Dr. James Vincent Lawler (born 1969) ( Working peers while at USAMRIID; Note that Dr. Bavari also has a long-time relationship with UNMC, which is where Dr. Lawler has been working since 2017 ; Also research collaboration - such as ("Cynomolgus macaque as an animal model for severe acute respiratory syndrome" (DOI: 10.1371/journal.pmed.0030149 / https://pubmed.ncbi.nlm.nih.gov/16605302/ ) )
Dr. Patrick Lynn Iversen (born 1955) ( Significant research effort collaboration between Iversen and Bavari in 2000s and 2010s. Several articles written in 2020 and 20201 regarding COVID19 vaccines, with only Bavari and Iversen as the authors. )
Dr. Jennifer Elizabeth Garrus (born 1973) ( Dr. Garrus worked directly for Dr. Sina Bavari in an intern-type role )
Dr. Jens Holger Kuhn (born 1972) ( Extensive professional collaboration )
Dr. Robert Wallace Malone (born 1959) - ( 2016 (April 16) - Collaboration between Dr. Robert Malone and Dr. Sina Bavari on "Zika virus: Accelerating development of Medical Countermeasures by re-purposing licensed drugs", by Dr. Jill Glasspool-Malone (born 1960) . Saved as PDF : [HW006R][GDrive]
Dr. David Michael Hone (born 1960) - (Collaboration on reearch papers; one shared US patent ( https://patents.justia.com/patent/20170274063 ) )
Veronica Soloveva (born 1966) ( Frequent research collaborator / peer at USAMRIID )
Dr. Gary Jan Nabel (born 1953) ( Collaboration between Dr. Sina Bavari of USAMRIID and Dr. Gary Nabel were ongoing as of 2002 with the Ebola vaccine research ( see PDF : [HN021Q][GDrive] ), and may have started earlier than this. )
Ayaad Assaad (born 1948) - Sina A Bavari (born 1959) has co-authored with Ayaad Assaad (born 1948) in a (heavily cenrsored paper as of May 2025) paper on Ricin, in 1996. Ayaad Assaad was identified as a potential suspect of the anthrax letters in early October 2001.
Zika virus epidemic (2015-2016) ( ... )
SARS-COV2 famotidine trials (2020) ( and the pursuit for available/existing therapeutic for the SARS-COV2 virus; Dr. Sina Bavari immediately gravitated to Remdesivir )
Remdesivir ( ... )
Sarepta Therapeutics (AVI BioPharma) ... Extensively evaluated anti-virals from Sarepta
https://newspaperarchive.com/fairbury-journal-news-jul-06-1993-p-4/
1993-070-06-fairbury-journal-news-pg-4a-clip-bavari.jpg
https://newspaperarchive.com/fairbury-journal-news-jan-09-1996-p-4/
1996-01-09-fairbury-journal-news-pg-4a-clip-bavari-holidays
Notes : https://www.acronymfinder.com/Masjed-Soleiman-(Iran-city)-(MIS).html : "MIS, Iran" stands for Masjed Soleiman (Iran city)
https://newspaperarchive.com/news-apr-03-1999-p-26/ - Debra L. Bavari
By Marilyn Chase / Staff Reporter of The Wall Street Journal / March 4, 2002 12:01 am ET / PDF : [HN021Q][GDrive]
This story also ran in the BBC : http://news.bbc.co.uk/2/hi/health/1854299.stm
Mentioned : Sina A Bavari (born 1959) / Dr. Gary Jan Nabel (born 1953) / Vical Incorporated /
A team of scientists has discovered how the deadly Ebola virus hijacks human cells, opening potential avenues to new drugs and a vaccine.
Ebola kills roughly 80% of those who contract it, usually causing them to bleed to death in a few weeks. Since its discovery in 1976, the virus has killed 1,000 people, according to the World Health Organization. Recent Ebola outbreaks in the Republic of Congo and neighboring Gabon in central Africa have killed several dozen people. The virus's mysterious appearances, rapid course and lack of treatment have made it a daunting challenge for public health -- and a potential weapon for terrorists.
