The L1 major capsid protein of HPV16 differentially modulates APC trafficking according to the vaccination or natural infection context

Human papillomavirus (HPV) infection, particularly type 16, is causally associated with cancer of the uterine cervix. The progression of cervical lesions suggests that viral antigens are not adequately presented to the immune system. The aim of this study was to determine whether HPV16 viral particles can influence the trafficking of human DC/Langerhans cells (LC), either by direct interactions with DC or following incubation with human normal keratinocytes that are in close contact with LC in the squamous epithelium. We first demonstrated that HPV16 L1 major capsid protein, when self-assembled into virus-like particles (VLP), is able to induce in DC an over-expression of CXC receptor 4 (CXCR4) via the activation of the NF-κB signaling pathway and to enhance DC motility in the presence of CXCL12, suggesting an ability to migrate towards lymph nodes. We also showed that conditioned media of HPV16 VLP-treated keratinocytes induce a lower LC migration than those from untreated keratinocytes and that prostaglandin E2 (PGE(2)), detected in HPV16 VLP-treated keratinocyte supernatants, may reduce LC recruitment into the squamous epithelium. Taken together, our data demonstrate that HPV16 VLP may differentially regulate the immune protective response according to their target cells.     

Two distinct chimeric potexviruses share antigenic cross-presentation properties of MHC class I epitopes

Chimeric VLPs made of papaya mosaic virus (PapMV) trigger a CTL response through antigenic presentation of epitopes on MHC class I. Here, a chimeric VLP composed of malva mosaic virus (MaMV) was shown to share similar properties. We demonstrated the capacity of both VLPs to enter human APCs. The chimeric constructions were cross-presented in CD40-activated B lymphocytes leading to in vitro expansion of antigen-specific T lymphocytes. We showed that high concentrations of chimeric MaMV induced cell death, suggesting that some modifications can trigger collateral effects in vitro. Results suggest that potexvirus VLPs are an attractive vaccine platform for inducing a CTL response.     

HPV-vaccination against cervical carcinoma: will it really work?

Prophylactic HPV vaccination provides an opportunity to profoundly affect cervical cancer incidence worldwide. The quadrivalent HPV VLP 6, 11, 16, 18 vaccine (Gardasil) and the bivalent HPV VLP 16, 18 vaccine (Cervarix) are effective for prevention of HPV infection and cervical precancerous lesions. The quadrivalent vaccine is also effective for prevention of vulvar and vaginal lesions and genital warts. With the introduction of the vaccines general issues have to be raised such as optimal age for vaccination, duration of protection after vaccination, impact on cervical cancer screening, vaccination of males and feasibility of application to developing countries. The prospects of a vaccine which will protect against the most common viral sexually transmitted infection and thereby, protect against the complications of HPV infection such as cervical cancer is extremely appealing. The success of HPV vaccination as a major public health prevention opportunity, however, will entirely depend on efficient infrastructures to deliver the vaccines and on the acceptance by individuals, parents and health care providers.     

Protection against a lethal H5N1 influenza challenge by intranasal immunization with virus-like particles containing 2009 pandemic H1N1 neuraminidase in mice

Highly pathogenic H5N1 influenza shares the same neuraminidase (NA) subtype with the 2009 pandemic (H1N1pdm09), and cross-reactive NA immunity might protect against or mitigate lethal H5N1 infection. In this study, mice were either infected with a sublethal dose of H1N1pdm09 or were vaccinated and boosted with virus-like particles (VLP) consisting of the NA and matrix proteins, standardized by NA activity and administered intranasally, and were then challenged with a lethal dose of HPAI H5N1 virus. Mice previously infected with H1N1pdm09 survived H5N1 challenge with no detectable virus or respiratory tract pathology on day 4. Mice immunized with H5N1 or H1N1pdm09 NA VLPs were also fully protected from death, with a 100-fold and 10-fold reduction in infectious virus, respectively, and reduced pathology in the lungs. Human influenza vaccines that elicit not only HA, but also NA immunity may provide enhanced protection against the emergence of seasonal and pandemic viruses.     

Evidence of immune memory 8.5 years following administration of a prophylactic human papillomavirus type 16 vaccine

Background

The duration of protection conferred by prophylactic human papillomavirus (HPV) L1 virus-like particle vaccines is a critical determinant of their public health impact. A feature of vaccines that confer long-term immunity is their ability to induce immune memory.

Objectives

We evaluated antibody responses against HPV types 6, 11, 16 and 18 following administration of the quadrivalent HPV-6/11/16/18 vaccine to women who had previously received a monovalent HPV-16 vaccine.

Study design

As part of an extended follow-up study conducted between 2006 and 2009 in Seattle, Washington, we administered the quadrivalent HPV-6/11/16/18 vaccine to 52 women (19 vaccine and 33 placebo recipients) who had participated in a monovalent HPV-16 vaccine trial 8.5 years earlier. Serum samples were tested for anti-HPV antibodies using competitive Luminex immunoassay.

