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BACKGROUND:Infections with human papilloma virus (HPV) can result in cervical, oropharyngeal, anal, and penile cancer and vaccination programs have been launched in many countries as a preventive measure. We report the characteristics of a number of patients with a syndrome of orthostatic intolerance, headache, fatigue, cognitive dysfunction, and neuropathic pain starting in close relation to HPV vaccination.

METHODS:Patients were referred for orthostatic intolerance following HPV vaccination. Symptoms of autonomic dysfunction were quantified by standardised questionnaire. The diagnosis of postural orthostatic tachycardia syndrome (POTS) rested on finding a sustained heart rate increment of>30 min(-1) (>40 min(-1) in adolescents) or to levels>120 min(-1) during orthostatic challenge.

RESULTS:35 women aged 23.3± 7.1 years participated. Twenty-five had a high level of physical activity before vaccination and irregular periods were reported by all patients not on treatment with oral contraception. Serum bilirubin was below the lower detection limit in 17 patients. Twenty-one of the referred patients fulfilled the criteria for a diagnosis of POTS (60%, 95%CI 43-77%). All patients had orthostatic intolerance, 94% nausea, 82% chronic headache, 82% fatigue, 77% cognitive dysfunction, 72% segmental dystonia, 68% neuropathic pain.

CONCLUSIONS:In a population referred for symptoms of orthostatic intolerance and other symptoms consistent with autonomic dysfunction that began in close temporal association with a quadrivalent HPV vaccination, we identified a 60% prevalence of POTS. Further work is urgently needed to elucidate the potential for a causal link between the vaccine and circulatory abnormalities and to establish targeted treatment options for the affected patients.

A 20-year-old man developed severe abdominal pain 1 week after being vaccinated with the first dose of quadrivalent human papillomavirus (HPV) vaccine (Gardasil(®)). Despite ongoing symptoms of nausea and pain, he received the second dose of the vaccine. Only 10 days later, laboratory results revealed significantly elevated pancreatic enzymes, and with concomitant abdominal pain and vomiting, he was diagnosed with acute pancreatitis. This case of acute pancreatitis after HPV vaccination is not a novel entity. Although confirming the relationship between pancreatitis and vaccine is challenging, some factors suggest a possible link, includingthe positive re-challenge upon repeated exposure to the vaccine, HPV vaccine as probable causal relationship to other autoimmune diseases and a probable mechanism of molecular mimicry. In conjunction with aluminum adjuvant, the induction of immunity through molecular mimicry may potentially culminate in production of cytotoxic autoantibodies with a particular affinity for pancreatic acinar cells.

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A 20-year-old white woman presented with bilateral acute visual loss (visual acuity: 20/60), panuveitis, and exudative retinal detachments 3 weeks after a second dose of quadrivalent human papillomavirus (HPV4) vaccine. She was treated with oral prednisolone for 6 weeks and responded rapidly. By week 4, vision had normalized and clinical signs resolved. Uveitis after HPV4 vaccination has been reported in two cases. Although the differential diagnosis includes Harada disease, temporal correlation with HPV4 and definitive response to a short course of treatment implicate the vaccine in this case. Vaccine-induced uveitis is rare and difficult to distinguish from coincidental autoimmune disease.

OBJECTIVE:Human papillomavirus (HPV) vaccination has been shown to have important health benefits, but vaccination rates are low. Parental and adolescent knowledge could possibly promote vaccination, but the relationship between knowledge and subsequent vaccination is unclear. This study examines how strongly HPV vaccination among high-risk adolescents is related to their or their parents' previous knowledge.

METHODS:A longitudinal cohort study enrolled participants from low-income, predominantly African American neighborhoods. Baseline questionnaires measuring knowledge of HPV and HPV vaccination, as well other variables, were completed by 211 adolescents and 149 parents of another adolescent sample. Adolescent vaccination was tracked prospectively for 12 months after baseline by using clinic reporting data. Analyses tested if parent or adolescent knowledge was associated with or predictive of adolescent HPV vaccination.

RESULTS:On average, parents and adolescents answered slightly less than 50% of knowledge items correctly at baseline, with 5% of parents and 10% of adolescents not answering any knowledge items correctly. Within 12 months, 20 of 149 (13.4%) of the parents' daughters received an HPV vaccination and 32 of 211 (15.2%) of the other adolescent sample did so. Neither parental nor adolescent knowledge was associated with or predictive of adolescent vaccination. For example, when testing the relationship between adolescent vaccination and parental knowledge scores, all R(2) values were<0.005. Results were independent of available potential confounders.

