Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 vaccine and HPV-6/11/16/18 vaccine: follow-up from months 12-24 in a Phase III randomized study of healthy women aged 18-45 years

In this observer-blind study (NCT00423046), women (N=1,106), stratified by age (18-26, 27-35, 36-45 y), were randomized (1:1) to receive the HPV-16/18 vaccine (Cervarix?, GlaxoSmithKline Biologicals, Months 0, 1, 6) or the HPV-6/11/16/18 vaccine (Gardasil? Merck & Co., Inc., Months 0, 2, 6). Month 7 results were previously reported; we now report Month 24 results. In the according-to-protocol cohort for immunogenicity (seronegative and DNA-negative at baseline for HPV type analyzed), seropositivity rates of neutralizing antibodies (nAbs) [pseudovirion-based neutralization assay] were, across all age strata, 100% (HPV-16/18 vaccine) and 97.5-100% (HPV-6/11/16/18 vaccine) for HPV-16, and 99.0-100% (HPV-16/18 vaccine) and 72.3-84.4% (HPV-6/11/16/18 vaccine) for HPV-18. Corresponding geometric mean titers (GMTs) were 2.4-5.8-fold higher for HPV-16 and 7.7-9.4-fold higher for HPV-18 with the HPV-16/18 vaccine versus the HPV-6/11/16/18 vaccine; HPV-16 and HPV-18 GMTs were significantly higher with the HPV-16/18 vaccine than the HPV-6/11/16/18 vaccine (p< 0.0001) in the total vaccinated cohort (received ≥1 vaccine dose, irrespective of baseline sero/DNA-status). Similar results were obtained using enzyme-linked immunosorbent assay (ELISA). Positivity rates and GMTs of antigen-specific IgG antibodies in cervicovaginal secretions (ELISA) were not significantly different between vaccines. At Month 24, CD4? T-cell responses for HPV-16 and HPV-18 were higher with the HPV-16/18 vaccine; memory B-cell response was higher for HPV-18 with the HPV-16/18 vaccine and similar between vaccines for HPV-16. Both vaccines were generally well tolerated. Although an immunological correlate of protection has not been defined, differences in the magnitude of immune response between vaccines may represent determinants of duration of protection.     

Correlation between levels of human papillomavirus (HPV)-16 and 18 antibodies in serum and cervicovaginal secretions in girls and women vaccinated with the HPV-16/18 AS04-adjuvanted vaccine

This pooled analysis of data from four Phase III clinical trials was undertaken to assess the correlation between levels of anti-human papillomavirus (HPV)-16/18 antibodies in serum and cervicovaginal secretions (CVS) in girls and women vaccinated with the HPV-16/18 AS04-adjuvanted vaccine. Serum and CVS samples were collected from a subset of women aged 10-65 years (N=350) at pre-specified time-points from 7 to 36 months post-vaccination. Anti-HPV-16/18 antibody levels in serum and CVS were measured by enzyme-linked immunosorbent assay. Pearson correlation coefficients between serum and CVS antibody levels, standardized for total immunoglobulin G, were calculated at each time-point in women with detectable antibodies in both serum and CVS. All subjects had seroconverted at Month 7 and remained seropositive through Month 36 for both antigens. Geometric mean titers of anti-HPV-16/18 antibodies in serum were substantially higher at all time-points than those in a control group of women who had cleared a natural HPV infection in another trial. In women with detectable antibodies in both serum and CVS, good correlation was seen between HPV-16/18 antibody levels at all time-points (Pearson correlation coefficient: 0.84-0.92 for HPV-16 and 0.90-0.91 for HPV-18). The strong correlation between levels of HPV-16/18 antibodies in serum and CVS up to 36 months post-vaccination in girls and women vaccinated with the HPV-16/18 AS04-adjuvanted vaccine supports transudation of serum antibodies as the mechanism by which antibodies are introduced into CVS. These CVS antibodies may play a role in the protective efficacy of this vaccine.     

