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Nachega J.B.,University of Cape Town | Uthman O.A.,University of Cape Town | Uthman O.A.,Keele University | Anderson J.,Johns Hopkins Hospital | And 10 more authors.
AIDS | Year: 2012

OBJECTIVE: To estimate antiretroviral therapy (ART) adherence rates during pregnancy and postpartum in high-income, middle-income, and low-income countries. DESIGN: Systematic review and meta-analysis. METHODS: MEDLINE, EMBASE, SCI Web of Science, NLM Gateway, and Google scholar databases were searched. We included all studies reporting adherence rates as a primary or secondary outcome among HIV-infected pregnant women. Two independent reviewers extracted data on adherence and study characteristics. A random-effects model was used to pool adherence rates; sensitivity, heterogeneity, and publication bias were assessed. RESULTS: Of 72 eligible articles, 51 studies involving 20153 HIV-infected pregnant women were included. Most studies were from United States (n=14, 27%) followed by Kenya (n=6, 12%), South Africa (n=5, 10%), and Zambia (n=5, 10%). The threshold defining good adherence to ART varied across studies (>80, >90, >95, 100%). A pooled analysis of all studies indicated a pooled estimate of 73.5% [95% confidence interval (CI) 69.3-77.5%] of pregnant women who had adequate (>80%) ART adherence. The pooled proportion of women with adequate adherence levels was higher during the antepartum (75.7%, 95% CI 71.5-79.7%) than during postpartum (53.0%, 95% CI 32.8-72.7%; P=0.005). Selected reported barriers for nonadherence included physical, economic and emotional stresses, depression (especially postdelivery), alcohol or drug use, and ART dosing frequency or pill burden. CONCLUSION: Our findings indicate that only 73.5% of pregnant women achieved optimal ART adherence. Reaching adequate ART adherence levels was a challenge in pregnancy, but especially during the postpartum period. Further research to investigate specific barriers and interventions to address them is urgently needed globally. Copyright © 2012 Lippincott Williams &Wilkins.