CONCLUSIONS:Those with higher levels of knowledge were not more likely to obtain vaccination for themselves or their daughters. Ideally, future interventions will target factors related to vaccination.

OBJECTIVE:To investigate the causes of neurological manifestations in girls immunized with the human papillomavirus (HPV) vaccine.

METHODS:During the past nine months, 44 girls visited us complaining of several symptoms after HPV vaccination. Four patients with other proven disorders were excluded, and the remaining forty subjects were enrolled in this study.

RESULTS:The age at initial vaccination ranged from 11 to 17 years, and the average incubation period after the first dose of the vaccine was 5.47±5.00 months. Frequent manifestations included headaches, general fatigue, coldness of the legs, limb pain and weakness. The skin temperature examined in 28 girls with limb symptoms exhibited a slight decrease in the fingers (30.4±2.6 °C) and a moderate decrease in the toes (27.1±3.7 °C). Digital plethysmograms revealed a reduced height of the waves, especially in the toes. The limb symptoms of four girls were compatible with the Japanese clinical diagnostic criteria for complex regional pain syndrome (CRPS), while those in the other 14 girls were consistent with foreign diagnostic criteria for CRPS. The Schellong test identified eight patients with orthostatic hypotension and four patients with postural orthostatic tachycardia syndrome. The girls with orthostatic intolerance and CRPS commonly experienced transient violent tremors and persistent asthenia. Electron-microscopic examinations of the intradermal nerves showed an abnormal pathology in the unmyelinated fibers in two of the three girls examined.

CONCLUSION:The symptoms observed in this study can be explained by abnormal peripheral sympathetic responses. The most common previous diagnosis in the studied girls was psychosomatic disease. The social problems of the study participants remained unresolved in that the severely disabled girls stopped going to school.

OBJECTIVES:We sought to investigate roles that Merck&Co Inc played in state human papillomavirus (HPV) immunization policymaking, to elicit key stakeholders' perceptions of the appropriateness of these activities, and to explore implications for relationships between health policymakers and industry.

METHODS:We used a series of state case studies combining data from key informant interviews with analysis of media reports and archival materials. We interviewed 73 key informants in 6 states that were actively engaged in HPV vaccine policy deliberations.

RESULTS:Merck promoted school-entry mandate legislation by serving as an information resource, lobbying legislators, drafting legislation, mobilizing female legislators and physician organizations, conducting consumer marketing campaigns, and filling gaps in access to the vaccine. Legislators relied heavily on Merck for scientific information. Most stakeholders found lobbying by vaccine manufacturers acceptable in principle, but perceived that Merck had acted too aggressively and nontransparently in this case.

CONCLUSIONS:Although policymakers acknowledge the utility of manufacturers' involvement in vaccination policymaking, industry lobbying that is overly aggressive, not fully transparent, or not divorced from financial contributions to lawmakers risks undermining the prospects for legislation to foster uptake of new vaccines.

CONTEXT: In June 2006, the Food and Drug Administration licensed the quadrivalent human papillomavirus (types 6, 11, 16, and 18) recombinant vaccine (qHPV) in the United States for use in females aged 9 to 26 years; the Advisory Committee on Immunization Practices then recommended qHPV for routine vaccination of girls aged 11 to 12 years.

OBJECTIVE: To summarize reports to the Vaccine Adverse Event Reporting System (VAERS) following receipt of qHPV.

DESIGN, SETTING, AND PARTICIPANTS: Review and describe adverse events following immunization (AEFIs) reported to VAERS, a national, voluntary, passive surveillance system, from June 1, 2006, through December 31, 2008. Additional analyses were performed for some AEFIs in prelicensure trials, those of unusual severity, or those that had received public attention. Statistical data mining, including proportional reporting ratios (PRRs) and empirical Bayesian geometric mean methods, were used to detect disproportionality in reporting.

MAIN OUTCOME MEASURES: Numbers of reported AEFIs, reporting rates (reports per 100,000 doses of distributed vaccine or per person-years at risk), and comparisons with expected background rates.

RESULTS: VAERS received 12 424 reports of AEFIs following qHPV distribution, a rate of 53.9 reports per 100,000 doses distributed. A total of 772 reports (6.2% of all reports) described serious AEFIs, including 32 reports of death. The reporting rates per 100,000 qHPV doses distributed were 8.2 for syncope; 7.5 for local site reactions; 6.8 for dizziness; 5.0 for nausea; 4.1 for headache; 3.1 for hypersensitivity reactions; 2.6 for urticaria; 0.2 for venous thromboembolic events, autoimmune disorders, and Guillain-Barré syndrome; 0.1 for anaphylaxis and death; 0.04 for transverse myelitis and pancreatitis; and 0.009 for motor neuron disease. Disproportional reporting of syncope and venous thromboembolic events was noted with data mining methods.

