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News Article | April 17, 2017
Site: www.eurekalert.org

"A vaccine that remains in the vial is 0% effective even if it is the best vaccine in the world," states a new editorial by Emory Vaccine Center leaders in Proceedings of the National Academy of Sciences (PNAS). Although vaccines against preventable infectious diseases have dramatically reduced global mortality rates, the editorial asserts, maintaining community confidence in vaccination and ensuring widespread coverage is essential to the continued success of vaccines. Rafi Ahmed, PhD, director of the Emory Vaccine Center, and Walter Orenstein, MD, associate director, emphasize that health care providers and community leaders must work together to increase vaccine confidence and acceptance by stressing the important health and economic benefits of vaccination both for those vaccinated and for their communities. "In some sense, vaccines have become victims of their own success. Diseases that once induced fear and sparked desire for vaccines are now rare, and there is a false and dangerous sense of complacency among the public," say Orenstein and Ahmed. Fears about vaccines and their side effects have been growing over recent years coupled with a lack of knowledge about the enormous health and economic benefits of vaccines, the authors say. Although multiple studies have found no support for vaccines as a cause of autism, and independent evaluation of the current immunization schedule has found it to be extremely safe, "translating the science into information capable of influencing vaccine skeptics has been difficult." Orenstein and Ahmed cite a CDC report on 159 measles cases reported between January 4 and April 2, 2015 in which 68 of those with measles were unvaccinated and 29 of those cited philosophical or religious objections to vaccination. And a national survey found the percentage of U.S. pediatricians reporting parental vaccine refusals increased from 74.5 percent in 2006 to 87 percent in 2013. Globally, a 67-country survey of vaccine confidence reported an average of 5.8 percent of respondents (and a high of 15 percent in some countries) who were skeptical about the importance of vaccines. The authors note several recent research studies on the benefits of vaccines: an analysis by the Centers for Disease Control and Prevention (CDC) of nine diseases that have been reduced by more than 90 percent and many that have either been eliminated or been reduced by 99 percent or more due to vaccines; research showing that vaccination has resulted in net economic benefits of almost $69 billion in the United States alone; and an economic analysis that estimates an investment of $34 billion for 10 vaccines in 94 low- and middle-income countries would result in $586 billion in reducing costs of illness and $1.53 trillion in overall economic benefits. Vaccines not only provide individual protection, but also community protection by reducing the spread of disease within a population, say the authors. This particularly benefits vulnerable populations who cannot be vaccinated, including those too young for recommended vaccines, those with an inadequate response to vaccines (sometimes the elderly), or those who are immune-compromised and cannot be vaccinated. And although the focus of vaccines has been on children, there is an ongoing need to enhance immunization rates in adults, as vaccine-preventable diseases in adults are a global health problem and vaccine coverage rates for adults are much lower than those in children. The National Vaccine Advisory Committee issued a report in 2015 with 23 recommendations to assure high levels of vaccine confidence, including creating a repository of evidence-based practices for informing, educating, and communicating with parents and others in ways that foster or increase vaccine confidence. Removing barriers to vaccination would also help boost vaccination rates, including providing recommended vaccines without cost to those who cannot afford them, and mandating vaccinations for children attending school. "In summary," say Orenstein and Ahmed, "vaccines are some of the most effective and also cost-effective prevention tools we have. But vaccines that are not administered to persons for whom they are recommended are not useful. It is incumbent upon all of us who work in the healthcare setting, as well as community leaders, to stress to our friends and colleagues the importance of vaccination both for the individual vaccinated as well as for the communities in which the individuals live. Also critically important, there remains an urgent need for greater emphasis on research to develop vaccines for global diseases for which vaccines either do not exist or need improvement."


