Gardasil: Does it Work and Is it Safe?

Gardasil is a vaccine made by Merck and it stimulates the immune system to recognize and attack various strains of the human papilloma virus.  Human papilloma virus causes warts, but particular strains of it also cause a sexually transmitted disease called genital warts, which are the beginnings of cervical carcinoma.  One-quarter-of-a-million women die each year, globally, from cervical cancer.

This vaccine has been the center of several political and policy debates.  The Gardasil debate has definitely caught the attention of the country. During the Republican presidential candidate debates, on September 12, 2011, candidates Congressman Ron Paul (TX) and Congresswoman Michele Bachmann (MN) attacked fellow candidate Texas Governor Rick Perry for his executive order to mandate the vaccination of Texas school children.  The next day, Congresswoman Bachmann said, on NBC’s Today Show, “I will tell you that I had a mother last night come up to me here in Tampa, Fla., after the debate and tell me that her little daughter took that vaccine, that injection, and she suffered from mental retardation thereafter.”  As much as I like Michelle Bachmann, that was a pretty astounding statement about this vaccine.

As the father of three girls, two of whom are in high school, believe me, I understand the issue. Parents want to make such significant choices for their families on their own without Big Brother doing it for them. Nevertheless, health care professionals and epidemiologists, who see the 250,000 deaths each year from cervical cancer want to see the herd immunity against human papilloma virus (HPV) to go up so that the carrier rates of this virus will fall. Mandating the vaccination is one way to do that. “Not so fast,” say many parents who have worked very hard to teach their children sexual ethics that are at odds with those of the culture. “We have taught our girls to save sex for marriage and prevented them from being exposed to the oversexed pop culture of modern youth and now you want us to vaccinate them against the rotten fruits of that culture?” It is a fair question.

What gets lost in all this is that the vaccine, Gardasil, made by the pharmaceutical giant Merck, based in Whitehouse Station, New Jersey, does exactly what the company says it does. There have been some movements on the web to discredit Gardasil. For example, The Truth About Gardasil is raising money to make a full-length film about the dangers of Gardasil. Other such campaigns are also found on the web.

On the other hand, journal Nature has summarized the results of the Gardasil trials, Future I and Future II. These trials enrolled 17,600 women across the Americas, Europe, and Asia-Pacific who received the vaccine between December 2001 and May 2003.

The results from these studies are pretty clear and positive. Gardasil, in these women, was 100% effective in preventing genital warts, the precursor to CIN or cervical intraepithelial neoplasia. While there were women diagnosed with CIN or AIS (adenocarcinoma in situ), the numbers were too low to draw any firm conclusions. Gardasil was not able to get rid of HPV in women with established infections at the time of injection, which is no surprise, since it is a vaccine and not a treatment.

Gardasil contains a mixture of peptides (polymers of amino acids) from four different strains of HPV: strains #6, #11, #16 and #18. Strains #16 & #18 are responsible for 70% of all cervical cancer cases globally. Strains #6 and #11 cause 90 percent of all genital warts. Therefore, Gardasil contains a mixture of the most troublesome strains of HPV. There are other strains of HPV that cause cervical cancer. For example, long-term infections with HPV strains #31 and #45 can also cause cervical cancer. Therefore, Gardasil does not prevent all types of cervical cancer. However, in those women who were vaccinated with it, it seems to prevent cervical cancer, at least over the course of 9-12 years.

If lots of women die each year from cervical carcinoma, then surely we should rejoice that many of these women who have been vaccinated will not contract cervical cancer. Men can also contract penile cancer from HPV. Therefore, this vaccination is also being marketed and given to men as well. Mind you, unchecked promiscuity has plenty of other risks and these risks should not be minimized. However, if some women will not die from HPV as a result of Gardasil, it seems to me that this is a good thing.

What about the side effects of Gardasil that are touted on sites like The Truth About Gardasil? In the Future I and Future II studies, there were no serious side effects reported. This is from a global population of young women. Therefore, the side effects mentioned on The Truth About Gardasil website might be 1) particular to those women, which certainly deserves much more research; 2) unrelated to the vaccine; or 3) related to the vaccine but only tangentially.

Should these side effects be ignored? Not at all. The CDC runs a web site where reactions to Gardasil and all other vaccines are monitored known as the Vaccine Adverse Event Reporting System (VAERS). According to this site, there were 12,424 reported adverse events after about 23 million doses of vaccine between June 2006 and December 2008. That’s an adverse reaction rate of 0.054% per dose. Folks, that’s pretty low. Also, if you consider that the vast majority of adverse reactions are really minor (fainting, headaches, sores at the site of the injection that resolve over time), this constitutes a pretty small number of adverse reactions.  The problem is the 32 deaths, but even here, the deaths are the result of embolisms (clots in the bloodstream) and these are caused by other things that are probably not related to the vaccine. The 32 deaths means that Gardasil has a 1 / 1,000,000 deaths per dose rate. This is rate that is so low that is seems very unlikely that the vaccine is causing the deaths, and the proximity of the death to the vaccine is coincidental at best.

