Thimerosal has been widely used as a preservative in human vaccines for decades. Thimerosal, a thiol capping agent with ethyl mercury being the active degradant, could have impacts on the vaccine potency due to potential thiol modification. The effects on the antigenicity and immunogenicity of human papillomavirus (HPV) virus-like particles (VLPs) in the presence of thimerosal was studied. In general, reduced binding activity was observed between HPV antigens and monoclonal antibodies (mAbs) upon thimerosal treatment, accompanied by reduced protein conformational stability. The immunogenicity of a pentavalent vaccine formulation (HPV6, HPV11, HPV16, HPV18 and hepatitis E virus) with or without thimerosal was studied in mice. The functional antibody titres, as well as the binding titres, were determined, showing a substantial decrease for vaccine formulations containing thimerosal for HPV16/18. Similarly, epitope-specific competition assays using specific and functional mAbs as tracers also showed a significant reduction in immunogenicity for HPV16/18 in the presence of thimerosal. Structural alterations in the capsid proteins for HPV18 were observed with cryo-electron microscopy and 3-dimensional reconstruction in the comparative structural analysis. The results should alert scientists in formulations development field on the choice for vaccine preservatives, in particular for thiol-containing antigens.

BACKGROUND:A quadrivalent human papillomavirus (HPV4) type 6/11/16/18 vaccine (GARDASIL/SILGARD®) has been licensed in many countries around the world for the prevention of cervical, vulvar, vaginal, and anal cancers and precancers, as well as external genital warts causally related to HPV types 6/11/16/18. Across 7 phase 3 clinical trials involving more than 29,000 males and females ages 9-45 years, vaccination was generally well tolerated. Because of its expected public health benefit in reducing cervical cancer and other HPV-related diseases, the vaccine has been implemented in the national vaccination programs of several countries, with over 178 million doses distributed worldwide.

METHODS:Extensive efforts to assess the safety of the vaccine in routine practice have been conducted over the past 9 years since licensure, including more than 15 studies in more than 1 million preadolescents, adolescents and adults from various countries. Most have been performed in the general population although there have been some in special populations (pregnant women, HIV-infected individuals and those with systemic lupus erythematosus).

RESULTS:We present a summary of the published, postlicensure safety data from active and passive surveillance. Only syncope, and possibly skin infections were associated with vaccination in the postlicensure setting. Serious adverse events, such as adverse pregnancy outcomes, autoimmune diseases (including Guillain-Barre Syndrome and multiple sclerosis), anaphylaxis, venous thromboembolism and stroke, were extensively studied, and no increase in the incidence of these events was found compared with background rates.

CONCLUSIONS:These results, along with the safety data from the prelicensure clinical trials, confirm that the HPV4 vaccine has a favorable safety profile. Key policy, medical and regulatory organizations around the world have independently reviewed these data and continue to recommend routine HPV vaccination.

Vaccination is generally considered safe in patients with multiple sclerosis (MS). We report five patients who presented with multifocal or atypical demyelinating syndromes within 21 days of immunization with the quadrivalent human papilloma virus (HPV) vaccine, Gardasil. Although the target population for vaccination, young females, has an inherently high risk for MS, the temporal association with demyelinating events in these cases may be explained by the potent immuno-stimulatory properties of HPV virus-like particles which comprise the vaccine. A prospective case-control study of patients with MS or clinically isolated demyelinating syndromes receiving the Gardasil vaccine may provide relevant safety data in this population.

Introduction:Genital warts are a frequent form of sexually transmitted disease. Cryotherapy represents the first line of therapy. Healing occurs in 94%, and recurrence in 10% . Side effects are common during the treatment.

Aim:The aim of this study is to determine the successfulness of cryotherapy of genital warts, frequency of recurrence, and side effects.

Patients and methods:In a retrospective study, data from 50 women with genital warts who were treated in the Gynecological Centre"Dr Mahira Jahić"in Tuzla in a period from 2012-2018 were analyzed. Every woman was treated with cryotherapy. Treatments were repeated every 7 days, maximal number of treatments being 7. In processing of data, X2statistical method was used.

