Randomized trial of the immunogenicity and safety of the Hepatitis B vaccine given in an accelerated schedule coadministered with the human papillomavirus type 16/18 AS04-adjuvanted cervical cancer vaccine

The human papillomavirus type 16/18 (HPV-16/18) AS04-adjuvanted cervical cancer vaccine is licensed for females aged 10 years and above and is therefore likely to be coadministered with other licensed vaccines, such as hepatitis B. In this randomized, open-label study, we compared the immunogenicity of the hepatitis B vaccine administered alone (HepB group) or with the HPV-16/18 AS04-adjuvanted vaccine (HepB+HPV group) in healthy women aged 20 to 25 years (clinical trial NCT00637195). The hepatitis B vaccine was given at 0, 1, 2, and 12 months (an accelerated schedule which may be required by women at high risk), and the HPV-16/18 vaccine was given at 0, 1, and 6 months. One month after the third dose of hepatitis B vaccine, in the according-to-protocol cohort (n = 72 HepB+HPV; n = 76 HepB), hepatitis B seroprotection rates (titer of ≥10 mIU/ml) were 96.4% (95% confidence interval [CI], 87.5 to 99.6) and 96.9% (CI, 89.2 to 99.6) in the HepB+HPV and HepB groups, respectively, in women initially seronegative for anti-hepatitis B surface antigen (HBs) and anti-hepatitis B core antigen (HBc). Corresponding geometric mean titers of anti-HBs antibodies were 60.2 mIU/ml (CI, 40.0 to 90.5) and 71.3 mIU/ml (CI, 53.9 to 94.3). Anti-HBs antibody titers rose substantially after the fourth dose of hepatitis B vaccine. All women initially seronegative for anti-HPV-16 and anti-HPV-18 antibodies seroconverted after the second HPV-16/18 vaccine dose and remained seropositive up to 1 month after the third dose. Both vaccines were generally well tolerated, with no difference in reactogenicity between groups. In conclusion, coadministration of the HPV-16/18 AS04-adjuvanted vaccine did not affect the immunogenicity or safety of the hepatitis B vaccine administered in an accelerated schedule in young women.     

结核菌Mtb8.4基因疫苗对结核杆菌感染小鼠的免疫保护效果研究

为研究Mtb8.4基因疫苗的免疫原性及对小鼠结核杆菌感染的免疫保护效果,将雌性C57BL/6N小鼠32只,随机分为4组,即Mtb8.4基因疫苗组、BCG组、pcDNA3.1(+)组和PBS组。小鼠脾细胞培养上清检测细胞因子水平;并按效靶比例分别为100∶1、50∶1、10∶1进行CTL杀伤活性检测。用结核杆菌H37Rv强毒株静脉攻击小鼠,计数肺和脾组织中的结核杆菌菌落数,对小鼠部分肺和脾组织作病理切片,HE染色观察组织病变程度,Z-N染色查抗酸杆菌,观察该疫苗对小鼠结核杆菌感染的免疫保护效果。结果表明,Mtb8.4基因疫苗对小鼠结核杆菌感染有一定的免疫保护效果,能够诱导较强的抗原特异性Th1型细胞免疫应答,细胞因子IFN-γ和IL-2分泌增加,IL-4分泌减少,特异性CTL活性增加;使小鼠肺和脾组织中的结核杆菌菌落数较空载体组显著减少,组织病变明显减轻。     

Efficacy of Human Papillomavirus 16 and 18 (HPV-16/18) AS04-Adjuvanted Vaccine against Cervical Infection and Precancer in Young Women: Final Event-Driven Analysis of the Randomized,Double-Blind PATRICIA Trial

