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Patent
ISIS INNOVATION Ltd and Okairos Inc. | Date: 2012-08-15

The invention provides recombinant adenoviral vectors which are capable of eliciting immunity against the pre-erythrocytic stage of the life cycle of the malaria parasite. In particular, the invention provides a recombinant, replication deficient simian adenoviral vector which encodes an antigen comprising the thrombospondin-related adhesion protein (TRAP), and also immunogenic compositions (e.g. vaccines) comprising the vector and methods of using such compositions.


Park H.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Serti E.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Eke O.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Muchmore B.,U.S. National Cancer Institute | And 4 more authors.
Hepatology | Year: 2012

Early, vigorous intrahepatic induction of interferon (IFN)-stimulated gene (ISG) induction is a feature of hepatitis C virus (HCV) infection, even though HCV inhibits the induction of type I IFNs in vitro. To identify the cytokines and cells that drive ISG induction and mediate antiviral activity during acute HCV infection, type I and III IFN responses were studied in (1) serial liver biopsies and plasma samples obtained from 6 chimpanzees throughout acute HCV infection and (2) primary human hepatocyte (PHH) cultures upon HCV infection. Type I IFNs were minimally induced at the messenger RNA (mRNA) level in the liver and were undetectable at the protein level in plasma during acute HCV infection of chimpanzees. In contrast, type III IFNs, in particular, interleukin (IL)-29 mRNA and protein, were strongly induced and these levels correlated with ISG expression and viremia. However, there was no association between intrahepatic or peripheral type III IFN levels and the outcome of acute HCV infection. Infection of PHH with HCV recapitulated strong type III and weak type I IFN responses. Supernatants from HCV-infected PHH cultures mediated antiviral activity upon transfer to HCV-replicon-containing cells. This effect was significantly reduced by neutralization of type III IFNs and less by neutralization of type I IFNs. Furthermore, IL-29 production by HCV-infected PHH occurred independently from type I IFN signaling and was not enhanced by the presence of plasmacytoid dendritic cells. Conclusion: Hepatocyte-derived type III IFNs contribute to ISG induction and antiviral activity, but are not the principal determinant of the outcome of HCV infection. © 2012 American Association for the Study of Liver Diseases.


Park S.-H.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Shin E.-C.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Shin E.-C.,KAIST | Capone S.,Okairos Inc. | And 5 more authors.
Gastroenterology | Year: 2012

BACKGROUND & AIMS: T cells are an important component for development of a vaccine against hepatitis C virus (HCV), but little is known about the features of successful vaccine-induced T cells. METHODS: We compared the phenotype, function, and kinetics of vaccine-induced and infection-induced T cells in chimpanzees with HCV infection using multicolor flow cytometry and real-time polymerase chain reaction. RESULTS: In chimpanzees successfully vaccinated with recombinant adenovirus and DNA against HCV NS3-5, HCV-specific T cells appeared earlier, maintained better functionality, and persisted at higher frequencies for a longer time after HCV challenge, than those of mock-vaccinated chimpanzees. Vaccine-induced T cells displayed higher levels of CD127, a marker of memory precursors, and lower levels of programmed death-1 (PD-1) than infection-induced T cells. Vaccine-induced, but not infection-induced, T cells were multifunctional; their ability to secrete interferon gamma and tumor necrosis factor α correlated with early expression of CD127 but not PD-1. Based on a comparison of vaccine-induced and infection-induced T cells from the same chimpanzee, the CD127+ memory precursor phenotype was induced by the vaccine itself rather than by low viremia. In contrast, induction of PD-1 correlated with viremia, and levels of intrahepatic PD-1, PD-L1, and 2,5-OAS-1 messenger RNAs correlated with peak titers of HCV. CONCLUSIONS: Compared with infection, vaccination-induced HCV-specific CD127+ T cells with high functionality that persisted at higher levels for a longer time. Control of viremia prevented up-regulation of PD-1 on T cells and induction of PD-1, PD-L1, and 2,5-OAS-1 in the liver. Early development of a memory T-cell phenotype and, via control of viremia, attenuation of the inhibitory PD1-PD-L1 pathway might be necessary components of successful vaccine-induced protection against HCV. © 2012 AGA Institute.


Callendret B.,Nationwide Childrens Hospital | Eccleston H.B.,Nationwide Childrens Hospital | Hall S.,Nationwide Childrens Hospital | Satterfield W.,University of Texas M. D. Anderson Cancer Center | And 7 more authors.
Hepatology | Year: 2014