Results:50% (N-25) of genital warts eliminated after 3 treatments with cryotherapy . Genital warts are eliminated in 78% (N-39) of women, while this treatment was unsuccessful in 18% (N-9). Recurrence after 3 months in 4% (N-2). Most common side effect was exudation in 78% (N-39), swelling in 72% (N-36) and pain in 66% (N-33). PAP smears in women with genital warts in 64% (N-34) of cases were inflammatory benign changes, while in 36% (N-18) mild abnormal changes in cells ASCUS and LSIL were found. LSIL lesions of cervix are more common (p<0,01) in women with genital warts of vulva.

Conclusion:Cryotherapy is a method with a high success rate in healing of genital warts, and it decreases the concentration of HPV virus and removes the trigger that allows the development of cancer.

In addition to its well-known effects on bone metabolism, vitamin D is an immunomodulating hormone. Serum vitamin D levels in males 18-25 years were measured at baseline, and HPV antibody titers were measured one month following the third quadrivalent HPV vaccine dose. Vitamin D levels were>30 ng/ml (normal) in 60 males and<30 ng/ml (low) in 113 males. Reverse cumulative distribution curves and scatter plots showed higher antibody titers with low vitamin D for all vaccine strains (P<0.05). In linear regression analyses, antibody titers for all HPV strains were significantly higher among those with lower vitamin D levels and among younger participants (P<0.05). These relationships add to the body of knowledge of the complex role of vitamin D in immunoregulation.

Cervical cancer is the fourth most common cancer in women and is almost exclusively caused by human papillomavirus (HPV) infection. HPV is also frequently associated with other cancers arising from mucosal epithelium, including anal and oropharyngeal cancers, which are becoming more common in both men and women. Viral persistence and progression through precancerous lesion stages are prerequisites for HPV-associated cancer and reflect the inability of cell-mediated immune mechanisms to clear infections and eliminate abnormal cells in some individuals. Cell-mediated immune responses are initiated by innate pathogen sensing and subsequent secretion of soluble immune mediators and amplified by the recruitment and activation of effector T lymphocytes. This review discusses early defensive mechanisms of innate responders to natural HPV infection, their influence on response polarization, and the underappreciated role of keratinocytes in this process.

CONTEXT: Viruslike particle human papillomavirus (HPV) vaccines were designed to prevent HPV infection and development of cervical precancers and cancer. Women with oncogenic HPV infections might consider vaccination as therapy.

OBJECTIVE: To determine whether vaccination against HPV types 16 and 18 increases the rate of viral clearance in women already infected with

HPV. DESIGN AND SETTING: Phase 3, masked, community-based randomized trial conducted in 2 provinces of Costa Rica.

PARTICIPANTS: A total of 2189 women aged 18 to 25 years who were recruited between June 2004 and December 2005. Participants were positive for HPV DNA at enrollment, had at least 6 months of follow-up, and had follow-up HPV DNA results.

INTERVENTION: Participants were randomly assigned to receive 3 doses of a bivalent HPV-16/18 L1 protein viruslike particle AS04 candidate vaccine (n = 1088) or a control hepatitis A vaccine (n = 1101) over 6 months. MAIN

OUTCOME MEASURES: Presence of HPV DNA was determined in cervical specimins by a molecular hybridization assay using chemiluminescence with HPV RNA probes and by polymerase chain reaction using SPF10 primers and a line probe assay detection system before vaccination and by polymerase chain reaction after vaccination. We compared rates of type-specific viral clearance using generalized estimating equations methods at the 6-month visit (after 2 doses) and 12-month visit (after 3 doses) in the 2 study groups.

RESULTS: There was no evidence of increased viral clearance at 6 or 12 months in the group who received HPV vaccine compared with the control group. Clearance rates for HPV-16/18 infections at 6 months were 33.4% (82/248) in the HPV vaccine group and 31.6% (95/298) in the control group (vaccine efficacy for viral clearance, 2.5%; 95% confidence interval, -9.8% to 13.5%). Human papillomavirus 16/18 clearance rates at 12 months were 48.8% (86/177) in the HPV vaccine group and 49.8% (110/220) in the control group (vaccine efficacy for viral clearance, -2.0%; 95% confidence interval, -24.3% to 16.3%). There was no evidence of a therapeutic effect for other oncogenic or nononcogenic HPV categories, among women receiving all vaccine doses, among women with single infections, or among women stratified by the following entry variables: HPV-16/18 serology, cytologic results, HPV DNA viral load, time since sexual debut, Chlamydia trachomatis or Neisseria gonorrhoeae infection, hormonal contraceptive use, or smoking.

