadrivalent HPV vaccine in HIV-infected and HIV-negative adolescents and young adults, aged 13–27 years. The seroconversion rate, assessed by antibody titers, 1 month after the administration of the third vaccine dose was 0.85 (95% CI 0.75–0.95) in the HIV-infected group and 0.91 (0.83–0.99) in the HIV-negative subjects (p=0.52). The vaccine was generally safe and well tolerated; the most common side effect was local pain and the most frequent systemic side effect was headache. This is the first report on response to HPV vaccination in both female and male HIV-infected adolescents and young adults and highlights that this population may benefit from HPV immunoprophylaxis. Further studies are needed to examine the long term efficacy of this vaccine in HIV-infected individuals.

Young Gay Men and the Quadrivalent Human Papillomavirus Vaccine--Much to Gain (and Lose)

Human papillomavirus (HPV) is the world’s most common viral sexually transmitted infection [1, 2]. Approximately 40 HPV types infect anogenital squamous epithelium and can be broadly divided into low-risk (eg, HPV 6, 11) and high-risk (eg, HPV 16, 18) phenotypes based on their historical association with cervical cancer. This relationship also holds true for other anogenital (anal, vulvar, vaginal) and oropharyngeal malignancies. Although most HPV infections are asymptomatic, when symptoms do occur, they often reflect the presence of warts, dysplasia, or frank malignancy. Anogenital HPV infection is mostly transient in both sexes, with persistent high-risk HPV infection associated with the development of squamous-cell cancers [3, 4]. HPV prevalence data vary by gender, with men being more likely to have higher-level detection over a wider age range than women, whose prevalence decreases from a peak in their early 20s [3, 5] However, it is men who have sex with men (MSM) who have the highest rates of anogenital HPV infection and also HPV-associated malignancy, particularly HPV 16–associated anal cancer [6, 7]. HPV vaccination has been shown to be safe and effective in preventing the acquisition of anogenital HPV infection and the development of dysplasia [8–10]. The challenge ahead is to ensure that vaccinations are available to those at risk in a manner that optimizes their efficacy. There are 2 licensed HPV vaccines: a bivalent vaccine directed against HPV 16 and 18 (Cervarix, GlaxoSmithKline, London, UK) licensed for females aged 9–25 years, and a quadrivalent HPV vaccine (qHPV) directed against HPV 6, 11, 16, and 18 (Gardasil, Merck, Whitehouse Station, NJ) licensed for females and males ages 9–26 years. Both vaccines’ indications include prevention of warts and female genital dysplasia/cancer, with qHPV also indicated for anal dysplasia/ cancer. These prophylactic vaccines induce high-titer HPV antibody levels with good efficacy and an excellent safety profile [11, 12]. In this issue of The Journal of Infectious Diseases, Zou and colleagues examined acquisition of anogenital HPV in a population of MSM. They enrolled men between the ages of 16 and 20 years who self-identified as same-sex attracted. Thus, they were able to assess incident HPV infection in MSM with limited sexual experience who might benefit from HPV vaccination if they had the same access to HPV vaccines as adolescent girls. Following recruitment from a variety of venues, participants were seen for assessments at baseline and then at 3, 6, and 12 months. At each visit, participants had a clinical exam, completed a sexual experience questionnaire, had a blood sample drawn for HPV serology, and swabs taken from penile, perianal, and intra-anal sites. An oral saline gargle was also collected. All these samples were tested for HPV DNA by polymerase chain reaction. Additionally, participants were tested for gonorrhea, chlamydia, syphilis, and HIV at each visit. At the 12-month visit, participants were offered the qHPV. The median age of study participants was 19 years and the majority had engaged in both receptive and insertive anal intercourse. Thirty-nine percent of participants had at least 1 of 37 HPV types tested for at the anatomical sites sampled, and 23% had at least 1 qHPV type. Overall, at least 1 high-risk HPV was detected in 31% of participants. In participants with 0 to ≥4 receptive and insertive anal-sex partners, the respective proportion of anal (P < .001) and penile (P < .014) HPV increased significantly. This trend also reached significance for detection of anal HPV 16. In another study conducted in a slightly older age group of 94 MSM with a mean age of 21 years, 70% had any of the 37 HPV types tested for, and 37% had HPV 16 or 18. The incidence of anal HPV infection in this group was 38.5 and 15.3 per 1000 Received and accepted 4 November 2013. Correspondence: Ross D. Cranston, MB ChB, MD, FRCP, University of Pittsburgh, 3520 Fifth Ave, Keystone Bldg, Ste 510, Pittsburgh, PA 15213 (rdc27@pitt.edu). The Journal of Infectious Diseases © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. DOI: 10.1093/infdis/jit627

