Drug Safety

, Volume 41, Issue 5, pp 541–543 | Cite as

Authors’ reply: Safety of Human Papillomavirus Vaccines

  • Kristine Macartney
  • Anastasia Phillips
  • Cyra Patel
  • Alexis Pillsbury
  • Julia Brotherton
Letter to the Editor

We strongly disagree with the assertions made by Chandler et al. [1] and Martinez-Lavin [2] regarding our use of evidence [3] and with the validity of the alternative information presented by the authors.

Chandler et al. [1] contend that a hierarchy of evidence is outdated and that we use epidemiological evidence to “trump” the findings of case reports and case series. The evidence hierarchy used to structure our review is a globally accepted paradigm in modern clinical medicine and healthcare [4]. Modifications to this hierarchy routinely place case series and case reports as the lowest level of evidence [5], reflecting their high risk of bias. We note that both Chandler et al. [1] and Martinez-Lavin [2] cite multiple very small and largely observational studies with no controls, several of which have been criticized [6, 7]. This is despite Martinez-Lavin [2] questioning the validity of “small” clinical trials.

The vast majority of evidence-based reviews on any topic do not include...


Compliance with Ethical Standards


No sources of funding were used to assist in the preparation of this study.

Conflicts of interest

Kristine Macartney, Anastasia Phillips, Alexis Pillsbury and Cyra Patel have no conflicts of interest that are directly relevant to the content of this study. Julia Brotherton is employed as the Director of the National HPV Vaccination Program Register, which is owned and funded by the Australian Government Department of Health. She has been an investigator on investigator-initiated HPV epidemiology studies that have received unrestricted partial funding for laboratory components from Seqirus (cervical cancer typing study) and Merck (recurrent respiratory papillomatosis study) but has never received any personal financial benefits.


