Infections in temporal proximity to HPV vaccination and adverse effects following vaccination in Denmark: A nationwide register-based cohort study and case-crossover analysis

BACKGROUND: Public trust in the human papilloma virus (HPV) vaccination programme has been challenged by reports of potential severe adverse effects. The reported adverse symptoms were heterogeneous and overlapping with those characterised as chronic fatigue syndrome (CFS) and have been described as CFS-like symptoms. Evidence suggests that CFS is often precipitated by an infection. The aim of the study was to examine if an infection in temporal proximity to HPV vaccination is a risk factor for suspected adverse effects following HPV vaccination. METHODS AND FINDINGS: The study was a nationwide register-based cohort study and case-crossover analysis. The study population consisted of all HPV vaccinated females living in Denmark, born between 1974 and 2006, and vaccinated between January 1, 2006 and December 31, 2017. The exposure was any infection in the period ± 1 month around time of first HPV vaccination and was defined as (1) hospital-treated infection; (2) redemption of anti-infective medication; or (3) having a rapid streptococcal test done at the general practitioner. The outcome was referral to a specialised hospital setting (5 national HPV centres opened June 1, 2015) due to suspected adverse effects following HPV vaccination. Multivariable logistic regression was used to estimate the association between infection and later HPV centre referral. The participants were 600,400 HPV-vaccinated females aged 11 to 44 years. Of these, 48,361 (9.7%) females had a hospital-treated infection, redeemed anti-infective medication, or had a rapid streptococcal test ± 1 month around time of first HPV vaccination. A total of 1,755 (0.3%) females were referred to an HPV centre. Having a hospital-treated infection in temporal proximity to vaccination was associated with significantly elevated risk of later referral to an HPV centre (odds ratio (OR) 2.75, 95% confidence interval (CI) 1.72 to 4.40; P < 0.001). Increased risk was also observed among females who redeemed anti-infective medication (OR 1.56, 95% CI 1.33 to 1.83; P < 0.001) or had a rapid streptococcal test (OR 1.45, 95% CI 1.10 to 1.93; P = 0.010). Results from a case-crossover analysis, which was performed to adjust for potential unmeasured confounding, supported the findings. A key limitation of the study is that the HPV centres did not open until June 1, 2015, which may have led to an underestimation of the risk of suspected adverse effects, but stratified analyses by year of vaccination yielded similar results. CONCLUSIONS: Treated infection in temporal proximity to HPV vaccination is associated with increased risk for later referral with suspected adverse vaccine effects. Thus, the infection could potentially be a trigger of the CFS-like symptoms in a subset of the referred females. To our knowledge, the study is the first to investigate the role of infection in the development of suspected adverse effects after HPV vaccination and replication of these findings are needed in other studies

Psychiatric conditions and general practitioner attendance prior to HPV vaccination and the risk of referral to a specialized hospital setting because of suspected adverse events following HPV vaccination: a register-based, matched case&ndash;control study

Tina Hovgaard L&uuml;tzen,1 Bodil Hammer Bech,2 Jesper Mehlsen,3 Claus H&oslash;strup Vestergaard,1 Lene Wulff Krogsgaard,1 J&oslash;rn Olsen,4 Mogens Vestergaard,1 Oleguer Plana-Ripoll,5 Dorte Rytter2 1Research Unit for General Practice, Department of Public Health, Aarhus University, Aarhus C, Denmark; 2Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus C, Denmark; 3Coordinating Research Centre, Frederiksberg Hospital, Frederiksberg, Denmark, 4Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus N, Denmark; 5National Center for Register-based Research, Aarhus University, Aarhus V, Denmark Aim: No association between human papilloma virus (HPV) vaccination and numerous diseases has been found. Still, a large number of Danish women are reporting suspected adverse events. Other factors may play a role, and the aim of this study is to examine the association between psychiatric conditions, general practitioner (GP) attendance and indicators of psychological symptoms prior to HPV vaccination and the risk of referral to an HPV center following vaccination. Study design and setting: Register-based, matched case&ndash;control study. Cases were identified from five Danish, regional HPV centers, and health data for cases and controls were obtained from national registries. Participants: Cases were defined as women referred to an HPV center between January 1, 2015 and December 31, 2015 (n=1,496). Each case was matched with five controls on age, region and time of first vaccine registration. The total study population consisted of 8,976 women. Results: Overall, women above 18 years who had been referred to an HPV center were more likely to have used psychiatric medication (odds ratio [OR]: 1.88 [95% CI 1.48&ndash;2.40]) or to have been hospitalized because of a psychiatric disorder within 5 years prior to the first vaccine registration (OR: 2.13 [95% CI 1.59&ndash;2.86]). Specifically, referred women were more likely to have used antipsychotics, antidepressants, attention deficit hyperactivity disorder (ADHD) medication or anxiolytics, and to have been hospitalized for affective disorders or anxiety, but not to have been hospitalized for schizoid, ADHD or eating disorders. In addition, they were more likely to have had talk therapy or psychometric test performed prior to vaccination (OR: 1.72 [95% CI 0.1.35&ndash;2.18] and OR: 1.67 [95% CI 1.30&ndash;2.13], respectively). Referred women of all ages had higher use of GP before vaccination. Population attributable fraction analyses indicated that psychiatric medication, hospitalization due to a psychiatric disorder and use of talk therapy, or psychometric test &ldquo;explained&rdquo; 13%, 10%, 12% and 11% of the referrals, respectively. Results did not change substantially when adjusted for potential confounders. Conclusion: Women referred to HPV centers because of suspected adverse events after vaccination more often had preexisting psychiatric conditions, psychological symptoms or frequent GP attendance prior to HPV vaccination. Keywords: papillomavirus vaccines, adverse drug events, psychoactive drugs, general practic