We report final event-driven analysis data on the immunogenicity and efficacy of the human papillomavirus 16 and 18 ((HPV-16/18) AS04-adjuvanted vaccine in young women aged 15 to 25 years from the PApilloma TRIal against Cancer In young Adults (PATRICIA). The total vaccinated cohort (TVC) included all randomized participants who received at least one vaccine dose (vaccine, n = 9,319; control, n = 9,325) at months 0, 1, and/or 6. The TVC-naive (vaccine, n = 5,822; control, n = 5,819) had no evidence of high-risk HPV infection at baseline, approximating adolescent girls targeted by most HPV vaccination programs. Mean follow-up was approximately 39 months after the first vaccine dose in each cohort. At baseline, 26% of women in the TVC had evidence of past and/or current HPV-16/18 infection. HPV-16 and HPV-18 antibody titers postvaccination tended to be higher among 15- to 17-year-olds than among 18- to 25-year-olds. In the TVC, vaccine efficacy (VE) against cervical intraepithelial neoplasia grade 1 or greater (CIN1+), CIN2+, and CIN3+ associated with HPV-16/18 was 55.5% (96.1% confidence interval [CI], 43.2, 65.3), 52.8% (37.5, 64.7), and 33.6% (−1.1, 56.9). VE against CIN1+, CIN2+, and CIN3+ irrespective of HPV DNA was 21.7% (10.7, 31.4), 30.4% (16.4, 42.1), and 33.4% (9.1, 51.5) and was consistently significant only in 15- to 17-year-old women (27.4% [10.8, 40.9], 41.8% [22.3, 56.7], and 55.8% [19.2, 76.9]). In the TVC-naive, VE against CIN1+, CIN2+, and CIN3+ associated with HPV-16/18 was 96.5% (89.0, 99.4), 98.4% (90.4, 100), and 100% (64.7, 100), and irrespective of HPV DNA it was 50.1% (35.9, 61.4), 70.2% (54.7, 80.9), and 87.0% (54.9, 97.7). VE against 12-month persistent infection with HPV-16/18 was 89.9% (84.0, 94.0), and that against HPV-31/33/45/51 was 49.0% (34.7, 60.3). In conclusion, vaccinating adolescents before sexual debut has a substantial impact on the overall incidence of high-grade cervical abnormalities, and catch-up vaccination up to 18 years of age is most likely effective. (This study has been registered at ClinicalTrials.gov under registration no. NCT001226810.)     

Differences in transformation activity between HPV-18 and HPV-16 map to the viral LCR-E6-E7 region.

Homologous, subgenomic fragments of the viral LCR and E6/E7 transforming genes of HPV-18 and HPV-16 were amplified from several primary cervical, penile, and vulvar tumors and cloned into a pUC-18-derived vector. When assayed by a quantitative transformation assay using primary human keratinocytes, the subgenomic regions of HPV-16 and HPV-18 exhibited transforming activities similar to that of the full-length, prototype HPV genomes. More importantly, the HPV-18 LCR-E6-E7 region was approximately 10- to 50-fold more active than that of HPV-16. These studies demonstrate (1) that the transforming activity differences previously observed between prototype HPV-16 and HPV-18 map to the LCR-E6-E7 region, and (2) that individual and independent isolates of HPV-16 and HPV-18 exhibit consistent differences in transforming potential, even when isolated from different anatomic sites.     

A prophylactic quadrivalent vaccine for the prevention of infection and disease related to HPV-6, -11, -16 and -18

Human papillomavirus infection causes cervical cancer, a significant portion of anal, genital and oropharyngeal cancers, genital warts and recurrent respiratory papillomatosis. In June 2006, a quadrivalent human papillomavirus-6/11/16/18 vaccine (GARDASIL/SILGARD?; Merck, NJ, USA) was licensed in the USA; subsequent approval has been granted in the EU (September 2006). It has since been approved in 121 countries with over 74 million doses distributed globally as of March 2011.     

Post Hoc Analysis of the PATRICIA Randomized Trial of the Efficacy of Human Papillomavirus Type 16 (HPV-16)/HPV-18 AS04-Adjuvanted Vaccine against Incident and Persistent Infection with Nonvaccine Oncogenic HPV Types Using an Alternative Multiplex Type-Specific PCR Assay for HPV DNA