News Article | April 18, 2017
Site: www.rdmag.com

A component of the skin mucus secreted by South Indian frogs can kill the H1 variety of influenza viruses, researchers from Emory Vaccine Center and the Rajiv Gandhi Center for Biotechnology in India have discovered. Frogs' skins were known to secrete "host defense peptides" that defend them against bacteria. The finding, scheduled for publication in Immunity, suggests that the peptides represent a resource for antiviral drug discovery as well. Anti-flu peptides could become handy when vaccines are unavailable, in the case of a new pandemic strain, or when circulating strains become resistant to current drugs, says senior author Joshy Jacob, PhD, associate professor of microbiology and immunology at Emory Vaccine Center and Emory University School of Medicine. The first author of the paper is graduate student David Holthausen, and the research grew out of collaboration with M.R. Pillai, PhD and Sanil George, PhD from the Rajiv Gandhi Center for Biotechnology. Jacob and his colleagues named one of the antiviral peptides they identified urumin, after a whip-like sword called "urumi" used in southern India centuries ago. Urumin was found in skin secretions from the Indian frog Hydrophylax bahuvistara, which were collected after mild electrical stimulation. Peptides are short chains of amino acids, the building blocks of proteins. Some anti-bacterial peptides work by punching holes in cell membranes, and are thus toxic to mammalian cells, but urumin was not. Instead, urumin appears to only disrupt the integrity of flu virus, as seen through electron microscopy. It binds the stalk of hemagglutinin, a less variable region of the flu virus that is also the target of proposed universal vaccines. This specificity could be valuable because current anti-influenza drugs target other parts of the virus, Jacob says. Because flu viruses from humans cannot infect frogs, producing urumin probably confers on frogs an advantage in fighting some other pathogen, he says. Delivered intranasally, urumin protected unvaccinated mice against a lethal dose of some flu viruses. Urumin was specific for H1 strains of flu, such as the 2009 pandemic strain, and was not effective against other current strains such as H3N2. Developing antimicrobial peptides into effective drugs has been a challenge in the past, partly because enzymes in the body can break them down. Jacob's lab is now exploring ways to stabilize antiviral peptides such as urumin, as well as looking for frog-derived peptides that are active against other viruses like dengue and Zika.


News Article | April 20, 2017
Site: www.futurity.org

A component of the skin mucus secreted by certain South Indian frogs can kill the H1 variety of influenza viruses, say researchers. Frogs’ skins are known to secrete peptides that defend them against bacteria. The findings of a new study suggest that the peptides represent a resource for antiviral drug discovery, too. Anti-flu peptides could come in handy when vaccines are unavailable—in the case of a new pandemic strain, or when circulating strains become resistant to current drugs, says senior author Joshy Jacob, associate professor of microbiology and immunology at Emory Vaccine Center and Emory University School of Medicine. Scientists named one of the antiviral peptides they identified urumin, after a whip-like sword called “urumi” used in southern India centuries ago. Urumin was found in skin secretions from the Indian frog Hydrophylax bahuvistara, which were collected after mild electrical stimulation. Peptides are short chains of amino acids, the building blocks of proteins. Some antibacterial peptides work by punching holes in cell membranes, and are thus toxic to mammalian cells. Some antiviral peptides from the frogs were toxic in this way, but urumin wasn’t. Instead, it appears to only disrupt the integrity of flu virus, as seen through electron microscopy. “I was almost knocked off my chair,” Jacob says. “In the beginning, I thought that when you do drug discovery, you have to go through thousands of drug candidates, even a million, before you get 1 or 2 hits. And here we did 32 peptides, and we had 4 hits.” It turns out that urumin binds the stalk of hemagglutinin, a less variable region of the flu virus that is also the target of proposed universal vaccines. This specificity could be valuable because current anti-influenza drugs target other parts of the virus, Jacob says. Because flu viruses from humans cannot infect frogs, producing urumin probably confers on frogs an advantage in fighting some other pathogen, Jacob says. Delivered intranasally, urumin protected unvaccinated mice against a lethal dose of some flu viruses. Urumin was specific for H1 strains of flu, such as the 2009 pandemic strain, and was not effective against other current strains such as H3N2. Developing antimicrobial peptides into effective drugs has been a challenge in the past, partly because enzymes in the body can break them down. Jacob’s lab is now exploring ways to stabilize antiviral peptides such as urumin, as well as looking for frog-derived peptides that are active against other viruses like dengue and Zika. The paper appears in the journal Immunity. The first author is graduate student David Holthausen, and the research grew out of a collaboration with M.R. Pillai and Sanil George of the Rajiv Gandhi Center for Biotechnology. Emory University and the Office of Research Infrastructure Programs funded the work.


