Debunking myths on genetics and DNA

Sunday, September 8, 2013

The HPV vaccine: a few things you should know

If you are a young woman under 25 years of age, or if you have a teenager at home, chances are, your doctor told you about the HPV vaccine. HPV, or Human Papillomavirus is a DNA virus that infects keratinocytes, cells found in the epidermis and in mucous membranes. Though in some cases the virus causes painful warts, HPV infections are often asymptomatic. So why bother screening an asymptomatic virus? Because while the majority of the infected people clear the virus within 1-2 years, in less than 10% of the cases the infection persists and can, eventually, lead to cancer.

Studies have shown that cancer is linked to persistent infections, and that on average it takes around 5 years to reach a pre-cancer state [1]:
"Persistent infections and precancer are established, typically within 5-10 years, from less than 10% of new infections. Invasive cancer arises over many years, even decades, in a minority of women with precancer, with a peak or plateau in risk at about 35-55 years of age [1]."
Unfortunately, there are no screenings currently available for HPV in men or infections that do not pertain the cervix. For cervical cancer in women, the current recommendation is to get a pap smear every 2-3 years, which has been highly effective in reducing the incidence of HPV-caused cervical cancers.

Like HIV, HPV has a highly diverse subpopulation: there are over one hundred different types of HPV strains, of which, only a small subset (less than 20) are carcinogenic. According to the CDC, about 26,000 cancers every year in the United States are caused by HPV, which is why the CDC recommends teenagers to be vaccinated, girls in particular:
"There are two [FDA-approved] HPV vaccines available (Gardasil and Cervarix) which protect against the types of HPV infection that cause most cervical cancers (HPV types 16 and 18). Both vaccines should be given as a three-shot series. Clinical trials and post-licensure monitoring data show that both vaccines are safe."
Types 16 and 18 are associated with slower viral clearance [1] and have been linked to about 70% of cervical cancers and 85% of anal cancers [2]. Because the vaccines are most effective prior to any exposure to the virus, the current recommendation is to administer the shots within the 13-25 age bracket.

So then the vaccine seems a good idea, right?

I certainly thought so until my friend Alex brought up the news that last June Japan withdrew HPV vaccine reccomendations.
"According to a report in the Japan Times, 8.29 million people had received the HPV vaccine as of December 2012, and there were 1968 cases of concerning adverse events reported as of March 2013. Of these adverse events, 106 were described as "serious cases of pains or body convulsions, pains in joints, or difficulty in walking."
And while all vaccines bring some risks, but the risks are outnumbered by the lives they save, if you do the math you'll find that
"Those numbers translate to a rate of 12.8 serious cases of adverse events per 1 million inoculations, according to the report. This compares unfavorably with the 0.9 serious adverse events per million influenza inoculations in Japan and the 2.1 serious adverse events per million inoculations of inactivated polio vaccine."
So I went back to the CDC page, found that nothing had changed in their recommendations, however, I found a transcript of a CDC press briefing from June 2012, in which a CDC employee claimed that they had found about a dozen US reports similar to the adverse cases reported in Japan, but that no causality had been established.

In the literature, I found a report that advocates for reforms in the Japanese vaccination program:
"This directive [to stop recommending the HPV vaccine] was issued due to fears of adverse events, especially complex regional pain syndrome. However, the present system of reporting adverse events does not follow a systematic process for identifying causality; a rigorous scientific approach is needed to investigate adverse events associated with HPV vaccines. [...] Japan's vaccination system suffers from a failure of governance—also reflected in other aspects of the vaccination schedule. Mumps, adult pneumococcal, rotavirus, and hepatitis B vaccines have yet to be introduced in the routine schedule, even though they are recommended by WHO."
What's the take home message out of all this?

You know I work on HIV vaccine design and I'm a long-time advocate for vaccines. If you look back in time, vaccines have saved far more lives than the supposed adverse effects. Our immune system is a brilliant machinery designed to recognize self from non-self and destroy whatever falls in the latter category. It's built on both genetics (native immunity) and experience (acquired immunity), as it constantly retunes to allow the body to adapt to a changing environment. Messing up with the immune system can have unforeseen, permanent consequences.

It takes decades for a vaccine to go from design to marketing. It needs to be tested on animals before it is tested on humans. The first phase I trials on humans have the sole "safety" objective, in other words, even before we know whether the vaccine is effective in preventive a certain disease, we need to prove it is safe to use and causes non harm. Neither vaccine would have been FDA approved had they not passed all the safety requirements.

