Transcutaneous immunization as preventative and therapeutic regimens to protect against experimental otitis media due to nontypeable Haemophilus influenzae

We have developed three nontypeable Haemophilus influenzae (NTHI) adhesin-derived immunogens that are significantly efficacious against experimental otitis media (OM) due to NTHI when delivered parenterally. We now expanded our preventative immunization strategies to include transcutaneous immunization (TCI) as a less invasive, but potentially equally efficacious, regimen to prevent OM due to NTHI. Additionally, we examined the potential of TCI as a therapeutic immunization regimen to resolve ongoing experimental OM. Preventative immunization with NTHI outer membrane protein (OMP) P5- and type IV pilus-targeted immunogens, delivered with the adjuvant LT(R192G-L211A), induced significantly earlier clearance of NTHI from the nasopharynges and middle ears of challenged chinchillas compared with receipt of immunogen or adjuvant alone. Moreover, therapeutic immunization resulted in significant resolution of established NTHI biofilms from the middle ear space of animals compared with controls. These data advocate TCI with the adhesin-directed immunogens as an efficacious regimen for prevention and resolution of experimental NTHI-induced OM

Safety and Reactogenicity of Canarypox ALVAC-HIV (vCP1521) and HIV-1 gp120 AIDSVAX B/E Vaccination in an Efficacy Trial in Thailand

A prime-boost vaccination regimen with ALVAC-HIV (vCP1521) administered intramuscularly at 0, 4, 12, and 24 weeks and gp120 AIDSVAX B/E at 12 and 24 weeks demonstrated modest efficacy of 31.2% for prevention of HIV acquisition in HIV-uninfected adults participating in a community-based efficacy trial in Thailand.Reactogenicity was recorded for 3 days following vaccination. Adverse events were monitored every 6 months for 3.5 years, during which pregnancy outcomes were recorded. Of the 16,402 volunteers, 69% of the participants reported an adverse event any time after the first dose. Only 32.9% experienced an AE within 30 days following any vaccination. Overall adverse event rates and attribution of relatedness did not differ between groups. The frequency of serious adverse events was similar in vaccine (14.3%) and placebo (14.9%) recipients (p = 0.33). None of the 160 deaths (85 in vaccine and 75 in placebo recipients, p = 0.43) was assessed as related to vaccine. The most common cause of death was trauma or traffic accident. Approximately 30% of female participants reported a pregnancy during the study. Abnormal pregnancy outcomes were experienced in 17.1% of vaccine and 14.6% (p = 0.13) of placebo recipients. When the conception occurred within 3 months (estimated) of a vaccination, the majority of these abnormal outcomes were spontaneous or elective abortions among 22.2% and 15.3% of vaccine and placebo pregnant recipients, respectively (p = 0.08). Local reactions occurred in 88.0% of vaccine and 61.0% of placebo recipients (p<0.001) and were more frequent after ALVAC-HIV than AIDSVAX B/E vaccination. Systemic reactions were more frequent in vaccine than placebo recipients (77.2% vs. 59.8%, p<0.001). Local and systemic reactions were mostly mild to moderate, resolving within 3 days.The ALVAC-HIV and AIDSVAX B/E vaccine regimen was found to be safe, well tolerated and suitable for potential large-scale use in Thailand.ClinicalTrials.govNCT00223080

Development of a method for assessing non-targeted radiation damage in an artificial 3D human skin model.

PURPOSE: Despite the increasing concern about the effect of doses below 0.5 Gy and non-targeted exposures of ionising radiation on living organisms, the majority of radiobiological studies are conducted using in vitro cell lines. In order to be able to extrapolate the in vitro results to in vivo models with confidence, it would be of great benefit to develop a reproducible tissue system suitable for critical radiobiological assays. This manuscript describes the development of a reliable protocol to harvest cells from tissue samples and investigate the radiation damage induced on a single cell basis. MATERIALS AND METHODS: To validate this approach as a potential tool for bystander experiments, the method focuses on analysing radiation damage in individual cells as a function of their relative position in the tissue. The experiments reported describe the micronucleus formation following partial irradiation with 3.5 MeV protons (0.1, 0.5 and 1 Gy) in an artificial human skin construct. RESULTS: The reproducible and low background frequency of micronuclei measured in this system allows detection of small increases following radiation exposures. The effect was statistically significant at doses as low as 0.1 Gy in the directly irradiated as well as in the bystander cells. CONCLUSIONS: The data presented provide evidence of a spatially dependent bystander effect whose magnitude decrease as a function of the distance from the directly exposed area