Clinical trials of human papillomavirus vaccines and beyond

Human papillomavirus (HPV) is the most common sexually transmitted infectious agent; its 14 oncogenic types are causally associated with 5-10% of all cancers. The major structural HPV protein self-assembles into immunogenic virus-like particles. Two licensed HPV vaccines--the bivalent vaccine comprising HPV types 16 and 18, and the quadrivalent vaccine comprising HPV types 6, 11, 16 and 18--have proven to be safe and efficacious against 6-month-persistent cervical infections of HPV16 and HPV18 and associated precancerous lesions, and both have efficacies of 90-100%. Among baseline HPV-negative adolescent females, vaccine efficacies against the immediate precursor of cervical cancer (intraepithelial neoplasia grade 3) irrespective of HPV type are 93.2% and 43.0% for the bivalent and quadrivalent vaccines, respectively. The quadrivalent vaccine is efficacious (>75% vaccine efficacy) against any of the more-severe precursors of vulval, vaginal and anal cancers. A strong increase in vaccine efficacy with increasing severity of the precancerous lesion is explained by accumulation of the most-oncogenic HPV types 16 and 18 in these lesions. Therefore, prophylactic HPV vaccination will exceed the best results from screening for cancer. With the extremely efficacious prophylactic HPV vaccines, the focus of organized intervention (vaccination and screening) programmes should, however, shift from reducing the HPV disease burden to controlling the prevalence of oncogenic HPV (and nononcogenic HPV) types. Eradication of the major oncogenic HPV types should be pursued.

Safety of Human Papillomavirus Vaccines: A Review

Vaccination to prevent human papillomavirus (HPV)-related infection leading to cancer, particularly cervical cancer, is a major public health breakthrough. There are currently two licensed HPV vaccines, both of which contain recombinant virus-like particles of HPV types 16 and 18 (which account for approximately 70 % of cervical cancer). One vaccine also protects against HPV types 6 and 11, which cause genital warts. The safety profile of both vaccines was assessed extensively in randomised controlled clinical trials conducted prior to licensure and has been further elucidated following licensure from surveillance and specific studies in large populations. This review aims to examine current evidence regarding the safety of HPV vaccines. In summary, both vaccines are associated with relatively high rates of injection site reactions, particularly pain, but this is usually of short duration and resolves spontaneously. Systemic reactions have generally been mild and self-limited. Post vaccination syncope has occurred, but can be avoided with appropriate care. Serious vaccine-attributable adverse events, such as anaphylaxis, are rare, and although not recommended for use in pregnancy, abnormal pregnancy outcomes following inadvertent administration do not appear to be associated with vaccination. HPV vaccines are used in a three-dose schedule predominantly in adolescent females: as such case reports linking vaccination with a range of new onset chronic conditions, including autoimmune diseases, have been made. However, well-conducted population-based studies show no association between HPV vaccine and a range of such conditions. Whilst this reassuring safety profile affirms the positive risk benefit of vaccination, as HPV vaccine use expands into more diverse populations, including males, ongoing safety assessment using well-conducted studies is appropriate.

Phylogenetic Considerations in Designing a Broadly Protective Multimeric L2 Vaccine

While the oncogenic human papillomavirus (HPV) types with the greatest medical impact are clustered within the α9 and α7 species, a significant fraction of cervical cancers are caused by α5, α6, and α11 viruses. Benign genital warts are caused principally by the α10 viruses HPV6 and HPV11. In an effort to achieve broad protection against both cervical cancer- and genital wart-associated types, we produced at high levels in bacteria a multimeric protein (α11-88x8) fusing eight polypeptides corresponding to a protective domain comprising L2 residues ∼11 to 88 derived from HPV6 (α10), HPV16 (α9), HPV18 (α7), HPV31 (α9), HPV39 (α7), HPV51 (α5), HPV56 (α6), and HPV73 (α11) and a truncated derivative with the last three units deleted (α11-88x5). Mice were immunized three times with α11-88x8 or α11-88x5 adjuvanted with alum or the licensed HPV vaccines and challenged intravaginally with HPV6, HPV16, HPV26, HPV31, HPV33, HPV35, HPV45, HPV51, HPV56, HPV58, or HPV59 pseudovirions. The α11-88x5 and α11-88x8 vaccines induced similarly robust protection against each HPV type tested and indistinguishable HPV16-neutralizing antibody titers. Passive transfer of α11-88x8 antisera was protective. Further, rabbit antisera to α11-88x8 and α11-88x5 similarly neutralized native HPV18 virions. These findings suggest that immunologic competition between units is not a significant issue and that it is not necessary to include a unit of L2 derived from each species to achieve broader protection against diverse medically significant HPV types than is achieved with the licensed HPV vaccines.

