Incidence and Types of Human Papillomavirus Infections in Adolescent Girls and Young Women Immunized With the Human Papillomavirus Vaccine.

Importance: Rates of human papillomavirus (HPV) infection have decreased since the introduction of HPV vaccines in populations with high vaccine uptake. Data are limited for adolescent and young adult populations in US metropolitan centers. Objective: To determine HPV infection rates in adolescent girls and young women aged 13 to 21 years in New York City following HPV vaccination. Design, Setting, and Participants: This cohort study of type-specific cervical HPV detection was conducted at a large adolescent-specific integrated health center in New York City between October 2007 and September 2019. Participants included an open cohort of adolescent girls and young adult women who received the HPV vaccine (Gardasil; Merck & Co) over a 12-year period following HPV vaccination introduction. Data analysis was concluded September 2019. Exposures: Calendar date and time since receipt of first vaccine dose. Main Outcomes and Measures: Temporal associations in age-adjusted postvaccine HPV rates. Results: A total of 1453 participants, with a mean (SD) age at baseline of 18.2 (1.4) years, were included in the cohort (African American with no Hispanic ethnicity, 515 [35.4%] participants; African American with Hispanic ethnicity, 218 [15.0%] participants; Hispanic with no reported race, 637 [43.8%] participants). Approximately half (694 [47.8%] participants) were vaccinated prior to coitarche. Age-adjusted detection rates for quadrivalent vaccine types (HPV-6, HPV-11, HPV-16, and HPV-18) and related types (HPV-31, and HPV-45) decreased year over year, with the largest effect sizes observed among individuals who had been vaccinated before coitarche (adjusted odds ratio [aOR], 0.81; 95% CI, 0.67-0.98). By contrast, detection was higher year over year for nonvaccine high-risk cervical HPV types (aOR, 1.08; 95% CI, 1.04-1.13) and anal HPV types (aOR, 1.11; 95% CI, 1.05-1.17). The largest effect sizes were observed with nonvaccine types HPV-56 and HPV-68. Conclusions and Relevance: Whereas lower detection rates of vaccine-related HPV types were observed since introduction of vaccines in female youth in New York City, rates of some nonvaccine high-risk HPV types were higher. Continued monitoring of high-risk HPV prevalence is warranted.

Was amorphous aluminium hydroxyphosphate sulfate adequately evaluated before authorisation in Europe?

The Merck Sharp & Dohme Corp aluminium adjuvant 'amorphous aluminium hydroxyphosphate sulfate' (AAHS), primarily used in the Gardasil vaccines against human papilloma virus, has been criticised for lack of evidence for its safety. Documentation from Danish authorities and answers from the European Medicines Agency (EMA) suggest that AAHS may not have been sufficiently evaluated. Documentation from the Danish Medicines Agency shows discrepancies in the trial documents of two prelicensure clinical trials with Gardasil in 2002 and 2003. For both trials, the Agency seems to have authorised potassium aluminium sulfate as the adjuvant and not AAHS. In addition, the participants in the trial launched in 2002 were informed that the comparator was saline, even though the comparator was AAHS in an expedient consisting of L-histidine, polysorbate-80, sodium borate and sodium chloride. According to the EMA, AAHS was first introduced in Europe in 2004 as the adjuvant in Procomvax, a vaccine against the hepatitis B virus and Haemophilus influenza type b. The EMA reports that AAHS was introduced without any prelicensure safety evaluation. The adjuvant is described by the company to be both physically and functionally distinct from all other previously used aluminium adjuvants. There is a need for rigorous evaluation of benefits and harms of the adjuvant AAHS.

Preclinical study of safety and immunogenicity of combined rubella and human papillomavirus vaccines: Towards enhancing vaccination uptake rates in developing countries.

