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Summary Background The European Medicines Agency (EMA) recently approved two-dose immunization schedules for bivalent (HPV 16/18) and quadrivalent (HPV 6/11/16/18) human papillomavirus (HPV) vaccines in nine to fourteen and thirteen year-old-girls, respectively. Registration was based on trials comparing immunogenicity of two-dose schedules in girls 9–14 years to three-dose schedules in young women 15–26 years. We evaluate comparability of antibody levels between and within age groups and discuss potential implications for monitoring the effectiveness of HPV vaccination. Methods A systematic literature search was performed for studies comparing immunogenicity of two- to three-dose schedules of HPV vaccination. We compared geometric mean concentrations (GMCs) of vaccine-type antibodies between different dosing schedules across different age groups. Meta-analysis was used to estimate pooled GMC ratios (bivalent vaccine) of two- compared with three-dose schedules within girls. Findings For both vaccines, two-dose immunization of girls yielded non-inferior GMCs relative to a three-dose schedule in young women up to respectively 36 and 48 months follow-up. Pooled GMC ratios for the bivalent vaccine within girls showed the two-dose schedule becoming inferior to the three-dose schedule in girls for HPV 16 at approximately two years after the first dose. For the quadrivalent vaccine, antibody responses for HPV-18 became inferior from 18 months follow-up onwards when comparing the two-dose schedule with the three-dose schedule within girls. Implications Two-dose immunization of girls has non-inferior immunogenicity compared to a three-dose schedule among young women. However, non-inferior immunogenicity of two- compared with three-dose schedules within girls has not been shown at all time points. Due to this inconclusive evidence, implementation of two-dose HPV vaccination needs to be monitored closely. [ABSTRACT FROM AUTHOR]

Abstract: Cross-protection against non-HPV16/18 types and the emergence of broad spectrum vaccines protecting against multiple HPV types will influence the cost-effectiveness of future screening. To assess this influence we used an individual-based simulation model describing the relation between 14 HPV types and cervical disease, allowing the occurrence of multiple type infections. Screening scenarios for vaccinated women were evaluated, firstly for HPV16/18 vaccination with partial cross-protection against HPV 31, 33, 45 and 58 and secondly, for broad spectrum vaccination against 5–13 HPV types. The vaccine-induced incidence reduction of type-specific infection was varied from 0 to 95% in the cross-protection setting and set at 100% in the setting of broad spectrum vaccines. Scenarios of either cytology or HPV DNA screening were considered under varying lifetime number of screening rounds. At a cost-effectiveness threshold of €20,000/QALY, four times HPV DNA screening between 30 and 60 years was the selected scenario in addition to HPV16/18 vaccination, whether or not cross-protection was conferred (€6707 and €9994/QALY, respectively). In the absence of cross-protection, a fifth screening round might be considered (ICER €22,967/QALY). In addition to broad spectrum vaccination, one screen during lifetime was cost-effective up to an 11-valent vaccine. If the vaccine-induced type-specific incidence reduction was lowered to 99%, one screen during lifetime was cost-effective even in addition to 13-valent vaccination. In conclusion, in a cohort of HPV16/18 vaccinated women, four rounds of HPV DNA screening is cost-effective. One screen during lifetime remains cost-effective in addition to broad spectrum vaccination offering protection against many high-risk HPV types. [Copyright &y& Elsevier]

Abstract: Background: The use of human papillomavirus (HPV) vaccines has been universally approved for women from age 12 to 25 years, but those older than 16 years receive no reimbursement for the cost of the vaccine in the Netherlands. Reductions in the vaccine price as well as new insights in the efficacy of HPV vaccines offer renewed arguments to consider HPV vaccination in adult women. We calculated the clinical benefit and cost-effectiveness of vaccinating women aged 17–25 years in 2010. Methods: The calculations were based on an individual-based simulation model for cervical carcinogenesis, with HPV infection risks obtained from a type-specific HPV transmission model. The indirect protective effect from vaccinating 12 to 16 year-old girls was adjusted for. Cervical screening in the model was incorporated according Dutch screening guidelines, i.e. 7 cytology-based rounds at 5-year intervals from the age of 30. As base-case, we assumed the vaccine to offer full protection against HPV16/18 only if no prior exposure to that type had occurred before vaccination. In sensitivity analyses, we considered partial cross-protection against types 31/33/45/58 and efficacy against all future infections, irrespective of previous or current infection status. Results: In base-case analyses, vaccinating 17 year-olds reduced their lifetime risk of treatment for precancerous lesions from 7.77% to 3.48% and their lifetime cervical cancer risk from 0.52% to 0.24%. These risks were 6.12% and 0.45%, respectively, for a 25 year-old vaccinee. The incremental cost-effectiveness ratio (ICER) for vaccinating 17–25 year-olds was €22,526 per quality-adjusted life-year (QALY) at a vaccine price of €65 per dose, a 50% reduction of the 2010 pharmacy price in the Netherlands. If cross-protection against types 31/33/45/58 was included, the ICER decreased to €14,734 per QALY. Results were robust to efficacy assumptions with respect to previous or current infection status. Conclusion: The clinical benefit of HPV vaccination of women up to 25 years moderately depends on cross-protection to non-vaccine types. Refunding the cost of the vaccine to 17–25 year-old women in the Netherlands can be considered cost-effective at anticipated price reductions. [Copyright &y& Elsevier]

