Major uncertainties over efficacy and safety for costly vaccines that only benefit the drug giants for sure. Prof. Joe Cummins and Dr. Mae-Wan Ho
Two years ago we reported on recombinant vaccines against the human papilloma virus (HPV) infection and cervical cancer [1] (Recombinant Cervical Cancer Vaccines, SiS 29). Clinical trials had been completed on two vaccine formulations, and these are being commercially released worldwide in government sponsored vaccination programmes that target women and girls (and even boys) as young as 9 years of age in a bid to prevent cervical and anogenital cancers [2]. This has aroused a great deal of controversy, which calls for a fuller discussion.
According to the US government’s National Cancer Institute [3], human papillomaviruses (HPVs) are a group of more than 100 viruses. Certain types cause warts or papillomas that are benign. The HPVs that cause the common warts on hands and feet are different from those that cause growth in the throat or genetial area. Some types are associated with cancer, and are called “high risk” HPVs.
Of the more than 100 types of HPVs, over 30 can be passed through sexual contact. Most HPV infections occur without any symptoms and go away without treatment over the course of a few years. However, HPV infection sometimes persists for many years, with or without causing detectable cell abnormalities.
Infection with certain “high risk” types of HPV is the major cause of cervical cancer. Almost all women will have HPV infections at some time in their lives but very few will develop cervical cancer, as the immune system of most women will usually suppress or eliminate HPVs. Only HPV infections that persist can lead to cervical cancer. An estimated 11 000 cases of this kind of cancer is diagnosed in 2007 in the United States, with less than 4 000 deaths; so cervical cancer is not among the major cancers in the US. Worldwide, cervical cancer strikes nearly half a million women each year, claiming more than a quarter of a million lives.
High risk” HPV types 16 and 18 are implicated in 70 percent of cervical cancers and are hence selected for vaccine targets.
The two vaccines are prophylactic, that is, they prevent cervical cancer but do not cure existing infections. They are based on the L1 virus-like particles that are required to achieve immunity against HPV. The L1 protein is capable of self assembling to form empty virus like particles which activate the human immune system to form antibodies. The HPVs targeted by the vaccines are “high risk” types 16 and 18 and “low risk” types 6 and 11. The two commercial HPV vaccines are Gardasil, manufactured by Merck, and Cervarix, manufactured by GlaxoSmithKline. Both are made using genetically modified (GM) microbes in a laboratory.
Gardasil protects against all four HPV types because it contains virus like particles with mixtures of the four subunit proteins, and is called a tetravalent vaccine. The vaccine contains an aluminum adjuvant. Protection requires a first inoculation and booster shots at .1 and 6 months after the first. The four L1 proteins are manufactured using GM baker’s yeast.
Cervarix protects against the HPV types 16 and 18, and is a bivalent vaccine containing an aluminum adjuvant along with a compound called 3-O-deacyclated-4’-monophosphoryl lipid A. Vaccination is repeated at 1 and 6 months after the first injection. The vaccine is manufactured using GM baculovirus produced in cultured insect cells [4].
A 2007 study [5] found that the prevalence of HPV infection among females in the United States was 26.8 percent in a sample of 1 921 individuals between 14 to 59 years: 23.3 percent were among 652 females aged 14 to 19 years, 44.8 percent among 189 women aged 20 to 24 years, 27.4 percent among 174 women aged 25 to 29 years, 27.5 percent among 328 women aged 30 to 39 years, 25.2 percent among 324 women aged 40 to 49 years, and 19.6 percent among 254 women aged 50 to 59 years. There was a statistically significant trend for increasing HPV prevalence with each year of age from 14 to 24 followed by a gradual decline thereafter.
HPV vaccine types 6 and 11 (low-risk types) and 16 and 18 (high-risk types), however, were detected in only 3.4 percent of females: HPV-6 in 1.3 percent, HPV-11 in 0.1 percent, HPV-16 in 1.5 percent, and HPV-18 in 0.8 percent. Independent risk factors for HPV detection were age, marital status, and increasing numbers of lifetime and recent sex partners. The relatively low prevalence of the vaccine types observed in the study questions the value and effectiveness of the vaccination programme in the United States
In comparison, the HPV prevalence observed in Pap smears of the women in a rural Nigerian village showed 21.6 percent had HPV, and high risk HPV was present in 16.6 percent of the women [6].
While previous reports showed a remarkable 100 percent efficacy of the tetravalent vaccine in women with no previous exposure to the vaccine types of HPVs, reports on two large, ongoing randomized, placebo-controlled trials give a fuller picture [7, 8], which elicited an Editorial comment in the New England Journal of Medicine [9].