Quadrivalent human papillomavirus (HPV) types 6, 11, 16, 18 vaccine: for the prevention of genital warts in males

The quadrivalent HPV types 6, 11, 16, 18 vaccine (Gardasil?) is a recombinant vaccine comprising purified virus-like particles derived from the L1 capsid proteins of HPV types 6, 11, 16 and 18. The vaccine was highly immunogenic. Geometric mean titres (GMTs) and seroconversion rates for all four HPV types at month 7 in males aged 10-15 years were noninferior to those in females aged 16-23 years, and those in males aged 9-15 years were noninferior to those in females aged 9-15 years. In addition, GMTs and seroconversion rates in males aged 16-26 years receiving the vaccine were higher than those receiving amorphous aluminium hydroxyphosphate sulfate adjuvant (AAHS) control. The quadrivalent HPV vaccine was significantly more effective than AAHS control at decreasing the incidence of HPV 6-, 11-, 16- or 18-related external genital lesions (primary endpoint) in a randomized, double-blind, placebo-controlled, multicentre study in males aged 16-26 years. The most common clinical endpoint was HPV 6- and 11-related condyloma; efficacy was robust against these lesions. The vaccine is also expected to be protective against genital warts in males aged 9-15 years, as the immune response in males of this age group was noninferior to that in males aged 16-26 years. The quadrivalent HPV vaccine was generally well tolerated in males aged 9-26 years. The most common adverse events reported were injection-site related, and most of these were of mild to moderate severity.     

重组人乳头瘤病毒双价(16/18型)疫苗免疫原性评价方法的研究

目的:探讨重组人乳头瘤病毒双价(16/18型)候选疫苗免疫原性评价方法。方法:对以假病毒为基础的中和实验(Zs-Green法)测定血清中和滴度,以微球为基础建立的Luminex法测定中和滴度和ELISA法测定抗体滴度的3种方法进行相关性研究以及体内效价测定(ED50法)和体外相对效力测定(IVRP法)的相关性分析,同时对5种免疫原性的评价方法进行重复性验证。结果:ZsGreen法、Luminex法测定的中和滴度和ELISA法测定的抗体滴度检测结果表明:滴度值呈明显的剂量效应以及侯选疫苗具有良好的免疫原性。采用SPSS统计软件分析,对于HPV 16L1 ZsGreen法、Luminex法和ELISA法的相关系数分别为0.791,0.800,0.747(Spearman相关系数)和HPV 18L1的相关系数分别为0.734,0.625,0.634(Spearman相关系数)。并且ED50法和IVRP法具有一定的相关性。5种方法重复性验证的RSD分别为:5.3%(ZsGreen)、5.2%(Luminex)、8.0%(ELISA)、32.3%(ED50)、6.3%(IVRP)。结论:建立的HPV 16和HPV 18...     

Persistence of immune response to HPV-16/18 AS04-adjuvanted cervical cancer vaccine in women aged 15-55 years

The HPV-16/18 AS04-adjuvanted vaccine (Cervarix?, GlaxoSmithKline Biologicals) has been shown to induce a robust immune response in women aged 15-55 years (103514/NCT00196937). This follow-up study is the first report of persistence of immune response and safety profile through 48 months after vaccination in women aged 15-55 years. In this open-label, age-stratified Phase III study in Germany and Poland (105882/NCT00196937), healthy women aged 15-55 years received 3 doses of HPV-16/18 AS04-adjuvanted vaccine at 0, 1, and 6 months. Anti-HPV-16/18 seropositivity rates and geometric mean antibody titers (GMTs) were assessed by enzyme-linked immunosorbent assay (ELISA) in women aged 15-25 (n=168), 26-45 (n=186) and 46-55 years (n=177) from the time of first vaccination through 48 months. At Month 48, all subjects were seropositive for anti-HPV-16 antibodies and 99.4% were seropositive for anti-HPV-18. Antibody kinetics were as previously reported, with peak response at Month 7 followed by a gradual decline tending towards a plateau in all age groups. Anti-HPV-16/18 GMTs were sustained at Month 48 in all age groups, including women aged 46-55 years in whom GMTs were respectively 11-fold and 5-fold higher than natural infection levels. The vaccine exhibited a clinically acceptable safety profile in all age groups. In summary, the HPV-16/18 AS04-adjuvanted vaccine induces high and sustained immune responses in women aged 15-55 years, with antibody levels remaining several-fold higher than natural infection levels for at least 4 years after the first vaccine dose.     