News Article | February 15, 2017
Site: www.eurekalert.org

The acid test for a vaccine is: "Does it protect people from infection?" Emory Vaccine Center researchers have analyzed this issue for a leading malaria vaccine called RTS,S, and their results have identified candidate signatures, or biomarkers, in the blood of vaccinated subjects which predict the likelihood of success from vaccination. Bali Pulendran, PhD, and colleagues, identified molecular signatures - sets of genes that are turned on and off in immune cells in the blood - that can discern whether volunteers in a malaria vaccine study were protected when they were exposed to mosquitoes carrying the Plasmodium falciparum parasite. The results are scheduled for publication in PNAS. The research could inform decisions on how RTS,S or other malaria vaccines are deployed or modified. RTS,S was developed by GlaxoSmithKline, and has been tested in Phase 3 clinical trials with support from the PATH Malaria Vaccine Initiative. The vaccine was shown to provide partial protection against malaria and is scheduled for roll-out through pilot projects in three African countries next year, according to the World Health Organization. Pulendran is Charles Howard Candler professor of pathology and laboratory medicine at Emory University School of Medicine and a researcher at Yerkes National Primate Research Center. He and his team have pioneered the use of systems biology approaches to identify signatures to define molecular signatures or biomarkers, induced within a few days of vaccination, that can be used to accurately predict the strength of the immune response weeks later. A major challenge in vaccinology has been whether such signatures could be used to predict, not merely the strength of the immune response, but the efficacy of vaccination - that is the extent to which vaccination protected against infection. The present study addressed this issue by vaccinating human subjects with the RTS,S malaria vaccine, and then deliberately challenging them with Plasmodium falciparum in a controlled experimental human infection model. This provides proof of concept of the utility of systems based approaches in identifying signatures that can be used to predict vaccine efficacy. "Many of the genes contained in the predictive signatures are known to be expressed in natural killer cells, which mediate critical immune functions against viruses," Pulendran says. "It was a surprise to see such a robust 'NK cell signature' in predicting success of vaccination against the malaria parasite, and raises the hypothesis that such cells may be playing a vital role in orchestrating immunity against malaria." Pulendran says that other elements such as the signatures of antibody-producing plasma cells in the blood, and activation of antiviral interferon pathways, were conserved with vaccines such as yellow fever and flu. "The extent to which these candidate signatures of protection can successfully predict vaccine efficacy in other field trials remain to be determined," he adds. The underlying malaria vaccine study was performed at Walter Reed Army Institute of Research from 2011 to 2012, and involved 46 volunteers who received two vaccine regimens, one with RTS,S only and another adding an adenovirus-based vector. About 50 percent of the participants were protected after exposure to parasite-carrying mosquitos for both regimens. After analyzing the immune responses, the researchers propose that the two vaccine regimens may be conferring protection against malaria by distinct mechanisms, with the RTS,S-only regimen relying on high levels of antibodies, and the other recruiting more T cells. The same signatures that predicted protection from infection were confirmed using data from an independent study that was also testing the RTS,S vaccine. The co-first authors of the paper are bioinformatics analyst Dmitri Kazmin and former Emory postdoc Helder Nakaya, now at University of Sao Paulo. Co-authors include Ripley Ballou, Robbert van der Most, Robert van den Berg and Erik Jongert from GlaxoSmithKline, Eva Lee from Georgia Tech, Daniel Zak and Alan Aderem at the Center for Infectious Disease Research, Jerald Sadoff at Crucell, and Ulli Wille Reece and Christian Ockenhouse at the PATH Malaria Vaccine Initiative. Emory co-authors include Rafi Ahmed and Jens Wrammert. The research was supported by the PATH Malaria Vaccine Initiative, the National Institute of Allergy and Infectious Diseases (U19AI090023 and U19AI057266), and the Office of Research Infrastructure Programs (Primate centers: P51OD11132).


