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Special Focus on Zika: Spring sees pharma and life-sciences entities spring into action on Zika
When the Ebola virus made a resurgent appearance in West Africa in early 2014, the global concern—and sometimes panic, depending on where you were and who you were—was palpable that year and throughout 2015. By March 2016, the World Health Organization (WHO) had declared that Ebola was no longer a Public Health Emergency of International Concern (PHEIC) and, by June, the WHO further declared the end of Ebola virus transmission in the Republic of Guinea and in Liberia.
Many companies, institutes and academic facilities in the therapeutic and diagnostic realms rose to the occasion to bring leads and products to bear in the fight against the virus—and to perhaps stave off any future such outbreaks or rein them in more quickly.
And now the Zika virus arrives in force, and a similar response and trajectory are seen.
Like Ebola, Zika is not new. The virus was first discovered in 1947 and is named after the Zika Forest in Uganda. In 1952, the first human cases of Zika were detected and since then, outbreaks of Zika have been reported in tropical Africa, Southeast Asia and the Pacific Islands, though it is unclear how many cases occurred between then and now because of challenges of diagnosis and reporting. In May 2015, the Pan American Health Organization issued an alert regarding the first confirmed Zika virus infection in Brazil, and then in February 2016, the WHO declared Zika virus a PHEIC, as local transmission has been reported in many other countries and territories and Zika virus will likely continue to spread to new areas, carried primarily by the Aedes aegypti and Aedes albopictus mosquitoes. In addition to Zika disease itself, characterized by mild fever, skin rashes, conjunctivitis, muscle and joint pain, malaise or headache and lasting two to seven days, a growing body of evidence links Zika virus infection in pregnant women with an increased risk of congenital microcephaly.
But this new viral outbreak does beg the question whether Zika is a crisis or a sentinel event, according to an article written in April by Dr. Jane M. Orient, executive director of the Association of American Physicians and Surgeons. Pointing to much more serious diseases such as dengue fever in Mexico and yellow fever in Africa, she notes that Zika is rarely if ever lethal, unlike Ebola, and is not so readily transmitted as Ebola either. She also noted that while Zika can lead to birth defects, and Zika virus has been found in the brains of a few babies born with microcephaly, more than 90 percent of the Brazilian babies that had recently been confirmed to have microcephaly tested negative for Zika—and microcephaly is overwhelmingly caused by other factors.
Orient is much more concerned about why a disease that was being brought under good control decades ago is re-emerging now. And her answer is a failure of vector control, saying, “Alarm about Zika will be a public relations exercise, covering the waste of millions of human lives and billions of dollars on ineffective or harmful campaigns, if it does not open a discussion of why diseases on their way out in the 1970s are coming back now.”
She’s not the only one with that notion in mind, as research and consulting firm GlobalData noted in mid-June in the report “The Zika Virus: An Update on the Outbreak and the Fight Against It” that the development of a protective vaccine against the Zika virus represents only one step in providing a long-term solution to the disease, and should be viewed in the context of tackling all mosquito-borne diseases.
“The Zika virus is a member of the genus Flavivirus, a group of single-stranded RNA viruses that also includes dengue, West Nile, yellow fever, Japanese encephalitis and chikungunya virus, all of which are transmitted by mosquitoes,” said Dr. Mirco Junker, a GlobalData analyst covering infectious diseases. “Approaches to combating the vector instead of the virus include the prevention of vector reproduction through limiting the breeding ground, insecticides, direct genetic manipulation or the usage of bacteria ultimately leading to the demise of the mosquitoes.”
In terms of potential vaccines, the vast majority of Zika vaccine products are currently in early preclinical trials, indicating that it will take many years until one of them receives market approval, GlobalData points out, with Junker noting: “The majority of companies that have entered the race are smaller biotech companies with limited resources, while the large pharmaceutical companies, including GlaxoSmithKline, Johnson & Johnson, Merck, Pfizer, Sanofi and Takeda, are currently only evaluating how their abilities and experiences can help in the fight against Zika.”
However, while vector control may be the more central issue, life-sciences researchers are often inspired to look into diseases anyway to better understand what they do—including things we don’t yet know they do or things we assume they do but they don’t—and also to better understand, prevent and treat other diseases. Zika may not generally be a threat to life, but it is a flavivirus, and thus related to those more serious viruses that Junker rattled off a few paragraphs ago.