Now, a research team says it has answered important basic questions about how Ebola, and a related virus, Marburg, commandeer human cells. Their findings shed light on possible ways to design drug therapies. The Ebola virus, shaped like a shepherd's crook, targets tiny fat platforms called "lipid rafts" that float atop the membrane of human cells. These cholesterol-rich rafts are the viruses' gateway into cells, the assembly platform for making new virus particles, and the exit point where new virus particles bud.
This virus-like particle, the harmless hollow shell of the Ebola virus, may one day be useful in creating an Ebola vaccine. The particle has been disarmed of its genetic material and is unable to replicate.
The team's report, set to be published Monday in the Journal of Experimental Medicine, "is highly significant," says Eric Freed, principal investigator in the laboratory of molecular microbiology at the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health in Bethesda, Md. "It adds another human pathogen to the growing list of viruses that use lipid rafts."
The findings add new insight into the life cycle of viruses and how they subvert human cellular mechanisms. It is a critical early step toward one day creating drugs that would stop viruses from replicating. Ebola and Marburg, both members of a family of hemorrhagic-fever viruses called filoviruses, share the reproduction strategy of viruses ranging from measles and influenza to HIV, which causes AIDS. Their ability to traffic aboard lipid rafts may help them evade the human immune system, researchers speculate.
One of the researchers, [Sina A Bavari (born 1959)], at the U.S. Army Medical Research Institute of Infectious Diseases in Fort Detrick, Md., says, "By understanding how Ebola and Marburg are entering into and budding from the cells, it gives us an avenue to come up with new therapeutics that would alter these pathways." Dr. Bavari's co-author is M. Javad Aman, of Clinical Research Management Inc. in Frederick, Md.
The push to probe Ebola has assumed greater urgency since the Sept. 11 terror attacks, as fears have grown about the existence of weaponized forms of Ebola or Marburg. Such bioterror weapons were in development within the former Soviet Union, according to Kenneth Alibek, a Soviet bioweapons scientist who defected to the U.S. and wrote the 1999 book "Biohazard."
Says [Sina A Bavari (born 1959)], "It doesn't take a Nobel laureate to figure out that something so deadly could be transformed into a bioterror agent." Yet-to-be-developed vaccines and antiviral drugs could be critical elements of bioterror defense against the viruses.
Because their targets, the lipid rafts, are made of fat, known agents such as the popular cholesterol-lowering statin drugs may offer one possible model for new drug therapies. Antifungal drugs, such as nystatin and filipin, that break up fat could be other possible models.
In their research, [Sina A Bavari (born 1959)] and [Drs.] Aman produced harmless copies of the Ebola virus that, it turns out, may be a possible vaccine candidate. The virus-like particles, known as VLPs, are hollow protein shells, gutted of their virulent genome. The researchers say the hollow proteins could elicit an immune defense, because they signal the body that an Ebola invasion is under way without actually causing disease.
"You're basically fooling the body," [Sina A Bavari (born 1959)] says, "but the virus cannot replicate itself." The hollow-protein model is one approach being used in the search for a vaccine for HIV. Future studies will examine whether such a strategy is safe and effective against Ebola and Marburg, he adds.
The researchers say their creation of the hollow VLPs could allow Ebola research to take place more freely in laboratories across the country, on regular lab benches outfitted with suction hoods, to prevent the escape of particles. At present, scientists have to wear space suits and work behind air-locked doors in high-containment Biosafety Level 4 labs when handling live Ebola virus.
Another National Institutes of Health researcher working on Ebola, [Dr. Gary Jan Nabel (born 1953)], of the Vaccine Research Center at NIAID, applauds the report. Dr. Nabel has published studies showing that Ebola vaccine created using experimental "naked DNA" -- the opposite of the hollow VLPs, in a way -- protected monkeys against lethal Ebola infection when given with a booster shot of the vaccine. His team is partnering with [Vical Incorporated], a San Diego biotech company, to produce the vaccine prior to launching studies of its safety in humans.
"People are waiting with bated breath for a drug or vaccine," [Dr. Gary Jan Nabel (born 1953)] said. "These [studies] show that we're on the road that will get us there."