Human papillomavirus quadrivalent (types 6, 11, 16, 18) recombinant vaccine (Gardasil)

Human papillomavirus (HPV) quadrivalent recombinant vaccine is a mixture of virus-like particles derived from the L1 capsid proteins of HPV types 6, 11, 16 and 18. It is administered intramuscularly in a three-dose regimen, with the initial injection followed by subsequent doses at months 2 and 6. The vaccine is indicated for use in the prevention of cervical cancer, vulvar and vaginal precancer and cancers, precancerous lesions and genital warts associated with HPV types 6, 11, 16 or 18 infection in adolescents and young women. The quadrivalent vaccine has demonstrated good immunogenicity in young women (16-26 years) and male and female adolescents (aged 9-15 years), inducing high and persistent anti-HPV antibody titres. In a randomised phase III trial designed to bridge efficacy in young women to adolescents (using immunogenicity as a surrogate), the quadrivalent HPV vaccine in adolescents was at least as immunogenic as that in young women. In randomised, double-blind, placebo-controlled trials in >20 000 young women (aged 16-26 years), the vaccine was highly effective in preventing cervical dysplasia of any grade and external genital lesions related to HPV types 6, 11, 16 and 18 infection. These women were followed up for an average of 2 years.black triangle The vaccine was well tolerated, with injection-site reactions and fever being the most common vaccine-related adverse events.     

Baseline demographic characteristics of subjects enrolled in international quadrivalent HPV (types 6/11/16/18) vaccine clinical trials

ABSTRACT

Background: In Phase II/III trials, administration of quadrivalent human papillomavirus (HPV) (types 6/11/16/18) L1 virus-like-particle vaccine was highly effective in preventing HPV6/11/16/18-related cervical intraepithelial neoplasia and non-invasive cervical cancer in women aged 16–26 years who were naïve to these HPV types at enrollment. However, the makeup and extent of catch-up vaccination programs among young women is unclear, because a proportion of this population will likely already have been exposed to one or more vaccine-HPV-types.

Objective: Herein we analyze baseline data from the quadrivalent HPV vaccine clinical trial program to investigate variables which may help shape catch-up vaccine implementation policies.

Methods: Female adolescents and young adults aged 16–26 years were randomized into five clinical trials. Baseline data regarding demographics, sexual history, pregnancy history, and other characteristics were collected at enrollment. At the baseline gynecological examination during enrollment, specimens were obtained for Pap testing. Swabs of external genital, lateral vaginal, and cervical sites for HPV polymerase chain reaction (PCR) testing were taken, and serum samples were obtained for HPV serology testing. Regional analyses of data were conducted.

Results: Overall, 72?%?of subjects enrolled worldwide were naïve by both serology and PCR to all four vaccine HPV types. Few subjects were seropositive and/or PCR positive for more than two vaccine-related HPV types. Of all subjects with HSIL at enrollment, 78?%?were positive to at least one vaccine-related HPV type at enrollment. Regional differences in HPV and STD prevalence were evident. Study limitations included under-representation of women with ≥4?sexual partners and possible underestimation of prior HPV exposure.