This means that if you search the literature, you will find published studies on the safety of for either the Gardasil or the Cervarix HPV vaccines. For example, I found a pooled analysis of 11 cohorts published by Landes Bioscience, in which you can find all statistics of adverse effects, from a common headache to more serious ones. In their discussion, the authors (affiliated with GlaxoSmithKline Biologicals) bring up the fact that there could be a correlation between underlying auto-immune disorders and the reported adverse effects, and that a direct causality with the HPV vaccine, once again, could not be established.

At the end of the day, we are individuals, not statistics. It's fine to read that a certain condition or side effect is so rare it happens once in a billion cases, yet we don't want to be that one in a billion case. HPV is more likely to cause cancer in smokers. Maintaining a healthy life should be our foremost priority. For cervical cancer in particular (which covers the vast majority of HPV-caused cancers), given how long it takes for the virus to establish a persistent infection, doing the pap test every other year will likely catch the infection before it gets to a precancer stage.

Do your homework. Read. Exercise. Eat healthy. Then do more homework. It's your life, make informed decisions.

[1] Helen Trottier, Salaheddin Mahmud, José Carlos M Prado3, Joao S Sobrinho, Maria C Costa, Thomas E Rohan, Luisa L Villa and Eduardo L Franco (2008). Type-Specific Duration of Human Papillomavirus Infection: Implications for Human Papillomavirus Screening and Vaccination Infectious Diseases DOI: 10.1086/587698

[2] Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, & Wacholder S (2007). Human papillomavirus and cervical cancer. Lancet, 370 (9590), 890-907 PMID: 17826171


  1. Is it at all possible that the greater rate of problems in Japan has to do with Japan having a more homogeneous, less diverse population than we have in the U.S.?

    1. sorry, I replied but my comment ended up at the bottom, please scroll down to see it. Thanks, Mike!

  2. Do we even know that there is a greater rate of problems in Japan? I haven't seen any statistics yet. It's quite possible the Japanese government is simply reacting to antivaccinatinist sentiment.

    EE, if you really want to write an objective piece about this, shouldn't you be basing your decision on a comparison of the risk of dying from cancer with and without the vaccine?

    According to about 80%-85% of women aged 18 to 64 already get screened for cancer at least once every three years... yet even so,
    according to , even so, the lifetime risk of dying from cervical cancer is 1 in 435. Your recommendation for everyone to get tested won't make much of a difference, I fear, since by and large they already are.

    Getting vaccined is expected to reduce risk of cancer by about half on average, reducing the lifetime risk of dying from cervical cancer to something like 1 in 900.

    Against these odds, the 1 in a million reported rate of death after vaccination is simply insignificant; your odds are far better if you get vaccinated.

    Your last paragraph is telling: it says "Screw the statistics. Let fear guide you." That's not objective advice - that's emotional, and it's not founded in evidence.

    1. Dan Kegel, I haven't made any decision. If you read carefully through my post, I only state facts (and numbers) I've retrieved from the internet, I give you the source of everything I cite so you can make your own decision. I'm not a physician, so the last thing I want to do is give people recommendations.

      I've looked at the stats of people dying from HPV-caused cancer. They are usually smokers and, in the case of cervical cancer, women who did not take pap smears.

      You make your own conclusions.

    2. Also, you're the one who's not being objective, Dan, because that last paragraph is not even close to what I was saying. If you read that into my words, you're the one who's emotional about this.

    3. I'm a statistician, the last thing you'll ever hear from me is "screw the stats."

  3. Mike Martin, you bring up a good point, but that's the kind of things that are really really hard to prove because it's usually not just one reason, and usually the genetics are so intertwined with environment and behaviors that it is really hard to pull them apart.

    For example, breast cancer is less prevalent in Japan than it is in the US. However, if you follow second generation Japanese women who grew up in teh US, their likelihood to develop breast cancer is the same as US women. With stomach cancer it's the opposite, as it's more prevalent in Eastern Asian countries, but the second generation that grew up in teh US has the same risk as the global US. So, is it genetics or is it environment/behaviors/diet?

    Maybe if we can follow vaccinated people in Hawaii we can find out a bit more about this puzzle, as Hawaiians are mostly of Japanese descent.


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