Currently Approved Prophylactic HPV Vaccines

Diane M Harper

Disclosures

Expert Rev Vaccines. 2009;8(12):1663-1679. 

In This Article

Safety

Safety documentation is a priority in all phases of the vaccine clinical trials. Safety is categorized as local reactions from the injection itself and as systemic reactions that may occur throughout the trials. The randomized, controlled trials are the appropriate mechanism for determining safety in general for the regulatory licensure process. Postlicensure surveillance is critically important for population-based safety because the more rare adverse events cannot be detected until millions of doses have been administered.

In general, the randomized, controlled trials have shown that both vaccines are safe for the vast majority of recipients when considering pregnancy-related outcomes, fetal and infant morbidity and mortality, as well as new onset of chronic or autoimmune diseases. However, serious adverse events do occur at a low frequency that must be disclosed to the parents and young women prior to vaccination. It is possible that with whole genome-scanning, transcriptomics, epigenetics, proteinomics and newly associated biostatistical approaches, individuals will be screened prior to vaccination to avoid serious adverse events (immunogenetics). Entire populations may be classified by immunogenomics to identify groups of people who are at the highest risk from serious adverse events from vaccination. Despite low-frequency occurrences, the fact that serious adverse events have been reported means that individuals, if not entire subpopulations, will be able to be identified prior to vaccination for maximal vaccine safety.[56]

The safety data for 10–14-year-olds were documented from a study of 158 young adolescent girls for Cervarix, and from a study of 1123 girls 9–15 years of age for Gardasil, both studies ending at 1 year after the three-dose series was completed.[51,52,54] The local adverse events reported within the first 5–7 days after vaccination in the adolescent ages included pain in 75–80%, erythema in 20–35% and swelling in 20–30% of the recipients. These local adverse events occurred in the same proportion in the 16–26-year-old women.

Systemic adverse events in the trials of adolescents and young women were reported within 30 days of vaccination and then at intermittent follow-up visits throughout the studies. The most commonly reported adverse events were myalgias, arthralgias, headaches and gastrointestinal symptoms, which occurred equally often in those receiving the control injection.[17,26]

The serious adverse events were those medical events that resulted in hospitalization, disability, congenital anomaly or death. Only Gardasil has been subjected to postmarketing surveillance through the US-based Vaccine Adverse Events Reporting System (VAERS), as Cervarix has just been approved in the USA. The VAERS has limitations. If a positive association is found statistically between the events and receiving Gardasil, the association exists. However, the association, ipso facto, does not mean causation. Likewise, when no association is found in the analysis of VAERS, there is no reassurance that an association is not present as VAERS is insignificantly powered. Of all the adverse events reported to VAERS, Merck was responsible for 68%, an unusually high proportion of reports coming from industry rather than the physician, patient, pharmacist or other reporter. Frustratingly for the US FDA, 89% of the reports Merck submitted did not contain sufficient information for the US CDC to evaluate; this includes four of the cases of death.[57]

Anaphylaxis has been reported at a rate of 2.6 per 100,000 doses in an Australian school-based national vaccination program.[58] Although rare and methodologically disputed by critics,[59] this incidence rate is higher than that associated with other routinely given vaccines in this age group. The only published report shows that syncope and venous thromboembolism are occurring at frequencies statistically higher than expected in the general population.[60] FDA warnings about syncope have been issued since 2007 to prevent the falls, contusions, fractures, concussions, lacerations and intracerebral hemorrhages that have ensued after loss of consciousness.

The other remarkable serious adverse events include 12 verifiable cases of Guillain–Barré syndrome (GBS), which were confirmed by the Clinical Immunization Safety Assessment (CISA) network of six academic centers whose mission is to research vaccine adverse events.[106] Of these, nine cases manifested within 41 days of vaccination, the biologically plausible timeframe for GBS to occur. Four cases occurred in women where Menactra™ (MCV4) and Gardasil were coadministered. A preliminary analysis by the Vaccine Safety Datalink, a CDC-sponsored surveillance group based at eight managed care organizations throughout the USA, did not find a statistically significant increased risk for GBS in persons who received Gardasil compared with a historic reference population.[107] Nevertheless, Merck has revised the quadrivalent and pentavalent HPV vaccine study consent forms to include a possible low-frequency increased risk of GBS in study participants. If there are multiple opportunities to vaccinate young girls, it would seem wise to separate their vaccinations to different days, to lessen the likelihood of unknown adverse interactions.

Less frequently occurring motor neuron diseases resulting in permanent disability or death have been reported after Gardasil use as well. These events are very rare, but the incidence of juvenile amyotrophic lateral sclerosis (ALS) in the general population, a uniformly fatal disease, is also very rare, at rates similar to the incidence of reported ALS-like symptoms triggered after Gardasil injection. There are four confirmed cases of ALS-like syndromes after Gardasil injection, with two of the four girls already dead [Shapiro B, Pers. Comm.]. Other rare demyelinating, autoimmune diseases and other events have been reported in low frequencies.[61–68]

Pregnancy Concerns

Clinical recommendations for vaccine administration are split into three conditions:

  • Do not vaccinate a woman during pregnancy

  • If she has received one dose prior to pregnancy, the series of three doses can be restarted after delivery

  • If she has received two doses prior to pregnancy, the final dose can be given after delivery

There is no medical reason to interrupt a pregnancy owing to partial vaccine administration. There are no contraindications to vaccination during lactation. Some would suggest immediately starting the vaccination series postpartum as an effective strategy to ensure completion of the three doses as she will already be interacting with the medical profession for her infant follow-up visits.

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