And, just as academia is often moved to explore connections and root causes to see if there’s more to a disease than meets the eye—such as microcephaly and Zika’s possible connection to it in some cases—pharmas, biotechs and other life-sciences companies and institutions are also moved by issues of public relations, humanitarianism and potential profit when a disease makes the news prominently and suddenly. To that end, read on to explore our roundup of Zika news from April to June to find out what various players are doing right now in the arenas of discovery, research and development, preclinical work, clinical trials and diagnostics.
Zika discovery and R&D
Among those tackling the earliest stages of therapeutic development are clinical-stage vaccine and immunotherapy company Immunovaccine and health, national security and infrastructure solutions company Leidos, which recently joined forces to develop a Zika virus vaccine candidate. This collaboration is the first to expand on Immunovaccine’s previously announced research project, in which the company will apply its DepoVax platform to development of a Zika virus vaccine candidate. The project builds upon earlier promising results with DepoVax vaccines targeting the Ebola virus, anthrax and respiratory syncytial virus.
“While we remain focused on immuno-oncology, collaborations with partners like Leidos allow us to expand the use and potential value of our platform technology in other applications and markets. This first collaboration on a Zika virus vaccine builds on our previous success in developing candidate vaccines that show promise in providing one-dose, fast-acting protection,” said Frederic Ors, Immunovaccine’s CEO.
Under the terms of the agreement, Leidos will utilize its Virtual Pharmaceutical Development Program to lead an antigen discovery and development team to identify the best candidate antigens for protecting against infection by the Zika virus. Immunovaccine will then formulate new antigens in its DepoVax delivery system for preclinical testing. Together, the companies hope this project could serve as a replicable model for expediting the development and manufacture of vaccines to address current and future health emergencies.
“Our virtual pharma approach ensures that we are not beholden to a particular technology or laboratory,” said Jerry Hogge, deputy group president at Leidos. “We are able to seek the best solutions to suit the project at hand. This includes our partnership with Immunovaccine, which leverages the best capabilities of both companies.”
On the academic front, work at the University of California, San Diego (UC San Diego), may have identified one way Zika infection can damage developing brain cells and possibly be the reason it increases the risk of microcephaly. The researchers, based in the UC San Diego School of Medicine, also say these new findings hint at a new therapeutic approach to mitigating the effects of prenatal Zika virus infection.
Using a 3D, stem cell-based model of a first-trimester human brain, the team discovered that Zika activates TLR3, a molecule human cells normally use to defend against invading viruses. In turn, hyper-activated TLR3 turns off genes that stem cells need to specialize into brain cells and turns on genes that trigger cell suicide. When the researchers inhibited TLR3, brain cell damage was reduced in this organoid model.
“We all have an innate immune system that evolved specifically to fight off viruses, but here the virus turns that very same defense mechanism against us,” said senior author Dr. Tariq Ranaa, a professor of pediatrics at the UC San Diego School of Medicine. “By activating TLR3, the Zika virus blocks genes that tell stem cells to develop into the various parts of the brain. The good news is that we have TLR3 inhibitors that can stop this from happening.”
While promising, this research has been conducted only in human and mouse cells growing in the laboratory thus far. In addition, the Zika virus strain used in this study (MR766) originated in Uganda, while the current Zika outbreak in Latin America involves a slightly different strain that originated in Asia.
“We used this 3D model of early human brain development to help find one mechanism by which Zika virus causes microcephaly in developing fetuses,” Rana said, “but we anticipate that other researchers will now also use this same scalable, reproducible system to study other aspects of the infection and test potential therapeutics.”
In other UC San Diego news related to Zika, the university in May joined IBM’s World Community Grid, scientists from Brazil and Rutgers New Jersey Medical School to launch OpenZika, a project to find drug candidates to treat Zika.
The World Community Grid provides massive amounts of supercomputing power to scientists, free of charge, by harnessing the unused computing power of volunteers’ computers and Android devices. For the OpenZika project, the World Community Grid is powering virtual experiments on chemical compounds that could form the basis of antiviral drugs to treat the virus. The project will screen more than 20 million compounds from existing databases against models of Zika protein structures.
