Human Papilloma Virus Immunization in Adolescent and Young Adults: A Cohort Study to Illustrate What Events Might be Mistaken for Adverse Reactions

Claire-Anne Siegrist, MD; * Edwin M. Lewis, MPH; † Juhani Eskola, MD; ‡ Stephen J. W. Evans, MSc; § Steven B. Black, MD


Pediatr Infect Dis J. 2008;26(11):979-984. 

In This Article

Abstract and Introduction


Background: The large-scale implementation of human papilloma virus (HPV) immunization will be followed by cases of autoimmune diseases occurring in temporal association with immunizations. To anticipate events that might be mistakenly assumed to be caused by immunization, their prevalence was monitored before vaccine introduction.
Method: Cohort study carried out within a database of female adolescents (n = 214,896) and young adults (n = 221,472) followed in the pre-HPV vaccine era (2005), computing rates of emergency consultations, hospitalizations and outpatient consultations, and estimation of risks of coincident associations.
Results: Immune-mediated conditions were a frequent cause (10.3%) of emergency room consultation by adolescent girls. Nonallergic immune-mediated conditions affected 86 per 100,000, diabetes ranking first. In 2005, 53 per 100,000 adolescents and 389 per 100,000 women were hospitalized for diseases of presumed autoimmune origin, thyroiditis being the most frequent diagnosis. If HPV immunization had been used with 80% coverage, 3 per 100,000 adolescents would have required emergency care for asthma/allergy within 24 hours and 2 per 100,000 for diabetes within 1 week of an injection. The risks of hospitalization in temporal association with immunization are 4 times higher for thyroiditis than for multiple sclerosis or Guillain-Barré's syndrome, and more than 20 times higher in young women than in adolescents.
Conclusion: The distinction between HPV vaccine-caused adverse reactions and events only observed by chance in temporal association is difficult. The prior use of population-based data allows for identification of issues of potential concern, for monitoring the impact of large-scale interventions and for addressing rapidly vaccine-safety issues that may compromise vaccine programs.


Concerns about supposed adverse effects of vaccines seem to occur regularly. Usually the evidence for the adverse effect leading to the scare derives from some case reports rather than from trials or carefully conducted comparative studies. Spontaneous reports of suspected adverse drug reactions, including those to vaccines, remain an important source of new information for monitoring the safety of medicines. However, suspicion about an event does not demonstrate causality. Many suspected adverse drug reactions are simply coincident in time with administration of the drug or vaccine.

During the next few years, there will be vaccines introduced to groups of people who have not traditionally been vaccinated. Pandemic flu vaccine may be given to age groups who have not been, in large scale, recipients of vaccines. The human papilloma virus (HPV) disease burden and the outstanding efficacy profile of the novel HPV vaccines are such that these vaccines are currently being implemented[1] or considered for implementation in many industrialized countries. Surveys predict that vaccine acceptance will be high, despite significant misunderstanding about HPV infection, cervical cancer screening, and the sequelae of HPV infection.[2,3,4,5] The interest of parents, young women, and health care providers in HPV vaccines will doubtless be strongly supported by large-scale promotional events led by 2 competing major pharmaceutical companies. This should result in rapid vaccine uptake by adolescents targeted by national immunization programs. In addition, catch-up immunizations will be implemented in some countries for young women, as prior exposure to HPV does not prevent vaccine-induced efficacy against other HPV genotypes.[6] Altogether, this is expected to lead to a rapid uptake of HPV vaccines by adolescent girls and young women in industrialized countries able to afford them.

The rapid large-scale implementation of a vaccine in the young adult population of industrialized countries is not without precedent. In the early 1990s, the recommendation to immunize adolescents with hepatitis B vaccines (HBV) was supported by such vigorous promotional efforts in France that it rapidly led to the immunization of 20 million individuals, mostly adolescents and young adults.[7] A few years later, reports of temporal association between HBV immunization and the onset of multiple sclerosis (MS)[8] were sufficient to fuel major vaccine-safety controversies associating HBV immunization to MS and other autoimmune diseases.[9] Public confidence was lost and national HBV vaccination efforts interrupted. A decade later, the existence of an increased risk of MS after HBV immunization in adults has still not been demonstrated.[10] However, as the best epidemiology studies may never exclude the existence of a risk, the debate continues, especially in France,[11] where HBV vaccine coverage remains below 25%.[12] This vaccine-safety issue spread internationally, including in developing countries, despite worldwide efforts for explanation and reassurance.[13] More recently, the large-scale implementation of a quadrivalent conjugate vaccine against meningococcal disease (Menactra) in adolescents led to 5 cases of Guillain-Barré's syndrome within 6 weeks of immunization. Although this did not exceed the expected baseline incidence, it was sufficient for the U.S. authorities to launch an alert.[14] A year later, an update indicated that because of the ongoing risk for meningococcal disease and the limitations of the data indicating a small risk for Guillain-Barre syndrome after a vaccination with quadrivalent conjugate vaccine against meningococcal disease, current Centers for Disease Control and Prevention recommendations remained unchanged. [15]

The novel HPV vaccines (Gardasil and Cervarix) share similarities with HBV vaccines. Both HPV and HBV vaccines are recommended as a 3-dose schedule given in at least 6 months, and include aluminum salts (Gardasil) or a new potent adjuvant (Cervarix) for which large-scale surveillance data is not yet available. Gardasil is produced by yeast, as was one of the HBV vaccines used in France in the 1990s. Both vaccines protect against sexually transmitted viral infections that may result in cancer (ie, will be implemented on a large scale not only in adolescents but also in the young adult population). Although the safety profile of the 2 HPV vaccines appears to be as excellent[16,17] as that of HBV vaccines,[13] they have formally been tested on less than 50,000 women. Thus, their safety databases are limited and rare (<1 per 10,000), severe adverse events may not yet have been identified. Consequently, reports of immune-mediated diseases issued from the postmarketing surveillance could be considered as possible adverse events, at least initially. These signals will be difficult to address given the limited availability of the incidence of most immune-mediated diseases in the adolescent and young adult population.

We are concerned that the large-scale implementation of HPV vaccines in industrialized countries could reactivate the vaccine-safety debates linking vaccination to autoimmune diseases. This could possibly represent a major issue for the sustainability of HPV immunization programs in industrialized countries, and consequently for their implementation in developing countries where they are most needed.[18] To anticipate the crisis and identify the potential danger signals, we have computed the utilization of health resources by the entire female adolescent and young adult population registered within the Northern California Kaiser Permanente (NCKP) Medical Care Program health maintenance organization (HMO) during 2005 The number of emergency consultations, hospitalizations, and outpatient consultations were used to identify the most frequent immune-mediated conditions, ie, those most likely to be temporally associated with a putative HPV vaccine administration.


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