News Article | April 24, 2017
Site: www.eurekalert.org

In lung cancer patients who were taking immunotherapy drugs targeting the PD-1 pathway, testing for CD8 T cell activation in their blood partially predicted whether their tumors would shrink. The results are scheduled for publication in PNAS. Drugs targeting PD-1 or its ligand PD-L1 re-activate "exhausted" CD8 T cells by promoting their expansion and unleashing their ability to destroy cancer cells. Researchers at Emory Vaccine Center, led by co-senior author Rafi Ahmed, PhD, have been intensively studying the cells that are revived after inhibitory signals from PD-1 are blocked. Ahmed is director of the Vaccine Center and a Georgia Research Alliance Eminent Scholar. Winship Cancer Institute investigators Rathi Pillai, MD and Suresh Ramalingam, MD, Winship's deputy director, teamed up with Alice Kamphorst, PhD and Ahmed's group to examine blood samples from 29 advanced non-small cell lung cancer patients undergoing immunotherapy treatment. The patients were being treated at Winship Cancer Institute of Emory University with drugs blocking the PD-1 pathway, known as checkpoint inhibitors (nivolumab, pembrolizumab or atezolizumab). Blood samples were obtained before starting treatment and before each new treatment cycle, which lasted two to three weeks. Most patients (70 percent) displayed an increase in the number of proliferating CD8 T cells in their blood after starting PD-1 targeted treatment -- an observable effect on the immune system. However, not all patients with an immunological response experienced a "partial clinical response", meaning that their tumors shrank by at least 30 percent. All patients with partial responses survived at least one year, while just one out of seven patients with progressive disease was reported to survive one year. Survival times for three patients were not available. An early increase in activated PD-1+ CD8 T cells appears important. 80 percent of patients with clinical benefit exhibited PD-1+ CD8 T cell responses within 4 weeks of treatment initiation. In contrast, 70 percent of patients with disease progression had either delayed or absent PD-1+ CD8 T cell responses. "We hypothesize that re-activated CD8 T cells first proliferate in the lymph nodes, then transition through the blood and migrate to the inflamed tissue," Ahmed says. "We believe some of the activated T cells in patients' blood may be on their way to the tumor." Proliferating CD8 T cells displayed high levels of PD-1, as well as other molecules that influence their activity, which may be targets for combination therapies. The Emory/Winship team recently published a paper in Science, incorporating data from this study, showing that the costimulatory molecule CD28 is required for proliferation following PD-1-targeted treatment. The current study supports a straightforward idea: if CD8 T cells appear to respond to immunotherapy, that's a good sign. "Our ability to detect proliferating T cells in the blood and correlate this with clinical benefit is exciting since this captures a real-time assessment of the immune system's response to PD-1 directed therapies and is a readily accessible test from our patients' perspective," Pillai says. While looking for activated T cells in the blood is not yet predictive enough for routine clinical use, such tests could provide timely information, says co-senior author Ramalingam. Monitoring the immune response could potentially help oncologists and patients decide, within just a few weeks of starting immunotherapy drugs, whether to continue with current treatment or combine it with something else. "We are already doing larger studies to confirm these observations and extend them to other cancers beyond lung cancer," he says. This work was funded in part by the National Institutes of Health and the T. J. Martell Foundation.


