Volume 126, Issue 8 p. 1602-1604
Editorial
Free Access

More evidence suggesting that 1-dose human papillomavirus vaccination may be effective

Julia M. L. Brotherton BMed(Hons), MPH(Hons), PhD

Corresponding Author

Julia M. L. Brotherton BMed(Hons), MPH(Hons), PhD

VCS Population Health, VCS Foundation, Melbourne, Victoria, Australia

Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia

Corresponding Author: Julia M. L. Brotherton, BMed(Hons), MPH(Hons), PhD, VCS Population Health, VCS Foundation, Level 6, 176 Wellington Parade, East Melbourne, VIC 3002, Australia ([email protected]).Search for more papers by this author
Karin Sundström MD, PhD

Karin Sundström MD, PhD

Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden

Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden

Search for more papers by this author
First published: 10 February 2020
Citations: 2
See referenced original article on pages 1656-67, this issue.

Abstract

Evidence is mounting that 1 dose of a human papillomavirus vaccine may be effective against cervical disease. This editorial discusses public health implications of an article in this issue of Cancer by Rodriguez et al, who have found estimated equal effectiveness associated with 1, 2, and 3 doses of a human papillomavirus vaccine against precancerous cervical lesions.

The study by Rodriguez et al1 in this issue of Cancer is a timely addition to the literature on the possible effectiveness of just 1 dose of a prophylactic human papillomavirus (HPV) vaccine. This evidence base is becoming an increasingly critical issue for cancer prevention policy because of both the current HPV vaccine shortage, which affects the planned scale-up of vaccination globally,2, 3 and the call for action by the World Health Organization to achieve the elimination of cervical cancer as a public health problem by the end of the century (ie, reaching a rate of <4 per 100,000).4 The draft elimination strategy sets out targets for countries to meet by the year 2030 in order for elimination to be achieved. Importantly, this strategy includes an HPV vaccination target of 90% completion for all girls by the age of 15 years. Although some countries have been able to achieve such coverage levels with a 3- or 2-dose vaccination schedule, most have not, even if uptake of the first dose is high.5, 6 Completing vaccination series in adolescents is a demonstrable challenge whether they are in school settings, where uptake is generally higher,6, 7 or out of school. If 1 dose of an HPV vaccine were sufficient for effective protection, HPV vaccine implementation and scale-up would require less logistics (while being amenable to a periodic campaign approach), available doses could be extended further, and the overall cost would be lower. The findings of this new study by Rodriguez et al add to emerging population-based studies supporting 1-dose effectiveness against cervical precancer.8-10 These studies are now able to analyze cervical outcomes among women vaccinated predominantly before their sexual debut because some HPV vaccine programs have been implemented for more than a decade.

Using deidentified data from a claims database of one of the largest private insurance companies in the United States, Rodriguez et al1 undertook a retrospective matched cohort study. They identified females aged 9 to 26 years who had received quadrivalent HPV vaccination between 2006 and mid-2015, with event data extracted to the end of 2016. To maximize the chance that all HPV vaccination doses were recorded, only women who had continuous insurance enrollment both 1 year before and 18 months after vaccination were included.

The follow-up time (for observing cytological and histopathological cervical outcomes in the form of preinvasive lesions) commenced with the first screening at least 1 year after vaccination; this incorporated a buffer period to minimize the impact of any HPV infection and HPV-related disease already prevalent at vaccination. Vaccinated women were matched to unvaccinated women with the same continuous enrollment criteria and by geographical region, age, history of sexual transmitted infections (STIs), and pregnancy in the year before the cases’ first HPV vaccination date. These criteria resulted in the inclusion of 133,082 women (66,541 vaccinated and 66,541 unvaccinated). The results were stratified by the number of HPV vaccine doses and by the age at vaccine initiation, which is a known predictor of vaccine effectiveness because of its strong correlation with the likelihood of a preexisting HPV infection. In agreement with other studies of vaccinated populations, Rodriguez et al1 found that women who had received only 1 dose were demographically different from, and likely had a higher baseline risk of HPV infection than, fully vaccinated women.

