HPV vaccines and cervical cancer – a success in animals is a success for humans

A recent article in the journal Pediatrics reported that vaccination against human papilloma virus (HPV) resulted in a 64% reduction in infections in girls aged 14-19 (1).

The vaccine, Gardasil, came onto market in June of 2006 and protects again four different HPV types: the two most prevalent high-risk viruses, HPV16 and HPV18, and the two most common causes of benign genital warts, HPV6 and HPV11. Protection against HPV16 and HPV18 is particularly important to human health given that these viruses are responsible for 70% of cervical cancers in women – a cancer which caused 270,000 deaths in 2012. The effectiveness of the HPV vaccine is excellent news in our quest to reduce the deadly toll of cervical cancer, and received widespread coverage in the mainstream media.

Vaccination against HPV prevents cervical cancer. Photo: Art Writ
Vaccination against HPV prevents cervical cancer. Photo: Art Writ
Where did the HPV vaccine come from?

As with most medical discoveries, animal research played a vital role in the development of the HPV vaccine, one that is discussed in depth in a recent issue of FASEB’s “Breakthrough in Bioscience” . From rabbits, to mice, to non-human primates, many species were involved in uncovering the link from HPV-cervical cancer and in developing the first effective vaccine.

Early observiations

In the early 1930s, Richard Shope isolated viral particles from wart-like tumors (papillomas) on the Eastern cottontail rabbit. These particles were then applied to non-infected rabbits, and within six to 12 days these rabbits, too, had developed warts. Shope also observed that the warts of the infected rabbits often progressed to cancer after about four months. This was the first animal model showing the progression from viral infection to cancer.

Papillomaviruses are highly species specific. That is, a rabbit papillomavirus will only replicate in rabbits, and a human papillomavirus will only infect humans. As such, an animal model that would effectively grow human papillomavirus was necessary to begin to understand the virus better. Immunocompromised mice (mice that lack a functional immune system) proved to be an effective model in which to grow human papillomaviruses. This breakthrough provided researchers the means understand the virus’s lifecycle as well as the host’s immune response paving the way towards the development of the HPV vaccine.

 Wild rabbit with tumors caused by papillomavirus infection

Wild rabbit with tumors caused by papillomavirus infection

While much was being learned about the biology of papillomaviruses through  animal studies, the demonstration by Harald zur Hausen and colleagues at the University of Freiburg that HPV was present in the majority of cases of cervical cancer suggested that vaccination may provide a means to prevent this deadly disease.

The path to a vaccine against cervical cancer

It wasn’t until the early 1990s that scientists were able to determine what the components of a vaccine should be. Because HPV is a DNA virus, it would have been unsafe to deliver the DNA since it alone is enough to cause cancer. Researchers needed an alternative, and they found that in the discovery of virus-like particles (VLPs), which are multiple copies of the main structural protein of HPV. Injection of bovine papillomavirus capsid protein L1, a protein that forms the outer shell of the virus, was found to induce a strong immune response in rabbits, and that the rabbits produced antibodies that bound strongly to bovine papillomavirus in vitro.  Researchers now needed to determine if delivering the VLPs were safe and effective protecting against HPV.

Because of the species-specificity of the papilloma viruses, animal efficacy trials had to be done with the animal equivalent of the vaccine. Investigators relied upon the biological effects of nonhuman papillomaviruses in nonhuman models to form the groundwork for HPV studies. The  bovine VLP based vaccine was found to  protect against the virus in cattle, and subsequent species-specific versions of the VLP vaccines were tested in rabbits and dogs. The vaccinated animals produced high levels of antibodies and the vaccines were at least 90 percent effective at preventing warts following exposure to papillomavirus. Next, VLPs of human papillomaviruses were tested in nonhuman primates to see if they could induce an immune response, and they did.

Clinical trials with human volunteers showed that the HPV VLP vaccines induced high levels of antibodies against HPV. Women vaccinated in the trials were also protected from persistent HPV infection and precancerous cervical changes. Because of the success in the human trials, Gardasil, the first vaccine against HPV, was approved by the FDA in 2006. In 2015, FDA approved a new version of the vaccine that is effective against nine types of HPV.

The value of vaccines…the need for animal research

The widespread coverage of the study showing the effectiveness of vaccination against HPV in preventing cervical cancer is a sign of how people appreciate  the importance of vaccination to protect against disease, despite ongoing misinformation campaigns  by misguided – and sometimes sadly high-profile – anti-vaccine activists.

Another sign of the importance people place on vaccines play protecting human health from disease comes from the UK, where a petition to the UK Parliament  asking the Government to “Give the Meningitis B vaccine to ALL children, not just newborn babies” has become the most popular UK Government e-petition to date. The UK was the first country to introduce a vaccination programme – with the Bexsero vaccine –  in babies against Meningitis B, and MPs and the government will need to weigh the benefits of increasing protection against the cost of the vaccine carefully.

Whatever their decision, it is good to note that the public recognize the critical role vaccines play in protecting health. They should also remember the critical role played by animal research in vaccine development, indeed, in an earlier post on this blog we discussed the innovative “reverse immunology” approach in mice that led to the development of Bexsero.

While we rightly celebrate the benefits of vaccination, and advocate for vaccines to be made available to all who need them, we should also remember where those vaccines come from, and ensure that the animal research that is so vital to their development continues.

Anne Deschamps

  1. Lauri E. Markowitz, Gui Liu, Susan Hariri, Martin Steinau, Eileen F. Dunne, Elizabeth R. Unger “Prevalence of HPV After Introduction of the Vaccination Program in the United States” Pediatrics, Published Online 19 February 2016. http://pediatrics.aappublications.org/content/early/2016/02/19/peds.2015-1968

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