Effect of Human Papillomavirus 16/18 L1 Viruslike Particle Vaccine Among Young Women With Preexisting Infection

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 35.29). 09/2007; 298(7):743-53. DOI: 10.1001/jama.298.7.743
Source: PubMed


Viruslike particle human papillomavirus (HPV) vaccines were designed to prevent HPV infection and development of cervical precancers and cancer. Women with oncogenic HPV infections might consider vaccination as therapy.
To determine whether vaccination against HPV types 16 and 18 increases the rate of viral clearance in women already infected with HPV.
Phase 3, masked, community-based randomized trial conducted in 2 provinces of Costa Rica.
A total of 2189 women aged 18 to 25 years who were recruited between June 2004 and December 2005. Participants were positive for HPV DNA at enrollment, had at least 6 months of follow-up, and had follow-up HPV DNA results.
Participants were randomly assigned to receive 3 doses of a bivalent HPV-16/18 L1 protein viruslike particle AS04 candidate vaccine (n = 1088) or a control hepatitis A vaccine (n = 1101) over 6 months.
Presence of HPV DNA was determined in cervical specimins by a molecular hybridization assay using chemiluminescence with HPV RNA probes and by polymerase chain reaction using SPF10 primers and a line probe assay detection system before vaccination and by polymerase chain reaction after vaccination. We compared rates of type-specific viral clearance using generalized estimating equations methods at the 6-month visit (after 2 doses) and 12-month visit (after 3 doses) in the 2 study groups.
There was no evidence of increased viral clearance at 6 or 12 months in the group who received HPV vaccine compared with the control group. Clearance rates for HPV-16/18 infections at 6 months were 33.4% (82/248) in the HPV vaccine group and 31.6% (95/298) in the control group (vaccine efficacy for viral clearance, 2.5%; 95% confidence interval, -9.8% to 13.5%). Human papillomavirus 16/18 clearance rates at 12 months were 48.8% (86/177) in the HPV vaccine group and 49.8% (110/220) in the control group (vaccine efficacy for viral clearance, -2.0%; 95% confidence interval, -24.3% to 16.3%). There was no evidence of a therapeutic effect for other oncogenic or nononcogenic HPV categories, among women receiving all vaccine doses, among women with single infections, or among women stratified by the following entry variables: HPV-16/18 serology, cytologic results, HPV DNA viral load, time since sexual debut, Chlamydia trachomatis or Neisseria gonorrhoeae infection, hormonal contraceptive use, or smoking.
In women positive for HPV DNA, HPV-16/18 vaccination does not accelerate clearance of the virus and should not be used to treat prevalent infections.
clinicaltrials.gov Identifier: NCT00128661.

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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.
    Vaccine 09/2014; 32(39). DOI:10.1016/j.vaccine.2014.06.038 · 3.62 Impact Factor
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    • "Although currently available two prophylactic HPV vaccines have been shown to effectively prevent HPV-associated anogenital disease in young women and men [8,9], only 32% of teenagers who qualify for immunization have received all three recommended doses of the vaccine in the USA [10]. These vaccines did not show a therapeutic effect on pre-existing cervical infection or cervical lesions [11,12]. Moreover, conventional primary treatments for early stage cervical cancer showed a recurrence rate of about 15% [13,14]. "
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    ABSTRACT: Background To identify the novel epitopes from the human papillomavirus type 18 E7 which can sensitize PBMCs of four different major HLA class I A allele.Methods Twenty-four synthetic overlapping 15-amino acid peptides were screened by measuring the frequency of CD8+ cytotoxic T lymphocytes (CTLs)-producing interferon-¿ (IFN-¿) by using flow cytometry and ELISpot assays and selected peptides were validated for cytolytic activity by using the 51Cr release assay. Truncated peptides in the selected epitopes were tested to determine the important residues using ELISpot and 51Cr release assay.ResultsAmong 24 peptides, E781-95DDLRAFQQLFLNTLS (#21) and E789-103LFLNTLSFVCPWCAS (#23) induced significantly higher Th 1 response including IFN-¿ production and in vitro cytotoxicity of PBMCs of four different HLA-A alleles against cervical cancer cells than that of other peptides and the negative control (no peptide sensitization). In E781¿95 (#21), amino acid position 81, 82 (N-terminus) and 92, 94, 95 (C-terminus) for HLA-A*02:02 and 24:02, and 81, 82 (N-terminus) and 92, 95 (C-terminus) for HLA-A*11:01 and 33:03 were important to elicit Th1 response of PBMCS. In E789¿103 (#23), residue 100 and103 (C-terminus) were important to elicit the CD8+ CTL response in HLA-A*02:01, 11:01 and 33:03 and 100, 101, and 103 (C-terminus) were important to elicit the CD8+ CTL response in HLA-A*24:02.ConclusionsE781¿95 (#21) and E789¿103 (#23) were identified as novel epitopes from HPV18 E7 which could sensitized PBMCs of four different HLA class I (HLA-A*02:01, 24:02, 11:01 and 33:03). These epitopes could be useful for immune monitoring and immunotherapy for HPV 18+ cervical cancer.
    Journal of Translational Medicine 08/2014; 12(1):229. DOI:10.1186/s12967-014-0229-7 · 3.93 Impact Factor
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    • "However, irrespective of reporting errors, finding HPV in specimens collected from girls who report no previous vaginal sex remains important. Vaccine efficacy is highest in those who have not previously been exposed to the vaccine-related HPV genotypes, and age of vaccination is based on the assumption that girls are HPV negative prior to self-reported sexual debut [21]. Our data reinforce WHO recommendations that vaccination should be targeted at younger girls [10] and suggest that the vaccination target age should be several years before the median age of self-reported sexual debut in the population. "
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    ABSTRACT: Background. Human papillomavirus (HPV) vaccines are recommended for girls prior to sexual debut because they are most effective if administered before girls acquire HPV. Little research has been done on HPV prevalence in girls who report not having passed sexual debut in high HPV-prevalence countries. Methods. Using attendance registers of randomly selected primary schools in the Mwanza region of Tanzania, we enrolled girls aged 15–16 years who reported not having passed sexual debut. A face-to-face interview on sexual behavior and intravaginal practices, and a nurse-assisted self-administered vaginal swab were performed. Swabs were tested for 13 high-risk and 24 low-risk HPV genotypes. Results. HPV was detected in 40/474 (8.4%; 95% confidence interval [CI], 5.9–11.0) girls. Ten different high-risk and 21 different low-risk genotypes were detected. High-risk genotypes were detected in 5.3% (95% CI, 3.5–7.8). In multivariable analysis, only intravaginal cleansing (practiced by 20.9%) was associated with HPV detection (adjusted odds ratio = 2.19, 95% CI, 1.09–4.39). Conclusion. This cohort of adolescent Tanzanian girls had a high HPV prevalence prior to self-reported sexual debut, and this was associated with intravaginal cleansing. This most likely reflects underreporting of sexual activity, and it is possible that intravaginal cleansing is a marker for unreported sexual debut or nonpenetrative sexual behaviors.
    The Journal of Infectious Diseases 04/2014; 210(6). DOI:10.1093/infdis/jiu202 · 6.00 Impact Factor
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