We report the course of a 16-year-old girl who presented with near complete visual loss associated with chiasmal neuritis and a biopsy proven tumefactive demyelinating lesion on magnetic resonance imaging (MRI) in association with a recent immunization against human papilloma virus.

A 15-year-old young woman received the Human papillomavirus (HPV) vaccines. Following the second HPV vaccination, intermittent fever, myalgia, arthritis and malar rash developed, and she was admitted to our hospital. Laboratory studies showed positive results for antinuclear antibody, anti-dsDNA antibody and anti-Sm antibody. Systemic lupus erythematosus (SLE) was diagnosed according to the Systemic Lupus International Collaborative Clinics 2012. Magnetic resonance imaging showed abnormal hyperintense areas in the fascia, and en bloc biopsy showed fasciitis. Treatment with prednisolone resulted in an amelioration of the symptoms. Reportedly, SLE developed after HPV vaccinations in some patients. Most such patients have a past or family history of autoimmune disease and presented SLE symptoms after the second vaccination. We describe herein a patient in whom SLE developed in association with HPV vaccination.

GARDASIL (Merck&Co., Inc., Whitehouse Station, NJ, USA) is a quadrivalent human papillomavirus (HPV4) vaccine. An epidemiological study was undertaken to evaluate concerns about the potential for HPV4 vaccination to induce serious autoimmune adverse events (SAAEs). The vaccine adverse event reporting system (VAERS) database was examined for adverse event reports associated with vaccines administered from January 2006 through December 2012 to recipients between 18 and 39 years old with a listed residence in the USA and a specified female gender. It was observed that cases with the SAAE outcomes of gastroenteritis (odds ratio (OR) = 4.6, 95% confidence interval (CI) = 1.3-18.5), arthritis (OR = 2.5, 95% CI = 1.4-4.3), systemic lupus erythematosus (OR = 5.3, 95% CI = 1.5-20.5), vasculitis (OR = 4, 95% CI = 1.01-16.4), alopecia (OR = 8.3, 95% CI = 4.5-15.9), or CNS conditions (OR = 1.8, 95% CI = 1.04-2.9) were significantly more likely than controls to have received HPV4 vaccine (median onset of SAAE symptoms from 6 to 55 days post-HPV4 vaccination). Cases with the outcomes of Guillain-Barre syndrome (OR = 0.75, 95% CI = 0.42-1.3) or thrombocytopenia (OR = 1.3,95% CI = 0.48-3.5) were no more likely than controls to have received HPV4 vaccine. Cases with the general health outcomes of infection (OR = 0.72, 95% CI = 0.27-1.7), conjunctivitis (OR = 0.88, 95% CI = 0.29-2.7), or diarrhea (OR = 1.01, 95% CI = 0.83-1.22) were no morelikely than controls to have received HPV4 vaccine. Previous case series of SAAEs and biological plausibility support the observed results. Additional studies should be conducted to further evaluate the potential biological mechanisms involved in HPV4 vaccine-associated SAAEs in animal model systems, and to examine the potential epidemiological relationship between HPV4 vaccine-associated SAAEs in other databases and populations.

PURPOSE OF REVIEW:The cause of primary ovarian insufficiency (POI) is multifactorial. Known causes include external factors such as chemotherapy, radiotherapy, exposure to endocrine-disrupting chemicals, infections that lead to a permanent insult to the ovary, autoimmune conditions, and genetic causes. An association between the quadrivalent antihuman papilloma vaccine (HPV4) and POI was recently suggested.

RECENT FINDINGS:An increasing number of cases of POI post-HPV4 are being reported. Possible mechanisms for the suspected effect of HPV on female reproductive function are a toxic effect or an autoimmune response. The trigger could be the vaccine immunogen contents or the adjuvants, the latter are used to increase the immune reaction. The adjuvant in HPV4 contains aluminum. Animal models have shown aluminum exposure to inhibit expression of female reproductive hormones and to induce histologic changes in the ovaries. Specific genetic compositions may be more susceptible to developing an autoinflammatory syndrome after exposure to an environmental factor.