On account of the rarity of incident cervical cancer, precancerous cervical lesions are used as surrogate outcomes for cervical cancer. Adenocarcinoma in the cervix is a rare lesion widely considered a precursor of cancer. Cervical neoplasia (abnormal cell growth) is graded from 1 to 3. Grade 1 indicates active HPV infection and is not considered to be pre-cancerous; current guidelines discourage treatment of this condition. Grade 2 is treated in most women but is not an irrefutable cancer surrogate, as up to 40 percent of such lesions regress spontaneously; current guidelines suggest that some young women with such lesions do not need treatment. Grade 3 cervical neoplasia has the lowest likelihood of regression and the strongest potential to become cancerous. The US Food and Drug Administration considers grade 2 and 3 cervical lesions and adenocarcinoma acceptable surrogate outcomes for cervical cancer, while others consider only grade 3 and adenocarcinoma to be more appropriate surrogates.
The trials were called Females United to Unilaterally Reduce Endo/Ectocervical Disease (Future) I and II. In FUTURE I trial, the rates of grades 1 to 3 cervical neoplasia or adenocarcinoma per 100 persons were 4.7 and 5.9 in vaccinated and unvaccinated women respectively. This is a very modest efficacy of 20 percent; moreover, the reduction was largely attributed to the reduction of grade 1 cervical lesions, and no efficacy was demonstrated by higher grade disease. Vaccinated women also had lower rates of external anogenital and vaginal lesions (1.3 vs 2.1).
In the larger FUTURE II trial, the rates of grade 2 or 3 cervical neoplasis or adenocarcinoa were 1.3 in vaccinated women and 1.5 in unvaccinated women, an efficacy of 17 percent, and only significant for grade 2 neoplasia, not for grade 3 neoplasia or adenocarcinoma.
The low efficacy is due to two factors. First, 93 percent of FUTURE II subjects were nonvirgins. In contrast to the Centers for Disease Control’s guidelines, the American Cancer Society does not recommend universal vaccination among women between 18 and 26 years, on ground of probable diminished vaccine efficacy as the number of lifetime sexual partners increases. Second, at least 15 oncogenic (cancer associated) HPV types have been identified, so targeting just two types may be insufficient. FUTURE II trial found that the contribution of nonvaccine HPV to overall grade 2 or 3 cervical neoplasia or adenocarinoma was considerable. In contrast to a plateau in the incidence of disease related to HPV types 16 or 18, among vaccinated women, the overall disease incidence regardless of HPV type continued to increase over time, raising the possibility that other oncogenic HPV types have taken over after types 16 and 18 were eliminated. An interim report submitted to the FDA showed a disproportionate, though not statistically significant number of cases of grade 2 or 4 cervical neoplasia related to nonvaccine HIV types among vaccinated women.
Nothing can be inferred from the trials about the potential effect of vaccination among girls younger than 16, as the trials did not enrol subjects in this age group. Within these trials, subgroups of subjects with no evidence of previous exposure to relevant vaccine HPV types were evaluated separately for vaccine efficacy. In these subgroups, efficacy of nearly 100 percent against all grades of cervical neoplasia and adenocarcinoma were reported. However, the overall rates of grade 2 or 3 neoplasia or adenocarinoma regardless of HPV types were not given. Without these data, the Editorial stated [9]: “it is difficult to infer both the effectiveness of vaccination and the role of nonvaccine HPV type in overfal rates of precancerous lesions.”
So, despite the vaccination, the women still need to continue cervical cancer screening, on account of the risk of exposure to other oncogenic HPV types and the unknown duration of the anti-HPV immunity. Caution is needed in view of the unanswered questions, and adverse effects that may emerge, and longer term studies are called for.
More than a year later, another Editorial in the same Journal repeated these warnings, as no longer-term results from the studies have been published [10]. And in the meantime, there has been pressure on policymakers worldwide to introduce the HPV vaccine in national or statewide vaccination programmes. “How can policymakers make rational choices about the introduction of medical interventions that might do good in the future, but for which evidence is insufficient, especially since we will not know for many years whether the intervention will work or – in the worst case – do harm?”
Adverse results following clinical trial or the vaccination programmes must be reported to the government. The United States FDA and Center for Disease Control published compilations of the adverse reports associated with Gardasil [11]. Merck distributed over 16 million doses of Gardasil up to June 2008, and. 9 749 adverse events were reported: 94 percent classified as non-serious, and 6 percent serious. Non-serious events included fainting, pain at the injection site, headache, and nausea. Serious events totalled 589, and included 20 deaths following inoculation but these were explained away “by factors other than the vaccine” following autopsy. Guillian-Barre syndrome (an autoimmune disease affecting the nervous system) was observed in individuals vaccinated but the disease was claimed to have appeared at the normal frequency for a large population. Blood clots were reported in some people vaccinated but those individuals were found to be taking oral contraceptives known to cause blood clotting at low frequency. So according to the FDA: “Gardasil continues to be safe and effective, and its benefits continue to outweigh its risks.”