CONCLUSION: In women positive for HPV DNA, HPV-16/18 vaccination does not accelerate clearance of the virus and should not be used to treat prevalent infections.

TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00128661.

This article investigates the effect of hypnosis on immunity and whether this is the key mechanism in the hypnotic treatment of the genital infection caused by human papillomavirus (HPV). HPV is the most common sexually transmitted disease and can lead to cervical and other cancers. Current medical treatments are aimed at tissue assault (acids, freezing, surgery). Medical wart clearance rates are only 30% to 70% and reoccurrence is common. Our research contrasted hypnosis-only with medical-only therapies, using both urban hospital and rural community samples. Both hypnosis and medical therapy resulted in a statistically significant (p<.04) reduction in areas and numbers of lesions. Yet, at the 12-week follow-up, complete clearance rates were 5 to 1 in favor of hypnosis.

INTRODUCTION:We carried out an active surveillance of common adverse events occurring among women (9 to 26 years old) receiving human papillomavirus vaccine (Gardasil® and Cervarix®) in 9 Italian Regions.

METHODS:Common adverse events occurring in the two weeks following each dose administration were collected using a structured diary.

RESULTS:From August 2008 to September 2011, 12,066 immunised women (9,084 receiving Cervarix® and 2,982 Gardasil®) were included in the surveillance for a total of 29,494 administered doses. 53% of women concluded the vaccination cycle (74% with Gardasil® and 47% with Cervarix®). 61% of women experienced an adverse event after the administration of the first dose. The high proportion of adverse events reported is mainly due to the design of the study, since women were requested to report all events occurring after the vaccination; however the majority of events were mild and transient.

DISCUSSION:As for all vaccines, and in particular for newly marketed ones, the surveillance of adverse events represents an essential step in the evaluation of a vaccination programme.

OBJECTIVE:To describe the outcomes of clinical evaluation, skin testing, and vaccine challenge in adolescent schoolgirls with suspected hypersensitivity to the quadrivalent human papillomavirus vaccine introduced in Australian schools in 2007.

DESIGN:Retrospective cohort study.

SETTING:Two tertiary paediatric allergy centres in Victoria and South Australia, Australia.

PARTICIPANTS:35 schoolgirls aged 12 to 18.9 years with suspected hypersensitivity reactions to the quadrivalent human papillomavirus vaccine.

MAIN OUTCOME MEASURES:Clinical review and skin prick and intradermal testing with the quadrivalent vaccine and subsequent challenge with the vaccine.

RESULTS:35 schoolgirls with suspected hypersensitivity to the quadrivalent human papillomavirus vaccine were notified to the specialised immunisation services in 2007, after more than 380 000 doses had been administered in schools. Of these 35 schoolgirls, 25 agreed to further evaluation. Twenty three (92%) experienced reactions after the first dose. Thirteen (52%) experienced urticaria or angio-oedema, and of these, two experienced anaphylaxis. Thirteen had generalised rash, one with angio-oedema. The median time to reaction was 90 minutes. Nineteen (76%) underwent skin testing with the quadrivalent vaccine: all were skin prick test negative and one was intradermal test positive. Eighteen (72%) were subsequently challenged with the quadrivalent vaccine and three (12%) elected to receive the bivalent vaccine. Seventeen tolerated the challenge and one reported limited urticaria four hours after the vaccine had been administered. Only three of the 25 schoolgirls were found to have probable hypersensitivity to the quadrivalent vaccine.

CONCLUSION:True hypersensitivity to the quadrivalent human papillomavirus vaccine in Australian schoolgirls was uncommon and most tolerated subsequent doses.

