Human papillomavirus(HPV) vaccine efficacy and immunogenicity in women with existing HPV infections

Proposal
11384

Title of Proposed Research

Lead Researcher

Fanghui Zhao

Affiliation

National Cancer Center & Cancer Hospital,Chinese Academy of Medical Sciences

Funding Source

Potential Conflicts of Interest

Data Sharing Agreement Date

05 June 2020

Lay Summary

Human papillomavirus(HPV) infection is a common viral infection that is often spread through sexual contact. There are more than 100 different types of HPV. Many types do not cause problems in most people, but some types are linked to cancer, especially cervical cancer. These oncogenic types are called high-risk HPV(HR-HPV) types, causing nearly all cervical cancers (99.7%). Effective HPV vaccines are currently available to protect against cervical cancer caused by some of these HR-HPV types. However, these vaccines are all prophylactic and do not cure pre-existing infections. Therefore, HPV vaccines are most effective before sexual exposure and are recommended mainly in adolescent girls. However, there are a percentage of unvaccinated women who might be currently infected with HR-HPV (HR-HPV DNA positive), which raises the question about how much the HPV vaccine can benefit this population.We thus proposed research to analyze efficacy and immunogenicity purely in women who are HR-HPV DNA positive at first vaccination. In previous published papers, data in this population are always combined with data from DNA negative women. The efficacy trials for AS04-HPV-16/18 vaccine were sponsored by GSK with similar study design and registered on https://clinicaltrials.gov. This provide chance to look at the vaccine benefit in HR-HPV DNA positive women, which would not have been feasible in individual trials due to a limited sample size.By pooling the data, we propose to address the research question from the following 4 aspects: 1. In women infected with any HR-HPV types, whether the residual benefit of preventing infection associated with other non-infected HR-HPV types would be sufficient to warrant vaccination? 2. In women DNA positive for HPV-16 or HPV-18, what's the vaccine efficacy against re-infections associated with HPV-16/18 after their immune system clears the baseline infection? 3. What's the long-term immune response in women DNA positive for HPV-16 or HPV-18 at first dose? 4. In women allocated in control arm in selected trials, whether women DNA positive for one type of HR-HPV have increased risks in later years to be infected with other HR-HPV types? This research will help to address the very real confusion existing among both clinicians and adult women about HPV benefit in HR-HPV DNA positive women and thus hold promise for reinforcing the confidence for extending vaccine benefit to this population.

Study Data Provided

[{ "PostingID": 1516, "Title": "GSK-104798", "Description": "A phase II study to assess the efficacy, immunogenicity and safety of GSK Biologicals' HPV-16/18 L1 VLP AS04 (Cervarix TM) vaccine administered intramuscularly according to a 0, 1, 6 month schedule in healthy Japanese female subjects aged 20 - 25 years." },{ "PostingID": 1517, "Title": "GSK-104820", "Description": "A study to evaluate safety, immunogenicity and efficacy of GSK Biologicals HPV-16/18 L1/AS04 vaccine administered intramuscularly according to a three-dose schedule (0, 1, 6 month) in healthy adult female subjects aged 26 years and above" },{ "PostingID": 1528, "Title": "GSK-580299/008", "Description": "A phase III, double-blind, randomized, controlled, multi-center study to evaluate the efficacy of GlaxoSmithKline Biologicals. HPV-16/18 VLP AS04 vaccine compared to hepatitis A vaccine as control in prevention of persistent HPV-16 or HPV-18 cervical infection and cervical neoplasia, administered intramuscularly according to a 0, 1, 6 month schedule in healthy females 15-25 years of age." },{ "PostingID": 2794, "Title": "GSK-107638", "Description": "Efficacy, immunogenicity and safety of GlaxoSmithKline Biologicals’ HPV GSK 580299 vaccine in healthy Chinese female subjects" },{ "PostingID": 2795, "Title": "GSK-112949", "Description": "Long-term extension study of the efficacy of the 580299 vaccine in the prevention of HPV-16 and/or HPV-18 associated cervical intraepithelial neoplasia (CIN) in Japanese women vaccinated in the primary vaccination study NCT00316693" }]