09/12/07 9:01 AM EDT / Saved as PDF : [HC006M][GDrive]
See Sarepta Therapeutics (AVI BioPharma) ( its alias : AVI BioPharma) / Defense Threat Reduction Agency / Sina A Bavari (born 1959)
PORTLAND, Ore. [AVI BioPharma], Inc. (Nasdaq:AVII) announced today the presentation of data from two studies evaluating the company's NEUGENE(R) PLUS therapeutic antisense compounds in the treatment of nonhuman primates (NHP) exposed to the Ebola virus. Results of the studies were presented at the National Institutes of Health's Filovirus Animal Workshop by [Sina A Bavari (born 1959)], principal investigator, U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID).
The studies were conducted in collaboration with USAMRIID and funded as part of AVI's two-year, $28 million research contract with the [Defense Threat Reduction Agency] (DTRA) of Fort Belvoir, Va., an agency of the Department of Defense.
The two Ebola studies involved 10 NHP subjects, including two controls. In the first study, three of four treated NHPs survived and the Ebola viral infection was completely eliminated. In the second study, all four treated NHPs survived substantially beyond untreated subjects and all completely eliminated the Ebola virus. Subjects were initially challenged with a 1000pfu of Ebola Zaire and then treated one hour following exposure with a 20 mg/kg dose of two NEUGENE PLUS antisense drugs via subcutaneous (SC) and intraperitoneal (IP) injection. Researchers continued treatment daily for 10 to 14 days via SC and IP injection at 20mg/kg.
[Sina A Bavari (born 1959)] also presented data for two studies evaluating NEUGENE PLUS therapeutics in the treatment of mice and guinea pigs exposed to different strains of the Marburg virus. One hundred percent survival was observed in mice challenged with Marburg, Ravn strain and 100 percent survival was observed in guinea pigs challenged with Marburg, Musoke strain. The NEUGENE PLUS therapeutic is expected to be effective against all known strains of Marburg. These studies were also supported by the $28 million DTRA contract.
"These studies clearly demonstrate the ability of a NEUGENE PLUS treatment to protect against viremia and death associated with Ebola or Marburg exposure," said K. Michael Forrest, AVI's interim CEO. "This research provides the basis for a viable therapeutic response as part of our nation's biodefense preparedness. It also establishes much-needed scientific evidence of therapeutic benefit against two currently untreatable hemorrhagic viruses that trigger devastating outbreaks."
Associated mouse studies demonstrated that AVI's Ebola NEUGENE PLUS therapies are safe and well-tolerated in mice at 50 times the dose used in the NHP studies.
The NEUGENE PLUS molecules used in the study represent a small but significant chemical modification to AVI's antisense "backbone." This change, which creates a positively charged therapeutic molecule that binds more readily with negatively charged RNA virus particles, is one result of an ongoing initiative at AVI to innovate the antisense platform for improved pharmacokinetics and bioavailability in certain therapeutic areas, including the treatment of infectious diseases.
AVI researchers are in the process of conducting additional GMP and GLP toxicology and safety studies using the NEUGENE PLUS compounds as part of the ongoing collaboration between USAMRIID and AVI. The next step in evaluating clinical efficacy of the NEUGENE PLUS drugs against Ebola exposure will measure the impact of delayed treatment of Ebola Zaire threats in a NHP population.
About Ebola Zaire and Marburg Viruses
About AVI BioPharma
[...]
Peer-Reviewed Publication : US ARMY MEDICAL RESEARCH INSTITUTE OF INFECTIOUS DISEASES / Saved as PDF : [HI007Y][GDrive]
Mentioned : Sina A Bavari (born 1959) / Dr. Patrick Lynn Iversen (born 1955) / AVI BioPharma /
New studies show that treatments targeting specific viral genes protected monkeys infected with deadly Ebola or Marburg viruses. Furthermore, the animals were protected even when therapeutics were administered one hour after exposure—suggesting the approach holds promise for treating accidental infections in laboratory or hospital settings.
The research, which appears in today's online edition of the journal Nature Medicine, was conducted by the U.S. Army Medical Research Institute of Infectious Diseases in collaboration with [AVI BioPharma], a Washington-based biotechnology firm.
Working with a class of compounds known as antisense phosphorodiamidate morpholino oligomers, or PMOs, scientists first performed a series of studies with mouse and guinea pig models of Ebola to screen various chemical variations. They arrived at a therapy known as AVI-6002, which demonstrated a survival rate of better than 90 percent in animals treated either pre- or post-exposure.