The efficacy of the human papillomavirus type 16 (HPV-16)/HPV-18 AS04-adjuvanted vaccine against cervical infections with HPV in the Papilloma Trial against Cancer in Young Adults (PATRICIA) was evaluated using a combination of the broad-spectrum L1-based SPF₁₀ PCR-DNA enzyme immunoassay (DEIA)/line probe assay (LiPA₂₅) system with type-specific PCRs for HPV-16 and -18. Broad-spectrum PCR assays may underestimate the presence of HPV genotypes present at relatively low concentrations in multiple infections, due to competition between genotypes. Therefore, samples were retrospectively reanalyzed using a testing algorithm incorporating the SPF₁₀ PCR-DEIA/LiPA₂₅ plus a novel E6-based multiplex type-specific PCR and reverse hybridization assay (MPTS12 RHA), which permits detection of a panel of nine oncogenic HPV genotypes (types 16, 18, 31, 33, 35, 45, 52, 58, and 59). For the vaccine against HPV types 16 and 18, there was no major impact on estimates of vaccine efficacy (VE) for incident or 6-month or 12-month persistent infections when the MPTS12 RHA was included in the testing algorithm versus estimates with the protocol-specified algorithm. However, the alternative testing algorithm showed greater sensitivity than the protocol-specified algorithm for detection of some nonvaccine oncogenic HPV types. More cases were gained in the control group than in the vaccine group, leading to higher point estimates of VE for 6-month and 12-month persistent infections for the nonvaccine oncogenic types included in the MPTS12 RHA assay (types 31, 33, 35, 45, 52, 58, and 59). This post hoc analysis indicates that the per-protocol testing algorithm used in PATRICIA underestimated the VE against some nonvaccine oncogenic HPV types and that the choice of the HPV DNA testing methodology is important for the evaluation of VE in clinical trials. (This study has been registered at ClinicalTrials.gov under registration no. {"type":"clinical-trial","attrs":{"text":"NCT00122681","term_id":"NCT00122681"}}NCT00122681.)     

Evaluation of HPV-16 and HPV-18 genotyping for the triage of women with high-risk HPV+ cytology-negative results

The ATHENA (Addressing THE Need for Advanced HPV Diagnostics) HPV study evaluated the clinical usefulness of the cobas HPV Test (Roche Molecular Systems, Pleasanton, CA) for high-risk human papillomavirus (HR-HPV) testing (14 HR types) and individual HPV-16/HPV-18 genotyping in women undergoing routine cervical cytology screening in the United States. For the study, 47,208 women were recruited, including 32,260 women 30 years or older with negative cytology. All women with positive results for HR-HPV (n = 4,219) plus a subset of HR-HPV- women (n = 886) were referred for colposcopy and biopsy. The overall prevalence of HR-HPV was 6.7% and of HPV-16/HPV-18 was 1.5%. Cervical intraepithelial neoplasia grade 2 (CIN 2) or worse was found in 1.2% of women examined. The estimated absolute risk of CIN 2 or worse in HPV-16+ and/or HPV-18+ women was 11.4% (95% confidence interval [CI], 8.4%-14.8%) compared with 6.1% (95% CI, 4.9%-7.2%) in HR-HPV+ and 0.8% (95% CI, 0.3%-1.5%) in HR-HPV- women. These analyses validate the 2006 American Society of Colposcopy and Cervical Pathology guidelines for HPV-16/HPV-18 genotyping, which recommend referral to colposcopy of HPV-16/HPV-18+ women with negative cytology.     

Small-animal model to measure efficacy and immunogenicity of Shigella vaccine strains.

The development of a small-animal model to test the protective efficacy and immunogenicity of a vaccine strain against shigellosis would greatly facilitate the evaluation of potential vaccine candidates. In guinea pigs, the ability of shigellae to invade and multiply within the corneal epithelium, causing keratoconjunctivitis, closely mimics the invasion process in the intestinal epithelium (B. Sereny, Acta Microbiol. Acad. Sci. Hung. 4:367-376, 1957). The serum response of animals recovering from a Shigella keratoconjunctival infection was determined and found to be consistent with that shown by convalescent humans and primates. This model was used to test the efficacy of two vaccine candidates, and the immune response of the guinea pigs to the vaccine strains was examined. Both vaccine strains demonstrated significant protection against challenge by homologous virulent Shigella strains, and the results were comparable with results obtained in trials with monkeys. The guinea pig model also provides a rapid and inexpensive means of evaluating different immunization regimens as well as of testing other variables such as length of protection against disease.     