ОПАСНОСТЬ ИЛИ РЕАЛЬНОСТЬ РАСПРОСТРАНЕНИЯ НОВОЙ ВОЛНЫ ЭПИДЕМИИ ВИЧ-ИНФЕКЦИИ НА СЕВЕРО-ЗАПАДЕ РФ

Based on the analysis of detection of new HIV cases in defined territories, the risk and possible causes of a new wave of HIV epidemic in the Northwest Region of Russia have been assessed. Materials and methods. Retrospective and ongoing analysis of HIV incidence using standard reporting forms and sentinel studies in certain groups of population. Results. With account of total HIV incidence and of parameters specific for defined groups of population, such as IDUs, MSMs, commercial sex workers, STD patients, and external and internal migrants, it is concluded that, following the first expressed wave of HIV infection at the turn of the centuries, a new slow rise in the rates of newly found HIV cases is observed primarily in Saint-Petersburg, Leningrad Oblast, and Murmansk and will be evident in 4 to 5 years in other territories. Starting from 2013, concern is being aroused by considerable increments in the numbers of HIV cases in Arkhangelsk Oblast, the Republic of Komi, and Kaliningrad Oblast and Vologda Oblast. A part of these territories aligns to the subjects of the Russian Federation where the second wave of HIV infection takes place already. It is likely that a new wave of HIV spread in the Northwest of the Russian Federation is real rather than possible.На основании анализа выявления новых случаев ВИЧ-инфекции в отдельных территориях региона оценена опасность и вероятные причины развития второй волны эпидемии в Северо-Западном федеральном округе. Материалы и методы. Ретроспективный и текущий анализы заболеваемости по стандартным формам отчетности, а также данные дозорных исследований по отдельным группам населения на территории округа. Результаты исследования. Рассматривая общие данные заболеваемости и конкретные показатели по отдельным группам населения: потребители инъекционных наркотиков, мужчины, имеющие секс с мужчинами, работники коммерческого секса, больные инфекциями, передающимися половым путем, внутренние и внешние мигранты, авторы приходят к выводу, что после выраженной первой волны эпидемии на рубеже веков начался медленный подъем числа новых случаев в первую очередь в Санкт-Петербурге, Ленинградской и Мурманской областях, который через 4-5 лет продолжился на других территориях округа. Начиная с 2013 года, вызывает настороженность значительный прирост числа больных с ВИЧ в Архангельской области, в Республике Коми, Калининградской и Вологодской областях. Часть этих территорий граничит с субъектами РФ, где ранее началась вторая волна роста заболеваемости ВИЧ-инфекции. По-видимому, существует не только опасность, но и реальность новой волны распространения ВИЧ на Северо-Западе России

A dendritic cell targeted vaccine induces long-term HIV-specific immunity within the gastrointestinal tract

Despite significant therapeutic advances for HIV-1 infected individuals, a preventative HIV-1 vaccine remains elusive. Studies focusing on early transmission events, including the observation that there is a profound loss of gastrointestinal (GI) CD4(+) Tcells during acute HIV-1 infection, highlight the importance of inducing HIV-specific immunity within the gut. Here we report on the generation of cellular and humoral immune responses in the intestines by a mucosally administered, dendritic cell (DC) targeted vaccine. Our results show that nasally delivered alpha-CD205-p24 vaccine in combination with polyICLC, induced polyfunctional immune responses within naso-pulmonary lymphoid sites that disseminated widely to systemic and mucosal (GI tract and the vaginal epithelium) sites. Qualitatively, while alpha-CD205-p24 prime-boost immunization generated CD4(+) T-cell responses, heterologous prime-boost immunization with alpha-CD205-p24 and NYVAC gag-p24 generated high levels of HIV-specific CD4(+) and CD8(+) Tcells within the GI tract. Finally, DC-targeting enhanced the amplitude and longevity of vaccine-induced immune responses in the GI tract. This is the first report of a nasally delivered, DC-targeted vaccine to generate HIV-specific immune responses in the GI tract and will potentially inform the design of preventative approaches against HIV-1 and other mucosal infectionsclos