Investigating Reports of Complex Regional Pain Syndrome: An Analysis of HPV-16/18-Adjuvanted Vaccine Post-Licensure Data

Abstract

Complex regional pain syndrome (CRPS) is a chronic pain disorder that typically follows trauma or surgery. Suspected CRPS reported after vaccination with human papillomavirus (HPV) vaccines led to temporary suspension of proactive recommendation of HPV vaccination in Japan. We investigated the potential CRPS signal in relation to HPV-16/18-adjuvanted vaccine (Cervarix®) by database review of CRPS cases with independent expert confirmation; a disproportionality analysis and analyses of temporality; an observed versus expected analysis using published background incidence rates; systematic reviews of aggregate safety data, and a literature review.The analysis included 17 case reports of CRPS: 10 from Japan (0.14/100,000 doses distributed) and seven from the United Kingdom (0.08/100,000). Five cases were considered by independent experts to be confirmed CRPS. Quantitative analyses did not suggest an association between CRPS and HPV-16/18-adjuvanted vaccine. Observed CRPS incidence after HPV-16/18 vaccination was statistically significantly below expected rates. Systematic database reviews using search terms varying in specificity and sensitivity did not identify new cases. No CRPS was reported during clinical development and no unexpected results found in the literature.There is not sufficient evidence to suggest an increased risk of developing CRPS following vaccination with HPV-16/18-adjuvanted vaccine. Post-licensure safety surveillance confirms the acceptable benefit-risk of HPV-16/18 vaccination.

Human papilloma virus in oral cancer

“…The development of the biHPV vaccine by GSK began in 1998, received FDA approval in 2009, and is now licensed in more than 100 countries and approved in more than 60 countries56. This biHPV vaccine includes the AS04 self-developed adjuvant system, which is composed of MPL, and activates cellular and humoral immune responses with the general adjuvant aluminum hydroxide adsorbed form57.…”

“…This biHPV vaccine includes the AS04 self-developed adjuvant system, which is composed of MPL, and activates cellular and humoral immune responses with the general adjuvant aluminum hydroxide adsorbed form57. MPL, the major constituent of AS04, is a modified diphosphoryl lipid A derived from Salmonella minnesota R595 that removes phosphate and fatty acid groups5657. The safety of the biHPV vaccine and the degree of immune response induction against monovalent/biHPV VLP types 16 and 18 were first confirmed through a phase I clinical study.…”

HPV Vaccination and Complex Regional Pain Syndrome: Lack of Evidence

“…In 2013, subsequent to a concern about Complex Regional Pain Syndrome (CRPS) after receipt of HPV 16/18 vaccine, Japan temporarily suspended the national HPV vaccination recommendation. In this issue of EBioMedicine, the risk of CRPS after receipt of HPV 16/18 vaccine is explored in a study by Huygen et al (2015) .…”

“…In Japan, a 40-person case-series of peripheral sympathetic nerve dysfunction in adolescent girls after HPV vaccination was described; 18 of the cases were considered to have CRPS ( Kinoshita et al, 2014 ). More research into the possible association of HPV vaccination and CRPS is needed, and Huygen et al used the worldwide GSK safety database, a proprietary passive reporting system, to conduct such research ( Huygen et al, 2015 ).…”

“…Huygen identified 18,391 adverse event reports regarding persons who received HPV 16/18 vaccine ( Huygen et al, 2015 ). Of these, 17 were reports of CRPS; 5 were classified as confirmed CRPS.…”