Rubella vaccine was not part of national immunization programs (NIP) in several countries in the Middle East and North Africa (MENA), South-East Asia (SEA), and South Africa regions until the year 2000. Therefore, immunization coverage of females older than 20 years old in these countries has been the focus of national campaigns for rubella elimination in developing countries. Vaccines against human papillomavirus (HPV) are not part of NIPs in developing countries. To enhance the advantages of rubella-directed immunization campaigns and to increase HPV vaccine uptake in developing countries, this study aimed to test the stability, potency, efficacy and safety of a combined rubella and HPV vaccine. Female BALB/c mice were immunized subcutaneously with proposed combined HPV16/HPV18 VLP and rubella vaccine at weeks (W) 0, 3 then with HPV vaccine at W 7. Immunized mice developed antigen-specific antibodies against rubella and HPV significantly higher than mice immunized with rubella or HPV vaccine alone. The combined vaccine induced significantly higher splenocyte proliferation than control groups. In addition, pro-inflammatory cytokines IL-4, IL-6, IL-2, and IFNγ levels were significantly higher in mice immunized with the combined vaccine than control groups. Overall, the combined vaccine was safe and immunogenic offering antibody protection as well as eliciting a cellular immune response against rubella and HPV viruses in a single vaccine. This combined vaccine can be of great value to females above 20 years old in the SEA, MENA and South Africa regions offering coverage to rubella vaccine and a potential increase in HPV vaccine uptake rates after appropriate clinical testing.

Risk of Spontaneous Abortion After Inadvertent Human Papillomavirus Vaccination in Pregnancy.

OBJECTIVE: To evaluate the risk of spontaneous abortion after quadrivalent human papillomavirus (4vHPV) vaccination before and during pregnancy across seven integrated health systems within the Vaccine Safety Datalink. METHODS: Within a retrospective observational cohort, we compared risks for spontaneous abortion after 4vHPV in three exposure windows: distal (16-22 weeks before the last menstrual period [LMP]), peripregnancy (within 6 weeks before the LMP), and during pregnancy (LMP through 19 weeks of gestation). Women 12-27 years of age with a pregnancy between 2008 and 2014, with continuous insurance enrollment 8 months before and through pregnancy end, and with a live birth, stillbirth, or spontaneous abortion were included. Pregnancies were identified through validated algorithms. Spontaneous abortions and stillbirths were verified by chart review with spontaneous abortions adjudicated by clinical experts. We excluded multiple gestations, spontaneous abortions before 6 weeks of gestation, and women using medications increasing risk of spontaneous abortion. Spontaneous abortion risk after 4vHPV during pregnancy was compared with distal vaccination using time-dependent covariate Cox models. Spontaneous abortion risk for peripregnancy compared with distal vaccination was evaluated with standard Cox models. RESULTS: We identified 2,800 pregnancies with 4vHPV exposure in specified risk windows: 919 (33%) distal, 986 (35%) peripregnancy, and 895 (32%) during pregnancy. Mean age was 22.4 years in distal and peripregnancy groups compared with 21.4 years among women vaccinated during pregnancy. Among women with distal 4vHPV exposure, 96 (10.4%) experienced a spontaneous abortion. For peripregnancy and during pregnancy exposures, spontaneous abortions occurred in 110 (11.2%) and 77 (8.6%), respectively. The risk of spontaneous abortion was not increased among women who received 4vHPV during pregnancy (adjusted hazard ratio 1.10, 95% CI 0.81-1.51) or peripregnancy 1.07 (0.81-1.41). CONCLUSION: Inadvertent 4vHPV exposure during or peripregnancy was not significantly associated with an increased risk of spontaneous abortion.

Phospholipid supplementation can attenuate vaccine-induced depressive-like behavior in mice.

Human papillomavirus vaccine (HPVv) is used worldwide for prevention of infection. However several reports link this vaccine, with immune-mediated reactions, especially with neurological manifestations. Our previous results showed that HPVv-Gardasil and aluminum-immunized mice developed behavioral impairments. Studies have shown a positive effect of phospholipid supplementation on depression and cognitive functions in mice. Therefore, our goal was to evaluate the effect of a dietary supplement on vaccine-induced depression. Sixty C57BL/6 female mice were immunized with HPVv-Gardasil, aluminum or the vehicle (n = 20 each group), and half of each group were fed 5 times per week with 0.2 ml of a dietary supplement enriched with phosphatidylcholine. The mice were evaluated for depression at 3 months of age, by the forced swimming test. Both the Gardasil and the aluminum-treated mice developed depressive-like behavior when compared to the control group. The HPVv-Gardasil-immunized mice supplemented with phosphatidylcholine significantly reduced their depressive symptoms. This study confirms our previous studies demonstrating depressive-like behavior in mice vaccinated with HPVv-Gardasil. In addition, it demonstrates the ability of phosphatidylcholine-enriched diet to attenuate depressive-like behavior in the HPVv-Gardasil-vaccinated mice. We suggest that phosphatidylcholine supplementation may serve as a treatment for patients suffering vaccine-related neurological manifestations.