News Article | April 18, 2017
Site: www.eurekalert.org

A component of the skin mucus secreted by South Indian frogs can kill the H1 variety of influenza viruses, researchers from Emory Vaccine Center and the Rajiv Gandhi Center for Biotechnology in India have discovered. Frogs' skins were known to secrete "host defense peptides" that defend them against bacteria. The finding, scheduled for publication in Immunity, suggests that the peptides represent a resource for antiviral drug discovery as well. Anti-flu peptides could become handy when vaccines are unavailable, in the case of a new pandemic strain, or when circulating strains become resistant to current drugs, says senior author Joshy Jacob, PhD, associate professor of microbiology and immunology at Emory Vaccine Center and Emory University School of Medicine. The first author of the paper is graduate student David Holthausen, and the research grew out of collaboration with M.R. Pillai, PhD and Sanil George, PhD from the Rajiv Gandhi Center for Biotechnology. Jacob and his colleagues named one of the antiviral peptides they identified urumin, after a whip-like sword called "urumi" used in southern India centuries ago. Urumin was found in skin secretions from the Indian frog Hydrophylax bahuvistara, which were collected after mild electrical stimulation. Peptides are short chains of amino acids, the building blocks of proteins. Some anti-bacterial peptides work by punching holes in cell membranes, and are thus toxic to mammalian cells, but urumin was not. Instead, urumin appears to only disrupt the integrity of flu virus, as seen through electron microscopy. It binds the stalk of hemagglutinin, a less variable region of the flu virus that is also the target of proposed universal vaccines. This specificity could be valuable because current anti-influenza drugs target other parts of the virus, Jacob says. Because flu viruses from humans cannot infect frogs, producing urumin probably confers on frogs an advantage in fighting some other pathogen, he says. Delivered intranasally, urumin protected unvaccinated mice against a lethal dose of some flu viruses. Urumin was specific for H1 strains of flu, such as the 2009 pandemic strain, and was not effective against other current strains such as H3N2. Developing antimicrobial peptides into effective drugs has been a challenge in the past, partly because enzymes in the body can break them down. Jacob's lab is now exploring ways to stabilize antiviral peptides such as urumin, as well as looking for frog-derived peptides that are active against other viruses like dengue and Zika. Holthausen is in the Immunology and Molecular Pathogenesis graduate program. Jacob's lab is based at Yerkes National Primate Research Center. The research was supported by Emory University and by the Office of Research Infrastructure Programs (Primate centers: P51OD11132).


Pulendran B.,Emory Vaccine Center | Pulendran B.,Emory University | Li S.,Emory Vaccine Center | Nakaya H.I.,Emory Vaccine Center
Immunity | Year: 2010

Vaccination is one of the greatest triumphs of modern medicine, yet we remain largely ignorant of the mechanisms by which successful vaccines stimulate protective immunity. Two recent advances are beginning to illuminate such mechanisms: realization of the pivotal role of the innate immune system in sensing microbes and stimulating adaptive immunity, and advances in systems biology. Recent studies have used systems biology approaches to obtain a global picture of the immune responses to vaccination in humans. This has enabled the identification of early innate signatures that predict the immunogenicity of vaccines, and identification of potentially novel mechanisms of immune regulation. Here, we review these advances and critically examine the potential opportunities and challenges posed by systems biology in vaccine development. © 2010 Elsevier Inc.


Cortese M.,Emory Vaccine Center | Sinclair C.,Emory Vaccine Center | Pulendran B.,Emory Vaccine Center
Cell Metabolism | Year: 2014

Growing evidence supports a role for glycolysis in immune activation. Everts et al. (2014) now show that TLR-mediated stimulation of dendritic cells rapidly induces glycolysis, which regenerates NADPH and TCA intermediates to support fatty acid production. This enhances ER and Golgi membrane synthesis and innate activation of dendritic cells. © 2014 Elsevier Inc.