News Article | November 10, 2016
Site: www.eurekalert.org

Silver Spring, Md. - Researchers have found that an investigational treatment combining a therapeutic vaccine and an immune stimulator improves virologic control and delays viral rebound following the discontinuation of antiretroviral therapy (ART) in non-human primates infected with SIV, the simian form of HIV. The proof-of-concept study examined the combined effects of therapeutic vaccination with an adenovirus serotype 26 vector vaccine and an MVA vector vaccine (Ad26/MVA) and TLR-7 agonist stimulation in ART-suppressed, SIV-infected monkeys. Findings were published online today in Nature. The study was a collaboration led by the Beth Israel Deaconess Medical Center (BIDMC) and the U.S. Military HIV Research Program (MHRP) of the Walter Reed Army Institute of Research (WRAIR), and includes scientists from Janssen Vaccines & Prevention B.V., one of the Janssen Pharmaceutical Companies of Johnson & Johnson, and Gilead Sciences, Inc. All rhesus monkeys were started on suppressive ART seven days after infection with SIV. After 24 weeks, groups of animals then either received a placebo treatment, Ad26/MVA, TLR7 agonist or a combination intervention of Ad26/MVA and TLR-7. TLR7 agonist. At 72 weeks, ART was discontinued to test the ability of the investigational therapies to affect continued virological control. "We found the combination of Ad26/MVA vaccination and TLR7 stimulation proved more effective than either component alone," said Col. Nelson Michael, Director of MHRP, who helped design the preclinical study. "This was especially striking for viral load set-point, which impacts future disease." In the combination group, the mean viral load set-point was reduced by 100 fold in all animals. Researchers saw a 2.5-fold delay of viral rebound as compared with the other groups. TLR-7Stimulation of TLR7 alone did not impact viral load or rebound. The vaccine alone reduced viral load set-point by 10 fold and only marginally delayed rebound. Though all monkeys eventually experienced viral rebound following ART interruption, three of the monkeys in the combination intervention group showed effective virologic control to undetectable viral loads following ART discontinuation. "Current antiretroviral drugs, although they're lifesaving, do not cure HIV. They merely hold it in check. We are trying to develop strategies to achieve ART-free, long-term viral suppression," said senior author Dan Barouch, MD, PhD, Director of the Center for Virology and Vaccine Research at BIDMC and Professor of Medicine at Harvard Medical School. "We reasoned that if we can activate the immune cells that might harbor the virus, then the vaccine-induced immune responses might perform better seeking them out and destroying them." A critical barrier to HIV cure is the viral reservoir that remains hidden and infects cells throughout the body, leading to viral rebound in the vast majority of HIV-infected individuals after they discontinue ART. According to Dr. Merlin Robb, Deputy Director for Clinical Research at MHRP, "the combination of Ad26/MVA vaccination and TLR7 stimulation resulted in decreased levels of viral DNA in both lymph nodes and peripheral blood. With further optimization this combination strategy may show promise to achieve a functional cure for HIV." Additionally, cellular immune breadth correlated inversely with set-point viral loads and correlated directly with time to viral rebound. According to Michael, "This gives us an immunologic correlate which can potentially be used to predict responses in humans, but this needs to be confirmed in human clinical studies." Ad26/MVA is a prime boost vaccine regimen. MHRP, in collaboration with Janssen, recently began evaluating this regimen as a therapeutic vaccine in HIV infected adults who initiated ART during acute HIV infection. That study is being conducted at the Thai Red Cross in Bangkok, and the protocol chair is Dr. Jintanat Ananworanich, MHRP's Associate Director for Therapeutics. The Ad26 vaccine was developed in partnership between the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), BIDMC and Janssen. MHRP developed the MVA vaccine in collaboration with the Laboratory of Viral Diseases at NIAID/NIH. The TLR7 agonist (GS-986) was developed by Gilead. Funding for the study was provided by the U.S. Army Medical Research and Materiel Command and the Military HIV Research Program, Walter Reed Army Institute of Research through its cooperative agreement with the Henry M. Jackson Foundation (W81XWH-11-2-0174); NIH (AI096040, AI124377, AI126603); the Ragon Institute of MGH, MIT, and Harvard. About the Walter Reed Army Institute of Research Headquartered in Silver Spring, Maryland, the Walter Reed Army Institute of Research (WRAIR) is the oldest and most diverse biomedical research laboratory in the Department of Defense. WRAIR provides unique research capabilities and innovative solutions to a range of force health and readiness challenges currently facing U.S. Service Members, along with threats anticipated during future operations. With comprehensive research units in Africa, Asia, and the Caucasus region, WRAIR is comprised of two Centers of Excellence, the Center for Infectious Disease Research and the Center for Military Psychiatry and Neuroscience.