SUMMARY:The mechanisms responsible for POI are not yet fully understood. Although case reports cannot establish causation, awareness of a possible link between HPV4 and POI will help to identify and manage future cases that may arise.

Birth rates in the United States have recently fallen. Birth rates per 1000 females aged 25-29 fell from 118 in 2007 to 105 in 2015. One factor may involve the vaccination against the human papillomavirus (HPV). Shortly after the vaccine was licensed, several reports of recipients experiencing primary ovarian failure emerged. This study analyzed information gathered in National Health and Nutrition Examination Survey, which represented 8 million 25-to-29-year-old women residing in the United States between 2007 and 2014. Approximately 60% of women who did not receive the HPV vaccine had been pregnant at least once, whereas only 35% of women who were exposed to the vaccine had conceived. For married women, 75% who did not receive the shot were found to conceive, while only 50% who received the vaccine had ever been pregnant. Using logistic regression to analyze the data, the probability of having been pregnant was estimated for females who received an HPV vaccine compared with females who did not receive the shot. Results suggest that females who received the HPV shot were less likely to have ever been pregnant than women in the same age group who did not receive the shot. If 100% of females in this study had received the HPV vaccine, data suggest the number of women having ever conceived would have fallen by 2 million. Further study into the influence of HPV vaccine on fertility is thus warranted.

In last centuries, vaccines reduced the incidence of several infectious diseases. In last decades, some vaccines aimed at preventing also some cancers, where viruses play a causative role. However, several adverse events have been described after vaccines, but a causal relationship has been established only in a minority of cases. Here, we describe a pseudo-neurological syndrome occurred shortly after the administration of the bivalent HPV vaccine. Some autoimmune disorders, including neurological demyelinating diseases, have been reported after HPV vaccines, but the patient showed no organic lesions. The patient was diagnosed as having a functional somatoform syndrome, which was supposed to be autoimmune/inflammatory syndrome induced by adjuvants (ASIA), seen the temporal link with vaccination and the presence of anti-phospholipid autoantibodies. Immunological mechanisms of vaccines-and of adjuvants-have not been completely elucidated yet, and although there is no evidence of statistical association with many post-vaccination events, a causal link with vaccine cannot be excluded in some individuals.

BACKGROUND:In Italy, HPV vaccination is offered to 11-year-old girls since 2007. In 2012 coverage was 69%. Strategies for offering and promoting HPV vaccination and coverage rates (26-85%) vary among Regions and Local Health Authorities (LHAs). We conducted a national study to identify strategies to improve HPV vaccination uptake.

METHODS:In 2011-2012 we invited the 178 LHAs to fill a web-questionnaire, inquiring implementation of HPV vaccination campaigns (immunization practices, logistics of vaccine delivery, training, activities to promote vaccination, barriers, local context). We described type of offer and vaccination promotion in each LHA and studied the association of these factors with vaccination coverage rates.

RESULTS:We analyzed 133 questionnaires. The communication tools more frequently used to promote vaccination were: brochures/leaflets (92% of LHAs), fliers/posters (72%). Television (24%) and radio (15%) were less used. Using≥3 communication channels was associated to a coverage ≥70% (ORadj=5.9, 95%CI 2.0-17.4). The probability to reach a coverage ≥70% was higher if the invitation letter indicated a pre-assigned date for HPV vaccination (ORadj=7.0, 95%CI 1.2-39.8) and>1 recall for non-respondents was planned (ORadj=4.1, 95%CI 1.8-9.3). Immunization services and paediatricians were involved in informative and training activities in most LHAs (80-90%), instead general practitioners, women and family's healthcare services and public gynaecologists in 60-70%, cervical cancer screening services and private gynaecologists in 20-40%. The main factors that negatively affected vaccination uptake were: poor participation to training events of professional profiles different from personnel of immunization services (reported by 58% LHAs), their mistrust towards HPV vaccination (55%) and insufficient resources (56%).

CONCLUSION:The synergy of multiple interventions is necessary for a successful vaccination programme. Practices such as pre-assigning vaccination date and repeatedly recalling non-respondents could improve vaccination uptake. Efforts are required to strengthen the training of different professional profiles and services and encourage their collaboration. Economical resources are needed to promote vaccination.

