By Lucija Tomljenovic, PhD
February 1, 2011
All drugs are associated with some risks of adverse reactions and vaccines are no exception. In weighing risks versus benefits, one has to keep in mind that vaccines represent a special category of drugs since they are generally given to healthy individuals. If there are uncertain benefits from a vaccine, only a small level of risk of harmful effects may be acceptable. If the benefits are certain, then a greater risk of side effects may be tolerated. Here I review the current evidence which indicates that the former case applies to Gardasil, the quadrivalent human papillomavirus (qHPV) vaccine:
1) The efficacy of Gardasil in preventing cervical cancer has not been demonstrated and the marketing campaign has been misleading. The efficacy of Gardasil remains unsubstantiated since the vaccine hasn’t been adequately tested on the primary age group to which it is currently given.
Merck promoted Gardasil primarily as a vaccine against cervical cancer, rather than promoting it as a vaccine against HPV infection or sexually transmitted diseases 1.
According to recent reports published in two highly respected scientific journals, Nature Biotechnology and Journal of American Medical Association (JAMA):
“Most genital infections are asymptomatic and resolve spontaneously, but the virus can persist and cause precancerous lesions that can become malignant over the subsequent 20-30 years.“ (Nature Biotechnology, 2007 2)
“So how should a parent, physician, politician, or anyone else decide whether it is a good thing to give young girls a vaccine that partly prevents infection caused by a sexually transmitted disease (HPV infection), an infection that in a few cases will cause cancer 20 to 40 years from now? (JAMA, 2009 3)
The fact is that malignant cervical cancer takes decades to develop 2 3 and yet the longest clinical trial on Gardasil was only four years in duration 4. In other words, Gardasil was never shown to prevent cervical cancer [emphasis added]. Furthermore, in all clinical trials conducted by Merck the cervical intraepithelial neoplasia (CIN) 2/3 precancerous lesion was used as the efficacy endpoint for evaluating the Gardasil 4. What is the problem with using the CIN 2/3 lesion as the standard for efficacy? First, if the marketing claim for Gardasil is that the vaccine “protects against cervical cancer” 1 2 5, then cervical cancer should have been used as the endpoint for efficacy, not a surrogate marker such as a CIN 2/3 precancerous lesion [emphasis added].
Second, in the natural course of cervical cancer, only a small fraction of the CIN 2 lesions will progress to CIN 3 lesions and only a small fraction of CIN 3 lesions will eventually progress to cervical cancer 6. Furthermore, even CIN 3 lesions are heterogeneous 7. Therefore, in any female population (and that includes those who have undergone Gardasil clinical trials) there are many more CIN 2 lesions than a combination of CIN 3 lesions and cervical cancers.
As a result, the vast majority of the “CIN 2/3 or worse” cases used for evaluation of efficacy, and listed in Merck‟s report to FDA Vaccines and Related Biological Products Advisory Committee (VRBPAC Background Document on Gardasil HPV Quadrivalent Vaccine 8), must have been CIN 2 lesions.
In a review of the literature from 1950-1992, it was noted that 60% of CIN 1 lesions regressed, 10% progressed to CIN 3, and only 1% progressed to invasive cancer. The corresponding approximations for CIN 2 were 40%, 40%, 20%, and 5%, respectively. The likelihood of CIN 3 regressing was 33% and that of progressing to invasive cancer was greater than 12% 6.
The author of the study, Andrew G Östör, MD, from the Departments of Obstetrics and Gynaecology and Pathology, University of Melbourne noted 6:
“It is obvious from the above figures that the probability of an atypical epithelium becoming invasive increases with the severity of the atypia, but does not occur in every case. Even the higher degrees of atypia may regress in a significant proportion of cases. As morphology by itself does not predict which lesion will progress or regress, future efforts should seek factors other than morphological to determine the prognosis in individual patients.” [emphasis added]
The above remark leads us to a third reason why a surrogate morphological marker is not an adequate endpoint for assessing the efficacy of cervical cancer vaccines 9:
“CIN 2 is not a true biologic entity but an equivocal diagnosis of pre-cancer, representing an admixture of HPV infection and pre-cancer. The existence of CIN 2 biopsy results as a clinical entity may be the consequence of the inaccuracies of colposcopy and colposcopically directed biopsy, which could result in less than-perfect representation of the underlying disease state.” [empahsis added]
Furthermore, the same report by the National Cancer Institute (NCI 9) states that:
“That CIN2 is the least reproducible of all histopathologic diagnoses may in part reflect sampling error…”
Finally, according to second report by the NCI 10:
“Approximately 40% of undiagnosed CIN 2 will regress over two years” (this also precisely corroborates the findings of the study by Östör)
Gardasil is marketed as the vaccine that prevents cervical cancer 1 2 5.This statement is incorrect. Based on the above NCI findings, we can conclude that the data presented in the VRBPAC Background Document on Gardasil HPV Quadrivalent Vaccine 8 only supports the claim that Gardasil can prevent “an equivocal diagnosis of pre-cancer, representing an admixture of HPV infection and pre-cancer” – about half of which are self-reversing to normal cases and not reflect actual cervical cancer. [emphasis added]
There was yet another important oversight in assessing the efficacy of Gardasil. Most cervical cancers are believed to be linked to infection with genital HPV types 6, 11, 16, and 18 2 3 11. According to NCI, the only reliable HPV genotyping method is a “PCR system with short target sequences” 12 or alternatively, “ ’sentinel-base’ genotyping by PCR” 13 Ironically, these HPV genotyping methods were never used to determine the HPV type associated with precancerous lesions in the clinical trials for evaluation of the efficacy of Gardasil to prevent type-specific HPV infections.
2) Cervical cancer is a rare disease in developed countries which invalidates the recommendations for universal immunization with any HPV vaccine. The incidence of cervical cancer has dropped substantially since implementation of regular Pap screening procedures. Currently, in the US, the death rate from cervical cancer (2.4/100,000 women) is lower than the rate of reported serious adverse events, including death, from Gardasil (3.34/100,000 doses distributed)
The severity of cervical cancer should not be undermined. Advanced cervical cancer is a deadly disease, especially in areas where the resources and infrastructure to fully implement
Papanicolaou (Pap) smear tests are limited such as Latin America, Africa, India and South Asia 2. In the past four decades, industrialized countries such as the US, have cut cervical cancer mortality and incidence rates by 74% largely through the use of the Pap smear 2 [emphasis added].
Thus, as noted by Diane Harper, MD, Professor and Vice Chair, Obstetrics and Gynecology, Community and Family Medicine and Informatics and Personalized Medicine, who conducted the phase 2 and phase 3 trials for Gardasil, authoring their publications, in developed countries such as the US, which have regular Pap screening programs in place, the HPV vaccine will do little to decrease the already very small cancer rate. In fact, Harper noted that if women who are vaccinated stop going for Pap smears, the incidence rate for cervical cancer would increase 14. [emphasis added]