The seroprevalence of IgG antibodies to human papillomavirus (HPV) types HPV-16, HPV-18, and HPV-11 capsid-antigens in mothers and their children

Human papillomavirus (HPV) types causing anogenital lesions and cancer are accepted as being sexually transmitted. The methods whereby children acquire these anogenital type HPV infections are unclear. The present study determined the prevalence of anti-HPV-16, HPV-11 and HPV-18 IgG antibodies in mothers and their children in an attempt to identify evidence of HPV transmission from mother to child. HPV virus-like particles (VLP) VLP-16, VLP-11 and VLP-18 were used in enzyme-linked immunosorbent assay to identify IgG antibodies in serum from 100 mothers and their 111 children. Antibodies to VLP-16, VLP-11 and VLP-18 were found in serum from 17%, 21% and 16% of mothers, respectively and seroprevalences were 9%, 11.7% and 9.9%, respectively amongst the children. Of the 111 children, 23 (20.7%) showed antibodies to one or more of the three HPV types tested. Seven of these (30.4%) HPV IgG positive children had the same antibodies to one or more HPV types as their mothers. The prevalence of HPV-11 was similar in children of seropositive compared with seronegative mothers (14% and 11%, respectively). The prevalence of HPV-16 and HPV-18 was higher in children of seropositive mothers compared with seronegative mothers (for HPV-16, 18% and 7%, respectively, P = 0.1, for HPV-18, 19% and 8%, respectively, P = 0.2). None of these differences were statistically significant indicating a lack of correlation between antibodies in mothers and children and no evidence to support vertical or horizontal mother to child transmission of HPV infection. Indications were of multiple sources of HPV infection in the children.     

Correlation of laryngeal squamous cell carcinoma and infections with either HHV-8 or HPV-16/18

Each year more than 159,000 new cases of laryngeal cancer are diagnosed globally, and more than 9000 patients die due to this malignancy. Viral infections are a known risk factor for this malignancy. Thus, this study aimed to evaluate the role of HPV-16/18 and HHV-8 infection in patients with laryngeal cancer.     

Worldwide genomic diversity of the human papillomaviruses-53, 56, and 66, a group of high-risk HPVs unrelated to HPV-16 and HPV-18

Among more than 200 human papillomavirus (HPV) types presumed to exist, 18 "high-risk" HPV types are frequently found in anogenital cancer. The best studied types are HPV-16 and 18, which are only distantly related to one another and form two separate phylogenetic branches, each including six closely related types. HPV-30, 53, 56, and 66 form a third phylogenetic branch unrelated to HPV-16 and 18. Worldwide comparison of HPV-16 and 18 isolates revealed a distribution of variant genomes that correlated with the geographic origin and the ethnicity of the infected cohort and led to the concept of unique African, European, Asian, and Native American HPV-16 and 18 variants. Here, we address the question whether similar phylogenies are found for HPV-53, 56, and 66 by determining the sequence of the long control regions (LCR) of these HPVs in samples from Europe, Asia, and Africa, and from immigrant societies in North and South America. Phylogenetic trees calculated from point mutations and a few insertions/deletions affecting 2-4.2% of the nucleotide sequences were distinct for each of the three HPVs and divergent from HPV-16 and 18. In contrast to the "star-phylogenies" formed by HPV-16 and 18 variants, 44 HPV-53 isolates represented nine variants, which formed two deep dichotomic branches reminiscent of the beginning split into two new taxa, as recently observed for subtypes of HPV-44 and 68. A total of 66 HPV-56 isolates represented 17 variants, which formed three branches preferentially containing European, Asian, and African variants. Variants of a fourth branch, deeply separated from the other three, were characterized by a 25 bp insertion and created a dichotomy rather than star-like phylogeny. As it contained isolates from cohorts in all continents, it may have evolved before the spread of humans into all continents. 18 of 31 HPV-66 isolates represented the prototype clone, which was found in all parts of the world, while the remaining 13 clones formed 11 branches without any geographic association. Our findings confirm the notion of a quantitatively limited genomic diversity of each HPV type with some correlation to the geographic origin of the sample. In addition, we observed in some variants of these three HPV types mutations that affect the amino acid sequence of the E6 oncoproteins and the L1 capsid protein, supporting the possibility of immunogenic and oncogenic diversity between variants of any HPV type.     

