Proof-of-Principle Evaluation of the Efficacy of Fewer Than Three Doses of a Bivalent HPV16/18 Vaccine

Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 6120 Executive Blvd, EPS/7084, Rockville, MD 20852, USA.
Journal of the National Cancer Institute (Impact Factor: 12.58). 09/2011; 103(19):1444-51. DOI: 10.1093/jnci/djr319
Source: PubMed


Three-dose regimens for human papillomavirus (HPV) vaccines are expensive and difficult to complete, especially in settings where the need for cervical cancer prevention is greatest.
We evaluated the vaccine efficacy of fewer than three doses of the HPV16/18 vaccine Cervarix in our Costa Rica Vaccine Trial. Women were randomly assigned to receive three doses of the HPV16/18 vaccine or to a control vaccine and were followed for incident HPV16 or HPV18 infection that persisted in visits that were 10 or more months apart (median follow-up 4.2 years). After excluding women who had no follow-up or who were HPV16 and HPV18 DNA positive at enrollment, 5967 women received three vaccine doses (2957 HPV vaccine vs 3010 control vaccine), 802 received two doses (422 HPV vs. 380 control), and 384 received one dose (196 HPV vs. 188 control). Reasons for receiving fewer doses and other pre- and post-randomization characteristics were balanced within each dosage group between women receiving the HPV and control vaccines.
Incident HPV16 or HPV18 infections that persisted for 1 year were unrelated to dosage of the control vaccine. Vaccine efficacy was 80.9% for three doses of the HPV vaccine (95% confidence interval [CI] = 71.1% to 87.7%; 25 and 133 events in the HPV and control arms, respectively), 84.1% for two doses (95% CI = 50.2% to 96.3%; 3 and 17 events), and 100% for one dose (95% CI = 66.5% to 100%; 0 and 10 events).
Four years after vaccination of women who appeared to be uninfected, this nonrandomized analysis suggests that two doses of the HPV16/18 vaccine, and maybe even one dose, are as protective as three doses.

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    • "Sexual behaviour, natural history and cervical screening parameters were identified by fitting the model to 782 sexual behaviour, HPV epidemiology and screening data target points, taken from the literature, population-based datasets, and original studies [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37] (see Van de Velde et al. [8] and Vaccine-type and cross-protective efficacy estimates were based on a recent metaanalysis [38] (see Supplementary Table 1), and assumed to be equal for two-and three-dose schedules based on the shortterm results of the noninferiority trial [13]. Type-specific efficacy and cross-protection were assumed to be equal for cervical and non-cervical sites. "
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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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    • "Through this fund, Latin American countries may acquire the vaccine at around $14 US dollars per dose as opposed to the initial commercial price of about $120 US dollars per dose. Concerning vaccine delivery, pilot projects have shown that highest coverage is reached through school-based programs, and a sub-analysis within the Guanacaste HPV vaccine trial in Costa Rica has revealed that less than 3 doses may confer good protection 25 ; schedules with less than 3 doses will facilitate high coverage. Preferably, HPV vaccines should be introduced as part of a coordinated strategy to prevent cervical cancer and should not undermine effective cervical cancer screening programs in those countries where these programs are in place. "
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    ABSTRACT: Objective: To describe the incidence, mortality, time trends and prognostic factors for cervical cancer in Cali, Colombia, and to review the molecular epidemiological evidence showing that HPV is the major and necessary cause of cervical cancer and the implications of this discovery for primary and secondary prevention. Materials and methods: Incidence rates of cervical cancer during a 45-year period (1962-2007) were estimated based on the population-based cancer registry of Cali and the mortality statistics from the Municipal Health Secretariat of Cali. Prognostic factors were estimated based on relative survival. Review of the molecular epidemiological evidence linking HPV to cervical cancer was focused on the studies carried out in Cali and in other countries. Results: Incidence rates of squamous cell carcinoma (SCC) declined from 120.4 per 100 000 in 1962-1966 to 25.7 in 2003-2007 while those of adenocarcinoma increased from 4.2 to 5.8. Mortality rates for cervical cancer declined from 18.5 in 1984-1988 to 7.0 per 100 000 in 2009-2011. Survival was lower in women over 65 years of age and in clinical stages 3-4. Review of the molecular epidemiological evidence showed that certain types of HPV are the central and necessary cause of cervical cancer. Conclusions: A decline in the incidence and mortality of SCC and an increase in the incidence of adenocarcinoma during a 45-year period was documented in Cali, Colombia.
    Full-text · Article · Oct 2014
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    • "To date, results from the Costa Rica HPV-16/18 vaccine trial (CVT) have shown that (1) the vaccine is highly effective at preventing new persistent infections with HPV-16/18 [12], (2) the vaccine confers partial protection against HPV types phylogenetically related to HPV-16/18 [13], (3) the vaccine does not help treat infections [14], (4) fewer than 3 doses of the vaccine appear to protect as well as the full 3-dose series for at least 4 years against persistent HPV-16/18 infections [15], (5) there are indications that the vaccine protects against HPV infection at the anus and oral cavity [16] [17], (6) the vaccine does not impact overall rates of pregnancies/pregnancy outcomes [18], (7) the impact of vaccination declines with increasing age at vaccination [12], (8) the initial impact of young adult vaccination on colposcopy referral/treatment rates in well-screened populations are modest [19], (9) within the same age group, levels of antibodies achieved longterm following two doses (0 and 6 months) of the vaccine are high and only slightly lower than those observed after three doses and antibodies achieved long-term following one dose of the vaccine are lower than those observed with 3 doses but stable [20], (10) vaccination induces cross-neutralizing potential in sera of vaccinees [21], and that (11) modest antibody levels generated by natural HPV infection provide partial protection against re-infection [22]. We now extend those findings by presenting results from the blinded analysis conducted at the end of the first four years of follow-up. "
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    ABSTRACT: A community-based randomized trial was conducted in Costa Rica to evaluate the HPV-16/18 AS04-adjuvanted vaccine (NCT00128661). The primary objective was to evaluate efficacy of the vaccine to prevent cervical intraepithelial neoplasia 2 or more severe disease (CIN2+) associated with incident HPV-16/18 cervical infections. Secondary objectives were to evaluate efficacy against CIN2+ associated with incident cervical infection by any oncogenic HPVs and to evaluate duration of protection against incident cervical infection with HPV-16/18. Vaccine safety and immunogenicity over the 4-year follow-up were also evaluated.
    Full-text · Article · Sep 2014 · Vaccine
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