Introduction Because of the long interval between infection with high-risk human papillomavirus (hrHPV) and development of cervical cancer surrogate markers for cancer incidence are necessary to monitor vaccine effectiveness (VE). The aim of this study was to calculate VE of HPV16/18 vaccination by annually assessing incident and persistent infections among (un)vaccinated girls from the general Dutch population up to 3 years after vaccination. Methods In 2009, 1668 girls (54% vaccinated) aged 14–16 years were enrolled in a prospective cohort study. Annually, questionnaire data were obtained, and a vaginal swab was tested for type-specific HPV DNA with SPF 10 -LiPA. VE was estimated by a Poisson model comparing type-specific infection rates in (un)vaccinated girls. Results The adjusted VE (95% CI) was 73% (49–86%) against incident infections with HPV16/18 and 72% (52–84%) against HPV16/18/31/45. VE against persistent HPV16/18 was 100% and 76% (−17 to 95%) against HPV16/18/31/45. This number was lower (36%) when girls who were positive for HPV16 and 18 at baseline were included in the analysis. The overall VE for hrHPV types combined was small. Although 96% of girls were HPV-naïve at baseline, the cumulative 36-month incidence for any HPV was 20%, indicating high sexual activity. Discussion Vaccination is effective against incident and persistent infections with HPV16/18 and HPV16/18/31/45. Low VE against persistent HPV16/18 infection in girls positive at baseline indicates importance of vaccination before sexual debut. [ABSTRACT FROM AUTHOR]

Abstract: Background: Certain human papillomaviruses (HPVs) are the causative agents of cervical carcinomas in humans. The identification of the link between infection and cancer has resulted in the successful establishment of clinical strategies such as screening or vaccination programs, aiming to prevent this pathology. More than 150 different HPVs have been described and classified and the large majority of them are not related to cancer. The genus Alphapapillomavirus encompasses many PVs, some of which are identified in humans as oncogenic, according to the epidemiological connection between infection and cervical cancer. Variants of some of these “high-risk” HPVs may have an increased involvement in cervical cancer, although definitive data are still wanting. The aim of the present work was to analyze the presence of HPV33, HPV45 and HPV58 variants in cases of cervical cancer. Methods: Samples from cervical lesions in the context of different cervical cancer surveys were analyzed for presence of HPV DNA. Samples positive for HPV33, HPV45 or HPV58 DNA were selected and the E6/E7 genes were amplified and sequenced. The phylogenetic relationships of these sequences were inferred using an evolutionary placement algorithm and accordingly classified at the variant level. Results: All viral E6/E7 sequences were successfully placed in the classification schemes of the corresponding viruses. For HPV33 (n =23), 45 (n =61) or 58 (n =29), the distribution of variants found in cases of cervical cancer is not a random sample of the corresponding diversity. In all three HPVs, the respective A variants were more prevalent in the viral DNA-positive cases of cervical cancer analyzed. This is the first study trying to discern the phylogenetic connection between variants of the oncogenic HPV33, 45 and 58, and squamous cell carcinoma of the cervix. [Copyright &y& Elsevier]

Abstract: Background: We assessed age- and type-specific HPV prevalence, incidence and persistence and their associated risk factors in young women prior to vaccination, to enable monitoring of the impact of introduction of HPV vaccination in the years before participation in the cervical screening program. Methods: The HPV status was assessed in 3282 women aged 16–29 who participated in a Chlamydia trachomatis screening implementation program, of which 2014 women (61%) participated in two rounds (one year apart). Self-collected vaginal swab were analyzed by SPF10 LiPA on the presence of HPV DNA. Risk factors for prevalent, incident and persistent HPV infections were calculated using generalized estimating equation. Results: The prevalence of any HPV in the first round amounted to 54%, while 34% of the women who participated in the second round had a persistent infection and 45% an incident infection. The five most common HPV types found in this study were HPV16, −51, −52, −31 and −53. HPV16 and/or HPV18 prevalence, incidence and persistence in the second round were 15%, 8% and 9%, respectively and for HPV6 and/or HPV11 6%, 4% and 2%, respectively. Relatively to other HPV genotypes, hrHPV types were found more often as a persistent infection than as an incident infection. Furthermore, there is an age-dependent increase within this age range for persistent infections but not for incident infections. Conclusion: The HPV prevalence (54%), incidence (45%) and persistence (34%) is high among sexually active young women in the Netherlands. The different HPV type distribution and risk factors for prevalent, incident and persistent infections, as well as the observed age-trends should be taken into account in interpreting data obtained after vaccine introduction. Repeating measurements post-immunization are particularly relevant until the age when screening starts (i.e. 30 years in the Netherlands). [Copyright &y& Elsevier]