No Abstract Available

Three young women who developed premature ovarian insufficiency following quadrivalent human papillomavirus (HPV) vaccination presented to a general practitioner in rural New South Wales, Australia. The unrelated girls were aged 16, 16, and 18 years at diagnosis. Each had received HPV vaccinations prior to the onset of ovarian decline. Vaccinations had been administered in different regions of the state of New South Wales and the 3 girls lived in different towns in that state. Each had been prescribed the oral contraceptive pill to treat menstrual cycle abnormalities prior to investigation and diagnosis. Vaccine research does not present an ovary histology report of tested rats but does present a testicular histology report. Enduring ovarian capacity and duration of function following vaccination is unresearched in preclinical studies, clinical and postlicensure studies. Postmarketing surveillance does not accurately represent diagnoses in adverse event notifications and can neither represent unnotified cases nor compare incident statistics with vaccine course administration rates. The potential significance of a case series of adolescents with idiopathic premature ovarian insufficiency following HPV vaccination presenting to a general practice warrants further research. Preservation of reproductive health is a primary concern in the recipient target group. Since this group includes all prepubertal and pubertal young women, demonstration of ongoing, uncompromised safety for the ovary is urgently required. This matter needs to be resolved for the purposes of population health and public vaccine confidence.

OBJECTIVE: To describe the most frequent adverse reactions produced by the human papillomavirus (HPV) vaccine.

DESIGN: Cross-sectional descriptive study using a telephone survey.

SETTING: A province in the Andalusian Public Health System.

PARTICIPANTS: Females vaccinated against HPV in Andalusia, selected by simple random sampling representative of the province.

MAIN MEASUREMENTS: A total of 3,135 telephone calls were made by the public service "Health Answers" using telephone operators supervised by health personnel.

RESULTS: Of the 2,880 calls that fulfilled the inclusion criteria, 1,207 people (41.9% response) took part in the survey. Of the 2,124 surveys made there was some type of adverse reaction (fever, inflammation, pain or rash) in 467 doses (22%): 6.6% was fever, 49.5% inflammation, 72.4% pain, and 6% a rash.

CONCLUSIONS: It can be said that HPV vaccine is safe, which is in agreement with that published in the summary of the product characteristics and in the literature.

BACKGROUND:In Canada, private purchase of human papilloma virus (HPV) vaccines has been possible since 2006. In Alberta, Canada, a publicly funded quadrivalent HPV vaccine program began in the 2008/2009 school year. There have been concerns about adverse events, including venous thromboembolism (VTE) associated with HPV vaccines. We describe the frequencies of adverse events following HPV vaccination among Alberta females aged 9 years or older and look at VTE following HPV vaccination.

METHODS:We used the Alberta Immunization and Adverse Reaction to Immunization (Imm/ARI) repository (publicly funded vaccine), the population-based Pharmaceutical Information Network (PIN) information system (dispensing of a vaccine), and the Alberta Morbidity and Ambulatory Care Abstract reporting system (MACAR) for June 1, 2006-November 19, 2014. Deterministic data linkage used unique personal identifiers. We identified all reported adverse events following immunization (AEFI) and all emergency department (ED) utilization or hospitalizations within 42 days of immunization. We calculated the frequency of AEFI by type, rates per 100,000 doses of HPV vaccine administered and the frequencies of ICD-10-CA codes for hospitalizations and emergency department visits.

RESULTS:Over the period 195,270 females received 528,913 doses of HPV vaccine. Of those receiving at least one dose, 192 reported one or more AEFI events (198 AEFI events), i.e., 37.4/100,000 doses administered (95% CI 32.5-43.0). None were consistent with VTE. Of the women who received HPV vaccine 958 were hospitalized and 19,351 had an ED visit within 42 days of immunization. Four women who had an ED visit and hospitalization event were diagnosed with VTE. Three of these had other diagnoses known to be associated with VTE; the fourth woman had VTE among ED diagnoses but not among those for the hospitalization.