Furthermore, women who had received only 1 dose were older at vaccination and were more likely to have been pregnant or to have had an STI in the year before vaccination. Accordingly, outcomes were age-stratified and adjusted for census region, STI history, and pregnancy history. The main finding of the study was that the adjusted hazard ratios for histologically confirmed preinvasive cervical disease among women vaccinated at the ages of 15 to 19 years with 1, 2, and 3 doses were equivalent at 0.64 (95% CI, 0.47-0.88), 0.72 (95% CI, 0.54-0.95), and 0.66 (95% CI, 0.55-0.80), respectively. Few cases occurred in the <15-year age group (this limited the statistical power and inference in this age group), and no significant effectiveness of vaccination was observed for women who were 20 years old or older when they were vaccinated. (The latter finding is not surprising in a real-world evidence setting because the HPV vaccine is prophylactic against incident infections rather than therapeutic against prevalent infections, and the likelihood of previous HPV exposure in women older than 20 years at vaccination would have been substantial.)

The key strengths of the current study by Rodriguez et al1 include the large numbers and proportions of women who had received only 1 dose in comparison with other studies (20.5% vs <5%9, 10) and the ability to adjust for STI and pregnancy history. Most population-based data sets have no or limited data elements that can be used as a proxy for sexual behavior, and this study thus contributes valuable knowledge. The limitations of the current study include the lack of data on ethnicity or socioeconomic status and the use of billing codes for identifying outcomes, with a resulting likely misclassification of some outcomes. However, this misclassification should have been nondifferential between groups and may thus have had limited impact on the study conclusions. In the primary analysis, the follow-up time for outcome ascertainment was to the end of the study period or the cessation of insurance enrollment. This may in fact have overestimated the time attributed to a disease-free status if Papanicolaou-negative women did not return for a repeat test at the expected interval because their disease status at the cervix would then have been unknown (rather than the women being necessarily free from disease). If this behavior was differential between dose groups, this could have affected the global risk estimates. Importantly, though, the authors addressed this concern by undertaking 3 sensitivity analyses truncating the follow-up time to 3 years after the last Papanicolaou test, restricting outcome measurements to only those with more than 1 test during follow-up, and including only matched cases and controls with more than 1 test during follow-up. All these analyses showed consistent findings, and this is reassuring.

The study adds to the observational evidence starting to emerge from other countries showing that 1 dose is effective in cohorts that are HPV naive at vaccination. Studies from Denmark, Sweden, and Australia have made similar recent observations.8-10 The consistency of this finding, despite the diversity of settings and analytic approaches, gives the 1-dose effectiveness hypothesis further credibility. The idea that HPV vaccines could possibly be effective with only 1 dose, unlike traditional subunit protein vaccines, originally arose from post hoc analyses of the bivalent HPV vaccine trial, which showed equal efficacy against infection among women who did not complete the course.11, 12 The strong immunogenicity of the vaccines may be underpinned by the antigen display provided by the virus-like particles, which provide spacing of the antigen to the immune system that is equivalent to antigen presentation by the actual virus.13 Initial observational data from vaccination programs did not support equivalent 1-dose protection against genital warts or cervical disease, but such data may have been confounded by potentially higher risk characteristics of women who only ever received 1 or 2 doses of an intended 3-dose course (ie, women noncompliant with the vaccine program [amplified by the monitoring of outcomes among the initial catch-up populations of already infected women]) and by the inherent bias that prevalent infection/disease is more likely to become apparent coincidently with the earlier doses in a vaccine course.14 More recently, an interrupted randomized controlled trial in India, which has become a de facto observational cohort because some girls received only 1 of 2 or 3 planned doses, has suggested equivalent 1-dose quadrivalent vaccine effectiveness against infection.15

In summary, these data add to the growing evidence suggesting that there may truly be no major difference in protection against cervical preinvasive lesions, up to 10 years so far, conferred by 1, 2, or 3 doses of HPV vaccination.

Funding Support

Julia M. L. Brotherton is an investigator with the National Health and Medical Research Council–funded Centre of Research Excellence in Cervical Cancer Control (APP1135172).

Conflict of Interest Disclosures

Julia M. L. Brotherton was an investigator on investigator-initiated research grants that provided funding for laboratory testing for a study of cervical cancers (Seqirus) and recurrent respiratory papillomatosis (Merck) more than 3 years ago, but she has never received personal financial benefits. Karin Sundström has received research funds for her affiliated institution for register-based studies on human papillomavirus vaccine effectiveness in Sweden from Merck and Co, Inc, and MSD Sweden; she has never received any personal financial benefits from said entities.