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

BMJ 2019; 365 doi: (Published 31 May 2019) Cite this as: BMJ 2019;365:l2268

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

To the Editor:

In her thoughtful analysis, Dr. Chandler discusses the difficulties in HPV vaccine adverse event pharmacovigilance due to the non-specific nature of the serious dysautonomia symptoms reported to the surveillance agencies [1].

In our critical review published in 2017, we described that serious adverse event signals were already present in the largest phase III randomized HPV vaccine trials. Nevertheless, these signals were either ignored or minimized by the investigators [2]. Compared to 2871 women older than 25 years receiving aluminum placebo, the group of 2881 women injected with the bivalent HPV vaccine had more deaths in the four year follow-up period (14 vs. 3, p = 0.012). The authors downplayed this statistically significant difference, instead highlighting the fact that a post-hoc unblinded review ruled that no deaths were related to vaccination [3]. A Cochrane meta-analysis confirmed the higher fatality rate in the follow-up period among mid-adult women receiving HPV vaccine (relative risk = 2.36, 95%CI 1.1 to 5.0; participants = 10,737; randomized studies = 3, with no differences between different vaccines. The meta-analysis authors state that the high fatality rate may be a “chance occurrence since there was no pattern either in the causes of death or in the timing of the occurrence of death” [4]. This appears to be a tenuous argument, there is no known chronic disease ending with a similar cause or timing of death. In large randomized trials, the post-hoc unblinded expert opinion should not overrule the hard statistical data.

A safe vaccine should not have an adverse event biological gradient. Nine-valent HPV vaccine has more than twice the virus-like particles and aluminum adjuvant of the 4-valent dose. In the largest HPV vaccine trial (14,149 participants), those individuals receiving the 9-valent dose had more vaccine-related systemic adverse events, 29.5% vs 27.3% (our calculated p value = 0.003), and more serious systemic adverse events (3.3% vs. 2.6%, our calculated p value = 0.01) than those receiving the 4-valent dose [5]. The authors (and reviewers) ignored these crucial statistical differences [2]. Compared to the 4-valent dose, the 9-valent HPV vaccine number needed to seriously harm is 140. (95% CI 79 - 653) [2].

A similar post- HPV vaccination syndrome of neuropathic pain and dysautonomia has been reported by independent clinicians in different places, circumstances, and times [6]. As described by Chandler, the largest world drug adverse events database (VIGIBASE) received similar dysautonomia symptoms clusters reports after HPV vaccination [7].

In view of the mounting scientific data questioning HPV vaccine security, implementation of the precautionary principle appears in order.

1. Chandler R. Modernising vaccine surveillance systems to improve detection of rare or poorly defined adverse events BMJ 2019; 365 :12268.
2. Martínez-Lavín M, Amezcua-Guerra L. Serious adverse events after HPV vaccination: a critical review of randomized trials and post-marketing case series. Clin Rheumatol 2017;36:2169-78
3. Skinner SR, Szarewski A, Romanowski B, Garland SM, Lazcano-Ponce E, Salmerón J, Del Rosario-Raymundo MR, Verheijen RH Quek SC, da Silva DP, Kitchener H, Fong KL, Bouchard C, Money DM, Ilancheran A, Cruickshank ME, Levin MJ, Chatterjee A, Stapleton JT, Martens M, Quint W, David MP, Meric D, Hardt K, Descamps D, Geeraerts B, Struyf F, Dubin G (2014) 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;84:2213–27
4. Arbyn M, Xu L, Simoens C, Martin-Hirsch PP. Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and its precursors. Cochrane Database Syst Rev 2018 May 9;5:CD009069. doi: 10.1002/14651858.CD009069.pub3
5. Joura EA, Giuliano AR, Iversen OE, Bouchard C,Mao C, MehlsenJ, Moreira ED Jr, Ngan Y, Petersen LK, Lazcano-Ponce E, Pitisuttithum P, Restrepo JA, Stuart G, Woelber L, Yang YC, Cuzick J, Garland SM, Huh W, Kjaer SK, Bautista OM, Chan IS, Chen J, Gesser R, Moeller E, Ritter M, Vuocolo S, Luxembourg A. A 9-valent HPV vaccine against infection and intraepithelial neoplasia in women. N Engl J Med 2015;372:711–23
6. Blitshteyn S, Brinth L, Hendrickson JE, Martinez-Lavin M. Autonomic dysfunction and HPV immunization: an overview. Immunol Res 2018;66:744-54
7. Chandler RE, Juhlin K, Fransson J, Caster O, Edwards IR, Norén GN. Current safety concerns with human papillomavirus vaccine: a cluster analysis of reports in VigiBase. Drug Saf 2017:40:81–90

Competing interests: No competing interests

03 June 2019
Manuel Martinez-Lavin
Chief Rheumatology Department
National Institute of Cardiology
Juan Badiano 1. 14080 Mexico City