Encouraged by these results, the team conducted "proof of concept" studies in which 9 rhesus monkeys were challenged with lethal Ebola virus. Treatment was initiated 30-60 minutes after exposure to the virus. In these studies, 5 of 8 monkeys survived, while the remaining animal was untreated. Further experiments, including a multiple-dose evaluation, also yielded promising results, with 3 of 5 monkeys surviving in each of the AVI-6002 treatment groups when they received a dose of 40 mg per kg of body weight.
According to first author Travis K. Warren of USAMRIID, antisense drugs are useful against viral diseases because they are designed to enter cells and eliminate viruses by preventing their replication. The drugs act by blocking critical viral genetic sequences, essentially giving the infected host time to mount an immune response and clear the virus.
Ebola and Marburg cause hemorrhagic fever with case fatality rates as high as 90 percent in humans. The viruses, which are infectious by aerosol (although more commonly spread through blood and bodily fluids of infected patients), are of concern both as global health threats and as potential agents of biological warfare or terrorism. Currently there are no available vaccines or therapies. Research on both viruses is conducted in Biosafety Level 4, or maximum containment, laboratories, where investigators wear positive-pressure "space suits" and breathe filtered air as they work.
The USAMRIID team next turned its attention to Marburg virus, again screening various compounds in mice and guinea pigs to select a candidate for further testing. They settled upon AVI-6003, a drug that consistently conferred a high degree of efficacy (better than 90 percent survival) in both models.
Investigators conducted two pilot studies in cynomolgus monkeys to assess the efficacy of AVI-6003 against lethal challenge with Marburg virus. As with the Ebola studies, treatments were initiated 30-60 minutes after infection. All 13 animals receiving AVI-6003 survived. Additional research provided important information about the optimal therapeutic dose range of the compound, with a 40 mg per kg body weight dose protecting 100 percent of the monkeys following challenge.
"This report of successful early post-exposure treatment of filovirus hemorrhagic fever is significant on its own," said Colonel John P. Skvorak, USAMRIID commander, "but the drug characteristics of these PMOs also support investigation of potentially broader therapeutic applications."
Senior author [ Sina A Bavari (born 1959)] said USAMRIID has been collaborating with AVI BioPharma since 2004. In February of that year, an Institute scientist working in a Biosafety Level 4 laboratory stuck her thumb with a needle while treating Ebola-infected mice with antibodies. As a precaution, USAMRIID medical experts recommended the investigator be isolated for 21 days to ensure that she had not been infected.
Coincidentally, earlier that very day, [Dr. Patrick Lynn Iversen (born 1955)] from AVI BioPharma had presented a seminar at USAMRIID concerning the efficacy of novel antisense drugs against a range of viruses. When he found out that a USAMRIID scientist had potentially been exposed to Ebola virus, the company volunteered to design and synthesize compounds against the virus to treat her if the need arose.
The team at AVI worked for four straight days to generate human-grade anti-Ebola compounds. In the meantime, their regulatory staff worked with USAMRIID physicians to gain emergency approval from the U.S. Food and Drug Administration to use the compounds if necessary. Five days after the exposure, AVI delivered the compounds to USAMRIID's medical team.
Fortunately, the scientist had escaped infection with Ebola virus, so the compounds were never used. However, USAMRIID went on to test them in animal models, and has been collaborating with AVI ever since.
According to the authors, the investigational new drug applications (IND) for AVI-6002 and AVI-6003 have been submitted to the U.S. Food and Drug Administration, and they are now open to proceed with clinical trials.
NOTES:
Mentioned : Sarepta Therapeutics (AVI BioPharma) ( its alias : AVI BioPharma) / Sina A Bavari (born 1959)
https://psb.stanford.edu/previous/psb13/conference-materials/PSB13-proceedings.pdf
2013-pacific-symposium-on-biocomputing-conference-materials.pdf
David Kroll, Former Contributor / I'm a Denver-based natural products pharmacologist
Aug 7, 2014,08:52pm EDT
2014-08-07-forbes-fda-moves-on-tekmiras-ebola-drug.pdf
2014-08-07-forbes-fda-moves-on-tekmiras-ebola-drug-img-1.jpg
The treatment of the two Ebola-stricken, American medical missionaries with the well-documented, ZMapp "plantibodies" drug developed by U.S. and Canadian companies and federal agencies has raised questions of bioethics and process.