Results

Following administration of the first dose of the quadrivalent HPV-6/11/16/18 vaccine, the anti-HPV-16 geometric mean titer among monovalent HPV-16 vaccine recipients (GMT = 5024.0 milli-Merck units per milliliter [mMU/mL]; 95% confidence interval [CI]: 2710.1, 9313.6 mMU/mL) substantially exceeded that among the placebo recipients (GMT = 136.1; 95% CI: 78.5, 235.8 mMU/mL; p < 0.01) and their own highest anti-HPV-16 response observed during the original trial (GMT at month 7 of the original trial = 1552.7 mMU/mL; 95% CI: 1072.6, 2247.7 mMU/mL; p < 0.01).

Conclusions

The findings suggest that the administration of the three-dose regimen of the monovalent HPV-16 vaccine had produced memory lymphocytes, characterized by a heightened immune response following administration of the quadrivalent HPV-6/11/16/18 vaccine that effectively served as an antigen challenge.     

Turnip yellow mosaic virus forms infectious particles without the native beta-annulus structure and flexible coat protein N-terminus

Structural studies have implicated the TYMV N-terminal amino acids of the coat protein (CP) in both static (virion stabilization) and dynamic (RNA encapsidation and disencapsidation) roles. We have deleted residues 2-5, 2-10 and 2-26 from the N-terminus and expressed the mutant CPs in E. coli to assess assembly in the absence of genomic RNA and in plant infections to assess infectivity and virion properties. In E. coli, the deletion constructs formed virus-like particles, but in decreased yield. All mutants were infectious in Chinese cabbage, producing normal symptoms but with a slight delay and decreased viral yields. Virions were progressively less stable with increasing deletion size and also more accessible to small molecules. These results show that the N-terminal 26 amino acids are not essential for viral processes in vivo, although removal of these residues decreases stability and increases porosity, both important factors for virion integrity and survival outside the host.     

Vaccination with a Human Papillomavirus (HPV)-16/18 AS04-Adjuvanted Cervical Cancer Vaccine in Korean Girls Aged 10-14 Years

The human papillomavirus (HPV)-16/18 AS04-adjuvanted cervical cancer vaccine has been demonstrated to be highly efficacious and immunogenic with a favorable safety profile. This study assessed the immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine in healthy Korean girls aged 10-14 yr. This multi-center, observer-blind trial randomly assigned 321 healthy girls to receive three doses (0, 1, 6-month schedule) of HPV-16/18 AS04-adjuvanted vaccine or hepatitis A vaccine. Immunogenicity against vaccine antigens was assessed one month post-Dose 3. Solicited and unsolicited adverse events (AEs) and serious AEs (SAEs) were recorded. In the according-to-protocol analysis, all initially seronegative subjects vaccinated with the HPV-16/18 AS04-adjuvanted vaccine had seroconverted at Month 7, with a peak geometric mean titer (GMT) that was 600-fold higher than the natural infection titer of 29.8 EU/mL for HPV-16 and a peak GMT that was 400-fold higher than the natural infection titer of 22.6 EU/mL for HPV-18. The vaccine was well tolerated with no increase in reactogenicity with subsequent doses and no reports of vaccine-related SAEs. In conclusion, the HPV-16/18 AS04-adjuvanted vaccine is shown to be highly immunogenic and generally well-tolerated in Korean girls aged 10-14 yr.     

急性脑梗死对心率变异性、QT离散度及心室晚电位的影响

 目的 探讨脑梗死及其梗死部位、病情严重程度对心脏电活动的影响.方法 选择急性脑梗死患者107例为病例组,同期体检健康者79例为健康对照组.分析两组病例中前循环梗死患者与后循环梗死患者及轻症梗死患者与重症梗死患者之间心率变异性(heart rate variability,HRV)指标R-R间期标准差(standard diviation of normal to normal intervals,SDNN)、QT间期离散度(QT dispersion,QTd)及心室晚电位(ventricular late potential,VLP)阳性率的差别.结果 脑梗死患者的SDNN低于健康对照组,而QTd及VLP阳性率高于健康对照组,差异均有统计学意义(P＜0.01).后循环梗死患者的SDNN低于前循环梗死患者,差异有统计学意义(P＜0.05);而其QTd及VLP阳性率高于前循环梗死患者,差异有统计学意义(P＜0.01).重症梗死患者的SDNN低于轻症梗死患者,而QTd及VLP阳性率高于轻症梗死患者,差异有统计学意义(P＜0.01).结论 脑梗死及其梗死部位、病情严重程度可影响心脏电活动.脑梗死患者,尤其是后循环梗死及重症梗死患者,其SDNN减低,而QTd及VLP阳性率增高.