News Article | November 7, 2016
Site: www.eurekalert.org

SILVER SPRING, Md. - The Walter Reed Army Institute of Research (WRAIR) began vaccinations today in a Phase 1 human clinical trial to test the safety and immunogenicity of the Zika purified inactivated virus (ZPIV) vaccine. Seventy-five healthy adults will be recruited to participate in the trial at WRAIR's Clinical Trial Center in Silver Spring, Md. Given the concerns for immune enhancement with other similar flaviviruses, like yellow fever and Japanese encephalitis, ZPIV will be tested in some volunteers who will first be vaccinated against one of these other flaviviruses. This is of particular military relevance, as service members are often vaccinated against these diseases and then deployed to areas where Zika is increasingly becoming endemic. WRAIR scientists developed the ZPIV vaccine candidate earlier this year. The inactivated flavivirus vaccine platform was the same technology the Institute used to create its Japanese encephalitis vaccine, which was licensed in 2009. An earlier preclinical study found that rhesus monkeys that were vaccinated with ZPIV developed a strong immune response and were protected against two strains of Zika virus. The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), helped identify the viral strain used in the ZPIV vaccine, supported the preclinical safety testing, and is sponsoring the conduct of this trial. WRAIR, NIAID, and the Biomedical Advanced Research and Development Authority (BARDA) have established a joint research collaboration agreement to support the development of this vaccine. In addition to concerns about infection during deployment and travel, most military installations in the continental U.S. are concentrated in the southern states, where climate conditions and mosquito populations are favorable for Zika transmission. Col. Nelson Michael, director of WRAIR's Military HIV Research Program (MHRP) and Zika program co-lead noted that, "The Army has moved efficiently from recognizing Zika virus as a threat, producing ZPIV for use in animals and demonstrating its effectiveness in mice and monkeys, producing ZPIV for human testing, and now initiating clinical trials to establish its safety and build the case for subsequent efficacy trials. All of this was done in 10 months." This study is part of the U.S. Department of Defense response to the ongoing outbreak of Zika virus in North and South America and Southeast Asia. As of November 2, there were 149 confirmed cases of Zika virus within the military health system, including four pregnant service members and one pregnant family member. "Asymptomatic Zika infections can lead to severe birth defects and neurological complications. A safe and effective Zika vaccine that prevents infection in those at risk is a global public health priority," said Maj. Leyi Lin, principal investigator of the study. The Pilot Bioproduction Facility at WRAIR manufactured the ZPIV vaccine being used in Phase 1 clinical studies, and the Army recently signed a cooperative research and development agreement to transfer the ZPIV technology to Sanofi Pasteur to explore larger scale manufacturing and advanced development. BARDA recently awarded a six-year contract to Sanofi Pasteur to further develop this vaccine to licensure. "The Army was able to move so quickly in developing, manufacturing and testing a Zika vaccine because of its extensive experience with this vaccine platform and long standing investments in the understanding and mitigation of flaviviruses, like yellow fever, dating back to the founding of WRAIR," said Dr. Kayvon Modjarrad, Zika program co-lead and associate director for Emerging Infectious Disease Threats at WRAIR's MHRP. WRAIR's ZPIV candidate will also be included as a part of a NIH trial that began in August. That study will test ZPIV in a group of people who first receive the DNA vaccine and then are boosted with the ZPIV vaccine. Three additional Phase 1 trials using ZPIV are scheduled to begin this year: The WRAIR trial that began today is sponsored by NIAID and funded by the Departments of the Army and Defense. About the Walter Reed Army Institute of Research Headquartered in Silver Spring, Maryland, the Walter Reed Army Institute of Research (WRAIR) is the oldest and most mission diverse biomedical research laboratory in the Department of Defense. WRAIR provides unique research capabilities and innovative solutions to a range of force health and readiness challenges currently facing U.S. Service Members, along with threats anticipated during future operations. With comprehensive research units in Africa, Asia, and the Caucasus region, WRAIR is comprised of two Centers of Excellence, the Center for Infectious Disease Research and the Center for Military Psychiatry and Neuroscience.


Cohen S.B.,Cornell University | Cohen S.B.,Center for Infectious Disease Research | Denkers E.Y.,Cornell University
Journal of Immunology | Year: 2015

The function of mucosal dendritic cell (DC) subsets in immunity and inflammation is not well understood. In this study, we define four DC subsets present within the lamina propria and mesenteric lymph node compartments based on expression of CD103 and CD11b. Using IL-12p40 YFP (Yet40) reporter mice, we show that CD103+CD11b2 mucosal DCs are primary in vivo sources of IL-12p40; we also identified CD103-CD11b- mucosal DCs as a novel population producing this cytokine. Infection was preferentially found in CD11b+ DCs that were negative for CD103. Lamina propria DCs containing parasites were negative for IL-12p40. Instead, production of the cytokine was strictly a property of noninfected cells. We also show that vitamin A metabolism, as measured by ALDH activity, was preferentially found in CD103+CD11b+ DC and was strongly downregulated in all mucosal DC subsets during infection. Finally, overall apoptosis of lamina propria DC subsets was increased during infection. Combined, these results highlight the ability of intestinal Toxoplasma infection to alter mucosal DC activity at both the whole population level and at the level of individual subsets. © 2015 by The American Association of Immunologists, Inc.