CONCLUSIONS:Rates of AEFI after HPV immunization in Alberta are low and consistent with types of events seen elsewhere.

BACKGROUND:A 9-valent human papillomavirus (9vHPV) vaccine has recently been reported to be safe and highly efficacious against infection and disease related to HPV6/11/16/18/31/33/45/52/58. We evaluated the immunogenicity and safety of the 9vHPV vaccine administered concomitantly with REPEVAX (diphtheria, tetanus, acellular pertussis and inactivated poliomyelitis vaccine).

METHODS:This open-label, randomized, multicenter study enrolled 1054 males and females ages 11-15 years. Subjects were randomly assigned to each group in a 1:1 ratio. Subjects received a 0.5 mL dose of 9vHPV vaccine intramuscularly at day 1, months 2 and 6 and a 0.5 mL dose of REPEVAX either on day 1 (concomitant vaccination group; n = 526) or at month 1 (nonconcomitant vaccination group, n = 528). Serologic responses for each vaccine component were tested by 1-sided tests of noninferiority between groups. Systemic and injection-site adverse experiences (AEs) and serious AEs were monitored.

RESULTS:Noninferiority of anti-HPV geometric mean titers and seroconversion rates for all 9vHPV antigens were demonstrated for the concomitant group compared with the nonconcomitant group. Seroconversion rates for the 9vHPV vaccine types were≥99.8% in both groups at month 7. For REPEVAX, noninferiority of immune response was established for diphtheria, tetanus, all polio and pertussis antigens for both groups. There were no vaccine-related serious AEs.

CONCLUSION:Overall, concomitant administration of 9vHPV vaccine and REPEVAX was generally well tolerated and did not interfere with the immune response to either vaccine. This strategy would minimize the number of visits required to deliver each vaccine individually.

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.

Our recent experience in a post-licensure safety study of autoimmune conditions following the quadrivalent human papillomavirus vaccine in 189,629 girls and young women ages 9-26 years led us to question the adequacy of the exclusion of Day 0 events to prevent the erroneous association of prevalent conditions with vaccination. Of the 18 confirmed cases of Graves' disease diagnosed in days 1-60 following vaccination, only 6 cases appeared to be truly new onset. Among the remaining 12 cases, 2 cases had abnormal thyroid stimulating hormone or thyroxine labs drawn prior to or on Day 0 but had no documented pre-existing symptoms. The other 10 cases had mention of symptoms of hyperthyroidism referencing a period prior to first HPV-4 dose. This 'unmasking' phenomenon, due to health care visits that include vaccination and new workups of preexisting symptoms, may not be adequately controlled through the exclusion of Day 0 events.

BACKGROUND:In 2007, Australia implemented the National human papillomavirus (HPV) Vaccination Program, which provides quadrivalent HPV vaccine free to all women aged 12-26 years. Following notification of 7 presumptive cases of anaphylaxis in the state of New South Wales, Australia, we verified cases and compared the incidence of anaphylaxis following HPV vaccination to other vaccines in comparable settings.

METHODS:We contacted all patients with suspected anaphylaxis and obtained detailed histories from telephone interviews and a review of medical records. A multidisciplinary team determined whether each suspected case met the standardized Brighton definition. Some participants also received skin-prick allergy testing for common antigens and components of the HPV vaccine.

RESULTS:Of 12 suspected cases, 8 were classified as anaphylaxis. Of these, 4 participants had negative skin-prick test results for intradermal Gardasil. From the 269 680 HPV vaccine doses administered in schools, 7 cases of anaphylaxis were identified, which represents an incidence rate of 2.6 per 100 000 doses (95% CI 1.0-5.3 per 100 000). In comparison, the rate of identified anaphylaxis was 0.1 per 100 000 doses (95% CI 0.003-0.7) for conjugated meningococcal C vaccination in a 2003 school-based program.

INTERPRETATION:Based on the number of confirmed cases, the estimated rate of anaphylaxis following quadrivalent HPV vaccine was significantly higher than identified in comparable school-based delivery of other vaccines. However, overall rates were very low and managed appropriately with no serious sequelae.