Evaluating the immunogenicity and protective efficacy of a DNA vaccine encoding Lassa virus nucleoprotein

Several viruses in the Arenavirus genus of the family Arenaviridae cause severe, often fatal, hemorrhagic fever. One such virus, Lassa virus (LV), is a frequent cause of disease in Africa, and survivors often are left with substantial neurological impairment. The feasibility of protective immunization against LV infection, and the associated disease, has been demonstrated in animal models, using recombinant vaccinia viruses to deliver Lassa proteins. Circumstantial evidence implicates cellular immunity in this Lassa-induced protection, but this has not been confirmed. Here, we describe DNA vaccines that encode LV proteins. A single inoculation of a plasmid encoding full-length Lassa nucleoprotein (LNP) can induce CD8(+) T cell responses in mice and can protect against challenge with two arenaviruses, lymphocytic choriomeningitis virus (LCMV) and Pichinde virus (PV). A DNA minigene vaccine encoding a 9 amino acid sequence from LNP also induces CD8(+) T cells and protects against arenavirus challenge, thus confirming prior speculation that protective cellular immunity is induced by LV proteins.     

手足口病CA16型VP1亚单位疫苗的构建制备及免疫原性初步分析

目的 制备CA16型VP1蛋白疫苗并进行免疫原性初步分析,为手足口病CA16疫苗的深入研究提供资料.方法 利用RT-PCR技术获得CA16 VP1基因,克隆到载体pFastBac HT A,与Bacmid DNA重组,转染Sf9昆虫细胞,重组CA16 VP1蛋白与Al(OH)_3佐剂混合制备重组CA16 VP1蛋白疫苗,腹腔免疫BALB/c小鼠,2次免疫后进行免疫效果初步评价.结果 用间接免疫荧光、SDS-PAGE和Western blot法,证明重组CA16 VP1蛋白在昆虫细胞Sf9中得到表达,用ELISA和微量中和法检测到免疫小鼠血清有特异IgG和中和抗体产生,最佳免疫抗原剂量为20μg,其特异IgG效价为1:1600,中和抗体效价为1:250;通过淋巴细胞增殖试验和细胞因子测定,证明诱导T细胞应答,诱发Th1/Th2型免疫应答.结论 CA16 VP1基因克隆成功,并在Sf9昆虫细胞中获得表达,构建的蕈组CA16 VP1亚单位疫苗具有诱导特异性细胞免疫和体液免疫应答的能力,为今后研制手足口病CA16疫苗奠定了基础.     

Inactivated hepatitis A vaccine: immunogenicity,efficacy, safety and review of official recommendations for use

There is 10 years of marketing experience with the hepatitis A vaccine Havrix. It is highly immunogenic, provides lasting protection in healthy individuals and generates protective levels of antibodies in patients with chronic liver disease or impaired immunity. Postmarketing surveillance data have confirmed the outstanding safety profile of the vaccine. The timing of the booster dose is not critical to effectiveness, which has advantages for the protection of travelers to regions of high endemicity. The vaccine is effective in curbing outbreaks of hepatitis A and also when administered postexposure, due to rapid seroconversion and the long incubation period of the disease. In intermediate endemic regions, an epidemiological shift in hepatitis A infection has driven the development of universal preventive strategies to be added to the targeting of at-risk groups. Existing official recommendations and future directions for vaccine use are reviewed.     

A review of the efficacy, immunogenicity and tolerability of a combined hepatitis A and B vaccine

Hepatitis A and B are two of the most common vaccine-preventable liver diseases and continue to be a significant cause of morbidity and mortality worldwide, with their severity related to the individual's age upon initial infection. Twinrix (GlaxoSmithKline), a combined vaccine providing protection against both hepatitis A and B, has been available in more than 72 countries worldwide since 1997. This paper provides a critical review of clinical data on the efficacy, immunogenicity and tolerability of the combined vaccine, with particular focus on the clinical benefits of dual vaccination.     

