Human papillomavirus (HPV) vaccination for young females has been promoted as an important public health initiative to reduce the risk of cervical cancer in later life. However, some have questioned whether HPV vaccination promotes autoimmunity. This issue is especially relevant for patients with pre-existing autoimmune disorders, who may be at increased risk of persistent HPV infection and cervical dysplasia (Feldman & Kim. Expert Rev Vaccines 2014; Jun 17:1-4).
There have been a number of case reports of HPV-vaccinated patients who developed auto-antibodies (Colafrancesco et al. Am J Reprod Immunol 2013;70:309-316), systemic lupus erythematosus-like disease (Gatto et al. Clin Rheumatol 2013;32:1301-1307), and CNS demyelinating syndromes, such as optic neuritis and myelitis (Karussis & Petrou. Autoimmun Rev 2014;13:215-224; Alvarez-Soria et al. Rev Neurol 2011;52:472-476). A confound, however, is that immune-mediated conditions (most commonly thyroiditis) are a frequent cause of emergency room visits by non-vaccinated adolescent females, so an association between HPV vaccination and autoimmunity is difficult to ascertain (Siegrist et al. Pediatr Infect Dis J 2007;26:979-984).
Two HPV vaccines are widely used: Gardasil, a quadrivalent vaccine that protects against HPV types 6, 11, 16 and 18; and Cervarix, a bivalent vaccine against HPV types 16 and 18. Vaccination involves three injections at months 0, 2 and 6 (Gardasil) or months 0, 1 and 6 (Cervarix).
The safety of these vaccines has recently been examined in three studies. A case-control study in France recruited 211 females aged 14-26 years with autoimmune disorders and matched them with 875 controls (Grimaldi-Bensouda et al. J Intern Med 2014;275:398-408). The autoimmune disorders were idiopathic thrombocytopenic purpura (ITP), CNS demyelination/multiple sclerosis (MS), Guillain-Barré syndrome, connective tissue disorders (systemic lupus erythematosus, rheumatoid arthritis/juvenile arthritis), type 1 diabetes and autoimmune thyroiditis. There was no evidence of an increased risk of autoimmune disorders in patients following vaccination with Gardasil (adjusted odds ratio 0.9).
A registry study in Sweden and Denmark assessed adverse events in 296,826 females aged 10-17 years who received at least one dose of quadrivalent HPV vaccine versus 700,759 unexposed subjects (Arnheim-Dahlstrom et al. Br Med J 2013;347:5906). Vaccination was associated with Behcet’s syndrome (rate ratio 3.37), Raynaud’s disease (RR 1.67), and type 1 diabetes (RR 1.29). However, further analysis concluded that there was no evidence supporting an association between exposure to HPV vaccine exposure and autoimmunity in the 6 months following vaccination. There was no association between vaccination and neurological outcomes such as optic neuritis (incidence rate: vaccinated 2.61; unvaccinated 2.57). The rates for epilepsy (IR 50.90 vs. 72.32) and paralysis (IR 8.71 vs. 12.76) were lower in the vaccinated cohort.
A pooled analysis of 42 studies compared safety results for patients who received Cervarix alone (n=31,173) or in combination with another vaccine n=2,166) versus controls (24,241) (Angelo et al. Pharmacoepidemiol Drug Saf 2014;23:466-479). The 1-year incidence of immune-mediated disorders was 0.2% in patients with and without HPV vaccination. The risk of other adverse events and serious adverse events was similar for those vaccinated versus controls.
Comment:
Dr. Daniel Selchen: The issue of the risk of possible autoimmunity related to vaccines has a long and sometimes ugly history dating back to the Swine flu epidemic of the 1970s. There is actually a known association between one H1N1 vaccine (Pandemrix) and narcolepsy. The bizarre history of the alleged relationship between childhood vaccines and autism is well known and perhaps the most common haunt of conspiracy theorists in medicine. While there is still considerable controversy about the utility of HPV vaccination, these studies demonstrate that as with most vaccines, there does not appear to be a relationship with autoimmune diseases.