Immunogenicity of 2 Doses of HPV Vaccine in Younger Adolescents vs 3 Doses in Young Women A Randomized Clinical Trial

Department of Pediatrics, University of British Columbia, Vancouver, Canada.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 05/2013; 309(17):1793-802. DOI: 10.1001/jama.2013.1625
Source: PubMed


Global use of human papillomavirus (HPV) vaccines to prevent cervical cancer is impeded by cost. A 2-dose schedule for girls may be possible.
To determine whether mean antibody levels to HPV-16 and HPV-18 among girls receiving 2 doses was noninferior to women receiving 3 doses.
Randomized, phase 3, postlicensure, multicenter, age-stratified, noninferiority immunogenicity study of 830 Canadian females from August 2007 through February 2011. Follow-up blood samples were provided by 675 participants (81%).
Girls (9-13 years) were randomized 1:1 to receive 3 doses of quadrivalent HPV vaccine at 0, 2, and 6 months (n = 261) or 2 doses at 0 and 6 months (n = 259). Young women (16-26 years) received 3 doses at 0, 2, and 6 months (n = 310). Antibody levels were measured at 0, 7, 18, 24, and 36 months. MAIN OUTCOMES AND MEASURES: Primary outcome was noninferiority (95% CI, lower bound >0.5) of geometric mean titer (GMT) ratios for HPV-16 and HPV-18 for girls (2 doses) compared with young women (3 doses) 1 month after last dose. Secondary outcomes were noninferiority of GMT ratios of girls receiving 2 vs 3 doses of vaccine; and durability of noninferiority to 36 months.
The GMT ratios were noninferior for girls (2 doses) to women (3 doses): 2.07 (95% CI, 1.62-2.65) for HPV-16 and 1.76 (95% CI, 1.41-2.19) for HPV-18. Girls (3 doses) had GMT responses 1 month after last vaccination for HPV-16 of 7736 milli-Merck units per mL (mMU/mL) (95% CI, 6651-8999) and HPV-18 of 1730 mMU/mL (95% CI, 1512-1980). The GMT ratios were noninferior for girls (2 doses) to girls (3 doses): 0.95 (95% CI, 0.73-1.23) for HPV-16 and 0.68 (95% CI, 0.54-0.85) for HPV-18. The GMT ratios for girls (2 doses) to women (3 doses) remained noninferior for all genotypes to 36 months. Antibody responses in girls were noninferior after 2 doses vs 3 doses for all 4 vaccine genotypes at month 7, but not for HPV-18 by month 24 or HPV-6 by month 36.
Among girls who received 2 doses of HPV vaccine 6 months apart, responses to HPV-16 and HPV-18 one month after the last dose were noninferior to those among young women who received 3 doses of the vaccine within 6 months. Because of the loss of noninferiority to some genotypes at 24 to 36 months in girls given 2 doses vs 3 doses, more data on the duration of protection are needed before reduced-dose schedules can be recommended. Identifier: NCT00501137.

