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Analysis

Modernising vaccine surveillance systems to improve detection of rare or poorly defined adverse events

BMJ 2019; 365 doi: https://doi.org/10.1136/bmj.l2268 (Published 31 May 2019) Cite this as: BMJ 2019;365:l2268

Rapid Response:

Re: Modernising vaccine surveillance systems to improve detection of rare or poorly defined adverse events

Improving detection of rare or poorly defined adverse events – Analysis poorly grounded in evidence

The Analysis published on May 31st in the BMJ, opens by linking gaps in “vaccine safety infrastructure” to lapses in public confidence in vaccines, vaccine hesitancy and the re-emergence of measles. However, it quickly becomes apparent this is a smokescreen for the notion of “suspected harm” from HPV vaccine, specifically that investigating links to postural orthostatic tachycardia syndrome (POTS) has been impeded in various ways. (1)

The numerous problems in this piece – among them selective citation of the literature and inappropriate application of pharmacovigilance methods to the complexities of POTS - are not immediately apparent, because on superficial reading the arguments appear well-structured and to raise legitimate questions. Dr Chandler states that POTS is a complex disorder – so far, so good - but the references cited lack relevant background for adolescents. (2-4) First, POTS overlaps chronic fatigue syndrome (CFS) which is common – around 0.5% of adolescents, with common symptoms (chronic fatigue and/or nausea, and/or dizziness, and/or pain) identified as POTS by “intermittent intolerance of upright positions associated with postural tachycardia of more than 40 beats per minute.” (2) Importantly, clinical evidence of POTS is found in 25-50% of CFS cases. (3) Second, symptoms typically arise within a year or two of the beginning of puberty, 70% in girls. (4) Third, about two thirds of POTS patients have headaches, and the most common cause of headache in adolescents is migraine, which shares symptoms with POTS. (2). POTS is more common in Caucasians and around 15% of affected adolescents have a parent or sibling with similar symptoms, suggesting genetic predisposition. (2)

As POTS, viewed as a subset of CFS, is common, with onset in early to mid-adolescence and strong female predominance, reports after HPV vaccine are not surprising. What is surprising is the notion that data mining of the global pharmacovigilance database VigiBase is any more than hypothesis generation. (1) Numerically, VigiBase reports are predominantly from countries with high Caucasian populations where young adolescent females have been targeted for broad HPV vaccine programs (5), and association with fatigue and/or headache and/or syncope inevitable. (2-4) In the analysis of which Dr Chandler is the lead author, among 40,000 reports associated with HPV vaccine, 76% of 694 subjects in four clusters were identified by individual review as “relevant to ongoing safety concerns.” (6) In contrast, analysis of reports to the US Vaccine Adverse Event Reporting System (VAERS) found no signal for POTS and HPV vaccination. Among 160 potential subjects from 40, 735 reports, only 29 fully met POTS criteria and 20/29 had a pre-existing medical condition, CFS in five. (7) It is notable that only two reports came from Australia, which has high HPV coverage and historically high reporting to VigiBase (5), whereas 88 came from Denmark with 20% of Australia’s population. (6)

Carefully validated case definitions are essential to determine the post-vaccination risk of validated adverse events, and initial findings can be overturned by subsequent studies of higher quality, as with venous thromboembolism and HPV vaccination (8). In our view, three studies, not referred to in the Analysis, have design characteristics to validly evaluate the POTS-HPV signal. Although they examine CFS, rather than POTS specifically, clinical overlap supports extrapolation. (2, 3) The methodologically strongest study is from Norway, where the ICD-10 code G93.3 is assigned by paediatricians using specific Norwegian guidelines for CFS, and HPV vaccination status recorded on a national register. (9) Among 176,453 girls born 1997-2002, 82% had at least one dose of 4v HPV vaccine and 407 cases of CFS were identified. HPV vaccine was not associated with CFS during total follow-up (adjusted hazard ratio (aHR) 0.86 (95% CI 0.69-1.08) or the first two years (aHR 0.96; 95% CI 0.64-1.43). Over the study period, reported incidence of CFS increased to a similar extent in boys and girls, despite only girls being eligible for HPV vaccination. Two other studies used the self-controlled case series method to calculate relative incidence (RI) pre and post HPV among CFS cases. No association was found in 187 cases (RI 1.07; 95% CI 0.57-2.00) in the UK (10) or 37 in the Netherlands (RI 0.62; 95% CI 0.07-5.49) (11).

