HPV vaccines currently on the market are meant as a prophylactic to prevent boys and girls as young as 9 from contracting the human papilloma virus and subsequent precancerous lesions that may arise from its more high-risk strains. While the long-term efficacy and concern over reports of serious adverse side effects have embroiled the makers of these vaccines in controversy and litigation, there is another vaccine that may be on the market in the near future. It’s aim: to fight CIN2 and CIN3 lesions caused by active or former infections.
Dr. Diane Harper, of the Family Medicine, Obstetrics and Gynecology at the University of Michigan, the once lead researcher on Merck’s Gardasil vaccine Phase II and Phase III safety and effectiveness studies, is once again resuming her role as a lead researcher for a Phase II study. This time, however, she is studying the effectiveness of a therapeutic vaccine called Tipapkinogen Sovacivec (TS) funded by Roche.
Dr. Harper stepped into the public spotlight in 2009 when she spoke up about concerns regarding Gardasil’s long-term efficacy, aggressive marketing, and questions regarding its cost-effectiveness analysis in a CBS news article. While maintaining that Gardasil is safe for most people, she argued patients need more complete disclosure of safety concerns. In addition, she expressed concerns that Gardasil’s 5-year efficacy may mean contraction of the virus may simply be “postponed, unless the protection lasts for at least 15 years, and over 70% of all sexually active females of all ages are vaccinated.”2 In later publications, she has stated she believes public benefit is negligible unless that percentage is 90%, as vaccination is not proven to convey life-long immunity.3
While many have taken her statements to mean she is against the HPV vaccine itself, her statements and subsequent research focus instead convey her concerns of Gardasil’s failure to fulfill its marketed promise to prevent cervical cancer and express this vaccine is not the be-all end-all many patients misperceive it to be. Even if one is vaccinated, routine Pap smears are crucial preventative measures as early detection of lesions is crucial to preventing cervical cancer as conferred benefit of the vaccine wanes. Indeed in a 2017 review article she co-authored explicitly states, “Vaccination does not replace screening. Prevention of cervical cancer must still rely on participation in ongoing screening programs.”4
Contrary to the belief of many, Dr. Harper is pro-vaccination, but she is pro-effective-vaccination. The evidence she helped compile in the aforementioned review article shows that, while falling short of the 15-year efficacy rate benchmark, Cervarix shows high-titers (level of antibodies) for HPV 16 and HPV 18 for at least 9.4 years. However Gardasil and its successor Gardasil 9 weren’t as successful – while high-titres are seen for at least 9 years for HPV 16, when it comes to HPV 18 that number falls short. For HPV 18, 1 in 5 women have undetectable anti-HPV titers after 2 years.
Even in their prevention of lesions, Cervarix came out better. In a three-dose scheme Cervarix has been found to be superior to Gardasil at preventing CIN 3 or worse, 93% to 43% (data for Gardasil9 is not yet available). In head-to-head trials looking at the response of the immune cells T-cells and B-cells, Cervarix is also superior at elliciting and immune response (immunogenecity) for both HPV16 and HPV18 than Gardasil.
In her cost-effectiveness scale, Cervarix comes out the victor.
Regardless of if you are Team Gardasil, Team Cervarix, or Team Neither, don’t let your opinion of this new vaccine be swayed by the opinions of the vaccines that came before. This new vaccine is different, because it does not act to prevent contraction of HPV. Instead this vaccine aims to help those who already have contracted the virus, especially those who have high-grade cervical intraepithelial neoplasia (CIN 2/3). These precancerous lesions CIN 1, CIN 2, and CIN 3, with CIN 3 being the most severe. Generally speaking, CIN 1 lesions have a high propensity to clear spontaneously so there is a real need to focus on these higher-grade lesions.
While surgical treatment is highly effective, there is a real risk of future pregnancy complications. Moreover there is a chance for recurrence if all of the affected cells are not removed and there is an active infection.
The vaccine, called Tipapkinogen Sovacivec (TS), is a therapeutic vaccine using the modified vaccinia virus Ankara (MVA) as a means to deliver genes into the body and kick-start a targeted immune reaction. In this scenario, the altered virus has a code for 3 genes: human cytokine interleukin 2, and modified forms for two HPV 16 proteins, called E6 and E7. The E6 and E7 are called oncogenes, which means they are capable of causing the chain-reactions that change healthy cells into cancerous cells. Thankfully though, the proteins in the vaccine have their highly dangerous parts removed.
The theory is following an injection, TS infects the cells in the nearby area and these foreign E6 and E7 proteins will be picked up by dendritic cells of your immune system which act as little deliverymen, carrying the proteins to your lymph nodes where they present them to brand new T-cells. Upon receiving the proteins, T-cells would be able to carry out a more targeted immune response when it next finds those proteins in the body.
In the multi-country Phase II trial, 192 women with CIN2/3 lesions were randomized and given the vaccine or placebo in a 2:1 ratio, such that 129 women received the vaccine and 63 received the placebo. Amongst all 192 women there were cases of 13 different HPV strains: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68. Some were carriers of a single strain, while others were carriers of multiple HPV strains.
Of the 129 women who received the vaccine, regardless of the type of HPV, nearly 1 in 4 had complete resolution of their lesion, compared to only 9.5% percent of those who had taken placebo. Moreover, the vaccine had the greatest effect on those with non-HPV 16-associated CIN 3 lesions (36.4%); by comparison none of the matching placebos had full clearance.
While initially this study aimed to assess how well the vaccine worked on those affected just with HPV 16, the real “wow factor” of this study was when they looked at the complete resolution rate in all other strains observed EXCEPT HPV 16. The percentage of those with complete resolution amongst women with HPV 16 was 18.2%, but amongst women with other strains the number was nearly doubled at 34.8%!
Overall, vaccine treatment significantly improved the likelihood of complete resolution.
Interestingly there may also be a genetic component to response to the vaccination – Non-Hispanic Black women and Hispanic women were much more likely than Non-Hispanic White Women to have resolution or respond to the vaccine.
More study needs to be done, but it certainly is an exciting prospect to be able to hope for non-surgical methods for treating high-grade HPV infections.
1Harper, D. M., Nieminen, P., Donders, G., Einstein, M. H., Garcia, F., Huh, W. K., . . . Calleja, E. (2019). The efficacy and safety of Tipapkinogen Sovacivec therapeutic HPV vaccine in cervical intraepithelial neoplasia grades 2 and 3: Randomized controlled phase II trial with 2.5 years of follow-up. Gynecologic Oncology,153(3), 521-529. doi:10.1016/j.ygyno.2019.03.250
2Attkisson, S. (2009, August 22). Gardasil Researcher Speaks Out. Retrieved from https://www.cbsnews.com/news/gardasil-researcher-speaks-out/
3Diane M Harper (2009) Gardasil® needs a new consent form, Expert Review of Vaccines, 8:12, 1613-1614, DOI: 10.1586/erv.09.120
4Harper, D. M., & Demars, L. R. (2017). HPV vaccines – A review of the first decade. Gynecologic Oncology,146(1), 196-204. doi:10.1016/j.ygyno.2017.04.004