Conclusions: Our findings demonstrate that sexually active 16–26 year-old women with ≤4 life time sex partners (LSP) in North America, Europe, Latin America, and Asia Pacific are generally naïve to most or all types targeted by the quadrivalent HPV6/11/16/18 vaccine and that they are at subsequent risk for infection and disease caused by these types.     

The knowledge levels and opinions of biomedical students regarding the human papillomavirus quadrivalent (types 6, 11, 16, and 18) recombinant vaccine

The objective of this research was to assess the knowledge levels and attitudes of all students enrolled in 1 biomedical university regarding the human papillomavirus quadrivalent (types 6, 11, 16, and 18) recombinant vaccine (Gardasil-Merck; the HPV vaccine). A survey of students from all 7 programs at the University was conducted in January 2009. A total of 1120 useable questionnaires were obtained. These programs included pharmacy, osteopathic medicine, physician assistant, physical therapy, occupational therapy, doctor of psychology, and master of biomedical sciences. Mean percentage correct on the HPV vaccine knowledge test was 73. Subjects scored highest on the question that asks whether the vaccine helps prevent cervical cancer (97% correct) and lowest on the one asking whether it helps prevent genital warts (41% correct). Eighty-eight percent thought that patients 18 years and older should be able to receive the HPV vaccine without parental consent. Only about 5% think that the vaccine would cause patients to become sexually active, or that it would cause patients to have unprotected sex. The results suggest that these students have reasonable but limited knowledge of the vaccine. Their positive attitudes suggest that they will likely recommend or provide the vaccine to their patients.     

Evolution of type-specific immunoassays to evaluate the functional immune response to Gardasil: a vaccine for human papillomavirus types 16, 18, 6 and 11

Epidemiological studies and clinical trials of vaccines depend on the accurate measurement of antibodies within the polyclonal response to infection or vaccination. The assay currently used to measure the antibody response to vaccination with GARDASIL [Quadrivalent Human Papillomavirus (Types 6, 11, 16, 18) Recombinant Vaccine]--a quadrivalent vaccine used against human papillomavirus (HPV) types 6, 11, 16, and 18--is a competitive Luminex assay (cLIA) that uses multiplex technology to detect type-specific neutralizing antibodies against all four HPV types in a single serum sample. Here we describe how the cLIA was developed, as well as how the monoclonal antibodies (mAbs), used as competitors in the assay, were characterized. An enzyme-linked immunosorbent assay (ELISA) was used to screen eight previously-identified mAbs for their ability to bind to HPV virus-like particles (VLPs) in a type-specific and conformation-dependent manner. Four of these mAbs, H6.M48, K11.B2, H16.V5, and H18.J4, met our specifications and were shown to have the potential to neutralize HPV infection in hemagglutination inhibition and pseudovirus neutralization assays. The competitive immunoassay format was able to distinguish type-specific antibodies in the sera of nonhuman primates vaccinated with HPV VLPs, whereas a traditional direct-bind ELISA could not. In addition, the serum antibodies measured by the competitive assay are known to be neutralizing, whereas the ELISA does not distinguish neutralizing and nonneutralizing antibodies in a serum sample. By detecting antibodies to neutralizing epitopes, the competitive assay both demonstrates sero-conversion and provides a potential functional link between sero-conversion and protective immunity in response to vaccination with GARDASIL.     

Safety and reactogenicity of a quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 viral-like-particle vaccine in older adolescents and young adults

