Definitions of medical terms used in this article
- abnormal tissue
- CIN 2 and CIN 3
- cervical intraepithelial neoplasia
- stages 2 and 3
- precancerous conditions, with 3 being
a more advanced stage than 2
- cervical adenocarcinoma in situ
- a precancerous condition one stage further advanced than CIN 3 and the last stage prior to cervical cancer
- VIN 2/3
- precancerous conditions, stages 2 and 3, of the vulva
- VaIN 2/3
- precancerous conditions, stages 2 and 3, of the vagina
by Susan Fletcher, BSc
“Gardasil is designed to prevent HPV 6-, 11-, 16- and/or 18-related cervical cancer, cervical dysplasias, vulvar or vaginal dysplasias, or genital warts.”
“The jury is out” says McGill University epidemiologist, Abby Lippman regarding the possible increased risk of cancer for females already infected with HPV vaccine-type virus at the time of vaccination. Obstetrician/gynecologist and editor of the New England Journal of Medicine (NEJM), George Sawaya, agrees.
However, an anonymous “HPV expert” consulted by a Deputy Editor of the Canadian Medical Association Journal (CMAJ) told her there’s no way the FDA would have approved Gardasil if this were so. Yet, there they are, written in two FDA documents submitted by Merck: tables which show a -44.6% efficacy against (i.e. a 44.6% increased risk of) precancerous conditions CIN 2 and 3 or worse amongst females who had tested seropositive (an indication of previous infection) and PCR positive (which shows ongoing infection) for vaccine-type HPV infection at initial vaccination.
Due to the “expert” opinion and despite having made revisions in order to eliminate anything that could possibly elicit lawsuits, my letter re the possible risk was initially rejected by the CMAJ Letters Committee. However, my vigorous objections changed their minds. The letter, as follows, was posted online:
Accurate testing imperative before administering HPV vaccine
FDA licensing applications for HPV vaccine showed a possible increased risk of cervical cancer in trial subjects who had been tested immediately prior to initial vaccination and found to be infected with any of the four HPV types in the vaccine. A negative efficacy, -44.6%, against HPV 6/11/16/18 CIN 2/3 or worse was found.
As well as females who are sexually active, females of any age may be infected with HPV and therefore at risk from HPV vaccine. HPV may be transferred mother to daughter at birth; through sexual molestation; and through other skin-to-skin contact (eg during innocent genital exploration between children). Regardless of age, only those females who have been recently tested using highly accurate testing methods and found to be free of infection with any of the four vaccine-type HPVs should be considered candidates for vaccination with HPV vaccine.
- VRBPAC Background Document; Gardasil™ HPV Quadrivalent Vaccine May 18, 2006 VRBPAC Meeting: 13-15. Available online (accessed 12 Jan 2008).
- Clinical Review of Biologics License Application for Human Papillomavirus 6, 11, 16, 18 LI Virus Like Particle Vaccine (S. cerevisiae) (STN 125126 GARDASIL), manufactured by Merck, Inc.: 168, 201, 364. Available online (accessed 12 Jan, 2008).
This evidence was first made known to me by Cynthia Janak’s article of Dec, 2007 and confirmed by references received from Hilary Butler. But although it’s compelling, it must be seen in context. It comes from an analysis of a small subgroup of 293 trial subjects from the FUTURE I Study that was included in the licence application for Gardasil. This subgroup study appears to have had some imbalance between test group and placebo group regarding risk factors for cervical cancer. Merck submitted a second analysis of a much larger subgroup of the FUTURE I Study with 1349 trial subjects. These had tested PCR positive and/or seropositive for vaccine-type HPV at the time of initial vaccination. Despite the fact that this analysis included some subjects who were not infected with vaccine-type HPV at initial vaccination and it was a much larger subgroup, it still showed a substantially negative efficacy (increased risk) of -33.7%. Nevertheless, the excuse of imbalance continued to be made.
In May, 2007, after the vaccine had been approved in USA and Canada, the FUTURE II Study was published in the NEJM. In females who were seropositive and PCR positive for vaccine-type HPV at the time of initial vaccination, a subgroup study of 630 subjects showed a very minor positive efficacy, 1.2%, against precancerous conditions similar to those tested for in the FUTURE I subgroup study which had shown the -44.6% efficacy.
Abby Lippman notes a study in the August, 2007 Journal of the American Medical Association which found that HPV virus cleared from infected females at similar rates whether or not they were vaccinated. This, she says, should give us some comfort in that the vaccine appeared to not slow down viral clearance. On the other hand, as the study’s conclusion admits, the vaccine “should not be used to treat prevalent infections.” Lippman remains supportive of a moratorium on school-based HPV vaccination programs.
