In the clinical trials for HPV vaccines cervical cancer was not a primary endpoint. An endpoint in a clinical trial is a disease or a symptom of interest. I want to explain why cancer was not an endpoint these efficacy studies. Instead surrogate endpoints were used.
Why not, given that is what the investigators wanted to prevent?
Because you can’t not treat a woman with cervical abnormalities to see if her lesions develop into cancer. That was tried once between 1955 and 1976, didn’t go down well and it led to a fairly monumental change in ethical research practices. For a detailed academic account of the ‘experiment’ check out A History of the Unfortunate Experiment by Medical Historian Lynda Bryder.
The point here is that you cannot monitor a person for cancer then not treat it at the first sign of trouble. So, when the HPV vaccines were being tested for efficacy cervical cancer could not be the endpoint.
So how can you test a vaccine against cervical cancer if you are not measuring cervical cancer?
Because you do not need to. Imagine removing oxygen or the fuel from a fire or the combustion process. In order to even start the fire you need heat. Imagine cervical cancer like a fire. If you remove heat, fuel and oxygen you have no fire.
Almost all (~99.7%), if not all, of cervical cancer is caused by a persistent infection with several particularly nasty types of Human papillomavirus, these are called the oncogenic types. Primarily types 16, 18, followed by 45, 31, 52, and 58, which collectively cause around 98%. Infection with one or more of these viruses is the first essential step. If you avoid infection you avoid cervical cancer, however, most women will become infected at some point in their lives and either clear the infection or not develop disease. But some do.
The next thing that has to happen after infection is the unchecked cell growth (cervical dysplasia) and this happens in stages. These changes are precancerous and like infection, a necessary step on the way to cervical cancer. Some of these lesions will resolve on their own, but not always. Cervical screening programmes have been instrumental in catching disease at this early stage. Many woman have avoided cervical cancer through cervical screening, although I am sure any woman who has been subjected to ablation, cone biopsy, resection of their cervix, or even hysterectomy would vote to avoid both the procedure and the anxiety.
In order to appreciate why the studies used infection, low grade, and high grade abnormalities check out the diagram below. You can see that there is a progression from one stage to the next. If you prevent the first stage or the second etc. cancer cannot develop.
If you want a more detailed description about the progression of cervical cancer check out the Nature Reviews article on the topic. It has a really good diagram.
How long does it take to progress form CIN2/3 to invasive cancer?
For most people it takes an average of 23.5 years with 1.6% taking less that 10 years.
Bit of background
So with all this in mind, to prove that HPV vaccines prevent cancer diagnosis was always going to take time. Time has now lapsed just enough for us to take a peek at cervical cancer among women who participated in the pivotal HPV vaccine clinical trials, those who received the vaccine first and plenty of time to check out the precancerous lesions over a longer period of time.
Cancer doesn’t appear overnight like a frost. Many changes need to occur before a minor infection becomes a minor abnormality, to become a major abnormality, to finally become cancer. Preventing the seemingly benign HPV infection is the first step because virtually all cervical cancer is caused by the human papillomavirus.
A recent follow-up study found none of the woman who received Gardasil in Scandinavia during the clinical trials has developed cervical cancer in a 12-year follow up. While not surprising this is more encouraging news for HPV vaccines.
Who was in the study?
The first women to receive Gardasil did so during the clinical trials. Of the ~23000 trial participants, some came from the Nordic countries where there were 2084 participants available to follow up on the national registries for cancer. The study used what is called ‘person years’ which is effectively the total number of years these participants contribute as a whole to the study. For example the first vaccine recipients have had more time to follow up (12-14-years) than the last ones (≤4-years). There were 13, 7935 person-years in this study.
In order to be able to draw any conclusions the study needed at least 2634 person-years to accrue for at least 4-years. This study actually had 3393 person years over 8-10 years. That means that enough time had lapsed to measure cervical cancer as an outcome. If vaccine efficacy was maintained at least 90% you would expect to see 3 cases of CIN2 or higher in these women.
Among these women vaccinated there were no cases of CIN2 or worse. Even if the vaccine was 90% effective we would expect 3 cases. IN other words, there were no cases of CIN2, CIN3, Adenocarcinoma in situ, cervical cancer, vulval cancer or vaginal cancer caused by HPV-types in the vaccine.
There was one case of CIN1 among these women. This woman began the study positive for HPV type 45 and 51 (cancer causing types). The lesions were positive for HPV 45.
What else do we know about the effectiveness?
Lots. Effectiveness is what happens in the real world after a vaccine gets licenced and implemented into a programme. Here are some key recent findings:
- In Sweden high grade cervical lesions declined by 75% in vaccinated cohort (girls vaccinated when they were under 17years). There were 1,333,691 girls and woman aged 13-29 in this study.
- In the USA where uptake of the vaccine is relatively low there are early indications of effectiveness against high grade lesions which by 2012 were around half the prevalence in vaccinated women compared with unvaccinated.
- In the USA, aside from observing lower rates of high grade lesions among the vaccinated, there has been a 64% decline in the prevalence of the HPV types included in the vaccine among girls and women aged 14-19 years and a 34% decline among the 20-24 year age group.
- In another USA study the prevalence of vaccine type viruses declined by over 90% among the vaccinated females, 32.3% among unvaccinated females with an overall 75% decline among all women.
HPV vaccine is obliterating the infection that causes cervical cancer and the cell changes that lead to cancer. Follow up of girls and women vaccinated first shows no pre-cancer or cancer.
Featured Image: Cartoon representation of the molecular structure of protein registered with 1svm code. Wikimedia Commons.