Background: Prophylactic vaccination with a quadrivalent HPV (types 6, 11, 16, 18) vaccine (qHPV) has been shown to prevent infection with HPV 6/11/16/18 and associated disease in women and more recently, in men. Here we report on the safety and reactogenicity of the qHPV vaccine in males. A total of 4,065 healthy males aged 16-26 years were enrolled into a randomized, placebo-controlled, double-blind trial. Subjects were randomized 1:1 to receive qHPV vaccine or placebo at day 1, month 2, and month 6. Safety and tolerability were assessed via the collection of reported adverse experiences (AEs). All serious AEs (vaccine- or procedure-related or not) and all deaths occurring during the study were recorded. Safety analyses were conducted in all subjects who received at least one dose of vaccine or placebo. The proportion of subjects who reported at least one injection-site AE was higher in the qHPV vaccine group versus the placebo group (60.1% vs 53.7%, respectively), however most of these AEs were mild/moderate in intensity. The incidence of at least one systemic AE was comparable between the vaccine and placebo groups (31.7% vs 31.4%, respectively). There were no vaccine-related serious AEs or deaths. The occurrence of AEs did not increase with each successive injection, and among trial participants who were seropositive for at least one vaccine HPV type at enrollment, the profile of adverse events was similar to that of the entire study cohort. The qHPV vaccine was generally well tolerated in males aged 16-26 years and had a favorable safety profile.     

Human papillomavirus types 16 and 18 vaccine (recombinant, AS04 adjuvanted, adsorbed) [Cervarix

Cervarix is a prophylactic vaccine comprised of a mixture of virus-like particles derived from the L1 capsid proteins of human papillomavirus (HPV) types 16 and 18 formulated with the AS04 adjuvant system. It is administered by intramuscular injection as a three-dose vaccine regimen at 0, 1 and 6 months. The vaccine is indicated for the prevention of high-grade cervical intraepithelial neoplasia (CIN 2 and CIN 3) and cervical cancer causally related to HPV types 16 and 18. In randomized, double-blind, phase II or III trials in >19,000 women aged 15-25 years, the HPV 16/18 vaccine showed high efficacy in preventing CIN 2+ associated with HPV 16/18. Cross-protection against new incident or 6-month persistent HPV 45 or HPV 31 infection was also evident. Phase II follow-up was for at least 5.5 years, and the phase III interim analysis was at approximately 15 months after the first vaccine dose. In a bridging study, in adolescent girls aged 10-14 years, the HPV 16/18 vaccine induced twice the already high antibody titres as it did in young women (aged 15-25 years). The immune response in older women (aged 26-55 years) at 24 months in another study was >or= 8-fold higher than antibody levels reported in younger age groups. Anti-HPV 16/18 antibody responses were greater with an AS04-adjuvanted HPV 16/18 vaccine than with an aluminium salt-adjuvanted formulation. The HPV 16/18 vaccine was generally well tolerated and injection-site reactions were the most common vaccine-related adverse events reported.     

Human papillomavirus vaccine for genotypes 6, 11, 16 and 18: new drug. Cervical cancer prevention: high hopes...

(1) Most cases of high-grade anogenital dysplasia and malignancy are caused by human papillomavirus (HPV) genotypes 16 and 18. Anogenital papilloma and condyloma acuminata are mainly caused by HPV6 and HPV11. (2) A recombinant vaccine covering these four genotypes is now marketed in the European Union for the prevention of condyloma, precancerous lesions, and cancers of the female lower genital tract. (3) A three-dose vaccination schedule (0, 2 and 6 months) elicits an immune response in almost all women, but the minimum antibody titre required for clinical protection is not known. Immune protection lasts at least 5 years, but no one knows what happens after that time. (4) Three double-blind randomised placebo-controlled trials involving a total of about 18 000 women aged 16 to 23 had sufficiently similar designs to pool results for analysis. Nearly all (around 98%) of women not yet infected with papillomavirus of a genotype covered by the vaccine were protected from dysplasia caused by one of these genotypes. The vaccine did not affect dysplasia caused by other genotypes, nor was it effective in women who were already infected. In total, among women not yet infected with a papillomavirus genotype covered by the vaccine, the vaccine prevented about 38% of high-grade dysplasias of all types (0.5 versus 0.8 cases per 100 woman-years). (5) The vaccine also markedly reduced the incidence of genital warts and high-grade vulvar and vaginal dysplasia. There are no data on efficacy beyond 4.5 years. (6) These results are somewhat undermined by methodological problems, such as follow-up lasting only a maximum of 4.5 years whereas cervical cancer takes much longer to develop. In addition, there were very few cases of dysplasia in each trial, and results were largely based on post hoc subgroup analyses. (7) Apart from local reactions, which occurred in more than 80% of vaccinated women, the only adverse effect of papillomavirus vaccination was fever (12.9% of those on the vaccine versus 11% on placebo). (8) There is no evidence thus far that prenatal exposure due to HPV vaccination during the month preceding conception is harmful. (9) The clinical results are promising but further follow-up is needed to answer ongoing questions, such as the incidence of cervical cancer after vaccination and the duration of protection. Cervical cancer screening remains necessary, even for vaccinated women, and a continued need exists for measures designed to prevent all sexually transmitted diseases.     