News Article | October 26, 2016
Site: www.eurekalert.org

A study by scientists at the Emory Vaccine Center, in collaboration with the biotechnology company Atreca, Inc., has found that antibodies generated from the blood of survivors of Ebola virus disease can strongly neutralize the Ebola virus in the laboratory and protect mice from a lethal viral challenge. The research was presented at the annual Grand Challenges Meeting of the Bill and Melinda Gates Foundation in London on Oct. 26, 2016. The Gates Foundation provided funding for the Atreca antibody research and the Defense Advanced Research Projects Agency (DARPA) provided funding for the studies led by Emory. Carl Davis, MD, PhD, a research fellow in the laboratory of Emory Vaccine Director Rafi Ahmed, and Guy Cavet, PhD, senior vice president and chief technology officer at Atreca, presented the research. Emory University Hospital treated four patients with Ebola virus disease in Fall of 2014 and, with the patients' permission, collected samples of their blood for further research. Using Atreca's Immune Repertoire Capture™ (IRC™) technology and methods previously described in the Ahmed lab, the research team was able to isolate antibodies from the blood of the survivors. These antibodies were evaluated by a DARPA-funded consortium that included teams at the Aaron Diamond Aids Research Center, the Centers for Disease Control and Prevention (CDC), the Scripps Research Institute, Stanford University, the University of Wisconsin School of Veterinary Medicine, and the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID). "This collaborative research has allowed us to broaden our understanding of the Ebola virus, as well as related viruses such as Marburg virus," says Ahmed. "We have learned a great deal about how the human immune system can develop effective antibodies against the Ebola virus and which parts of the virus may be most vulnerable to the immune response. The identification of neutralizing antibodies that can protect against a viral challenge from so few patients so quickly is also a very exciting outcome, offering the potential for further research that we hope can lead to both therapeutic agents and vaccines against a rapidly evolving Ebola virus."


News Article | October 26, 2016
Site: www.eurekalert.org

India suffers from the highest number of dengue infections in the world, but there are few studies, if any, to understand the immune cells involved in fighting the virus. A recent study published in the Journal of Virology, by joint efforts among scientists from Emory, India and Thailand, sheds novel insights on the properties of a class of immune cells known as CD8 T cells, which are involved in fighting dengue virus infection. Human infections with dengue virus often lead to debilitating illness, hemorrhage and death, especially among children. Currently one third of the global population is under the threat of dengue virus infection. The virus continues spreading globally, causing huge public health concern including the Americas. The study analyzed a large number of dengue-infected children from India. CD8 T cells expanded massively in the dengue patients, often reaching the levels seen in Ebola infected patients, the researchers say. The expansion was strikingly similar in dengue- infected children from different geographical regions across the continents. In addition to fighting the virus by killing infected cells, these CD8 T cells are notorious for releasing inflammatory cytokines, such as IFN-g. If all of these these massively expanding CD8 T cells produced these inflammatory cytokines, the patients would be expected to suffer from a dangerous "cytokine storm" like that seen in Ebola virus disease. Interestingly, the study shows that in the dengue patients, however, a vast majority of these massively expanding CD8 T cells kept their cytokine production under check while retaining the ability to kill virus-infected cells. According to Anmol Chandele, PhD, lead author of the study, harnessing this new knowledge for an understanding of how to maintain the balance between fighting the infection while inhibiting inflammation will be critical for developing more effective vaccines and therapeutics and could be a game changer in the fight against dengue. The study emphasizes the value of international collaboration and arises from a unique partnership established five years ago between Emory Vaccine Center and the International Centre for Genetic Engineering and Biotechnology (ICGEB) in New Delhi. Chandele is adjunct assistant professor of microbiology and immunology, and Murali Krishna Kaja, PhD, the study's senior author, is associate professor of pediatrics at Emory University School of Medicine and associate director for the ICGEB-Emory Vaccine Center partnership. The goal of the ICGEB-Emory Vaccine Center partnership is to bring state-of-the-art vaccine research to where it is needed most via international research collaborations and to increase India's capacity for vaccine and infectious disease research. The study was supported by a National Institutes of Health award for international collaboration in infectious disease research (ICIDR), and the Indian Government's Department of Biotechnology. This award to study dengue virus infection in India (principal investigators, Rafi Ahmed, Emory Vaccine Center and Navin Khanna, ICGEB) is the first ICIDR-funded project in India. In addition to scientists from the Emory Vaccine Center and ICGEB, scientists and physicians from Indian institutions such as All India Institute of Medical Sciences and the Translational Health Science and Technology Institute, and the Mahidol University of Thailand have played a critical role in this study. Journal of Virology: Characterization of human CD8 T cell responses in dengue virus infected patients from India


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).

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