Killam W.P.,University of Alabama at Birmingham | Killam W.P.,Center for Infectious Disease Research | Tambatamba B.C.,Ministry of Health Zambia | Chintu N.,Center for Infectious Disease Research | And 8 more authors.
AIDS | Year: 2010

BACKGROUND: The objective of the study was to evaluate whether providing antiretroviral therapy (ART) integrated in antenatal care (ANC) clinics resulted in a greater proportion of treatment-eligible women initiating ART during pregnancy compared with the existing approach of referral to ART. ANALYSIS DESIGN AND METHODS: The evaluation used a stepped-wedge design and included all HIV-infected, ART-eligible pregnant women in eight public sector clinics in Lusaka district, Zambia. Main outcome indicators were the proportion of treatment-eligible pregnant women enrolling into HIV care within 60 days of HIV diagnosis, and of these, the proportion initiating ART during pregnancy. Adjusted odds ratios (AORs) and confidence intervals (CIs) for enrollment and initiation proportions were estimated through a logistic regression model accounting for clinical site cluster and time effects. RESULTS: Between 16 July 2007 and 31 July 2008, 13 917 women started antenatal care more than 60 days before the intervention rollout and constituted the control cohort; 17 619 started antenatal care after ART integrated into ANC and constituted the intervention cohort. Of the 1566 patients found eligible for ART, a greater proportion enrolled while pregnant and within the 60 days of HIV diagnosis in the intervention cohort (376/846, 44.4%) compared with the control cohort (181/716, 25.3%), AOR 2.06, 95% CI (1.27-3.34); and initiated ART while pregnant in the intervention cohort (278/846, 32.9%) compared with the control cohort (103/716, 14.4%), AOR 2.01, 95% CI (1.37-2.95). CONCLUSION: An integrated ART in ANC strategy doubled the proportion of treatment-eligible women initiating ART while pregnant. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Di Paolo N.C.,Emory University | Shafiani S.,Center for Infectious Disease Research | Day T.,Center for Infectious Disease Research | Day T.,Fred Hutchinson Cancer Research Center | And 7 more authors.
Immunity | Year: 2015

The interleukin-1 receptor I (IL-1RI) is critical for host resistance to Mycobacterium tuberculosis (Mtb), yet the mechanisms of IL-1RI-mediated pathogen control remain unclear. Here, we show that without IL-1RI, Mtb-infected newly recruited Ly6Ghi myeloid cells failed to upregulate tumor necrosis factor receptor I (TNF-RI) and to produce reactive oxygen species, resulting in compromised pathogen control. Furthermore, simultaneous ablation of IL-1RI and TNF-RI signaling on either stroma or hematopoietic cells led to early lethality, indicating non-redundant and synergistic roles of IL-1 and TNF in mediating macrophage-stroma cross-talk that was critical for optimal control of Mtb infection. Finally, we show that even in the presence of functional Mtb-specific adaptive immunity, the lack of IL-1α and not IL-1β led to an exuberant intracellular pathogen replication and progressive non-resolving inflammation. Our study reveals functional interdependence between IL-1 and TNF in enabling Mtb control mechanisms that are critical for host survival. © 2015 Elsevier Inc.