宫颈糜烂及HPV16/18 E6的表达关系研究

目的:研究肉眼拟诊为宫颈糜烂的患者其组织学诊断及人乳头瘤病毒16型(或18型)E6蛋白(HPV16/18E6)的表达及其临床意义。方法:随机抽取年龄为18～65岁的肉眼观为宫颈糜烂的患者100例,分为宫颈轻度糜烂组(30例)、中度糜烂组(41例)、重度糜烂组(29例),光滑组100例(对照组)。分别行阴道镜下宫颈活检,作出病理组织学诊断,采用免疫组织化学法(SP法)测定宫颈组织中HPV16/18E6表达情况。结果:(1)各组宫颈活检的病理结果分为正常、宫颈炎、宫颈上皮内瘤样病变(CIN)Ⅰ、CINⅡ、CINⅢ及宫颈癌(Ca)。各组间疾病构成差异有统计学意义(P0.01),且CINⅡ、CINⅢ及Ca随着疾病严重程度亦呈增加趋势。(2)宫颈光滑组、轻度糜烂组、中度糜烂组及重度糜烂组的HPV16/18E6蛋白阳性率分别为21.0%、26.7%、31.7%及51.6%,差异有统计学意义(P0.01)。其中,光滑组与轻度糜烂组及中度糜烂组、轻度糜烂组与中度糜烂组阳性率差异无统计学意义(均P0.05);重度糜烂组与其他各组比较差异有统计学意义(P0.05或P0.01)。结论:肉眼拟诊为宫颈糜烂的患者其组织学诊断多样化,糜烂程度越高,发生宫颈上皮内瘤变及宫颈癌的可能性越大,HPV16/18E6的表达水平亦有随之升高的趋势。     

Comparison of the size distributions and immunogenicity of human papillomavirus type 16 L1 virus-like particles produced in insect and yeast cells

Insect and yeast cells are considered the expression systems of choice for producing virus-like particles (VLPs), and numerous types of VLPs have been produced in these systems. However, previous studies were restricted to identifying the characteristics of individual VLP preparations. No direct comparison of the structures and immunogenic properties of insect and yeast-derived VLPs has so far been made. In the present study, the size distribution and immunogenic properties of human papillomavirus type 16 (HPV16) L1 VLPs produced in Spodoptera frugipedra-9 insect cells and Saccharomyces cerevisiae were compared. The insect cell-derived VLPs were larger than the yeast ones (P?<?0.0001), with median sizes of 34 and 26 nm, respectively. In addition, the insect-derived VLPs appeared to be more diverse in size than the yeast-derived VLPs. Immunization of mice with 30 ng per dose of VLPs elicited 2.7- and 2.4-fold higher anti-HPV16 L1 IgG and anti-HPV16 neutralizing antibody titers than immunization with the same amounts of the yeast-derived VLPs after the 4th immunizations, respectively. Our results suggest that the choice of expression system critically affects the particle size and immunogenic property of HPV16 L1 VLPs.     

