Immune responses elicited by a fourth dose of the HPV-16/18 AS04-adjuvanted vaccine in previously vaccinated adult women

ArticleinVaccine 31(1) · October 2012with51 Reads
DOI: 10.1016/j.vaccine.2012.09.037 · Source: PubMed
Background: Vaccines are now available for the prevention of HPV-16/18-related cervical infections and pre-cancers, primarily targeting adolescent girls. Since the risk of HPV exposure potentially persists throughout a woman's sexual life, vaccine-derived immunity should be long-term. The current study, HPV-024 (NCT00546078,, assessed the immune memory in North American women who received three doses of HPV-16/18 AS04-adjuvanted vaccine 7 years earlier in HPV-001 (NCT00689741). Methods: Women vaccinated in HPV-001 received a 4th-dose of the HPV-16/18 vaccine (024-4DV group, N=65). Post 4th-dose immune responses were compared with post 1st-dose immune responses in cross-vaccination controls (024-3DV group, N=50). Reactogenicity was compared between the 4th-dose and the 1st-dose administration. Results: Pre 4th-dose, 100% of subjects in the 024-4DV group remained seropositive for anti-HPV-16/18 antibodies (ELISA). Compared to pre 4th-dose, GMTs for anti-HPV-16 and anti-HPV-18 antibodies were respectively 9.3-fold and 8.7-fold higher at day 7, and 22.7-fold and 17.2-fold higher at month 1. Compared to post 1st-dose, GMTs for anti-HPV-16 and anti-HPV-18 were respectively 80.5-fold and 205.4-fold higher at day 7, and 11.8-fold and 20.5-fold higher at month 1. Furthermore, 68.2% and 77.3% of women had HPV-16/18 specific memory B-cells, respectively, pre 4th-dose, rising to 100% one month post 4th-dose vaccination. The 4th-dose was generally well tolerated. Conclusion: A 4th-dose of HPV-16/18 AS04-adjuvanted vaccine triggered a rapid and strong anamnestic response in previously vaccinated women, demonstrating vaccine-induced immune memory.
    • "Waning of vaccine efficacy against HPV-18 and the other ten oncogenic HPV types (overall ~30.0% of cervical cancer cases) was assumed to begin 20 years after vaccination and after five years of a linear decrease in vaccine efficacy this value was assumed to be negligible. This scenario of waning vaccine efficacy was evaluated for vaccination with and without a booster vaccine dose 21 years after the first dose (33 years of age) administered to 95% of the cohort and assumed to result in lifetime protection [46]. Although duration of vaccine efficacy was demonstrated for 9.4 years (Naud et al. 2014) [21] and neutralizing antibody levels are projected to last more than 20 years (Naud et al. 2014 [21], David MP et al. 2009 [39]) waning scenarios against HPV 18 and cross protected HPV types were analyzed based on the results of the quadrivalent vaccine on HPV 18 (Einstein MH, et al. 2011 [47] and Olsson SE, et al. 2007 [48]) (see Additional file 1 for details). "
    [Show abstract] [Hide abstract] ABSTRACT: In Chile, significant reductions in cervical cancer incidence and mortality have been observed due to implementation of a well-organized screening program. However, it has been suggested that the inclusion of human papillomavirus (HPV) vaccination for young adolescent women may be the best prospect to further reduce the burden of cervical cancer. This cost-effectiveness study comparing two available HPV vaccines in Chile was performed to support decision making on the implementation of universal HPV vaccination. The present analysis used an existing static Markov model to assess the effect of screening and vaccination. This analysis includes the epidemiology of low-risk HPV types allowing for the comparison between the two vaccines (HPV-16/18 AS04-adjuvanted vaccine and the HPV-6/11/16/18 vaccine), latest cross-protection data on HPV vaccines, treatment costs for cervical cancer, vaccine costs and 6% discounting per the health economic guideline for Chile. Projected incremental cost-utility ratio (ICUR) and incremental cost-effectiveness ratio (ICERs) for the HPV-16/18 AS04-adjuvanted vaccine was 116 United States (US) dollars per quality-adjusted life years (QALY) gained or 147 US dollars per life-years (LY) saved, while the projected ICUR/ICER for the HPV-6/11/16/18 vaccine was 541 US dollars per QALY gained or 726 US dollars per LY saved. Introduction of any HPV vaccine to the present cervical cancer prevention program of Chile is estimated to be highly cost-effective (below 1X gross domestic product [GDP] per capita, 14278 US dollars). In Chile, the addition of HPV-16/18 AS04-adjuvanted vaccine to the existing screening program dominated the addition of HPV-6/11/16/18 vaccine. In the probabilistic sensitivity analysis results show that the HPV-16/18 AS04-adjuvanted vaccine is expected to be dominant and cost-saving in 69.3% and 77.6% of the replicates respectively. The findings indicate that the addition of any HPV vaccine to the current cervical screening program of Chile will be advantageous. However, this cost-effectiveness model shows that the HPV-16/18 AS04-adjuvanted vaccine dominated the HPV-6/11/16/18 vaccine. Beyond the context of Chile, the data from this modelling exercise may support healthcare policy and decision-making pertaining to introduction of HPV vaccination in similar resource settings in the region.