  1. 1.
    Chandler RE, Edwards IR, Lindquist M. Comment on “Safety of human papillomavirus vaccines: an updated review”. Drug Saf. 2018. Scholar
  2. 2.
    Martinez-Lavin M. Comment on: “Safety of Human Papillomavirus Vaccines: An Updated Review”. Drug Saf. 2018. Scholar
  3. 3.
    Phillips A, Patel C, Pillsbury A, Brotherton J, Macartney K. Safety of human papillomavirus vaccines: an updated review. Drug Saf. 2017;41(4). Scholar
  4. 4.
    Guyatt GH, Oxman AD, Kunz R, Vist GE, Falck-Ytter Y, Schunemann HJ. What is “quality of evidence” and why is it important to clinicians? BMJ. 2008;336(7651):995–8.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Murad MH, Asi N, Alsawas M, Alahdab F. New evidence pyramid. Evid Based Med. 2016;21(4):125–7.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Hanley S, Pollock K, Cuschieri K. Peripheral sympathetic nerve dysfunction in adolescent Japanese girls following immunization with the human papillomavirus vaccine [letter]. Intern Med (Tokyo, Japan). 2015;54(15):1953.CrossRefGoogle Scholar
  7. 7.
    Petousis-Harris H. Proposed HPV vaccination syndrome is unsubstantiated [letter]. Clin Rheumatol. 2015;35(3):833–4.CrossRefPubMedGoogle Scholar
  8. 8.
    Crawford NW, Hodgson K, Gold M, Buttery J, Wood N. Adverse events following HPV immunization in Australia: establishment of a clinical network. Hum Vaccin Immunother. 2016;12(10):2662–5.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    LaRussa PS, Edwards KM, Dekker CL, Klein NP, Halsey NA, Marchant C, et al. Understanding the role of human variation in vaccine adverse events: the clinical immunization safety assessment network. Pediatrics. 2011;127(Suppl 1):S65–73.CrossRefPubMedGoogle Scholar
  10. 10.
    Williams SE, Klein NP, Halsey N, Dekker CL, Baxter RP, Marchant CD, et al. Overview of the clinical consult case review of adverse events following immunization: clinical immunization safety assessment (CISA) network 2004–2009. Vaccine. 2011;29(40):6920–7.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Top KA, Zafack J, De Serres G, Halperin Serres G. SA, for the PI. Canadian paediatricians’ approaches to managing patients with adverse events following immunization: The role of the Special Immunization Clinic network. Paediatr Child Health. 2014;19(6):310–4.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Macartney K, Chiu C, Georgousakis M, Brotherton J. Safety of human papillomavirus vaccines: a review. Drug Saf. 2013;36(6):393–412.CrossRefPubMedGoogle Scholar
  13. 13.
    Chandler R, Juhlin K, Fransson J, Caster O, Edwards I, Norén G. Current safety concerns with human papillomavirus vaccine: a cluster analysis of reports in VigiBase®. Drug Saf. 2017;40(1):81–90.CrossRefPubMedGoogle Scholar
  14. 14.
    Schonberger LB, Bregman DJ, Sullivan-Bolyai JZ, Keenlyside RA, Ziegler DW, Retailliau HF, et al. Guillain-Barre syndrome following vaccination in the National Influenza Immunization Program, United States, 1976–1977. Am J Epidemiol. 1979;110(2):105–23.CrossRefPubMedGoogle Scholar
  15. 15.
    Sarkanen TO, Alakuijala APE, Dauvilliers YA. Partinen MM. Incidence of narcolepsy after H1N1 influenza and vaccinations: Systematic review and meta-analysis. Sleep Med Rev. 2018;38:177–86. Scholar
  16. 16.
    Miller E, Waight P, Farrington C, Andrews N, Stowe J, Taylor B. Idiopathic thrombocytopenic purpura and MMR vaccine. Arch Dis Child. 2001;84(3):227–9.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Bohlke K, Davis RL, Marcy SM, Braun MM, DeStefano F, Black SB, et al. Risk of anaphylaxis after vaccination of children and adolescents. Pediatrics. 2003;112(4):815–20.CrossRefPubMedGoogle Scholar
  18. 18.
    Poland GA, Ovsyannikova IG, Kennedy RB. Personalized vaccinology: A review. Vaccine. 2017. Scholar
  19. 19.
    Whitaker JA, Ovsyannikova IG, Poland GA. Adversomics: a new paradigm for vaccine safety and design. Expert Rev Vaccines. 2015;14(7):935–47.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Martinez-Lavin M. Vaccine-related serious adverse events might have been under-recognized in the pivotal HPV vaccine randomized trial. Clin Rheumatol. 2017;36(4):975.CrossRefPubMedGoogle Scholar
  21. 21.
    Hawkes D. Response to “Vaccine-related serious adverse events might have been under-recognized in the pivotal HPV vaccine randomized trial”. Clin Rheumatol. 2017;36(7):1691–2.CrossRefPubMedGoogle Scholar
  22. 22.
    Skinner SR, Szarewski A, Romanowski B, Garland SM, Lazcano-Ponce E, Salmeron J. Efficacy, safety, and immunogenicity of the human papillomavirus 16/18 AS04-adjuvanted vaccine in women older than 25 years: 4-year interim follow-up of the phase 3, double-blind, randomised controlled VIVIANE study. Lancet. 2014;384(9961):2213–27.CrossRefPubMedGoogle Scholar
  23. 23.
    European Medicines Agency. Assessment Report: Review under Article 20 of Regulation (EC) No 726/2004, Human papillomavirus (HPV) vaccines. London: European Medicines Agency; 2015. Available from: [cited February 2018].
  24. 24.
    World Health Organisation. Meeting of the Global Advisory Committee on Vaccine Safety, 7–8 June 2017. Wkly Epidemiol Rec. 2017;92(28):393–404.Google Scholar
  25. 25.
    Brotherton JML, Bloem PN. Population-based HPV vaccination programmes are safe and effective: 2017 update and the impetus for achieving better global coverage. Best Pract Res Clin Obstet Gynaecol. 2018;47:42–58.CrossRefPubMedGoogle Scholar
  26. 26.
    Drolet M, Benard E, Boily MC, Ali H, Baandrup L, Bauer H, et al. Population-level impact and herd effects following human papillomavirus vaccination programmes: a systematic review and meta-analysis. Lancet Infect Dis. 2015;15(5):565–80.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Gee J, Weinbaum C, Sukumaran L, Markowitz LE. Quadrivalent HPV vaccine safety review and safety monitoring plans for nine-valent HPV vaccine in the United States. Hum Vaccin Immunother. 2016;12(6):1406–17.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Vichnin M, Bonanni P, Klein NP, Garland SM, Block SL, Kjaer SK, et al. An overview of quadrivalent human papillomavirus vaccine safety: 2006–2015. Pediatr Infect Dis J. 2015;34(9):983–91.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Kristine Macartney
    • 1
    • 2
  • Anastasia Phillips
    • 1
  • Cyra Patel
    • 2
  • Alexis Pillsbury
    • 2
  • Julia Brotherton
    • 3
    • 4
  1. 1.The University of SydneySydneyAustralia
  2. 2.National Centre for Immunisation Research and Surveillance, Kids Research Institute, The Sydney Children’s Hospitals NetworkWestmeadAustralia
  3. 3.National HPV Vaccination Program Register, Victorian Cytology ServiceEast MelbourneAustralia
  4. 4.The University of MelbourneMelbourneAustralia

Personalised recommendations