Correlation between direct ELISA, single epitope-based inhibition ELISA and pseudovirion-based neutralization assay for measuring anti-HPV-16 and anti-HPV-18 antibody response after vaccination with the AS04-adjuvanted HPV-16/18 cervical cancer vaccine

To monitor immune status during clinical trials and after vaccine registration, several assays have been developed to measure type-specific human papillomavirus (HPV) serum antibody levels. These include neutralization assays, single epitope-based inhibition immunoassays, and direct enzyme-linked immunosorbent assays (ELISAs). Neutralization assays based on multiple epitopes and independent of vaccine material are considered the 'gold standard' for unbiased assessment of the protective potential of vaccine-induced antibodies. However, their use in large clinical trials is challenging. Here, we compare both the direct ELISA and the single epitope-based inhibition ELISA with the pseudovirion-based neutralization assay (PBNA) for HPV-16/18 antibody responses in vaccinated women enrolled in trials of Cervarix, GSK's cervical cancer vaccine. The direct ELISA, which is based on multiple epitopes, was shown to have a higher degree of sensitivity and correlation with the PBNA when compared with the single epitope-based inhibition ELISA. Among double-positive results, high correlations were observed between the PBNA and the direct ELISA (0.70-0.88 for HPV-16 and 0.82-0.94 for HPV-18) and also with the single epitope-based inhibition ELISA (0.60-0.89 for HPV-16 and 0.57-0.96 for HPV-18) in women aged 15-25 years. The correlation persisted up to 6.4 years after primary vaccination. Similar levels of correlation were observed for adolescents aged 10-14 years and women aged 46-55 years. Therefore, the direct ELISA appears to be an excellent surrogate for neutralizing activity and can be used to evaluate antibody response induced by L1 virus-like particle-based cervical cancer vaccines, regardless of time elapsed after vaccination (up to 6.4 years) and the age of the vaccine recipient.     

Safety and immunogenicity of a meningococcal (Groups A, C, Y, W-135) polysaccharide diphtheria toxoid conjugate vaccine in healthy children aged 2 to 10 years in Chile

Immune responses to meningococcal conjugate (Menactra; MCV-4) and plain polysaccharide (Menomune-A/C/Y/W-135; PSV-4) vaccines against serogroups A, C, Y, and W-135 were assessed in 220 of 1037 Chilean children aged 2 to 10 years participating in a comparative safety trial. Both vaccines were generally well tolerated. Geometric mean serum bactericidal antibody (SBA) titers 28 days postvaccination were comparable in both groups for all four serogroups. Seroconversion was evident in > 97% of MCV-4 and > 90% of PSV-4 vaccinees who tested seronegative at baseline. Menactra safely induced broad and robust immune responses against serogroups A, C, Y and W-135 in this population.     

Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine administered as a 2-dose schedule compared with the licensed 3-dose schedule: results from a randomized study

The immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (Cervarix?, GlaxoSmithKline Biologicals) administered according to its licensed vaccination schedule (3-dose, 3D) and formulation (20 μg of each HPV antigen; 20/20F) has previously been demonstrated. This partially-blind, controlled, randomized trial (NCT00541970) evaluated 2-dose (2D) schedules using the licensed 20/20F or an alternative formulation containing 40 μg of each antigen (40/40F), compared with the licensed 3D schedule. Healthy females stratified by age (9-14, 15-19, 20-25 y) were randomized to receive 2 doses of 20/20F at Months (M) 0,6 (n=240), 40/40F at M0,6 (n=241) or 40/40F at M0,2 (n=240), or 3 doses of 20/20F at M0,1,6 (licensed schedule/formulation, n=239). One month after the last dose, the 3D schedule was not immunologically superior to 2D schedules except in the 40/40F M0,2 group for HPV-16 (lower limit of 95% CI geometric mean antibody titer (GMT) ratio [2D/3D] < 0.5). For both HPV-16 and HPV-18, the 2D schedules in girls 9-14 y were immunologically non-inferior to the 3D schedule in women 15-25 y (the age group in which efficacy has been demonstrated) (upper limit of 95% CI for GMT ratio [3D/2D] < 2) one month after the last dose. At Month 24, non-inferiority was maintained for the 2D M0,6 schedules in girls 9-14 y versus the 3D schedule in women 15-25 y. All formulations had acceptable reactogenicity and safety profiles. These results indicate that the HPV-16/18 vaccine on a 2D M0,6 schedule is immunogenic and generally well tolerated in girls 9-14 y and that the 2D schedule is likely adequate for younger females.     

