In 1976, Harald zur Hausen, a German physician and researcher, first proposed that human papillomaviruses (HPVs) were the cause of cervical cancer. This hypothesis was controversial as the few known HPVs all caused benign skin warts. Additionally, many scientists believed that herpesviruses were implicated in cervical cancer and that the poorly studied HPVs were unlikely candidates for cancer agents. Nonetheless, zur Hausen persisted in his studies and was eventually proven correct. Over the 20 years following his initial proposal, work from zur Hausen and many other laboratories irrefutably established that virtually all cases of cervical cancer arose from infection with certain HPVs known as the high-risk types. Prominent among this high-risk group are HPVs 16 and 18, both discovered by zur Hausen (note that HPVs are numbered according to the order of their discovery: HPV 1, HPV 2, etc.). Together, types 16 and 18 account for nearly 80% of all cervical cancer cases with the remaining cases due to a variety of less common high-risk HPV types (types 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68). For his insight and scientific discoveries, Dr. zur Hausen shared the Nobel Prize in Physiology or Medicine in 2008.
To date, more than 200 HPV types have been identified. Of these 200, roughly 40 are classified as genital types which can infect the genitalia and the oral region. These genital types are transmitted via sexual activity and infection with one or more of these viruses typically occurs once an individual becomes sexually active. Fortunately, most genital HPVs are benign and cause only harmless warts, and the risk for cancer is only associated with infection by one of the high-risk HPV types. Even with high-risk infections, most women’s immune system eliminates the virus and they are not in danger of cervical cancer. However, in some women, the virus remains for years to decades, and these persistent infections can cause changes in the infected cells that lead to the development of cervical cancer. Currently, there is no antiviral treatment for these persistent infections, although regular Pap smears can detect cervical abnormalities in the early stages when they are treatable by removal of the precancerous tissue.
One of the most significant achievements in papillomavirus research was the development of an effective vaccine that prevents infection with selected HPVs. The HPV vaccine is quite simple and consists of a purified viral surface protein (part of the capsid) known as L1 (since the vaccine is only a protein and lacks any virus, it cannot cause HPV infection). L1 proteins differ somewhat between each HPV type, so a vaccine must include multiple L1 proteins if it is trying to protect against multiple HPVs. The first licensed vaccines, Cervarix and Gardasil, were targeted against 2 and 4 HPV types, respectively. Cervarix contains L1 proteins for the high-risk HPVs 16 and 18 while Gardasil has L1 for types 16 and 18 plus types 6 and 11 (types 6 and 11 do not cause cancer but do cause genital warts and were included as a bonus). The vaccines work by eliciting antibodies against the included L1 proteins. Upon subsequent exposure to the target virus, the antibodies bind the incoming viruses and render them non-infectious. Numerous clinical studies proved that both vaccines were highly effective at preventing infections by high-risk HPV 16 and 18. More recently, Gardasil9 was released to protect against types 6, 11, 16, and 18 along with 5 additional high-risk types: 31, 33, 45, 52, and 58.
The HPV vaccines were designed to prevent high-risk PV infections with the assumption that decreasing infections would ultimately reduce the number of cervical cancer cases. However, cervical cancer usually develops years to decades after HPV infection, so gathering data on cancer reduction is a long-term effort compared to just assessing the prevention of HPV infection. With the vaccines first being introduced in 2006 (Gardasil) and 2007 (Cervavix), we have just reached the point at which reliable comparisons can be made for the number of cervical cancer cases in vaccinated versus unvaccinated women. A British study, published in the journal “Lancet”, provides a first look at such comparisons. The study examined a cohort of 12 to 13-year-old girls given 3 annual doses of Cervarix starting in 2008. Cervical cancer incidence in this cohort over the 10 years since the last vaccination was contrasted with a similar cohort of unvaccinated girls of the same age group. The vaccinated group showed a remarkable 87% reduction in cervical cancer cases compared to the unvaccinated group. These are some of the very first data demonstrating that preventing high-risk HPV infection does protect against cervical cancer as predicted, although larger studies that continue for many years will be needed to completely confirm the vaccine benefits. Note that the cases that did occur in the vaccinated group were likely due to high-risk HPVs other than types 16 and 18 since only these two types are included in the Cervarix vaccine. The currently used Gardasil9 that protects against 7 high-risk types should even further reduce cervical cancer cases. These are exciting confirmatory results that should promote even more widespread adoption of HPV vaccination. The CDC currently recommends that all boys (boys can catch and spread HPV) and girls be vaccinated starting at age 11-12 (though it can be begun as early as age 9). Anyone up to the age of 26 who wasn’t vaccinated at an earlier age should also start the vaccination process. Individuals between 27-45 years old should consult with their physician about their need for vaccination. With universal HPV vaccine coverage, there may come a time when cervical cancer becomes merely a historical footnote rather than an ongoing concern for women.
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