But how can Ebola drugs be tested for efficacy if their use is restricted during the most widespread Ebola outbreak since 1976?
As a result, the World Health Organization has scheduled a meeting of medical ethicists for next week how drugs not previously tested in humans might be ethically mobilized during such a crisis. From the WHO announcement:
“We are in an unusual situation in this outbreak. We have a disease with a high fatality rate without any proven treatment or vaccine,” says Dr Marie-Paule Kieny, Assistant Director-General at the World Health Organization. "We need to ask the medical ethicists to give us guidance on what the responsible thing to do is.”
To recap, the ZMapp combination product of three, humanized antibodies against different parts of the Ebolavirus outer glycoprotein – which continues to be called a "secret serum" – was given to Dr. Kent Brantly and Nancy Writebol prior to their medivac journey from a hospital in Paynesville, Liberia, to the biosafety level-4 isolation ward in Atlanta's Emory University Hospital.
In her deeply-considered article yesterday, Laura Seay at The Washington Post wrote,
"The optics of the situation were already bad enough: at great expense, two white Americans were whisked away to safety and a level of health care that simply cannot be provided on the fly in a Liberian hospital. The black Liberians they had been treating were left to see whether fate would save or kill them under the same substandard health care system they have always lived under."
"That what now looks like a miracle cure was only given to the white Americans looks even worse. Why hadn’t anyone reached out to try the serum on Ebola patients sooner, especially if its potential to heal is so promising?"
However, this antibody combination had never been given to humans, not even healthy volunteers.
In contrast, at least two other companies have products that have already been subject to Phase 1 safety trials. Most widely publicized has been TKM-Ebola, a lipid nanoparticle, RNA-interference drug being developed by Vancouver-based, Tekmira Pharmaceuticals, together with a division of the Department of Defense.
Single-dose and multiple ascending dose studies have been progressing and the company announced on July 21 that the FDA was placing a hold on the trials as they conducted an interim analysis of the drug's safety profile.
However, Tekmira just announced today that the FDA verbally confirmed the modification of the trials' status to a "partial hold," thereby allowing the drug to be used in people infected with Ebola.
"We are pleased that the FDA has considered the risk-reward of TKM-Ebola for infected patients. We have been closely watching the Ebola virus outbreak and its consequences, and we are willing to assist with any responsible use of TKM-Ebola. The foresight shown by the FDA removes one potential roadblock to doing so," said Dr. Mark Murray, CEO and President, Tekmira Pharmaceuticals. "This current outbreak underscores the critical need for effective therapeutic agents to treat the Ebola virus. We recognize the heightened urgency of this situation, and are carefully evaluating options for use of our investigational drug within accepted clinical and regulatory protocols."
The Tekmira drug targets three of the seven genes of the Ebola virus. (Yes, the deadly Ebolavirus wreaks its havoc with only seven proteins. In comparison, we humans have just under 20,000.)
The second drug is a different type modified RNA molecule, AVI-7537, from Sarepta Therapeutics. AVI-7537 is directed against one of the three Ebolavirus genes (VP24) targeted by Tekmira's drug. But its chemistry platform, called PMOplus, is distinctly different from that of Tekmira's TKM-Ebola. AVI-7537 also works via a different mechanism to block the viral protein from being made.
For those interested in the technical aspects of the chemistry and mechanism, this open-access 2012 paper in the journal, Viruses, is invaluable.
AVI-7537 has already shown effectiveness in non-human primates against the Zaire Ebolavirus, the species implicated in the current outbreak. Moreover, Sarepta had been conducting Phase 1 safety trials with the drug alone and together another Ebola-directed PMOplus molecule (AVI-7539, with the combination called AVI-6002).
The work, done with the support of the Department of Defense, was part of a project put on hold in 2012 during the fiscal cliff fiasco.
The Ebola drug proved to have an excellent safety profile in a single dose escalation study and a two-week, daily dosing regimen. So the discontinuation was more likely due to economics than medical concerns. In support of that speculation, the DoD continued to support Sarepta's Marburg virus program.