However, lack of epidemiological evidence is insufficient to satisfy Dr Chandler, who argues a search for immune and genetic markers of individual susceptibility is needed. She cites the case of a 42 year old man with GBS after each of three doses of tetanus toxoid as exemplifying individual-level risk. However, a study of 989 vaccines given to people with previous GBS, identified only 6 cases of recurrence, only one tenuously vaccine-exposed (Measles-Mumps-Rubella vaccine 4 months prior). (12) It is difficult to see how a 1978 case report represents the “even-handed look at the evidence”required of a BMJ Analysis.

The final plank of Dr Chandler’s argument is that POTS, and other severe adverse events, are concealed by incomplete clinical trial reporting. Although barriers to accessing clinical trial data are lamentable, retrospective examination of individual trial records is onerous and problematic for non-specific and unmeasured events, such as POTS. What is needed is high quality post-marketing studies (9-11) and well delineated background rates. A prescient study looked at pre-HPV incidence of autoimmune conditions in a US female adolescent cohort, (13) and for POTS was recently reported from Finland. (14)

Understandably, anxiety about debilitating symptoms of unknown cause, such as with POTS, is front of mind while cancer prevention is more distant. However, the basis for a true HPV-POTS association is flimsy, in contrast to strong evidence that HPV programmes have prevented pre-cancerous lesions in many countries (15) and could ultimately eliminate cervical cancer as a public health problem globally. (16)

High quality pharmacovigilance is an essential component of any vaccination program. Unfortunately, the Analysis of May 31st combines selective citation with unjustified, impractical calls for individual risk assessment, both lines of argument reminiscent of broader anti-vaccine tropes. (17) Its publication in a quality journal bestows unwarranted credibility, risking validating unjustified anxieties. Anxieties which, if they take further hold, threaten to deny a generation of young people protection against cervical and other cancers.