INTRODUCTION:We report the case of a patient who developed symptoms of acute cerebellar ataxia (ACA) after administration of the human papilloma virus (HPV)-16/18 vaccine.

PATIENT AND METHOD:This patient developed symptoms of ACA, including nausea, vertigo, severe limb and truncal ataxia, and bilateral spontaneous continuous horizontal nystagmus with irregular rhythm, 12 days after administration of the HPV-16/18 AS04-adjuvanted cervical cancer vaccine. After this, the patient received methylprednisolone pulse and intravenous immunoglobulin (IVIG) therapies as well as immunoadsorption plasmapheresis.

RESULTS:Severe ACA symptoms did not improve after methylprednisolone pulse and IVIG therapies, but the patient recovered completely after immunoadsorption plasmapheresis.

CONCLUSION:This temporal association strongly suggests that ACA was induced by the vaccination.

In the last years numerous reports describing a possible association between administration of vaccines and development of autoimmune phenomena and overt autoimmune disease were published. Possible mechanisms of induction of autoimmune phenomena by vaccines and their excipients are probably similar to those implicated in induction by infectious agents. Here we report the case of an 11-year-old girl who developed autoimmune hepatitis type II after four weeks from vaccination against human papillomavirus. The possible relationships between the use of adjuvated vaccine against papillomavirus and autoimmune hepatitis are discussed. Although we do not provide evidence for a causal link, we suggest that the occurrence of the autoimmune hepatitis may be related to the stimulation of immune system by adjuvated-vaccine, that could have triggered the disease in a genetically predisposed individual. Therefore a monitoring of liver function test following administration of vaccine against papillomavirus may be useful in adolescent girl with signs of hepatopathy, as jaundice, dark urine or hepatomegaly, to early identify and to promptly treat autoimmune liver disorders.

This was a case study in which 3 patients with autoimmune/auto-inflammatory syndrome induced by adjuvants (ASIA) after quadrivalent human papillomavirus vaccination (HPV) were evaluated and described. All the patients were women. Diagnosis consisted of HLA-B27 enthesitis related arthritis, rheumatoid arthritis and systemic lupus erythematous, respectively. Our results highlight the risk of developing ASIA after HPV vaccination and may serve to increase the awareness of such a complication. Factors that are predictive of developing autoimmune diseases should be examined at the population level in order to establish preventive measures in at-risk individuals for whom healthcare should be personalized and participatory.

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Vaccine adjuvants and vaccines may induce autoimmune and inflammatory manifestations in susceptible individuals. To date most human vaccine trials utilize aluminum (Al) adjuvants as placebos despite much evidence showing that Al in vaccine-relevant exposures can be toxic to humans and animals. We sought to evaluate the effects of Al adjuvant and the HPV vaccine Gardasil versus the true placebo on behavioral and inflammatory parameters in female mice. Six-week-old C57BL/6 female mice were injected with either, Gardasil, Gardasil + pertussis toxin (Pt), Al hydroxide, or, vehicle control in amounts equivalent to human exposure. At 7.5 months of age, Gardasil and Al-injected mice spent significantly more time floating in the forced swimming test (FST) in comparison with vehicle-injected mice (Al, p = 0.009; Gardasil, p = 0.025; Gardasil + Pt, p = 0.005). The increase in floating time was already highly significant at 4.5 months of age for the Gardasil and Gardasil + Pt group (p ≤ 0.0001). No significant differences were observed in the number of stairs climbed in the staircase test which measures locomotor activity. These results indicate that differences observed in the FST were unlikely due to locomotor dysfunction, but rather due to depression. Moreover, anti-HPV antibodies from the sera of Gardasil and Gardasil + Pt-injected mice showed cross-reactivity with the mouse brain protein extract.Immunohistochemistry analysis revealed microglial activation in the CA1 area of the hippocampus of Gardasil-injected mice. It appears that Gardasil via its Al adjuvant and HPV antigens has the ability to trigger neuroinflammation and autoimmune reactions, further leading to behavioral changes.