New Approaches to Prophylactic Human Papillomavirus Vaccines for Cervical Cancer Prevention

The currently licensed human papillomavirus (HPV) vaccines are safe and highly effective at preventing HPV infection for a select number of papillomavirus types, thus decreasing the incidence of precursors to cervical cancer. It is expected that vaccination will also ultimately reduce the incidence of this cancer. The licensed HPV vaccines are, however, type restricted and expensive, and also require refrigeration, multiple doses and intramuscular injection. Second-generation vaccines are currently being developed to address these shortcomings. New expression systems, viral and bacterial vectors for HPV L1 capsid protein delivery, and use of the HPV L2 capsid protein will hopefully aid in decreasing cost and increasing ease of use and breadth of protection. These second-generation vaccines could also allow affordable immunization of women in developing countries, where the incidence of cervical cancer is high.

Quadrivalent human papillomavirus (HPV) vaccine: a review of safety, efficacy, and pharmacoeconomics

The introduction of vaccines has lead to a significant reduction in morbidity and mortality from diseases such as measles, rubella and poliomyelitis, as well as the eradication of smallpox (Ertl HC, Xiang Z (1996) The Journal of Immunology, 156, 3579-3582). A recent vaccine approved by the Food and Drug Administration (FDA) is the recombinant quadrivalent human papillomavirus (HPV) vaccine (Merck, Gardasil®). Concerns raised with this preventive measure include safety and efficacy issues as well as the financial implications. Furthermore, the use of the vaccine in women outside the currently approved age ranges and in adolescent boys and men has also been a source of debate. A review of two licensed HPV vaccines (Gardasil, Merck and Cervarix, GalxoSmithKline) in the light of these issues. Literature searches were conducted using the MEDLINE (1966-December 2008) and PubMed databases in addition to the Centers for Disease Control and Prevention website. Bibliographies of selected references were also evaluated for relevant articles. Published guidelines and press releases were utilized as were the manufacturer's package inserts. The collection of information for this review was limited to the most recently available human data. The HPV quadrivalent vaccine has been effective in the management of HPV by preventing vaccine subtype-related persistent infection and precancerous lesions as evidenced by numerous clinical trials. It is also regarded as a generally safe and well-tolerated vaccine, based on an assessment of reported adverse events submitted through governmental databases and analyzed by independent researchers. The majority of adverse events were non-serious and the vaccine has not been conclusively implicated with serious events. The FDA continues to focus on routine post-marketing surveillance monitoring of reported adverse events. The bivalent vaccine has also been shown to be effective in reported trials. Its adverse effect profile also appears acceptable. The HPV vaccines appear safe and effective. Additional clinical research on the vaccines on women outside the currently approved age ranges and in males is necessary. Studies on longer-term outcomes, including cervical cancer and the emergence of new viral genotypes are also necessary.

Human papillomavirus vaccine. Statement of the Consultive Committee of Immunizations on behalf of the Chilean Infectious Diseases Society. September 2008

The article briefly reviews the epidemiology of human papillomavirus (HPV) infection and associated diseases in the world and in Chile and the scientific information of the licensed HPV vaccines: Gardasil and Cervarix. Considering the available information, the Consultive Committee of Immunizations of the Chilean Society of Infectious Diseases, summarizes its conclusions and makes recommendations for vaccination against HPV in Chile.

Declaración del Comité Consultivo de Inmunizaciones de la Sociedad Chilena de Infectología respecto a la vacuna anti-virus papiloma humano: Septiembre 2008

The article briefly reviews the epidemiology of human papillomavirus (HPV) infection and associated diseases in the world and in Chile and the scientific information of the licensed HPV vaccines: Gardasil and Cervarix. Considering the available information, the Consultive Committee of Immunizations of the Chilean Society of Infectious Diseases, summarizes its conclusions and makes recommendations for vaccination against HPV in Chile.

Declaración del Comité Consultivo de Inmunizaciones de la Sociedad Chilena de Infectología respecto a la vacuna antivirus papiloma humano: Septiembre 2008

This article briefly reviews the epidemiology of human papillomavirus (HPV) infection and associated diseases globally and in Chile, and the scientific information of the licensed HPV vaccines: Gardasil and Cervari. Considering the available information, the Advisory Committee on Immunizations of the Chilean Society of Infectious Diseases recommends vaccination of teenage girls, ideally before initiating sexual activity, i.e., approximately at the age of 12 to 13 years and vaccination of women of any age if they have not started sexual activity. If women are vaccinated after initiating sexual activity, they should be informed of the lower efficacy of immunization if HPV infection has occurred. Education on responsible sexuality and sexually transmitted diseases should be maintained as a priority. Vaccination should be highly considered for inclusion in the National Immunization Program.