As well as the remaining possibility of cancer risk from the vaccine, The FUTURE Studies showed other areas of concern. Some of these are summarized by Sawaya and Smith-McCune, MD, PhD in their May 10 NEJM editorial about the Future II Study. They ask, “Why is vaccine efficacy modest in the entire cohort?” A low-medium efficacy of only 44% was found for all women randomized; some of these were infected (with HPV types of any kind) at the time of initial vaccination, others were not. The editors suggest vaccine-type HPV infection at initiation of vaccination may have precluded efficacy and contributed to the modest overall result. And they suggest a second possible reason for the modest efficacy: the relative predominance of HPV strains may have changed since the vaccine was formulated, and especially since its use began, one and a half years ago. (This may be even more concerning than a current risk of cancer directly from the vaccine.) The editorialists say, “In contrast to a plateau in the incidence of disease related to HPV types 16 and 18 among vaccinated women, the overall disease incidence regardless of HPV type continued to increase, raising the possibility that other oncogenic HPV types eventually filled the biologic niche left behind after the elimination of HPV types 16 and 18. An interim analysis of vaccine trial data submitted to the FDA showed a disproportionate, but not statistically significant, number of cases of grade 2 or 3 cervical intraepithelial neoplasia related to nonvaccine HPV types among vaccinated women. Updated analyses of data from these ongoing trials will be important to determine the effect of vaccination on rates of preinvasive lesions caused by nonvaccine HPV types.” Also in regard to the possible shifts in prevalence of HPV strains, they note “the surprising report of vulvar cancer in a 22-year old trial participant who received the vaccine; vulvar cancer is rare (overall incidence, 2.2 cases per 100,000 persons) and occurs at a median age of 68 years in the United States.”
The Gardasil licence application submitted to the FDA showed that Merck’s HPV vaccine development program was given “fast track designation” and that the FDA had agreed to grant a “priority review”. Upon reviewing the application, Nancy Miller, MD, was concerned about the FUTURE I subgroup analyses which showed increased risk, but said, “it is difficult to make any conclusion regarding these data”. She said, “The sponsor has committed to following these subjects over time and evaluate for development of disease in the post-marketing studies.” Miller’s review is dated June 8, 2006.
Seven postmarketing studies and reports committed to by Merck are listed in the FDA ‘Product Approval Information – Licensing Action’, also dated June 8, 2006. (Note that, according to Health Canada, “the median time from acquisition of infection to the development of cervical cancer is greater than 20 years.”):
- A short-term safety surveillance in a US Managed Care Organization. “The study will include approximately 44,000 vaccinated subjects who will be followed for 60 days for assessment of general short-term safety (i.e., emergency room visits, hospitalizations, and deaths). The subjects will also be followed for 6 months subsequent to vaccination for new autoimmune disorders, rheumatologic conditions, or thyroiditis. Also, a sufficient number of children 11-12 years of age will be studied to permit an analysis of safety outcomes. …The final study report will be submitted by September 30, 2009.”
- Assessment of long-term outcomes for efficacy and viral shift using cancer registries in four countries in the Nordic Region (Sweden, Norway, Iceland, and Denmark). “In this study, approximately 5,500 subjects…will be followed for a total of 14 years. Two major goals of this study are: 1) to assess the long-term effectiveness of GARDASIL® by evaluating biopsy specimens for presence of HPV 6/11/16/18-related incident breakthrough cases of CIN 2/3, AIS and cervical cancer, VIN 2/3 and vulvar cancer, and VaIN 2/3 and vaginal cancer; and 2) to assess whether administration of GARDASIL® will result in replacement of these diseases due to vaccine HPV types with diseases due to non-vaccine HPV types. …The final study report will be submitted by December 31, 2018.”
- A study to assess the impact of HPV vaccination on the following (This to be done in Norway if it adopts a national program for HPV vaccination, otherwise Merck will have to “propose alternative approaches to obtain this information in a timely manner.”): “The long-term burden of HPV disease including the incidence of HPV 6/11/16/18-related cervical disease; The long-term burden of HPV disease caused by types other than HPV 6/11/16/18; The overall incidence of cervical HPV disease; The incidence of HPV-related cancers and pre-cancers (CIN 2/3, AIS and cervical cancer; VIN 2/3 and vulvar cancer; and VaIN 2/3 and vaginal cancer); The interaction between administration of GARDASIL® and pregnancy outcomes, especially congenital anomalies [birth defects], by linking the vaccination registry with the Medical Birth Registry. …The final study report will be submitted 8 years after study initiation.”
- Final Clinical Study Reports (CSRs) for studies begun in 2003. This should have included final reports on the FUTURE I subgroups which had shown the -44.6% and -33.7% efficacies (44.6% and 33.7% increased risk). In her review of Merck’s 2006 US licence application, Nancy Miller wrote “The sponsor [ie, Merck] has also agreed to conduct additional analyses on the non-naïve subgroups [ie those which were found to be infected with vaccine-type HPV at the time of and/or prior to vaccination] on the close-out of studies 013 and 015 [FUTURE I and FUTURE II studies].” In its pre-licensing review for Gardasil™, Health Canada said nothing about the FURURE I subgroup studies that showed increased risk; it appears that the agreed-upon analyses are either missing or simply not being discussed. In fact, the FDA Gardasil® approval letter only specifies analyses for the possibility of viral shifts that could increase the risks for precancerous conditions and cancers of the cervix, vulva and vagina. It states, “The final reports for these studies (i.e., CSRs) to include the results of these analyses will be submitted by June 30, 2007.”