News Article | March 29, 2016
Site: www.biosciencetechnology.com

An international team of scientists have developed a blood test, based on biomarkers in gene activity that can reliably predict whether a person with the Mycobacterium tuberculosis bacterium will develop active tuberculosis (TB). According to the World Health Organization, TB is the top infectious disease killer globally.  In 2014, 9.6 million people became ill with TB and 1.5 million people died from the disease, which is spread from person to person through the air.  About one-third of the world’s population has latent TB, which means they carry the bacteria but have not become ill and cannot transmit the disease.  About 90 percent of people that carry the bacteria will not develop the illness, but 10 percent will develop symptoms. Up until now, there has been no way to predict wither a person infected by the bacteria will go on to develop active TB. For the study, published in online March 23 in The Lancet, researchers from the South African Tuberculosis Vaccine Initiative  and the Center for Infectious Disease Research obtained blood samples from more than 10,000 subjects in Gambia and South Africa and analyzed gene activity.  They collected blood samples from study participants every six months and monitored participants for two years. The findings identified a specific gene profile in immune cells in blood samples of people who eventually develop active TB, using whole blood RNA sequencing data from those who developed active TB compared to those who remained healthy. According to a statement the blood test can predict, with about 75 percent reliability, if active TB will develop. “Such a test could predict the occurrence of the disease more than a year before the disease develops,” lead investigator Willem Hanekom of the University of Cape Town said in a statement.  “This long lead period will give doctors enough time to initiate treatment.” A parallel study is being led by Stefan H.E. Kaufmann of the Max Planck Institute for Infection biology to develop a pan-African biomarker test for TB by observing groups of subjects from several parts of Africa.  The results will not be published until the end of the year, but findings so far suggest the same specific genes in immune cells are active, indicating an increased risk of developing active TB. “If we can predict early on that an individual will develop active tuberculosis, this will help greatly in containing the disease,” Kaufmann said in a statement. The blood test described in the recently published study will move to clinical trials to see if progression of the predicted active TB can be stopped with targeted treatment. Establish your company as a technology leader! For more than 50 years, the R&D 100 Awards have showcased new products of technological significance. You can join this exclusive community! Learn more.


Kaushansky A.,Center for Infectious Disease Research | Kappe S.H.I.,Center for Infectious Disease Research | Kappe S.H.I.,University of Washington
Current Opinion in Microbiology | Year: 2015

Plasmodium parasites belong to the Apicomplexan phylum, which consists mostly of obligate intracellular pathogens that vary dramatically in host cell tropism. Plasmodium sporozoites are highly hepatophilic. The specific molecular mechanisms, which facilitate sporozoite selection and successful infection of hepatocytes, remain poorly defined. Here, we discuss the parasite and host factors which are critical to hepatocyte infection. We derive a model where sporozoites initially select host cells that constitute a permissive environment and then further refine the chosen hepatocyte during liver stage development, ensuring life cycle progression. While many unknowns of pre-erythrocytic infection remain, advancing models and technologies that enable analysis of human malaria parasites and of single infected cells will catalyze a comprehensive understanding of the interaction between the malaria parasite and its hepatocyte host. © 2015 Elsevier Ltd.


Aachoui Y.,University of North Carolina at Chapel Hill | Kajiwara Y.,Mount Sinai School of Medicine | Leaf I.A.,Center for Infectious Disease Research | Mao D.,University of North Carolina at Chapel Hill | And 5 more authors.
Cell Host and Microbe | Year: 2015

The inflammatory caspases 1 and 11 are activated in response to different agonists and act independently to induce pyroptosis. In the context of IL-1β/IL-18 secretion, however, in vitro studies indicate that caspase-11 acts upstream of NLRP3 and caspase-1. By contrast, studying infection in vivo by the cytosol-invasive bacterium Burkholderia thailandensis, we find that caspase-1 activity is required upstream of caspase-11 to control infection. Caspase-1-activated IL-18 induces IFN-γ to prime caspase-11 and rapidly clear B. thailandensis infection. In the absence of IL-18, bacterial burdens persist, eventually triggering other signals that induce IFN-γ. Whereas IFN-γ was essential, endogenous type I interferons were insufficient to prime caspase-11. Although mice transgenic for caspase-4, the human ortholog of caspase-11, cleared B. thailandensis in vivo, they did not strictly require IFN-γ priming. Thus, caspase-1 provides priming signals upstream of caspase-11 but not caspase-4 during murine defense against a cytosol-invasive bacterium. © 2015 Elsevier Inc.

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