Immunogenicity and Safety of Human Papillomavirus Vaccine in Young Cancer Survivors in the United States: A Phase 2, Single-Arm, Open-label, Non-inferiority Study

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background

Young cancer survivors are at increased risk of cancer associated with human papillomavirus (HPV), which is primarily caused by oncogenic HPV types 16 and 18. We wanted to study the immunogenicity and safety of the three-dose HPV vaccine series in young cancer survivors.

Methods

We conducted an investigator-initiated, single-arm, open-label, phase 2, non-inferiority study in five National Cancer Institute-designated Comprehensive Cancer Centers in the United States. Eligible participants were cancer survivors who were HPV vaccine naive, were in remission between the ages of 9-26, and had completed cancer therapy between 1 and 5 years previously. Participants received three intramuscular doses of either a quadrivalent HPV vaccine (HPV4; ​​enrolled on or before March 1, 2016) or a non-avalanche HPV vaccine (HPV9; enrolled after March 1, 2016) over a period of 6 months (on the 1st month 6). We also received data from published clinical studies evaluating the safety and immunogenicity of HPV4 and HPV9 in 9 to 26 year olds from the general population as a comparison group. The primary endpoint was the antibody response to HPV types 16 and 18 at month 7 in the per-protocol population. Response was considered non-inferior when the lower bound of the multiplicity-corrected 95% CI for the ratio of the geometric means of anti-HPV-16 and anti-HPV-18 titers (GMTs) in cancer survivors was greater than 0.5 towards the general population. The response was examined separately by age group (ie 9-15 years and 16-26 years) in male and female participants. Safety was assessed in all participants who received at least one vaccine dose and for whom safety data were available. This study is registered with ClinicalTrials.gov, NCT01492582. This attempt is now complete.

Results

Between February 18, 2013 and June 22, 2018, we enrolled 453 cancer survivors, of whom 436 received one or more doses of vaccine: 203 (47%) participants had survived leukemia, 185 (42%) were female and 280 (64%) were non-Hispanic white. The mean age at the first dose was 15.6 years (SD 4.6). 378 (83%) of 453 participants had evaluable immunogenicity data; The main reasons for exclusion from the per-protocol analysis were loss of follow-up care, patient reasons, and medical reasons. Data from 26,486 general population controls were also obtained. The mean GMT ratio for anti-HPV types 16 and 18 in cancer survivors versus the general population was greater than 1 for all subgroups (ie, ages 9-15, ages 16-26, male and female groups ) in both vaccine cohorts (in the range of 1.64 [95% CI 1·12–2·18] for anti-HPV type 16 in female participants aged 9-15 years who received HPV9 to 4 x 77 [2·48–7·18] for anti-HPV type 18 in male participants 16-26 years of age who received HPV4. The non-inferiority criteria were met within each age and gender subgroup, except for HPV type 18 in female participants aged 16-26 who received HPV9 (4 × 30 [0·00–9·05]). Side effects were reported by 237 (54%) out of 435 participants; Injection site pain was most common (174 [40%] Attendees). One serious adverse event (ie, erythema nodosum) may have been vaccinated (HPV9; 16 to 26 year old female cohort).

interpretation

The immunogenicity and safety of the HPV vaccine three-dose series in cancer survivors is similar to that in the general population, demonstrating its use in this clinically vulnerable population.

financing

US National Cancer Institute, Merck, Sharp & Dohme, and American Lebanese Syrian Associated Charities.

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