Sarepta's president and CEO, Chris Garabedian, told Barron's earlier this week that the company had a drug that could be deployed and shipped if a request was made of the company and all permits and authorizations were cleared.
Garabedian told me on Tuesday that company does indeed have clinical trial-quality drug on hand. The Marburg program that has continued "uses the same backbone chemistry," so the safety studies that are continuing with that drug at higher human doses could be applied to AVI-7537.
"We're here to raise awareness that we do have a technology that might be helpful, and that we do have drug substance on hand if we received a request from a government agency," said Garabedian. "We, of course, would have to get the appropriate waivers and approvals from the Department of Defense who supported the development of this compound as well as the FDA in terms of an emergency use authorization."
The U.S. Army Medical Research Institute for Infectious Diseases (USAMRIID) is a co-assignee on the two patents, not expiring until 2025, that cover Sarepta's Ebolavirus drugs.
Beyond the fact that the U.S. government has already made a significant investment in Sarepta's drug, the company already holds an open IND for human clinical trials.
"We're just highlighting that we have drug substance available and we can go to convert that into finished product in vials. Assuming all approvals are there from the various agencies, we could have this ready in a week for compounding in a pharmacy for dosing into a patient," said Garabedian.
Should any agency or institution wish to make such a request, this wouldn't be the first time Sarepta had made a drug available on an emergency basis. In fact, the genesis of Sarepta's Ebola program was the government's acute need for a drug.
"This started with a real-world situation where a researcher at USAMRIID had a needle-stick injury with Ebola and the company was called to see if we could turn around a drug candidate over a weekend," said Garabedian. "Within five or six days, we had drug on a plane to dose this patient."
"Fortunately for this woman, she didn't test seropositive (indicating exposure to the virus) so she didn't receive the drug. But that started our animal work and led to a lot of other collaborations with the government."
We contacted USAMRIID's Dr. Sina Bavari, for more information on the potential clinical utility of AVI-7537. Bavari is the lead investigator in the government partnership and senior co-author on peer-reviewed publications with the Sarepta drugs. While he promptly acknowledged our request, press officer Cmdr. Amy Derrick-Frost, USN, from the Office of the Assistant Secretary of Defense for Public Affairs responded, "At this time, we are not doing interviews."
By Caree Vanderlinden, Army MedicineNovember 4, 2014 / PDF of article : [HG00GC][GDrive]
Also mentioned : Western African Ebola virus epidemic (2013 - 2016) /
FORT DETRICK, Md. (Oct. 22, 2014) -- From on-site laboratory support in Liberia, to training of key personnel, to accelerated research efforts on diagnostic, vaccine and treatment approaches, the U.S. Army Medical Research Institute of Infectious Diseases is playing a significant role in assisting the Ebola Virus Disease outbreak response in West Africa.
Ebola virus causes a severe, often fatal hemorrhagic disease in humans and non-human primates. Currently there are no licensed vaccines or drugs to fight the disease, and case fatality rates as high as 90 percent have been reported in past outbreaks. As of Oct. 15, the World Health Organization reported at least 8,997 cases and 4,493 deaths in seven affected countries. These include Guinea, Liberia, Nigeria, Senegal, Sierra Leone and Spain, as well as the first-ever case of Ebola diagnosed in the U.S.
That patient, a man who had recently traveled from Liberia to the U.S., died Oct. 8.
The U.S. Department of Defense is supporting the U.S. Agency for International Development as part of a U.S. whole of government response effort to the Ebola virus outbreak, as announced by President Barack Obama on Sept. 16. U.S. military personnel are deploying to West Africa in support of the effort, called Operation United Assistance. In addition to setting up a regional staging base to facilitate transportation of equipment, supplies and personnel, the U.S. military is establishing additional treatment centers in Liberia and providing medical personnel to train health-care workers in the region.
At the U.S. Army Medical Research Institute of Infectious Diseases, known as USAMRIID, the response effort spans the institute's research and support divisions and there is no sign of the operational tempo slowing any time soon, according to Col. Erin P. Edgar, commander of the institute.
"This is definitely not business as usual," he said.