- Four analyses concerning duration of immunity. The last final study report from these “will be submitted by 2018.”
- The establishment of a pregnancy registry in the U.S. to collect data on spontaneously-reported exposures to GARDASIL® during pregnancy. The FDA specified “annual reports and a final summary report of the U.S. pregnancy registry’s findings five years after initiation of patient accrual/data collection.”
- The report to the FDA and the VAERS contractor of all Gardasil adverse events reports Merck receives (except for those covered by a “15-day Alert report” requirement). This is to continue to June, 2009.
Moira Dolan, MD and others have argued that HPV may not even be the cause of cervical cancer. It’s known that several “risk factors” are associated with HPV infections. Perhaps it’s really these that are the cause of cervical cancer. Or, perhaps, both HPV and risk factors are necessary for cancer to occur. A study from the U of Michigan evaluated how well some factors (an older sex partner, more than three lifetime sex partners, a new sex partner within the past year, and use of illegal drugs within the past year) correlated with HPV infection. It found that, as the number of risk factors increased, vaccine-type HPV infection increased. It also found HPV in a considerable number of women who had none of the risk factors studied. But they may have had other risk factors that weren’t considered in the study. The Canadian National Advisory Committee on Immunization (NACI) lists many others: current and past use of tobacco, not using condoms during sexual intercourse, use of oral contraceptives, previous infection with chlamydia or herpes simplex virus, history of sexual abuse, early age of first sexual intercourse, having never married, not living with a sexual partner, having never been pregnant or having been pregnant but never having delivered a child, having immune suppression and having HIV.
Interestingly, the U of Michigan study found that, among the 3,276 young women who participated in the study, just 6% of the unvaccinated group tested positive for vaccine-type HPV. This may be one more indication of viral shift. Nevertheless, the NACI recommendations for the use of Gardasil remain unchanged since they were first published in Feb, 2007. They are that the vaccine be used for ALL females aged 9 to 26 regardless of whether or not they are sexually active; have had or have HPV infection of any type; have had genital warts; have had positive Pap results; have had cervical cancer; and are immunosuppressed. However, the NACI does make one exception. They say, “Gardasil™ vaccine is not recommended for use in pregnancy.”
The latest push for HPV vaccination comes from HPV Awareness Corporation whose president and spokesperson, Teresa Norris, is on a cross-Canada tour, speaking to young people about the dangers of HPV and ways to protect against the virus. In Feb, 2008 she was telling students in Nova Scotia about her best friend’s struggle with and death from cervical cancer. Her corporation is supported by the Society of Obstetricians and Gynaecologists of Canada, a group which strongly supports the NACI recommendations for Gardasil™ and was the recipient of a $1.5 million grant from Merck.
In those provinces where school-based programs are already underway–
The girls being injected don’t know if they’re infected. Needles are plunging, the virus is jostling. How soon will it be before “the jury” is in?
by Susan Fletcher, BSc
Continued in Part II
- Gardasil® Monograph; Merck & Co, Inc: Whitehouse Station, NJ 08889, USA; October, 2006.
- Personal communication with Dr Abby Lippman and George F Sawaya, MD, Feb, 2008.
- Janak Cynthia A. Gardasil — my error is the smoking gun. Renew America Dec 11, 2007.
- The Future II Study Group. Quadrivalent Vaccine against Human Papillomavirus to Prevent High-Grade Cervical Lesions. NEJM May, 2007; Volume 356: pp 1915-1927.
- Hildesheim, Allan, PhD et al. Effect of Human Papillomavirus 16/18 L1 Viruslike Particle Vaccine Among Young Women With Preexisting Infection. JAMA August, 2007; Volume 298, No 7.
- Sawaya, George F, MD, Smith-McKune, Karen, MD, PhD. HPV Vaccination – More Answers, More Questions. NEJM May, 2007; Volume 356: pp 1991-1993.
- Sawaya, Smith-McKune, The editorialists reply. NEJM Sept, 2007; Volume 357: Correspondence pg 1155.
- Summary Basis of Decision for Gardasil™. Health Canada, Centre for Biologics Evaluation; 2007/03/16.
- Dolan, Moira T, MD. Not so Miraculous. Medical Accountability Network Jan, 2007.
- Dempsey, Amanda F, MD, PhD, MPH et al. Using risk factors to predict human papillomavirus infection: Implications for targeted vaccine strategies in young adult women. Vaccine Dec, 2007; Volume 26, Issue 8.
- NACI Statement on Human Papillomavirus Vaccine. Canada Communicable Disease Report Feb, 2007; Volume 33-ACS-2.
- Regan, Sarah. Teaching from tragedy. The News, Pictou County, Nova Scotia Feb 13, 2008.
- Cassels, Alan, BA, MPA. Lock up your Daughters: Gardasil is on the loose. Common Ground Sept 2007.
Continued in Part II