CONCLUSIONS: Most of the AEFI rates were not greater than the background rates compared with other vaccines, but there was disproportional reporting of syncope and venous thromboembolic events. The significance of these findings must be tempered with the limitations (possible underreporting) of a passive reporting system.

Postural orthostatic tachycardia syndrome (POTS) is a heterogeneous disorder of the autonomic nervous system in which a change from the supine position to an upright position causes an abnormally large increase in heart rate or tachycardia (30 bpm within 10 min of standing or head-up tilt). This response is accompanied by a decrease in blood flow to the brain and hence a spectrum of symptoms associated with cerebral hypoperfusion. Many of these POTS-related symptoms are also observed in chronic anxiety and panic disorders, and therefore POTS is frequently under- and misdiagnosed.

We report the case of a 14-year-old girl who developed postural orthostatic tachycardia syndrome (POTS) with chronic fatigue 2 months following Gardasil vaccination. The patient suffered from persistent headaches, dizziness, recurrent syncope, poor motor coordination, weakness, fatigue, myalgias, numbness, tachycardia, dyspnea, visual disturbances, phonophobia, cognitive impairment, insomnia, gastrointestinal disturbances, and a weight loss of 20 pounds. The psychiatric evaluation ruled out the possibility that her symptoms were psychogenic or related to anxiety disorders. Furthermore, the patient tested positive for ANA (1:1280), lupus anticoagulant, and antiphospholipid. On clinical examination she presented livedo reticularis and was diagnosed with Raynaud's syndrome. This case fulfills the criteria for the autoimmune/auto-inflammatory syndrome induced by adjuvants (ASIA). Because human papillomavirus vaccination is universally recommended to teenagers and because POTS frequently results in long-term disabilities (as was the case in our patient), a thorough follow-up of patients who present with relevant complaints after vaccination is strongly recommended.

We describe a young woman who developed POTS with positive serum anti-NMDA receptor antibodies and no evidence of encephalitis after vaccination with HPV vaccine, Cervarix. Her symptoms improved significantly with immunomodulatory therapy and re-occurred after immunomodulatory therapy was stopped, suggesting an autoimmune etiology of POTS after vaccination.

BACKGROUND AND PURPOSE:Postural tachycardia syndrome (POTS) is a heterogeneous disorder of the autonomic nervous system that may have an autoimmune etiology.

METHODS:Six patients who developed new onset POTS 6 days to 2 months following human papillomavirus vaccination are reported.

RESULTS:Three patients also had neurocardiogenic syncope, and three patients were diagnosed with possible small fiber neuropathy. Symptoms in all patients improved over 3 years with pharmacotherapy and non-pharmacological measures but residual symptoms persisted. Molecular mimicry with formation of cross-reacting autoantibodies to the potential targets of the autonomic ganglia, neurons, cardiac proteins or vascular receptors is considered as a possible pathogenesis of new onset POTS after immunization.

CONCLUSION:Correct diagnosis of POTS and awareness that POTS may occur after vaccination in young women is essential for prompt and effective management of this condition.

In exploring the primary sequence of the human papilloma virus (HPV) 16 major capsid L1 protein for peptide sharing with human proteins, we find that 34 pentamers from the viral capsid protein are shared with human proteins that, when altered, have been linked to short QT syndrome, arrhythmogenic cardiac disorders, cardiovascular diseases and sudden death. In particular, nine out of the 34 viral pentamers are present in a human protein, titin, alterations of which have been linked to cardiac failure and sudden cardiac death. The present data may help evaluate the potential crossreactivity risks in anti-tumor vaccination protocols based on HPV16 L1 protein.

Premature ovarian failure in a well adolescent is a rare event. Its occurrence raises important questions about causation, which may signal other systemic concerns. This patient presented with amenorrhoea after identifying a change from her regular cycle to irregular and scant periods following vaccinations against human papillomavirus. She declined the oral contraceptives initially prescribed for amenorrhoea. The diagnostic tasks were to determine the reason for her secondary amenorrhoea and then to investigate for possible causes of the premature ovarian failure identified. Although the cause is unknown in 90% of cases, the remaining chief identifiable causes of this condition were excluded. Premature ovarian failure was then notified as a possible adverse event following this vaccination. The young woman was counselled regarding preservation of bone density, reproductive implications and relevant follow-up. This event could hold potential implications for population health and prompts further inquiry.