Late September, USAMRIID was asked to provide training to deploying U.S. forces, according to Lt. Col. Neal E. Woollen, who directs the institute's biosecurity program. Several personnel have volunteered to serve on mobile training teams that travel to deploying units to train and certify troops who will be working in Ebola-affected areas of West Africa. Training is focused on proper wearing of protective equipment, as well as decontamination procedures.
Since April 2014, USAMRIID and the National Institute of Allergy and Infectious Diseases-Integrated Research Facility have provided personnel, training and diagnostic laboratory support to the Liberian Institute for Biomedical Research on a continuous rotational basis, according to Randal J. Schoepp, Ph.D., chief of USAMRIID's Applied Diagnostics branch. He and several others helped to set up an Ebola virus testing laboratory in Liberia and trained local personnel to run diagnostic tests on suspected Ebola hemorrhagic fever clinical samples.
Schoepp said USAMRIID has been working on a collaborative project in West Africa since 2006 (see sidebar article below). Because the team was working on disease identification and diagnostics in the region, he added, "We had people on hand who were already evaluating samples and volunteered to start testing right away when the current Ebola outbreak started."
In addition to providing laboratory testing and training support for the current outbreak, USAMRIID has provided more than 10,000 Ebola laboratory tests, referred to in the medical community as assays, to support laboratory capabilities in Liberia and Sierra Leone. The institute also supplied personal protective equipment to Metabiota Inc., a non-government organization involved in the testing.
Edgar called the project "a great example of medical diplomacy at work."
"This collaboration allows USAMRIID to bring our expertise to bear in responding to an international health crisis," he said. "In addition, it enables us to test the medical diagnostics that we develop in a real-world setting where these diseases naturally occur."
USAMRIID research led to the only assay currently authorized to diagnose Ebola in U.S. citizens, according to David A. Norwood, Ph.D., chief of USAMRIID's Diagnostic Systems Division. The assay, which detects the Zaire strain of Ebola virus in patient samples, is called the Ebola Zaire Real-Time PCR Assay Test Kit. It was developed, manufactured and tested with help from the U.S. Army Medical Materiel Development Activity.
While the test has not been approved by the U.S. Food and Drug Administration, the FDA has authorized its use under an Emergency Use Authorization, granted in August 2014. According to Norwood, the EUA provides a legal basis for the use of unapproved medical products, including diagnostics, in a declared emergency when there are no alternatives. The test is available at authorized DOD laboratories in the U.S. and overseas, as well as select CDC Laboratory Response Network state public health labs throughout the country for testing U.S citizens.
"This assay is also being used in West Africa for rapid diagnosis of host nation patients," said Norwood. "So there is no disparity between the diagnostic capabilities that are being used in-country and those that are available for testing U.S. citizens. While the labeling and execution is somewhat different for regulatory purposes for testing U.S. citizens, the same capability is available for diagnostic testing for everyone."
Issuance of the EUA was a collaborative effort among several agencies: Medical Countermeasure Systems, U.S. Army Medical Command; Health Affairs, Readiness Division, Health Care Operations Directorate; Joint Program Executive Office Critical Reagents Program; the DOD Clinical Laboratory Improvement Program Office; and the recipient laboratories, including five DOD labs and 15 CDC-LRN state public health laboratories.
USAMRIID is leading the evaluation of several promising Ebola medical countermeasure candidates, including therapeutics and vaccines, according to scientific director [Sina A Bavari (born 1959)], Ph.D.
Bavari, an expert at building public-private partnerships, says the current outbreak offers researchers an opportunity to accelerate the development of medical products to prevent and treat the disease through collaboration with pharmaceutical companies and other government agencies.
Among the products being evaluated by USAMRIID are four potential therapies, including synthetically made, small-molecule drugs that have shown efficacy against a broad range of viral diseases, according to Bavari. One of these drugs, known as BCX4430, has been tested in animal models at USAMRIID; its parent company is in the process of filing an Investigational New Drug application with the FDA to begin Phase I clinical trials in humans.
Two other compounds of interest are oral favipiravir, dubbed T-705, which is already in Phase III clinical trials as a potential influenza treatment, and AL-8176, currently is in Phase II clinical trials for Respiratory Syncytial Virus.