Others disagree. The Washington DC based group Judicial Watch wants further investigation of the vaccine’s safety [12]. Because adverse reactions to medication tend to be underreported, the actual number is likely to be higher. Gardasil was fast-tracked and received FDA approval before its final safety evaluation trials were complete, and its final safety evaluation trials won’g be concluded until September 2009. Despite this, the drug is being aggressively mass-marketed on TV and at the movies in adverts pitched to young girls, including preteens, and state legislators were heavily lobbied to make the drug mandatory for school girls ages 11 and up. Parents are understandably reluctant to give the shots to daughters who are not yet sexually active, and the long-term impacts of which are entirely unknown.
Judicial Watch’s own report of adverse events include “vomiting, dizziness, seizuresw, paralysis and Guillain-Barre Syndrome, swelling at the injection site and in lymph nodes in the neck and goin, fevers, hives, shortness of breath, nausea and flu-like symptoms. There were reports of a sudden appearance of blisters on a 20-year-old’s upper arms and back and anogeniotal warts on a 12-year-old. A 15-year-old reported blisters in her vaginal area within two days of receiving the vaccine that spread to her upper body and behind her ears and knees. These lasted five to seven days, then developed scabs. The Judicial Watch report recorded only 18 deaths, 11 occurred less than a week after the girl had received the vaccine, seven in less than two days.
Judicial Watch highlighted 78 cases of groin and genital warts, “which weren’t supposed to happen considering that Gardasil is a vaccine against the two strains of HPV that caused 90 percent of such outbreaks.”
Cervarix is dispensed in Britain, and has been receiving adverse event reports since April 2006. For the most part, the reports were deemed to be unimportant. Interestingly, 870 women became pregnant during the clinical trials of Cervarix and the spontaneous abortion rate was not elevated. Nevertheless, pregnant women are advised not to take the inoculations. Serious adverse events such as swelling of the lymph nodes and cardiac disorders were observed at very low frequency, but were deemed not to have been caused by the inoculation [13]. The adverse event reports are significant but presumed not as serious as the cancers being prevented by the inoculation.
Vaccination with the HPV 16/18 L1 vaccine provides no benefit for women with pre-existing infection [14], and may leave them more susceptible to other oncogenic HPV types [9]. Pre-screening the potential vaccination candidate for HPV DNA would be desirable, but is not done. DNA screening proved superior to Pap tests in identifying infected individuals. Pap testing was 55 percent effective while the DNA tests were 95 percent effective in identifying high grade cervical neoplasia (precancerous lesions). The two tests combined were 100 percent effective in identifying the neoplasia [15]. The long term effectiveness of the HPV L1 vaccine is uncertain and may require booster shots later in life [10]. Currently, the cost of the vaccine is an obstacle to global deployment of the HPV L1 vaccine. Gardasil costs US$360 for the required three doses while Cevarix costs $ 33 5 [16 ]. The production cost of the Gardasil active ingredient is around $3 million per gram, which seems a bit pricey for yeast fermentation. Producing edible vaccines in transgenic crop plants is being posed as a cheaper alternative, but that approach is beset with problems of contaminating our food crops as well as drinking water and the general environment [1].
HPV infection is common in males as well as females, indeed males are a major source of female infections and vice versa. Vaccination young males would not only protect them against HPV but would also prevent much of the infection of females. In the United States, the infection of males with HPV was 31 percent of cancer causing virus infection at any given time. About 75 percent of infected men were clear of infection a year after the initial detection of infection [17]. The overall prevalence of HPV infection in men living in Brazil, Mexico and the United States was 62.5 percent. HPV prevalence was higher in Brazil than in the United States and Mexico [18]. HPV 16 and 18 are implicated in human penile carcinomas. The progression of penile and cervical cancers follows a similar course [19]. The association of HPV DNA with several different anogenital cancers other than cervical has been reported for the vulva, vagina, anus and penis. HPV DNA has also been identified in head and neck cancers in the oral cavity, the oropharynx and the larynx in both sexes. In men, 80-85 percent of anal cancers and close to 50 percent of penile cancers are associated with HPV16 infection [20]. HPV associated oral cancers are correlated with oral sex in both males and females. The majority are associated with HPV 16, and it is suggested that they could be prevented by vaccination with HPV L1 [21].
Much uncertainty and controversy over safety and efficacy surrounds the two HPV vaccines currently being marketed and promoted worldwide. They are also more expensive than they should be.
More long-term studies on efficacy and safety are needed before they are widely introduced, or worse, mandated by government.
Producing oral HPV vaccines using transgenic crop plants released into the environment too dangerous to be considered because the transgenes from the modified plants are likely to pollute the food supply. Such inadvertent and persistent oral vaccination would likely cause the human s to develop oral tolerance to HPV allowing the virus to thrive in them.
Article first published 05/01/09
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