Once the computer modeling phase of the project identifies a few promising candidate drugs, Dr. Jair Siqueira-Neto, an assistant professor in the UC San Diego Skaggs School of Pharmacy, will test them against real- world Zika virus.
Finally in our tour of discovery and R&D, Kerafast Inc., developer of an online platform that facilitates accessibility to bioresearch materials from laboratories across the globe, recently announced the availability of a Zika virus antibody from Vanderbilt University.
“Progress in the field of infectious disease is predicated on the availability of critical reagents, many of which can be difficult to source. We wanted to supply this Zika antibody to the global research community as quickly as possible,” said Alan Bentley, who heads up Vanderbilt University’s Center for Technology Transfer and Commercialization.
“At Kerafast, our mission promotes access to rare and unique research reagents by facilitating a community of both providing and procuring laboratories that work toward the cure of disease,” said Dr. Robert Bondaryk, Kerafast’s CEO. “We hope by making this Zika virus antibody available in our catalog we are helping to progress research toward a vaccine, treatment and cure for this worldwide health crisis.”
Preclinical and clinical trials landscape
May saw Pharos Biologicals LLC announce it had been awarded the exclusive worldwide licenses for a patented lysosome-associated membrane protein (LAMP) DNA vaccine technology, as well as for certain nanotechnologies to deliver the vaccines, by Johns Hopkins University School of Medicine. The worldwide licenses are for use in the development and delivery of vaccines for influenza and flaviviruses.
Pharos was formed in December 2015 by Dr. J. Thomas August, University Distinguished Service Professor of Pharmacology and Molecular Sciences and Oncology at the Johns Hopkins University School of Medicine and the Johns Hopkins Institute for NanoBioTechnology. The initial focus of the company is on the Zika vaccine development, to be followed by vaccines for dengue and influenza viruses. The company anticipates that it will be ready to begin Phase 1 clinical trials of its Zika vaccine candidate by fall of this year.
The LAMP technology, invented by August, represents a breakthrough in the application of DNA vaccines by the use of normal cellular mechanisms to enhance the immune response to the vaccine. Most vaccines use a weakened form of a pathogen in which a live but reduced virulence version of the virus is introduced into the body. The LAMP DNA vaccine is not a live virus vaccine, has a more rapid development timeline, delivers the pathogen antigen directly to cell proteins that bring about immunological responses and is highly stable.
Meanwhile, Inovio Pharmaceuticals Inc. announced in May that testing of its synthetic vaccine for the Zika virus had induced robust antibody and T cell responses in monkeys, demonstrating the product’s potential to prevent infection from this harmful pathogen.
Dr. J. Joseph Kim, Inovio’s president and CEO, said, “With positive large-animal results in hand we are moving aggressively to initiate and conduct our first Zika vaccine human trial in 2016.”
Inovio is developing its Zika vaccine, GLS-5700, with GeneOne Life Sciences and academic collaborators with whom Inovio has previously collaborated to advance its vaccines for Ebola and MERS into clinical development.
The preclinical data news was followed in June by word that the U.S. Food and Drug Administration (FDA) had given Inovio and GeneOne approval to initiate a Phase 1 human trial to evaluate GLS-5700. The trial will look at 40 healthy subjects to evaluate the safety, tolerability and immunogenicity of GLS-5700 administered intradermally with CELLECTRA, Inovio’s proprietary DNA delivery device.
In Belgium, virologists from KU Leuven showed evidence that an experimental antiviral drug against hepatitis C slows down the development of Zika in mice. The research team was led by Prof. Johan Neyts from KU Leuven’s Laboratory of Virology and Chemotherapy.
“As the Zika virus is related to the hepatitis C virus, we examined whether some inhibitors of the hepatitis C virus also prevent the multiplication of the Zika virus in human cells,” said Neyts. “We have identified at least one experimental drug that is effective against the Zika virus.”
With an initial candidate in hand, the researchers experimented on mice with a defect in their innate immune system that caused them, when infected with the Zika virus, to develop a number of the symptoms seen in human patients. Said Neyt: “Treating the infected mice with the hepatitis C virus inhibitor resulted in a clear delay in virus-induced symptoms.”