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  • [Show abstract] [Hide abstract] ABSTRACT: Protection against oncogenic non-vaccine types (cross-protection) offered by human papillomavirus (HPV) vaccines may provide a significant medical benefit. Available clinical efficacy data suggest the two licensed vaccines (HPV-16/18 vaccine, GlaxoSmithKline Biologicals (GSK), and HPV-6/11/16/18 vaccine, Merck & Co., Inc.) differ in terms of protection against oncogenic non-vaccine HPV types -31/45. The immune responses induced by the two vaccines against these two non-vaccine HPV types (cross-reactivity) was compared in an observer-blind study up to Month 24 (18 mo post-vaccination), in women HPV DNA-negative and seronegative prior to vaccination for the HPV type analyzed (HPV-010 [NCT00423046]). Geometric mean antibody titers (GMTs) measured by pseudovirion-based neutralization assay (PBNA) and enzyme-linked immunosorbent assay (ELISA) were similar between vaccines for HPV-31/45. Seropositivity rates for HPV-31 were also similar between vaccines; however, there was a trend for higher seropositivity with the HPV-16/18 vaccine (13.0-16.7%) versus the HPV-6/11/16/18 vaccine (0.0-5.0%) for HPV-45 with PBNA, but not ELISA. HPV-31/45 cross-reactive memory B-cell responses were comparable between vaccines. Circulating antigen-specific CD4+ T-cell frequencies were higher for the HPV-16/18 vaccine than the HPV-6/11/16/18 vaccine (HPV-31 [geometric mean ratio [GMR] =2.0; p=0.0002] and HPV-45 [GMR=2.6; p=0.0092]), as were the proportion of T-cell responders (HPV-31, p=0.0009; HPV-45, p=0.0793). In conclusion, immune response to oncogenic non-vaccine HPV types -31/45 was generally similar for both vaccines with the exception of T-cell response which was higher with the HPV-16/18 vaccine. Considering the differences in cross-protective efficacy between the two vaccines, the results might provide insights into the underlying mechanism(s) of protection.
    Full-text · Article · Dec 2011
  • [Show abstract] [Hide abstract] ABSTRACT: Naturally induced humoral immunity after human papillomavirus (HPV) infection is relatively low and often inconclusive. The main reason could be the local character of HPV disease because the immune system obtains little or no information about the on-going infection. Conversely, this is altered by HPV vaccination because the robust immune response is observed in most vaccines compared to naturally infected individuals. Although at present there is no immune correlate of protection, it is becoming evident that neutralizing IgG antibodies play one of the most crucial roles. Moreover, vaccine induced antibodies can transudate from the serum to the oral or vaginal mucosa where they take a part in virus elimination. Seroconversion rates and antibody levels are limited by the different specificity of detection antigens, cut-offs and the type of method. Current various serological assays measure not only total type-specific IgG antibodies but also functional neutralizing ones. Only a part of the total or neutralizing antibodies most likely can contribute to real protection against HPV. Even less than 1% of vaccine-induced antibodies is eligible to cross-react with other human papillomaviruses highly related to vaccine ones and neutralize them. While the antibody levels peak and subsequently decay within the first 6 months after vaccination, the matured antibody levels slightly but significantly increase to reach a plateau. Total type-specific IgG and neutralizing antibodies for all vaccine HPV types persist in lower levels related to their peak for at least 48 months following immunization regardless of the HPV vaccine used. Finally, long-lasting protection can be sustained with the vaccine generated immune memory independent of the presence or the absence of antibodies. Antibody response inversely correlates with age and the highest was observed in subjects younger than 12 years old regardless of gender. Interestingly, Black men had higher titers of neutralizing antibodies than did both Caucasian and Asian men. The post-vaccination response becomes stronger if the interval of the first two doses is extended over 6 months. Therefore, an alternative 2-dose regimen could eventually replace currently recommended 3-dose vaccination. A higher antigen content formulation of vaccines or a combination more than one antigen in multivalent vaccines did not alter immune response compared to licensed vaccines or monovalent candidate vaccines, respectively. The result of HPV vaccination is unaffected by concomitant immunization with other inactivated vaccines. Maternal antibodies of immunized women undergo transplacental transport during pregnancy and they can protect new-born infants at least in the short-term. In spite of poor response to HPV vaccination, there is a humoral and specific cell-mediated immunity confirmed in immunocompromised individuals.
    Article · Jan 2013 · Human vaccines
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