Where does this leave us?  The vaccine does what it says it does – prevent cervical cancer from the two major strains of HPV. It is not a cure for it. It is, as far as we can tell to date, safe. The rate of deaths after a Gardasil injection are not higher than immediate deaths in general and that seems to indicate that the deaths are not related to the vaccine. Also, the severe adverse reaction rates are well within the safety levels expected for a good vaccine.

Regardless of your views on whether or not Gardasil should be mandated, you must say that it works and that it is safe. The data support such a conclusion. Therefore, other statements about Gardasil should be about policy and not about the safety or efficacy of the vaccine. Gardasil works and is safe.

For studies on Gardasil, see the following:
1. Future II Study Group N. Engl. J. Med. 356, 1915–1927 (2007).
2. Garland, S. M. et al. N. Engl. J. Med. 356, 1928–1943 (2007).
3. Paavonen, J. et al. Lancet. 374, 301–314 (2009).
4. Future I/II Study Group BMJ 341, c3493 (2010).
5. Munoz, N. et al. J. Natl Cancer Inst. 102, 325–339 (2010).
6. Lehtinen, M. et al. Lancet Oncol. 13, 89–99 (2012).
7. Kreimer, A. R. et al. Lancet Oncol. 12, 862–870 (2011).
8. Donovan, B. et al. Lancet Infect. Dis. 11, 39–44 (2011).
9. Brotherton, J. M. L. Lancet Infect. Dis. (in press).
10. Brotherton, J. M. L. et al. Lancet 377, 2085–2092 (2011).
11. Australia Dept. Health and Aging. National HPV vaccination data for girls aged 15 in 2009. National HPV Vaccination Program (2011).
12. Shearer, B. D. HPV Vaccination: Understanding the impact on HPV disease. (2011).
13. Widgren, K. et al. Vaccine 29, 9663–9667 (2011).
14. Department of Health, UK. Annual HPV Vaccine Coverage in England in 2010/2011.
15. Centers for Disease Control and Prevention Morbid. Mortal. Weekly Rep. 60, 1117–1123 (2010).

Disclosure: I own no stock in Merck, and was neither paid by Merck for this article, nor contacted by them at any time in the writing of this article. These conclusions are mine, and therefore, if you disagree with me, please do not call me a paid shrill for Merck because I am not. Instead, please simply address where in the published data you think I have misunderstood, and I will do my best to respond.

Identifying the Actors Who Play the Part During Reprogramming

A remarkable paper in the journal Nature by Claudia Doege and others (Nature 488, 652-655 (2012)) has revealed the mechanism by which cells are reprogrammed to induced pluripotent stem cells (iPSCs).

Fully differentiated cells have those genes that induce pluripotency (that is, the ability to form any cell type in the adult body) completely shut off (see Takahashi and Yamanaka, Cell 126, 663-676 (2006)). However, if four different genes are introduced into these differentiated cells, namely Oct4, Sox2, c-Myc and Klf4, then the differentiated cell de-differentiates into an iPSC. However, how these genes do this has been rather elusive. However the Doege et al. paper has elucidated our understanding of this process.

To begin, we must understand that gene expression is jointly controlled by two classes of proteins and these include transcription factors, which bind to targets in DNA and activate DNA, and epigenetic regulators that alter the proteins that package DNA (histones). Doege and others have identified two epigenetic regulators called Parp1 and Tet2 that stimulate the expression of the dormant pluripotency genes in differentiated cells that convert them into iPSCs.

What do these proteins do? Parp1 and Tet2 induce the removal of a chemical tag (H3K27me3, for those who are interested) from those histones associated with pluripotency genes and induce the addition of a different chemical tag (H3K4me2, again for the interested). The first chemical tag on the histones shut down gene expression, but the second type of chemical tag induce gene expression.

Doege and his colleagues showed that these epigenetic changes occur before increased expression is detected in two pluripotency genes (Nanog and Esrrb). These epigenetic changes are highly correlated with the binding of the transcription factor Oct4 (also known as POU5F1). Oct4, you see, activates the expression of Parp1, and after the histones are properly modified, Oct4 can bind to the promoter of these genes and activate their expression.

This report shows, for the first time, that epigenetic regulators are equally as important as transcription factors in the status switch from differentiated state to iPSC. According to the accompanying summary of Doege’s article by Kyle Loh and Bing Lim, “reprogramming transcription factors liaise with endogenous epigenetic regulators to execute reprogramming.”

Source – Loh and Lim, Epigenetics: Actors in the cell reprogramming drama. Nature 488,599–600 (30 August 2012); doi:10.1038/488599a

Loh and Lim point out that this work also raises new questions. For example, how do Parp1 and Tet2 specifically activate these pluripotency genes rather than affecting the genome globally? Are there cell-type specific epigenetic regulators? Does this mechanism work for other cell types as well? Does this explain why some cell types become iPSCs so much more efficiently than others? Doege et al. have written an incredible paper that blasts open the door of on our understanding of iPSC formation. This should provide new insights into reprogramming in general.