Importance Human papillomavirus (HPV) infections cause anogenital cancers and warts. The 9-valent HPV vaccine provides protection against 7 high-risk types of HPV responsible for 90% of cervical cancers and 2 other HPV types accounting for 90% of genital warts.
Objective To determine whether HPV type–specific antibody responses would be noninferior among girls and boys aged 9 to 14 years after receiving 2 doses of the 9-valent HPV vaccine compared with adolescent girls and young women aged 16 to 26 years receiving 3 doses.
Design, Setting, and Participants Open-label, noninferiority, immunogenicity trial conducted at 52 ambulatory care sites in 15 countries. The study was initiated on December 16, 2013, with the last participant visit for this report on June 19, 2015. Five cohorts were enrolled: (1) girls aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (2) boys aged 9 to 14 years to receive 2 doses 6 months apart (n = 301); (3) girls and boys aged 9 to 14 years to receive 2 doses 12 months apart (n = 301); (4) girls aged 9 to 14 years to receive 3 doses over 6 months (n = 301); and (5) a control group of adolescent girls and young women aged 16 to 26 years to receive 3 doses over 6 months (n = 314).
Interventions Two doses of the 9-valent HPV vaccine administered 6 or 12 months apart or 3 doses administered over 6 months.
Main Outcomes and Measures The primary end point was prespecified as the antibody response against each HPV type assessed 1 month after the last dose using a competitive immunoassay. Each of the three 2-dose regimens was compared with the standard 3-dose schedule in adolescent girls and young women using a noninferiority margin of 0.67 for the ratio of the antibody geometric mean titers.
Results Of the 1518 participants (753 girls [mean age, 11.4 years]; 451 boys [mean age, 11.5 years]; and 314 adolescent girls and young women [mean age, 21.0 years]), 1474 completed the study and data from 1377 were analyzed. At 4 weeks after the last dose, HPV antibody responses in girls and boys given 2 doses were noninferior to HPV antibody responses in adolescent girls and young women given 3 doses (P < .001 for each HPV type). Compared with adolescent girls and young women who received 3 doses over 6 months, the 1-sided 97.5% CIs for the ratio of HPV antibody geometric mean titers at 1 month after the last dose across the 9 HPV subtypes ranged from 1.36 to ∞ to 2.50 to ∞ for girls who received 2 doses 6 months apart; from 1.37 to ∞ to 2.55 to ∞ for boys who received 2 doses 6 months apart; and from 1.61 to ∞ to 5.36 to ∞ for girls and boys who received 2 doses 12 months apart.
Conclusions and Relevance Among girls and boys aged 9 to 14 years receiving 2-dose regimens of a 9-valent HPV vaccine separated by 6 or 12 months, immunogenicity 4 weeks after the last dose was noninferior to a 3-dose regimen in a cohort of adolescent girls and young women. Further research is needed to assess persistence of antibody responses and effects on clinical outcomes.
Trial Registration clinicaltrials.gov Identifier: NCT01984697
Objective To examine the effect of the bivalent human papillomavirus (HPV) vaccine on
Design Observational long term follow-up of a randomized, double blinded trial combined
with an independent unvaccinated population based cohort.
Setting Single center study in Costa Rica.
Participants 7466 women in the trial and 2836 women in the unvaccinated cohort enrolled
at the end of the randomized trial and in parallel with the observational trial component.
Intervention Women in the trial were assigned to receive three doses of bivalent HPV
vaccine (n=3727) or the control hepatitis A vaccine (n=3739). Crossover bivalent HPV
vaccination occurred in the hepatitis A vaccine arm at the end of the trial. Women in the
unvaccinated cohort received (n=2836) no vaccination.
Main outcome measure Risk of miscarriage, defined by the US Centers for Disease
Control and Prevention as fetal loss within 20 weeks of gestation, in pregnancies exposed
to bivalent HPV vaccination in less than 90 days and any time from vaccination compared
with pregnancies exposed to hepatitis A vaccine and pregnancies in the unvaccinated
Results Of 3394 pregnancies conceived at any time since bivalent HPV vaccination, 381
pregnancies were conceived less than 90 days from vaccination. Unexposed pregnancies
comprised 2507 pregnancies conceived after hepatitis A vaccination and 720 conceived in
the unvaccinated cohort. Miscarriages occurred in 451 (13.3%) of all exposed pregnancies,
in 50 (13.1%) of the pregnancies conceived less than 90 days from bivalent HPV
vaccination, and in 414 (12.8%) of the unexposed pregnancies, of which 316 (12.6%) were
in the hepatitis A vaccine group and 98 (13.6%) in the unvaccinated cohort. The relative risk
of miscarriage for pregnancies conceived less than 90 days from vaccination compared with
all unexposed pregnancies was 1.02 (95% confidence interval 0.78 to 1.34, one sided
P=0.436) in unadjusted analyses. Results were similar after adjusting for age at vaccination
(relative risk 1.15, one sided P=0.17), age at conception (1.03, P=0.422), and calendar year
(1.06, P=0.358), and in stratified analyses. Among pregnancies conceived at any time from
bivalent HPV vaccination, exposure was not associated with an increased risk of
miscarriage overall or in subgroups, except for miscarriages at weeks 13-20 of gestation
(relative risk 1.35, 95% confidence interval 1.02 to 1.77, one sided P=0.017).
Conclusions There is no evidence that bivalent HPV vaccination affects the risk of
miscarriage for pregnancies conceived less than 90 days from vaccination. The increased
risk estimate for miscarriages in a subgroup of pregnancies conceived any time after
vaccination may be an artifact of a thorough set of sensitivity analyses, but since a genuine association cannot totally be ruled out, this signal should nevertheless be explored further in existing and future studies.
Effect of bivalent human papillomavirus vaccination on pregnancy outcomes: long term observational follow-up in the Costa Rica HPV Vaccine Trial by Orestis A Panagiotou, et al. on behalf of the Costa Rica HPV Vaccine Trial (CVT) Group
BMJ2015; 351 (Published 07 September 2015)