Immunogenicity and safety of the influenza A/H1N1 2009 inactivated split-virus vaccine in young and older adults: MF59-adjuvanted vaccine versus nonadjuvanted vaccine

Since initial reports in April 2009, the pandemic influenza A (H1N1) virus has spread globally. Influenza vaccines are the primary method for the control of influenza and its complications. We conducted a multicenter clinical trial to evaluate the immunogenicity and safety of H1N1 vaccine (Green Cross Co.) in young adults (18 to 64 years) and the elderly (≥ 65 years) using a two-dose regimen, with the doses administered 21 days apart. Three different regimens of hemagglutinin antigen were comparatively analyzed: 3.75 μg (MF59 adjuvanted) versus 7.5 μg (MF59 adjuvanted) versus 15 μg (nonadjuvanted) in young adults and 3.75 μg (MF59 adjuvanted) versus 7.5 μg (MF59 adjuvanted) in the elderly. In young adults, all three vaccine regimens met the European Agency for the Evaluation of Medicinal Products (EMA) criteria after the first dose. In the elderly, on day 21 after the first dose, the rates of seroprotection and seroconversion were significantly higher for the 7.5-μg dose of MF59 adjuvanted vaccine than for the 3.75-μg dose (58.0% versus 44.3% [P = 0.03] and 53.7% versus 37.2% [P < 0.01], respectively). After the second dose, the geometric mean titer (GMT) increment was blunted with a 15-μg dose of nonadjuvanted vaccine, whereas the GMT increased about 2-fold with MF59 adjuvanted vaccines. In conclusion, a single 7.5-μg dose of MF59 adjuvanted vaccine would have a practical advantage over a two-dose, 3.75-μg, MF59 adjuvanted vaccine priming schedule. Following a two-dose priming schedule, the increase in hemagglutinin inhibition titers was higher with MF59 adjuvanted vaccine than with nonadjuvanted vaccine.     

Tumor immunogenicity and responsiveness to cancer vaccine therapy: The state of the art

Despite enormous effort, promising pre-clinical data in animal studies and over 900 clinical trials in the United States, no cancer vaccine has ever been approved for clinical use. Over the past decade a great deal of progress has been in both laboratory and clinical studies defining the interactions between developing tumors and the immune system. The results of these studies provide a rationale that may help explain the failure of recent therapeutic cancer vaccines in terms of vaccine principles, in selecting which tumors are the most appropriate to target and instruct the design and implementation of state-of-the-art cancer vaccines.     

Viral recombinant vaccines to the E6 and E7 antigens of HPV-16

Most cancerous lesions of the uterine cervix are linked to persistent infections with human papillomaviruses (HPV), most notably HPV-16 or -18. Vaccine-induced immune responses to the HPV early antigens E6 and E7, which contribute to cell transformation and are thus expressed in these cervical cancers, could potentially eradicate malignant cells. We generated recombinant vaccines based on E1-deleted adenovirus human strain 5 or on vaccinia virus strain Copenhagen expressing either the E6 or E7 oncoproteins of HPV-16. The different vaccines were compared in two experimental mouse tumor models employing Balb/c or C57Bl/6 mice. Data presented here demonstrate that depending on the model either CD4(+) or CD8(+) T cells provide protection to tumor cell challenge, resulting in striking differences in the efficacy of the four vaccines under investigation.     

Tuberculosis subunit vaccine design: the conflict of antigenicity and immunogenicity

The attempts to find an effective antituberculous subunit vaccine are based on the assumption that it must drive a Th1 response. In the absence of effective correlates of protection, a vast array of mycobacterial components are being evaluated worldwide either on the basis of their ability to be recognized by T lymphocytes in in vitro assays during early stage of animal or human infection (antigenicity) or their capacity to induce T cell response following immunization in animal models (immunogenicity). The putative vaccine candidates selected using either of these strategies are then subjected to challenge studies in different animal models to evaluate the protective efficacy. Here we review the outcome of this current scheme of selection of vaccine candidates using an 'antigenicity' or 'immunogenicity' criterion on the actual protective efficacy observed in experimental animal models. The possible implications for the success of some of the leading vaccine candidates in clinical trials will also be discussed.