Seroprevalence of SARS-CoV-2 Antibodies in Denmark: Results of Two Nationwide Population-Based Surveys, February and May 2021

Lene Wulff Krogsgaard,1 Laura Espenhain,1 Siri Tribler,1 Charlotte Sværke Jørgensen,2 Christian Holm Hansen,1 Frederik Trier Møller,1 Ida Glode Helmuth,1 Ute Wolff Sönksen,3,4 Anne-Marie Vangsted,4 Henrik Ullum,5 Steen Ethelberg1,6 1Department of Infectious Disease Epidemiology and Prevention, Statens Serum Institut, Copenhagen, Denmark; 2Department of Virus & Microbiological Special Diagnostics, Statens Serum Institut, Copenhagen, Denmark; 3Department of Bacteria, Parasites and Fungi, Statens Serum Institut, Copenhagen, Denmark; 4TestCentre Denmark, Statens Serum Institut, Copenhagen, Denmark; 5Division of Infectious Disease Preparedness, Statens Serum Institut, Copenhagen, Denmark; 6Department of Public Health, University of Copenhagen, Copenhagen, DenmarkCorrespondence: Steen Ethelberg, Department of Infectious Disease Epidemiology and Prevention, Statens Serum Institut, 5 Artillerivej, 2300 Copenhagen, Denmark, Tel +45 3268 3545, Email [email protected]: Seroprevalence studies can be used to measure the progression of national COVID-19 epidemics. The Danish National Seroprevalence Survey of SARS-CoV-2 infections (DSS) was conducted as five separate surveys between May 2020 and May 2021. Here, we present results from the two last surveys conducted in February and May 2021.Methods: Persons aged 12 or older were randomly selected from the Danish Population Register and those having received COVID-19 vaccination subsequently excluded. Invitations to have blood drawn in local test centers were sent by mail. Samples were analyzed for whole Immunoglobulin by ELISA. Seroprevalence was estimated by sex, age and geography. Comparisons to vaccination uptake and RT-PCR test results were made.Results: In February 2021, we found detectable antibodies in 7.2% (95% CI: 6.3– 7.9%) of the invited participants (participation rate 25%) and in May 2021 in 8.6% (95% CI: 7.6– 9.5%) of the invited (participation rate: 14%). Seroprevalence did not differ by sex, but by age group, generally being higher among the < 50 than 50+ year-olds. In May 2021, levels of seroprevalence varied from an estimated 13% (95% CI: 12– 15%) in the capital to 5.2% (95% CI: 3.4– 7.4%) in rural areas. Combining seroprevalence results with vaccine coverage, estimates of protection against infection in May 2021 varied from 95% among 65+ year-olds down to 10– 20% among 12– 40 year-olds. In March–May 2021, an estimated 80% of all community SARS-CoV-2 infections were diagnosed by RT-PCR and captured by surveillance.Conclusion: Seroprevalence estimates doubled during the 2020– 21 winter wave of SARS-CoV-2 infections and then stabilized as vaccinations were rolled out. The epidemic affected large cities and younger people the most. Denmark saw comparatively low infections rates, but high test coverage; an estimated four out of five infections were detected by RT-PCR in March–May 2021.Keywords: seroepidemiological studies, COVID-19 serological testing, SARS-CoV-2, population register, questionnaire, ELIS