1. Chandler RE Modernising vaccine surveillance systems to improve detection of rare or poorly defined adverse events BMJ 2019; 365:l2268 doi:10.1136/bmj.l2268
2. Kzilbash SJ, Ahrens SP, Bruce BJ, Chelimsky G et al Adolescent fatigue, POTS and recovery: A guide for clinicians Curr Progl Adolesc Care 2014; 44:108-133
3. Johnson JN, Mack KJ, Kuntz NL, Brands CK et al Postural Orthostatic Tachycardia Syndrome: A clinical review Pediatr Neurol 2010; 42: 77-85
4. Stewart JM Chronic Orthostatic Intolerance and the postural tachycardia syndrome (POTS) J Pediatr 2004; 145: 725-30
5. Lindquist M VigiBase, the WHO Global ICSR Database system: Basic Facts Drug Information Journal 2008; 42: 409-419
6. Chandler RE, Juhlin K, Fransson J, Caster O et al Current safety concerns with Human Papilloma Virus Vaccine: cluster analysis of reports in VigiBase Drug Saf 2017; 40: 81-90
7. Arana J, Mba-Jonas A, Jankosky C, Lewis P, Moro PL, Shimabukuro TT, et al. Reports of Postural Orthostatic Tachycardia Syndrome After Human Papillomavirus Vaccination in the Vaccine Adverse Event Reporting System. Journal of Adolescent Health. 2017; 61:577-82.
8. Phillips A, Patel C, Pillsbury A, Brotherton J, Macartney K Safety of Human Papillomavirus Vaccines: An updated review Drug Saf 2018; 41: 329-346
9. Feiring B et al HPV vaccination and risk of chronic fatigue syndrome/myalgic encephalomyelitis: A nationwide register-based study from Norway Vaccine 2017; 35:4203-4212
10. Donegan K et al Bivalent human papillomavirus vaccine and the risk of fatigue syndromes in girls in the UK Vaccine 2013; 31: 4961-7
11. Schurink-van’t Klooster TM et al No evidence or an increased risk of long-term fatigue following human papillomavirus vaccination of adolescent girls Vaccine 2018; 36: 6796-6802
12. Baxter R, Lewis N, Bakshi N, Velloni C, Klein NP Recurrent Guillian-Barre syndrome following vaccination Clinical Infectious Diseases 2012; 54:800-4
13. Siegrist C-A, Lewis EM, Eskola J, Evans SJW, Black SB Human Papilloma Virus Immunization in Adolescent and Young Adults A cohort study to illustrate what events might be mistaken for adverse reactions Pediatr Infect Dis J 2007; 26: 979–984
14. Skufca J, Ollgren J, Ruokokoski E, Lyytikainen O, Nohynek H Incidence rates of Guillian Barre (GBS), chronic fatigue/systemic exertion intolerance disease (CFS/SEID) and postural orthostatic tachycardia syndrome (POTS) prior to introduction of human papilloma virus (HPV) vaccination among adolescent girls in Finland, 2002-12 Papillomavirus Research 2017; 3: 91-96
15. Drolet M, Benard E, Brisson and the HPV vaccination impact study group Population-level impact and herd effects following the introduction of human papilloma virus vaccination programmes: updated systematic review and meta-analysis Lancet 2019 http://dx.doi.org/10/1016/S0140-6736(19)30298-3)
16. World Health Organization. Cervical cancer elimination strategy [webpage]. https://www.who.int/cancer/cervical-cancer/cervical-cancer-elimination-s...
17. Wiley KE, Leask J, Burgess MA, McIntyre PB PhD thesis opposing immunization: Failure of academic rigour with real-world consequences Vaccine 2019; 37: 1541-1545

Competing interests: Peter McIntyre was from 2004-2017 Director of Australia's National Centre for Immunisation Research and Surveillance (NCIRS) which receives funding from the Australian and New South Wales governments, including funds to support vaccine safety surveillance activities. NCIRS also receives funding from competitive research grants but no monies from vaccine manufacturers. He was in 2008 a member of a panel convened by the Australian Therapeutic Goods Administration to examine reported cases of multiple sclerosis following HPV vaccination and in 2009 of a panel convened by the NSW government to examine reports of anaphylaxis after HPV vaccination but has not been a member of any advisory groups for manufacturers. He was a member of the Australian Technical Advisory Group on Immunisation (ATAGI) from 1998 to 2017 which considered HPV on multiple occasions over this period. He is a member of World Health Organisation committees and relevant travel costs are paid; his declaration of interests is also available on the WHO website. Statements in this rapid response are his alone in consultation with his co-authors. ​Julia Brotherton was Medical Director of Australia's National HPV Vaccination Program Register from 2010-2018, operated under contract to the Australian government. She is in receipt of competitive grant funding from Australia's National Health and Medical Research Council, The Australian Research Council, and Victorian Cancer Agency. She has served on non renumerated government technical advisory committee's in relation to HPV vaccines in Australia and has been an external advisor to WHO on HPV vaccines with travel costs reimbursed Anastasia Phillips is a public health physician, and PhD candidate in the area of vaccine safety including HPV with NCIRS, who is also employed by the Western Australian Department of Health. She has no financial interests to declare. Michael Tatley is Director of the New Zealand Pharmacovigilance Centre which contributes reports to VigiBase. The pharmacovigilance centre receives funding from the NZ Ministry of Health but does not receive any funding from pharmaceutical manufacturers.

09 July 2019
Peter B McIntyre
Professor
Anastasia Phillips Public Health Physician; Julia Brotherton Public Health Physician, Michael Tatley Director, New Zealand Pharmacovigilance Centre
Department of Women's and Children's Health, University of Otago, Dunedin, New Zealand
PO Box 56 Dunedin 9054 New Zealand