Abstract: Immunotherapy aiming at the combined activation of tumor associated antigen (TAA) specific cytotoxic T lymphocytes (CTL) and Natural Killer (NK) cells may be crucial to eradicate both MHC-I positive and negative tumors. Vaccination with mature dendritic cells (DC) transfected with mRNA encoding for TAA and the pro-inflammatory cytokines interleukin (IL)-12 and IL-18 may increase NK cell and TAA specific CTL activity. We demonstrate here that IL-12 over-expressing human DC induces increased NK cell activation and effector function and confirm the increase in TAA specific CTL by TAA/IL-12 double transfected DC. The effects of IL-18 transfection were limited to phenotypic activation and down-regulation of tissue homing receptors and did not add to the effect of IL-12 on NK cell effector function. In conclusion, co-transfection of TAA and IL-12 mRNA into mature DCs offers a vaccine for the induction of an anti-tumor immune response mediated by CTL and NK effector cells. [Copyright &y& Elsevier]

Abstract: A persistent infection with human papillomavirus (HPV) is a prerequisite for the development of cervical cancer. Clinical trials with HPV-vaccines have been very successful in preventing persistent HPV16/18 infections, the two most oncogenic HPV-genotypes. We assessed the introduction of universal HPV-vaccination for preadolescent girls in the Dutch National Immunization Programme. Long-term vaccine efficacy, the need and extent of a catch-up programme for young women, and the impact of vaccination on the cervical cancer screening programme are major unresolved issues. Preliminary conservative estimates (80% vaccine efficacy and no effects on the screening programme, transmission rate, non-cervical cancer incidence, and cross protection) predict an acceptable cost-effectiveness ratio for universal vaccination of preadolescent girls. [Copyright &y& Elsevier]

Abstract: Cytotoxic T lymphocytes (CTLs) play an important role in the defense against viral infections and malignant diseases. Interleukin (IL)-12 plays a crucial role in induction of antigen-specific primary CTL responses and enhances proliferation, interferon-γ (IFN-γ) production, and cytolytic activity of mitogen-stimulated T cells. However, the effects of IL-12 on proliferation and effector functions of previously in vitro or in vivo primed antigen-specific CTLs are less clear. Our results show that IL-12 induces an increase in proliferation of and IFN-γ production by influenza peptide-specific CTLs, but no increase in cytolytic activity on a per cell basis was observed in bulk cultures. Stimulation of a CTL clone confirmed these results; IL-12 supported an increase in IFN-γ production, but did not increase cytolytic activity. The extent of the effect of IL-12 on IFN-γ production differs per CTL clone and depends on the avidity of the clone and the peptide concentration on its target. Our data suggest that IL-12 is a good adjuvant for boosting CTL responses, in terms of proliferation and IFN-γ production, the latter particularly for CTLs with low to intermediate avidity, such as tumor-associated self-antigen-specific CTLs. [Copyright &y& Elsevier]

Summary: With the recent advent of cervical cancer vaccines, many questions relating to the best overall prevention methods for cervical disease are beginning to arise. A Markov model was used across five geographic regions (Canada, The Netherlands, Taiwan, UK, US) to examine the clinical benefits and cost-effectiveness of: (1) vaccination combined with screening, considering changes to screening-related parameters and (2) vaccination combined with screening, considering changes to screening policy. Given the assumptions used in this analysis, adding vaccination to current screening is likely to be cost-effective in the regions studied. When considering vaccination with several plausible changes to screening programmes, locations with the most frequent Papanicolaou smear testing may achieve the most efficiency gains by adopting a less frequent screening interval or incorporating HPV testing into their screening practices. Although it may be beneficial to change screening to maximize efficiency, the most cost-effective strategies for vaccination and screening combinations may not lead to the greatest reductions in cervical cancer; therefore such policy decisions may vary depending on region-specific goals. Finally, new screening paradigms such as primary HPV testing should be considered in future analyses. [Copyright &y& Elsevier]