高危HPV分型在东莞石碣妇女中的分布特点及易感因素研究

目的了解东莞市石碣镇户籍35~60岁妇女高危型人乳头瘤病毒(HPV)感染的情况及亚型分布,并查找分析可能的行为危险因素。方法 2012年1月~2014年12月期间,对石碣镇户籍35~60岁妇女进行宫颈癌筛查,收集宫颈口及宫颈管的脱落上皮细胞标本,检测高危型HPV(包括HPV-16,18,31,33,35,39,45,51,52,56,58,59,68)的感染情况及分型的分布特点,并调查受试者的年龄、初次性生活年龄、性伴侣个数、性伴侣的性对象数目、孕次、文化程度、有无不良爱好,包括是否吸烟与酗酒等,并探讨其与高危型HPV感染率的相关性。结果石碣镇户籍35~60岁妇女有约7000例接受宫颈癌筛查,有256例为高危型HPV阳性,2例考虑为高危亚型HPV,其中单一高危型HPV感染者223例,多重感染者33例。主要感染的高危型HPV是HPV-52(23.08%)、HPV-16(14.38%)、HPV-36(12.04%)、HPV-18(11.04%)。妇女的年龄越大、初次性行为年龄越早、性伴侣数量越多、文化程度越低高危型HPV感染越高。结论石碣镇户籍35~60岁妇女主要感染的高危型HPV是HPV-52,16,36和18型,且年龄越大、初次性行为年龄越早、性伴侣数量越多、文化程度越低高危型HPV感染率越高。     

Efficient expression of modified human papillomavirus 16 e6/e7 fusion protein and the antitumor efficacy in a mouse model

Infection with human papillomavirus, particularly type 16 (HPV16), is highly associated with the development of cervical intraepithelial neoplasia and cervical cancer. The two early viral oncogenes, E6 and E7, are selectively retained and constitutively expressed in tumor cells and are therefore attractive immunotherapeutic targets. Thus a vaccine strategy based on recombinant HPV16 E6/E7 fusion protein represents an efficient approach against HPV16-associated tumors. Although the expression level of HPV16 E6/E7 fusion protein was presumed to be low, direct experimental proof in vivo was lacking. To enhance the expression level and investigate its antitumor efficacy in vivo, we constructed a modified HPV16 E6/E7 fusion gene with three point-mutations and expressed it in Escherichia coli. The encoded protein, denoted mE6(1-120)/mE7(1-60), comprises 120 N-terminus amino acids of E6 and 60 N-terminus amino acids of E7 plus a histine tag, was purified on an affinity column, and subsequently characterized by Western blotting. Immunization of mice with mE6(1-120)/mE7(1-60) completely protected them against subsequent challenge and rechallenge with TC-1 tumor cells expressing HPV16 E6 and E7 proteins. In the therapeutic experiments, most mice eliminated the preexisting tumors and had a long-term protection. Consistent with the results of in vivo experiments, the splenocytes from immunized mice elicited cytotoxic T lymphocytes and specifically lysed TC-1 cells in vitro. More importantly, the expression level of mE6(1-120)/mE7(1-60) was significantly improved, meeting the necessary quantity required for a vaccine clinical trial. In conclusion, these data provide a scientific basis for the use of modified mE6(1-120)/mE7(1-60) in future human trials.