Age impact on human papillomavirus vaccination in France in 2014: A study from the National Health Insurance Database.

INTRODUCTION: Human papillomavirus (HPV) is the main cause of cervical cancer. In France, since March 2007, HPV vaccination has been recommended for girls aged 14, in addition to a catch-up program for girls aged 15 to 23. In October 2012, the target population was changed to 11- to 14-year-old girls. The main objective of the present study was to evaluate the impact of the recommendation change on HPV vaccination coverage and compliance. METHODS: We conducted a descriptive study of the Échantillon Généraliste des Bénéficiaires (EGB), which is a random 1/97 permanent sample from the French National Health Insurance Database. We focused our analyses on girls aged 11 to 17 years who were covered by the main insurance scheme (which covers 77% of the French population). RESULTS: We included 16,195 girls in this analysis. At the last update of the database (06/15/2014), 42% of 17-year-old girls had been vaccinated, with more than 50% of them having been vaccinated at age 14. Between January 2012 and June 2014, patients were reimbursed for a total of 7698 doses of the HPV vaccine. During the first trimester of 2013, the number of vaccinated 11- to 13-year-old girls increased, growing by more than 20-fold between the last trimester of 2012 (n=8) and the last trimester of 2013 (n=178). Less than 60% of the vaccinated patients received 3 injections. DISCUSSION: Implementation of the new recommendations was rapid but had only a slight impact on vaccination coverage.

Focal epithelial hyperplasia by human papillomavirus (HPV)-32 misdiagnosed as HPV-16 and treated with combination of retinoids, imiquimod and quadrivalent HPV vaccine.

Focal epithelial hyperplasia (FEH) or Heck's disease is a rare, benign and asymptomatic mucosal proliferation associated with human papillomavirus (HPV) infection, mainly with genotypes 13 and 32. We report a florid case of FEH in an 11-year-old Haitian girl with systemic lupus erythematosus receiving immunosuppressive therapy. Cryotherapy was previously performed on numerous occasions with no results. We decided to prescribe a non-invasive and more comfortable treatment. A combination of topical retinoid and imiquimod cream was well tolerated and led to an important improvement. The evidence of infection by HPV-16 detected by polymerase chain reaction (PCR) technique, prompted us to prescribe the quadrivalent HPV vaccine (types 6, 11,16 and 18). Subsequent PCR sequencing with generic primers GP5-GP6 and further BLAST comparative analysis confirmed that genomic viral sequence in our case truly corresponded with HPV-32. This molecular misdiagnosis can be explained by the similarity between genomic sequences of both HPV-16 and -32 genotypes. At the 1-year follow up, we observed total clinical improvement and no recurrences of the disease. Complete healing in this case may correspond to a potential action of topical retinoid, imiquimod and the cross-protection mechanism of the quadrivalent HPV vaccine.

Primary strategies for HPV infection and cervical cancer prevention.

Counseling messages for tobacco cessation, condom use, circumcision, and selective choice in the number of sexual partners can help reduce the risk of cervical cancer. Other sexual behavioral and reproductive risk factors for cervical cancer are a younger age at first intercourse and at first full-term pregnancy as well as increasing duration of combined hormonal oral contraceptive use. Micronutrients and supplements can reduce the risk of human papillomavirus infection, persistence, progression, and regression. Some human papillomavirus infections can be prevented by vaccination. Cervical cancer is best prevented by screening.

Update on the treatment of genital warts.

This review summarizes new treatments from the last seven years employed for the treatment of genital warts caused by human papillomavirus (HPV). Imquimod 3.75% is a new agent with fewer side effects and perhaps a better dosing schedule than imquimod 5%, but is not more effective. Sinecatechins/Polyphenon E 15%, a novel extract from green tea can be effective against genital warts but requires three times a day dosing and is not more effective than existing treatments; the treatment course is 12-16 weeks. Photodynamic therapy combined with other destructive modalities might increase the cure rate for genital warts. The quadrivalent vaccine against HPV 6, 11, 16, 18 is decreasing the incidence of warts in the western world but the evidence does not support vaccination as a treatment for those already infected by HPV. Hyperthermia and immunomodulators might be positive additions to the armamentarium of clinicians. In sum, there are new tools that physicians can use but none is really a great advance over what was available a decade ago.

Detection of human papillomavirus (HPV) L1 gene DNA possibly bound to particulate aluminum adjuvant in the HPV vaccine Gardasil.

