Written by Joyce Smith, BS. In a critical assessment of phase 2 and 3 efficacy trials of Gardisol and Vervarix HPV vaccine, researchers found insufficient evidence to conclude unequivocally that human papillomavirus (HPV) vaccine prevents the higher-grade abnormal cell changes that can develop into cervical cancer.
The HPV vaccine is available for 9-13 year old girls who presumably have not yet been infected with HPV. The CDC reports that approximately 13.1 out of 100,000 women annually are diagnosed with cervical cancer 1. Advocates promote the benefits of an HPV vaccine while evidence of the vaccine’s harms has fostered a climate of doubts and concerns. According to the International Agency for Research on Cancer (IARC), of the more than 100 types of HPV 2, only 12 are carcinogenic to humans and vary in prevalence and carcinogenicity. Gardacil-9 vaccine includes HPV types 16 and 18 (the two most virulent), and types 31, 33, 45, 52, and 58. Types 6 and 11 are associated with congenital warts and have been added as well.
In this current study, Rees and colleagues 3 found significant concerns when they critically evaluated the Phase 2 and 3 efficacy trials involving Gardisol and its association with cervical cancer prevention in women. In their opinion, the randomized controlled trials (RCTs) of Gardisol and Vervarix, overestimated the efficacy of the vaccine and failed to show that HVP vaccination prevents cervical cancer.
Of great concern was the fact that the trials had few participants and were of only 4-5 years duration, too short when compared to the decades required to obtain reliable results. In addition, the randomized controlled trials that have been done thus far may have over-diagnosed abnormal cell changes because cervical cytology was conducted at 6-12 months rather than the normal screening time of 36 months during which time lesions often regress spontaneously. (In England HPV positive patients who have a negative pap smear are not retested for 12 months) 4. The trials may also have overestimated efficacy when they used composite surrogate outcomes, combining high grade cervical cancer with frequently occurring low-grade cervical changes as seen in HPV-infection and cervical intraepithelial neoplasia grade 1 (CIN1) that often resolve spontaneously without progressing to cancer, but which can distort trial results. There was insufficient data to clearly conclude that HPV vaccine prevents the higher grade abnormal cell changes (CIN2, and 3 and adenocarcinoma in situ (AIS)) that can eventually develop into cervical cancer. Finally, the over-analyzing of underpowered subgroups may have increased the chance of false positives.
Another concern of Rees and team was the trial populations of predominantly older women that had limited relevance and validity for real world settings. The trials used older women compared to the 9- to 13-year-olds who typically receive vaccinations. Many vaccinated women were unaware of HPV exposure prior to vaccination and whether they were infected at time of vaccination. While sufficient data existed on the impact of the vaccine on CIN3, which is more likely than CIN1 and 2 to progress to cervical cancer, there was too little data regarding the impact on cervical disease of HPV types other than HPV 16 and 18. However, evidence shows that cervical screening significantly reduces the risk of cervical cancer in women regardless of whether or not they have been vaccinated 5; thus, women should still attend regular cervical screening because cervical screening prevents more than 80% of cervical cancers and there are more oncogenic types of HPV than those covered by the vaccines. In the UK alone, cervical cancer deaths have decreased dramatically and cervical cancer now accounts for only 1% of cancer deaths in women in the UK (854 deaths in 2016) 6.
Vaccine trials may offer protection to women from five to nine years post-vaccination, but we don’t know whether protection wanes after this time. Ongoing observational studies may tell us about the long-term effect on rates of cervical cancer, but it will take years of analysis. A recent observational study provided some evidence that vaccinating girls against CIN3+ before sexual debut 7 protected against high-grade cervical abnormalities, and that catch-up vaccination up to 18 years of age is most likely effective. The authors believe that ongoing observational studies are necessary for determining the long-term effect on cervical cancer rates in HPV vaccinated women.
Source: Claire P Rees, Petra Brhlikova, Allyson M Pollock. Will HPV Vaccination Prevent Cervical Cancer? J R Soc Med. 2020 Feb;113(2):64-78. doi: 10.1177/0141076819899308. Epub 2020 Jan 21.
© The Royal Society of Medicine 2020
Posted May 12, 2020.
Joyce Smith, BS, is a degreed laboratory technologist. She received her bachelor of arts with a major in Chemistry and a minor in Biology from the University of Saskatchewan and her internship through the University of Saskatchewan College of Medicine and the Royal University Hospital in Saskatoon, Saskatchewan. She currently resides in Bloomingdale, IL.
References:
- Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394-424.
- IARC. Biological Agents – A Review of Human Carcinogens – Human Papillomaviruses. 2012.
- Rees CP, Brhlikova P, Pollock AM. Will HPV vaccination prevent cervical cancer? J R Soc Med. 2020;113(2):64-78.
- England PH. Cervical screening: implementation guide for primary HPV screening. 2019; https://www.gov.uk/government/publications/cervical-screening-primary-hpv-screening-implementation/cervical-screening-implementation-guide-for-primary-hpv-screening. Accessed May 5, 2020.
- Peto J, Gilham C, Fletcher O and Matthews FE. The cervical cancer epidemic that screening has prevented in the UK. Lancet 2004; 364: 249–256.
- UK CR. Cervical Cancer Mortality Statistics. 2019; https://www.cancerresearchuk.org/health professional/cancer-statistics/statistics-by-cancer-type/cervical-cancer/mortality. Accessed May 5, 2020.
- Palmer T, Wallace L, Pollock KG, Cuschieri K, Robertson C, Kavanagh K, et al Prevalence of cervical disease at age 20 after immunisation with bivalent HPV vaccine at age 12. –13 in Scotland: retrospective population study. BMJ 2019; 365: l1161.