BACKGROUND: The potential adverse events associated with vaccination for infectious diseases underscore the need for effective analysis and definition of possible vaccine side effects. Using the HPV16 proteome as a model, we quantified the actual and theoretical risks of anti-HPV16 vaccination, and defined the potential disease spectrum derived from concomitant cross-reactions with the human organism.

METHODS: We searched the primary sequence of the HPV16 proteome for heptamer aminoacid sequences shared with human proteins using the Protein International Resource database.

RESULTS: The human proteome contains 82 heptapeptides and two octapeptides found in HPV16. The viral matches are spread among proteins involved in fundamental processes, such as cell differentiation and growth and neurosensory regulation. The human proteins containing the HPV16-derived heptamers include cell-adhesion molecules, leukocyte differentiation antigens, enzymes, proteins associated with spermatogenesis, transcription factors, and neuronal antigens. The number of viral matches and their locations make the occurrence of side autoimmune cross-reactions in the human host following HPV16-based vaccination almost unavoidable.

CONCLUSIONS: Any antigen-based vaccine needs to be carefully and thoroughly designed and critically screened for potential side effects by comparing sequence similarity at the molecular level.

Human papillomavirus (HPV) vaccine is widely used to prevent cervical cancer caused by certain types of HPV in girls and young women. Demyelinating disorders within months following HPV innoculation have been reported, but the causal link between HPV vaccination and the onset of demyelinating disorders have not been certain. We report a case of neuromyelitis optica spectrum disorder (NMOSD) that was noteworthy because optic neuritis (ON) occurred in a very close temporal association with both the first and second HPV vaccinations, which might suggest an association between HPV vaccination and the development of NMO-IgG and recurrent ON. This emphasizes the necessity for continuing surveillance for adverse events after HPV vaccination.

OBJECTIVE: To assess whether vaccination against human papillomavirus (HPV) increases the risk of miscarriage.

DESIGN: Pooled analysis of two multicentre, phase three masked randomised controlled trials

SETTING: Multicentre trials in several continents and in Costa Rica.

PARTICIPANTS: 26 130 women aged 15-25 at enrolment; 3599 pregnancies eligible for analysis.

INTERVENTIONS: Participants were randomly assigned to receive three doses of bivalent HPV 16/18 VLP vaccine with AS04 adjuvant (n=13 075) or hepatitis A vaccine as control (n=13 055) over six months.

MAIN OUTCOME MEASURES: Miscarriage and other pregnancy outcomes.

RESULTS: The estimated rate of miscarriage was 11.5% in pregnancies in women in the HPV arm and 10.2% in the control arm. The one sided P value for the primary analysis was 0.16; thus, overall, there was no significant increase in miscarriage among women assigned to the HPV vaccine arm. In secondary descriptive analyses, miscarriage rates were 14.7% in the HPV vaccine arm and 9.1% in the control arm in pregnancies that began within three months after nearest vaccination.

CONCLUSION: There is no evidence overall for an association between HPV vaccination and risk of miscarriage.

TRIAL REGISTRATION: Clinical Trials NCT00128661 and NCT00122681.

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.

This community-randomized controlled trial was initiated to assess the overall and herd effects of 2 different human papillomavirus (HPV) immunization strategies in over 80,000 girls and boys aged 12-15 y in 33 communities in Finland (ClinicalTrials.gov NCT00534638). Overall, 14,838 adolescents received HPV-16/18 vaccine (2,440 boys and 12,398 girls) and 17,338 received hepatitis-B virus (HBV) vaccine (9,221 boys and 8,117 girls). In an interim analysis, vaccine safety was assessed by active monitoring and surveillance via health registry linkage. Active monitoring showed that the HPV-16/18 vaccine has acceptable safety and reactogenicity in boys. In all study participants, the observed incidences (per 100,000 person-years) of serious adverse events (SAEs) possibly related to vaccination were 54.3 (95% Confidence Interval [CI]: 34.0-82.1) in the HPV-16/18 group and 64.0 (95% CI: 43.2-91.3) in the HBV group. During the follow-up period for this interim analysis, the most common new-onset autoimmune diseases (NOADs; with incidence rate ≥15 per 100,000) in any group based on hospital discharge registry (HILMO) download were ulcerative colitis, juvenile arthritis, celiac disease, insulin-dependent diabetes mellitus (IDDM) and Crohn's disease. No increased NOAD incidences were observed in HPV-16/18 vaccine recipients compared to HBV vaccine recipients. In both the SAE possibly related- and HILMO-analyses, a lower incidence of IDDM was observed in HPV-16/18 vaccinees compared to HBV vaccinees (relative risks, 0.26 [95% CI: 0.03-1.24] and 0.16 [95% CI: 0.03-0.55], respectively).