Memory CD8+ T cells generated by spontaneous resolution of hepatitis C virus (HCV) infection rapidly control secondary infections and reduce the risk of virus persistence. Here, CD8+ T-cell immunity and response to reinfection were assessed in a chimpanzee cured of an earlier chronic infection with an interferon (IFN)-free antiviral regimen. CD8+ T cells expanded from liver immediately before and 2 years after cure of chronic infection with two direct-acting antivirals (DAAs) targeted epitopes in the E2, nonstructural (NS)5a, and NS5b proteins. A second infection to assess CD8+ T-cell responsiveness resulted in rapid suppression of HCV replication by week 2, but viremia rebounded 3 weeks later and the infection persisted. The E2, NS5a, and NS5b proteins remained dominant CD8+ T-cell targets after reinfection. Resurgent HCV replication was temporally associated with mutational escape of NS5a and NS5b class I epitopes that had also mutated during the first chronic infection. Two epitopes in E2 remained intact throughout both persistent infections. Intrahepatic CD8+ T cells targeting intact and escape-prone epitopes differed in expression of phenotypic markers of functional exhaustion 2 years after successful DAA therapy and in the capacity to expand in liver upon reinfection. Conclusions: The intrahepatic HCV-specific CD8+ T-cell repertoire established during chronic infection was narrowly focused, but very stable, after cure with DAA. Existing intrahepatic CD8+ T cells targeting dominant epitopes of the challenge virus failed to prevent persistence. Vaccination after DAA cure may be necessary to broaden T-cell responses and reduce the risk of a second persistent infection. (Hepatology 2014;60:1531-1540) © 2014 by the American Association for the Study of Liver Diseases.


Patent
Okairos Inc. | Date: 2011-12-30

The invention relates to an expression system comprising polynucleotides encoding proteins, wherein the expression system comprises a first polynucleotide encoding at least one protein, peptide or variant thereof, which induces a T cell response, and a second polynucleotide encoding at least one protein peptide or variant thereof, which induces an anti-pathogenic B cell response. The invention further relates to protein mixtures encoded by the expression system and cells comprising the expression system or the protein mixture and pharmaceutical compositions comprising the expression system or the protein mixture. The expression system, polynucleotides, proteins, cells, and pharmaceutical compositions are useful in the prophylaxis or treatment of infections. The invention further relates to nucleotide constructs which comprises, essentially consists or consists of a polynucleotide encoding a modified influenza hemagglutinin (HA).


Patent
Okairos Inc. and Thegovernmentof The Unitedstatesof America Asrepre Sentedby Thesecretaryofthedept.Ofhealth&Humanser | Date: 2011-04-15

This invention provides vaccines for inducing an immune response and protection against filovirus infection for use as a preventative vaccine in humans. In particular, the invention provides chimpanzee adenoviral vectors expressing filovirus proteins from different strains of Ebolavirus (EBOV) or Marburg virus (MARV).


The present invention relates to administration regimens which are particularly suited for vaccine composition comprising polynucleotides which encode immunogenic polypeptides. Said administration regimens involve, the repeated administration of a vaccine composition and enhance the immune response against the immunogenic polypeptide.


News Article | May 11, 2015
Site: www.wired.com

On Saturday, May 9, Liberia joyously—cautiously—announced itself free from Ebola. It had been 42 days since the last known case. And though neighboring Guinea and Sierra Leone are still fighting, it seems like the sun is finally setting on the latest outbreak. But the disease will be back. Or if not Ebola, it will be MERS, polio, leishmaniasis, measles, or some other infectious killer. Liberia was among the hardest hit—4,716 out of the total 11,022 dead are Liberian. But outbreaks don’t have to be this bad. They don’t have to spread as far or kill as many. The lessons are right there, encoded in what happened with Ebola—if people can read them. Disaster relief comes from rich, peaceful places, and it goes to places that are poor and conflict-ravaged. Understanding the dynamics of both are key to getting the next relief effort right. Experts in the developed world understood that some kind of disease was likely to emerge from war-torn West Africa, yet somehow wealthier countries still responded slowly, as if surprised. And when help did arrive, it encountered resistance from the locals. On-the-ground workers had to learn to balance their urgency with respect and personal care. Ebola is what experts call a Neglected Tropical Disease. “Though the tropical part is a misnomer,” says Peter Hotez, dean of the National School of Tropical Medicine at Baylor College in Houston. NTD’s, as they are known, tend to emerge in poor, war-torn areas that often happen to be in the tropics. The world has seen outbreaks like Ebola before. From the 1970s to the 1990s, African Sleeping Sickness took over half a million lives in the war-ravaged Democratic Republic of Congo. The same thing happened after the Sudanese civil war, with kala azar—a type of leishmaniasis. The biggest factors? A breakdown in social services, preventative medicine, and public trust. Nigeria was the first to quell its Ebola outbreak, says Hotez, because the country had a stable medical infrastructure in place. Nigeria has seen some turbulence in recent years, but nothing like the conflicts in Sierra Leone, Guinea, and Liberia. If poverty and war are the horsemen that always precede pestilence, then aid groups should start working on plans for outbreaks in the Middle East and North Africa. The signs are already there. Leishmaniasis is showing up in Islamic State-held Syria. Coronavirus is cropping up in Yemen. Refugees across the region have shown an alarming number of cases of both polio and measles. And unlike Ebola—which can only be spread by direct contact—many of these diseases can transmit through the air. “The point is, in the Middle East the world might not get so lucky, if you call Ebola getting lucky,” says Hotez. Hotez says the world needs a new disaster-relief business model. His beef? It took way too long to develop an Ebola vaccine. The problem is, even in global emergencies, governments still rely on big, profit-driven pharmaceutical companies to bring treatments onto market. “The only reason that GlaxoSmithKline and Okairos got involved at the 11th hour, when Ebola was unfolding as an emergent tragedy, was there were financial incentives put into place,” he says. And Bill Gates’ idea for a global disease fund—paid into by all the world’s governments—isn’t good enough, because it still relies on big pharmas. The solution, says Hotez is non-profit vaccine development centers, such as the Developing Vaccine Groups and Product Development Partnerships that developed in the late 1990s as an alternative to develop treatments for Neglected Tropical Diseases. (Hotez is president of a PDP called the Sabin Vaccine Institute). For evidence, he points to the Ebola vaccine that US scientists developed over a decade ago, but never tested further than monkey trials because they had no financial incentive. The people most likely to get Ebola are the ones least likely to be able to afford a vaccine against it. Unfortunately, they’re also the ones least likely to assist in their own aid. Imagine you live in a small village where people have been getting sick. One day white jeeps show up, put on rubber suits, vinyl gloves, and plastic face guards and ask you to hand over your sick friends and relatives. “What we are doing creates a lot of fear”, says Ellen Watson-Stryker, a health promotion specialist with Médecins Sans Frontières (Doctors Without Borders). “You want to take time to build trust, but at the same time you are racing the clock against a spreading disease.” The first rule is to give people the opportunity—the power—to make their own decisions. “I think the solution is to really maintain the humanity of the situation, understand that you’re dealing with a rational human being who has the right to make a decision,” Watson-Stryker says. When the Guinean and Liberian government started rolling troops in, for example, was the wrong tack, even if the military’s intentions—to stem spread of disease—were right. Overall, the best way to prevent a disease outbreak is to maintain a working health care system. But in a conflict, those health care systems break down. And it’s not just that there are no vaccine programs during a conflict. Social support webs get fall apart. Children stop going to school, which wrinkles the path forward for a generation of home grown health care workers. “Maybe the solution is to not have conflict,” Watson-Stryker says, with a rueful laugh. Ebola isn’t over. The disease might never leave, becoming endemic—with its own season—like the flu in North America. And even as Liberia is celebrating its win over this disease, other diseases are on the rise. They always are.