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Available from: Monika Naus, Jul 05, 2014
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    • "in young girls . However , some countries independently opted for an off - label use of the vaccine , proposing the use of a two - dose schedule , possibly followed by a booster dose some years later . In particular , a ran - domized , phase III postlicensure noninferiority study was conducted in Canada on 830 age - strat - ified female subjects [ Dobson et al . 2013 ] . Girls aged 9 – 13 years were randomized 1 : 1 to receive three doses of quadrivalent HPV vaccine at M0 , 2 , 6 ( n = 261 ) or two doses at M0 , 6 ( n = 259 ) . Young women ( 16 – 26 years ) received three doses at M0 , 2 , 6 ( n = 310 ) . Antibody levels were meas - ured at M0 , 7 , 18 , 24 , 36 . The results showed that the GMT rat"
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    ABSTRACT: Human papilloma virus (HPV) vaccination has been implemented in several countries for about the past 7 years, mainly in the adolescent female population, with varying coverage results. Although the impact of immunization on cervical and other HPV-related cancers will be evident in the next decades, a marked decrease of prevalent HPV infections, precancerous lesions and genital warts is already dramatic in the vaccinated cohorts, and also in their sexual partners, thus providing clear evidence of the effectiveness of HPV vaccination, including a herd-protection effect. Today, recommendations and implementation of universal HPV vaccination for adolescent girls are a public-health priority in all countries of the world. Countries with limited resources are presently involved in demonstration projects and, in some cases, have launched national programmes with the help of international agencies and alliances. Extension of immunization offer to young women and to adolescent male subjects has become an important additional opportunity for several countries, with a special focus needed on homosexual men with HIV infection who are at particularly increased risk of HPV-related diseases. Public-health authorities are confronted with the need to enlarge HPV-vaccination offer to all target groups, especially pre-adolescent girls, so that they can be saved from dreadful cancers by reaching high immunization coverage.
    Full-text · Article · Jan 2015
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    • "First, the policy decisions regarding alternative HPV vaccine schedules will depend on the evaluation of risks and uncertainties related to the duration of protection of two and three doses. Policy-makers could decide that evidence is sufficient for the implementation of two-dose girls-only vaccination based on the following observations: (i) three doses in young women 16–26 years of age has shown sustained efficacy for almost 10 years [39], (ii) two doses in girls aged 9–13 years have shown noninferior immunogenicity compared to three doses in young women aged 16–26 years [14] and (iii) our results indicate that two-dose girls-only vaccination is cost-effective if the vaccine protects for longer than 10 years. On the other hand, the duration of vaccine protection with two doses remains uncertain. "
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    ABSTRACT: Background Recent evidence suggests that two doses of HPV vaccines may be as protective as three doses in the short-term. We estimated the incremental cost-effectiveness of two- and three-dose schedules of girls-only and girls & boys HPV vaccination programmes in Canada. Methods We used HPV-ADVISE, an individual-based transmission-dynamic model of multi-type HPV infection and diseases (anogenital warts, and cancers of the cervix, vulva, vagina, anus, penis and oropharynx). We conducted the analysis from the health payer perspective, with a 70-year time horizon and 3% discount rate, and performed extensive sensitivity analyses, including duration of vaccine protection and vaccine cost. Findings Assuming 80% coverage and a vaccine cost per dose of $85, two-dose girls-only vaccination (vs. no vaccination) produced cost/quality-adjusted life-year (QALY)-gained varying between $7900–24,300. The incremental cost-effectiveness ratio of giving the third dose to girls (vs. two doses) was below $40,000/QALY-gained when: (i) three doses provide longer protection than two doses and (ii) two-dose protection was shorter than 30 years. Vaccinating boys (with two or three doses) was not cost-effective (vs. girls-only vaccination) under most scenarios investigated. Interpretation Two-dose HPV vaccination is likely to be cost-effective if its duration of protection is at least 10 years. A third dose of HPV vaccine is unlikely to be cost-effective if two-dose duration of protection is longer than 30 years. Finally, two-dose girls & boys HPV vaccination is unlikely to be cost-effective unless the cost per dose for boys is substantially lower than the cost for girls.
    Full-text · Article · Oct 2014 · Vaccine
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    • "To test non-inferiority of one and two vaccine doses relative to three doses, we calculated the ratios of type-specific GMTs (1:3 dose and 2:3 dose), with multiplicity-adjusted 97.5% confidence intervals. We defined non-inferiority as the lower bound of the confidence interval of the GMT ratio greater than 0.50 [18] [32] [33]. Positivity at the laboratory's suggested cutoff (defined above) was used to dichotomize results. "
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    ABSTRACT: Background: Investigations of vaccine efficacy and immunogenicity for adult females receiving fewer than three doses of human papillomavirus (HPV) vaccine have suggested protection against infection and precancerous lesions. We investigated the immunogenicity of bivalent HPV vaccines among adolescent girls from Uganda who received one, two, or three vaccine doses. Methods: Young girls vaccinated through a government program in Uganda were invited to participate. HPV16- and HPV18-specific antibodies were measured at ≥24 months after the last vaccine dose using an enzyme linked immunoassay in girls who received one (n=36), two (n=145), or three (n=195) doses. Results: Nearly all subjects (99%) were HPV16 and HPV18 seropositive at the time of blood-draw. Geometric mean antibody levels (GMTs) were: HPV16₁-dose=230 EU/mL, HPV16₂-dose=808 EU/mL, and HPV16₃-dose=1607 EU/mL; HPV18₁-dose=87 EU/mL, HPV18₂-dose=270 EU/mL, and HPV18₃-dose=296 EU/mL. The GMT ratio for 2:3 doses was 0.50 (HPV16) and 0.68 (HPV18) and did not meet the non-inferiority criteria (i.e., lower bound of 97.5% confidence interval of the GMT ratio greater than 0.50). The GMT ratio for 1:3 doses for HPV16 and HPV18 was inferior, but absolute GMTs for one dose were higher than adult women who received one dose (HPV16=124 EU/mL, HPV18=69 EU/mL) where efficacy has been demonstrated. Conclusions: Even though immunogenicity with less than three doses did not meet a priori non-inferiority thresholds, antibody levels measured ≥24 months after last dose were similar to those of adult women who have been followed for more than eight years for efficacy.
    Full-text · Article · Sep 2014 · Vaccine
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