On the diagnostic front
In April, Rheonix Inc., in collaboration with New York University College of Dentistry (NYUCD), received funding to develop a rapid diagnostic for Zika virus infection. The $656,414 award was an administrative supplement to an existing Small Business Innovation Research Phase I/II fast-track grant from through the National Institutes of Health. The grant will allow the Rheonix/NYUCD team to pursue the development of a fully automated screening and self-confirming assay that will simultaneously detect and confirm the presence of Zika virus in a single small sample of saliva or blood. The proposed approach will build upon previous success in which the Rheonix/NYUCD team developed a dual assay for the simultaneous detection of HIV antibodies and viral RNA in a single specimen.
“As we continue to demonstrate the utility of our novel microfluidic- based technology, we remain committed to deploying the technology to address global health needs,” said Dr. Greg Galvin, CEO and chairman of Rheonix.
“We have had a long-standing and very productive collaborative relationship with Dr. Dan Malamud’s laboratory at New York University College of Dentistry, and it has been through those efforts that we successfully developed the dual assay for anti-HIV antibodies and viral RNA,” said Dr. Richard Montagna, senior vice president for scientific and clinical affairs at Rheonix, and the principal investigator on the grant. “It seemed to be a logical extension of those efforts to attempt the same approach for Zika virus.”
In other diagnostic news, a new paper-based test developed at the Massachusetts Institute of Technology (MIT) and other institutions reportedly can diagnose Zika virus infection within a few hours. The test, which distinguishes Zika from the very similar dengue virus, can be stored at room temperature and read with a simple electronic reader, making it potentially practical for widespread use.
“We have a system that could be widely distributed and used in the field with low cost and very few resources,” says James Collins, the Termeer Professor of Medical Engineering and Science in MIT’s Department of Biological Engineering and Institute for Medical Engineering and Science (IMES) and the leader of the research team.
Many infected people experience no symptoms, and when symptoms do appear they are very similar to those of related viruses such as dengue and chikungunya. Currently, patients are diagnosed by testing whether they have antibodies against Zika in their bloodstream, or by looking for pieces of the viral genome in a patient’s blood sample, using a polymerase chain reaction test. However, these tests can take days or weeks to yield results, and the antibody test cannot discriminate accurately between Zika and dengue.
The new device is based on technology that Collins and colleagues previously developed to detect the Ebola virus. In October 2014, the researchers demonstrated that they could create synthetic gene networks and embed them on small discs of paper. These gene networks can be programmed to detect a particular genetic sequence, which causes the paper to change color. Upon learning about the Zika outbreak, the researchers decided to try adapting their device to diagnose the virus.
The researchers envision that their approach and technology could also be adapted to other viruses that may emerge in the future. Collins now hopes to team up with other scientists to further develop the technology for diagnosing Zika.
“Here we’ve done a nice proof-of-principle demonstration, but more work and additional testing would be needed to ensure safety and efficacy before actual deployment,” he says. “We’re not far off.”
For their part, the companies Hologic and Grifols announced recently that the FDA had approved use of their Procleix Zika Virus assay to screen the U.S. blood supply under an IND study protocol. This news came on the heels of an announcement days earlier that the FDA also granted emergency use authorization for the Aptima Zika Virus assay made by Hologic.
And, in our final bit of news on the Zika diagnostic front, June 22 saw Avacta Group plc, developer of Affimer biotherapeutics and research reagents, announce it has identified three Affimer proteins capable of binding to a recombinant form of a secreted Zika virus NS1 protein (Non-Structural protein 1), which is diagnostic of Zika virus infection at the early, acute stage. These Affimer binders were identified and characterized within just 13 weeks of receiving the virus target and have the potential to be developed into new rapid point-of-care diagnostic tests for Zika infection.
The three Affimer binders are highly specific to the Zika NS1 protein and can differentiate in human serum from five other closely related viruses that give similar symptoms: dengue, yellow fever, West Nile, and Japanese and tick-borne encephalitis.
The Zika NS1 protein used in the study, together with the other NS1 proteins used for screening, was provided by the Native Antigen Company. This recombinant protein was identified as the best reagent available for the selection of Affimers for Zika diagnostics as it is uniquely produced in mammalian cells, and is therefore chemically and structurally very similar to the native viral antigen. It may also be used as a reference standard in future diagnostic kits.