Medical practitioners in nine countries submitted samples of Gardasil (Merck & Co.) to be tested for the presence of human papillomavirus (HPV) DNA because they suspected that residual recombinant HPV DNA left in the vaccine might have been a contributing factor leading to some of the unexplained post-vaccination side effects. A total of 16 packages of Gardasil were received from Australia, Bulgaria, France, India, New Zealand, Poland, Russia, Spain and the United States. A nested polymerase chain reaction (PCR) method using the MY09/MY11 degenerate primers for initial amplification and the GP5/GP6-based nested PCR primers for the second amplification were used to prepare the template for direct automated cycle DNA sequencing of a hypervariable segment of the HPV L1 gene which is used for manufacturing of the HPV L1 capsid protein by a DNA recombinant technology in vaccine production. Detection of HPV DNA and HPV genotyping of all positive samples were finally validated by BLAST (Basic Local Alignment Search Tool) analysis of a 45-60 bases sequence of the computer-generated electropherogram. The results showed that all 16 Gardasil samples, each with a different lot number, contained fragments of HPV-11 DNA, or HPV-18 DNA, or a DNA fragment mixture from both genotypes. The detected HPV DNA was found to be firmly bound to the insoluble, proteinase-resistant fraction, presumably of amorphous aluminum hydroxyphosphate sulfate (AAHS) nanoparticles used as adjuvant. The clinical significance of these residual HPV DNA fragments bound to a particulate mineral-based adjuvant is uncertain after intramuscular injection, and requires further investigation for vaccination safety.

The knowledge levels and opinions of biomedical students regarding the human papillomavirus quadrivalent (types 6, 11, 16, and 18) recombinant vaccine.

The objective of this research was to assess the knowledge levels and attitudes of all students enrolled in 1 biomedical university regarding the human papillomavirus quadrivalent (types 6, 11, 16, and 18) recombinant vaccine (Gardasil-Merck; the HPV vaccine). A survey of students from all 7 programs at the University was conducted in January 2009. A total of 1120 useable questionnaires were obtained. These programs included pharmacy, osteopathic medicine, physician assistant, physical therapy, occupational therapy, doctor of psychology, and master of biomedical sciences. Mean percentage correct on the HPV vaccine knowledge test was 73. Subjects scored highest on the question that asks whether the vaccine helps prevent cervical cancer (97% correct) and lowest on the one asking whether it helps prevent genital warts (41% correct). Eighty-eight percent thought that patients 18 years and older should be able to receive the HPV vaccine without parental consent. Only about 5% think that the vaccine would cause patients to become sexually active, or that it would cause patients to have unprotected sex. The results suggest that these students have reasonable but limited knowledge of the vaccine. Their positive attitudes suggest that they will likely recommend or provide the vaccine to their patients.

HPV vaccination - a paradigm shift in public health.

BACKGROUND: In 2006, the world's first quadrivalent human papillomavirus (HPV) vaccine (Gardasil) was made available to the Australian public. The quadrivalent HPV vaccine protects against cervical cancer, cervical abnormalities, and genital warts related to HPV types 6, 11, 16 and 18. General practitioners play a vital role in preventive medicine and as such should have a good understanding of the vaccine and its role in the primary prevention of cervical cancer and precancers. OBJECTIVE: This article provides an overview of the HPV vaccine including efficacy and safety as it relates to its approved use in Australia. DISCUSSION: The vaccine (Gardasil) is quadrivalent, providing protection against HPV types 6, 11, 16 and 18. These HPV types represent a significant burden on public health as they are responsible for 70% of cervical cancers, a substantial proportion of cervical abnormalities, and 90% of genital warts. The quadrivalent HPV vaccine (Gardasil) is indicated for females aged 9-26 years and males aged 9-15 years and should ideally be administered before the onset of sexual activity, however sexually active patients will also benefit.

GARDASIL: prophylactic human papillomavirus vaccine development--from bench top to bed-side.

GARDASIL (Merck, Whitehouse Station, NJ) is a non-infectious recombinant, quadrivalent vaccine prepared from the highly purified virus-like particles (VLPs) of the major capsid proteins of human papillomavirus (HPV) types 6, 11, 16, and 18. GARDASIL is the first vaccine approved for use in women aged 9-26 years for the prevention of cervical cancer and genital warts, as well as vulvar and vaginal precancerous lesions. This report describes some of the key preclinical efforts, achievements in pharmaceutical development, in vivo animal evaluation, and clinical trial data.