Background: Cutaneous warts are small skin lesions formed as a result of infection by the human papilloma virus (HPV). In the lesion, viral manipulation creates a microenvironment that favors virus survival and reproduction. Most lesions eventually regress, probably as a result of a Th1-mediated immune response. However, some warts fail to regress and become persistent. Objective: The efficacy of treatment of persistent HPV-caused warts with Energetics of Living Systems acupuncture and monitored immune system involvement was tested. Methods: Eighteen patients with persistent warts were recruited for the study; 9 received acupuncture treatment and 9 received placebo. Each patient was treated 4 times. Results: Clinical success was defined as total clearance of all lesions with no recurrence for 3 months. In the treatment group, clinical success was 36.6% versus 0% in the placebo group. In the treatment group, the level of interleukin (IL)-10 decreased. In a comparison of patients with cleared warts and overall patients with nonresponding warts, different expression levels of IL-8, IL-10, tumor necrosis factor-α, IL-6, and interferon-γ were found, although these differences were not always statistically significant. Trends of differences (not significant) were observed in leukocyte levels. Acupuncture eliminated persistent warts in some of the patients, along with inducing changes in immunologic parameters. Conclusions: Taking the clinical and immunologic outcomes together, clearance of persistent warts following acupuncture might be due to a shift toward a Th1 immune response, or an anti-inflammatory effect against the lesion-induced microenvironment.

The aim of the present population-based cohort study was to analyze the association between the prevalence of 32 types of human papilloma virus (HPV) in 615 female patients with abnormal cervical cytopathology findings. In total, 32 HPV types were screened by DNA array technology. HPV infection was detected in 470 women (76.42%), 419 of whom (89.15%) were infected with≥1 high-risk (HR)-HPV type. HPV16, which is recognized as the main HR-HPV type responsible for the development of cervical cancer, was observed in 32.98% of HPV(+) participants, followed by HPV42 (18.09%), HPV31 (17.66%), HPV51 (13.83%), HPV56 (10.00%), HPV53 (8.72%) and HPV66 (8.72%). The prevalence of HR-HPV types, which may be suppressed directly (in the case of HPV16 and 18), or possibly via cross-protection (in the case of HPV31) following vaccination, was considerably lower in participants ≤22 years of age (HPV16, 28.57%; HPV18, 2.04%; HPV31, 6.12%), compared with participants 23-29years of age (HPV16, 45.71%; HPV18, 7.86%; HPV31, 22.86%), who were less likely to be vaccinated. Consequently, the present study hypothesizes that there may be a continuous shift in the prevalence of HPV types as a result of vaccination. Furthermore, the percentage of non-vaccine HR-HPV types was higher than expected, considering that eight HPV types formerly classified as 'low-risk' or 'probably high-risk' are in fact HR-HPV types. Therefore, it may be important to monitor non-vaccine HPV types in future studies, and an investigation concerning several HR-HPV types as risk factors for the development of cervical cancer is required.

Infectious agents contribute to the environmental factors involved in the development of autoimmune diseases possibly through molecular mimicry mechanisms. Hence, it is feasible that vaccinations may also contribute to the mosaic of autoimmunity. Evidence for the association of vaccinations and the development of these diseases is presented in this review. Infrequently reported post-vaccination autoimmune diseases include systemic lupus erythematosus, rheumatoid arthritis, inflammatory myopathies, multiple sclerosis, Guillain-Barré syndrome, and vasculitis. In addition, we will discuss macrophagic myofasciitis, aluminum containing vaccines, and the recent evidence for autoimmunity following the use of human papillomavirus vaccine.

Human Papilloma Virus (HPV) is associated in most instances with cervical cancer. The HPV oncoproteins target P53 protein for degradation, leading to deregulation of cell cycle. We investigated whether stabilization of P53 in cervical cancer cells, by downregulating HPV transcription would restore the apoptotic ability of these cells. Our findings show that vitamin C downregulates the redox sensitive transcription factor AP-1 and decreases one of its transcription targets HPV E6, and stabilizes P53. This was associated with an increase in Bax and decrease in Bcl-2 and telomerase activity. Accumulation of P53 and its target gene bax then sensitized HeLa cells to cell-cycle arrest, cell death/apoptosis induced by cisplatin, and etoposide. Increasing drug sensitivity of cervical carcinoma cells by stabilizing P53 using vitamin C is a novel approach and has potential clinical relevance.