News Article | August 28, 2014
Site: www.fiercebiotech.com

When GlaxoSmithKline ($GSK) bought out Okairos last year for $325 million, the platform vaccine technology it acquired was focused on a slate of early-stage development programs covering a range of targets like hepatitis C, malaria and tuberculosis. But in recent weeks the international frenzy over a serious outbreak of Ebola in West Africa has pushed that program to center stage. And today the pharma giant--one of the world's top vaccine players--has joined hands with a global consortium of agencies, nonprofits and investigators to compress a years-long development effort into a matter of weeks as the outbreak worsens. Initially, GSK officials had sounded distinctly skeptical about whether the vaccine could be ready in time to help contain the outbreak. But this morning there was a distinct can-do attitude in its approach to the crisis. Using a $4 million grant, Oxford's Adrian Hill will launch a Phase I safety test in about two weeks, once it locks up the necessary paperwork. Hill's study in volunteers will take place alongside separate trials at the National Institute of Allergy and Infectious Diseases in the U.S. And after it's been run through small studies on the healthy volunteers, a green light from regulators would allow investigators to immediately broaden the work to an at-risk population in Gambia and Mali to evaluate whether or not it can contain the virus. While investigators are testing the vaccine in volunteers, GSK plans to simultaneously ramp up production of 10,000 doses, prepping for a quick vaccination campaign. If all goes well, GSK says the early-stage study can be wrapped in 3 months--virtual light speed in the pharma industry. The consortium is gambling on next-gen vaccine technology that was spun out of Merck back in 2007. Inspired by the research of Okairos founder Riccardo Cortese, investigators have been using deactivated chimp viruses to deliver genetic material to cells, triggering a powerful CD8 T cell response--an immune response that can be directed squarely at an invader like Ebola. Most of the attention for Okairos, a 2012 Fierce 15 winner, had been focused on its hepatitis C vaccine work. The lightning quick effort comes as the WHO notes that the number of people afflicted with the deadly Ebola virus could triple in coming months, noting that 40% of all reported cases have occurred in the past three weeks. The epidemic could ultimately hit more than 20,000 people as health officials try to end the outbreak in the next 6 to 9 months. GSK R&D chief Moncef Slaoui sounded a note of cautious optimism in his statement. "Today's announcement shows how private and public partners can pull together to respond to this critical public health emergency," said Slaoui. "Developing a new vaccine is complex with no guarantees of success and it's still early days for our Ebola vaccine candidate. But we are encouraged by progress so far and will do the best we can, along with WHO and our partners, to speed up development and explore ways in which the vaccine could contribute to the control of this or future Ebola outbreaks." Related Articles: Global fear of Ebola outbreak stokes a frenzy of new R&D, production plans Can GlaxoSmithKline go from 0 to 150 on an Ebola vaccine program? FDA switches course on Tekmira drug as Ebola panic triggers policy review

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