Statistical Analysis Plan

Demographics/baseline characteristics will be analyzed for women included in three analysis separately. Age at inclusion, type specific HR-HPV DNA status and HPV-16 and HPV-18 sero status will be analyzed for all trials. Cigarette smoking and marital status at baseline, age at first sexual intercourse, number of sexual partners during the past 12 months will also be analyzed for HPV-008/015 trials. For objective 1, the primary analysis set would be women with HR-HPV infection (i.e. HR-HPV DNA-positive, irrespective of HPV serostatus) at baseline in the total vaccinated cohort for efficacy (TVC-E). Subjects will be evaluated for subsequent development of HPV infection, cytology and histology abnormalities with the types they were DNA-negative to at baseline. Sensitivity analysis will also be conducted in according to protocol for efficacy(ATP-E) cohort.Based on the analysis of VE against HPV-16/18 and HPV-31/33/45 infection in women DNA-negative to the considered HPV type and DNA-positive to any of the 14 HR-HPV types (i.e. HPV-16/18/31/33/45/39/45/51/52/56/58/59/66/68) at baseline, further analyses will be performed in the following two subsets: (i) VE against HPV-16/18 associated endpoints in women DNA-negative to the considered HPV type and DNA-positive to any of the other 12 HR-HPV types (i.e. HPV-31/33/45/39/45/51/52/56/58/59/66/68; including HPV-16/18 coinfections) at baseline; (ii) VE against HPV-16/18 and HPV-31/33/45 associated endpoints in women DNA-positive to HPV-16/18 and DNA-negative to the considered HPV type at baseline.Endpoint cases will be calculated as number of subjects reporting at least one event in each group. Case counting started on the day after the first dose(for TVC-E) and on the day after the third dose(for ATP-E) and ended at the time of an endpoint event or until the end of the follow-up.For objective 2, analysis set would be women with cervical HPV-16/18 infection (DNA-positive) at the time of first vaccination but cleared naturally during later follow up. Clearance will be defined as two consecutive DNA negative results(at least 5 months apart) for the type women are DNA positive at baseline. Re-infection would be defined as the detection of the same type of HPV DNA or associated lesions after clearance. Sensitivity analysis will be conducted with clearance definition as one DNA negative results for the type women are DNA positive at baseline.Subjects will be evaluated for subsequent development of incident HPV re-infection, persistent infection(at 6 and 12 months), any ASC-US+ and any CIN associated with the type they cleared. Case counting started on the day after the second visits with negative DNA results and ended at the time of re-infection endpoint event or until the end of the follow-up. Similar additional analysis will be performed for HPV-31/33/45.For both objective 1 and 2, efficacy and confidence intervals (CIs) will be calculated based on the observed difference in event rates using accrued person time as the denominator. VE will be calculated using the conditional exact method. A lower limit of CI above 0 was considered as a significant result. For objective 2, baseline geometric mean titers(GMT) will be adjusted, due to some extent protection provided by high level natural antibodies. For objective 3, analysis sets would be limited in women with cervical HPV-16/18 infection (DNA-positive) at the time of first vaccination. For all subjects, for whom blood sample results are available: seropositivity rates with exact 95% confidence interval (CI) will be calculated for anti-HPV-16 and anti-HPV-18 antibodies by visits.  GMTs (with 95% CI and range) will be tabulated for anti-HPV-16 and anti-HPV-18 antibodies by visits. For objective 4, cumulative risk of 6M PI with any other types would be estimated and compared between women DNA positive for any HPV type and those DNA negative using the Kaplan-Meier method and log-rank test. Cox regression models will also be conducted to adjust for baselines age and sexual behaviors(for HPV-008 and HPV-015 trial).For abovementioned statistical analysis, a p value less than or equal to 0.05 (two-sided) will be considered statistically significant. Analyses will be performed using R software.

Publication Citation

Wen T-M, Xu X-Q, Zhao X-L, et al. Efficacy and immunogenicity of AS04-HPV-16/18 vaccine in females with existing cervical HR-HPV infection at first vaccination: A pooled analysis of four large clinical trials worldwide. Int J Cancer. 2024; 1-15
doi:10.1002/ijc.34882