"If we can evaluate a drug that's already in development for another use, and show that it has potential against Ebola virus, that saves us years of research and development," [Sina A Bavari (born 1959)] explained.
The fourth therapeutic candidate being studied at USAMRIID is Z-Mapp, a "cocktail" of three antibodies, one of which was developed by USAMRIID. This drug made headlines when it was used to treat a handful of people infected during the current outbreak, including two American aid workers who contracted Ebola in Liberia and recovered at Emory University Hospital in Atlanta, Georgia.
Previous studies at USAMRIID with an earlier version of Z-Mapp showed that it could protect monkeys from Ebola even when administered five days after infection, according to John M. Dye, Ph.D., branch chief for viral immunology. He said additional studies of Z-Mapp in nonhuman primates will begin at USAMRIID later this month. Those efforts will help to determine dosing -- the optimal amounts of antibody that can be safely administered and still provide protection.
In addition, there are a number of Ebola virus vaccine platforms in various stages of development, Dye said. Two that have been studied extensively at USAMRIID are the VLP (virus-like particle) and the VRP (virus replicon particle) vaccine approaches. Other vaccine approaches include those based on adenovirus (currently in Phase I clinical trials) as well as the rVSV (recombinant vesicular stomatitis virus) platform.
USAMRIID's Division of Medicine is providing medical monitor support to the Phase I clinical trial of the rVSV vaccine, scheduled to begin this month at the Walter Reed Army Institute of Research.
According to [Sina A Bavari (born 1959)], USAMRIID is continuing to investigate potential treatments and vaccine candidates for Ebola, with several laboratory and nonhuman primate studies scheduled for the near future. The success of these research efforts will depend, in part, on future funding levels.
It's not often that USAMRIID scientists get to take their expertise out of the laboratory and into a field setting. For Schoepp, the experience has been "rewarding," though he says he'll be ready to stay home for a while after completing his fourth trip to West Africa in just six months.
"What makes me really proud is that the laboratory staff we trained [in West Africa] jumped right into the fray, and thanks to the training we provided, they didn't even blink," said Schoepp. "They started testing right away; they knew what to do."
While the scientists at the Liberian Institute for Biomedical Research put in long, hot hours wearing protective gear in the laboratory, their work environment is far from the only challenge they face, according to Schoepp. Diagnostics personnel are under a great deal of pressure to run the tests accurately, because the results they provide to the health care team literally can mean the difference between life and death for a patient.
"It's critical to diagnose Ebola-infected individuals, of course, but it's also important to tell people they're not infected," he said. "Being able to give them an answer -- so they can go home and not worry -- that's pretty satisfying."
[...]
Sierra Leone Samples: Evidence of Ebola in West Africa in 2006
A study published in July 2014, in the journal, Emerging Infectious Diseases, showed that Ebola virus has been circulating in the region since at least 2006 -- well before the current outbreak.
According to first author Randal J. Schoepp, Ph.D., of USAMRIID, between 500 and 700 samples are submitted each year to the Kenema Government Hospital Lassa Diagnostic Laboratory in Sierra Leone. Generally, only 30 to 40 percent of the samples test positive for Lassa fever, so the aim of this study was to determine which other viruses had been causing serious illnesses in the region.
Using assays developed at USAMRIID that detect the presence of IgM, an early protein produced by the body to ward off infection, the research team found evidence of dengue fever, West Nile, yellow fever, Rift Valley fever, chikungunya, Ebola and Marburg viruses in the samples collected between 2006 and 2008. About two-thirds of the patients had been exposed to these diseases, and nearly 9 percent tested positive for Ebola virus.
In addition, of the samples that tested positive for Ebola, the vast majority reacted to the Zaire strain, which was unexpected, according to the authors.
"Prior to the current outbreak, only one case of Ebola had ever been officially reported in this region, and it was from the Ivory Coast strain," said Schoepp. "We were surprised to see that Zaire -- or a variant of Zaire -- was causing infection in West Africa several years ago."
The laboratory testing site in Kenema has been supported by the Armed Forces Health Surveillance Center-Global Emerging Infections Surveillance and Response System. In collaboration with the host country, the site enables collection of samples that can be used in research toward new medical countermeasures, and allows USAMRIID to evaluate the performance of previously developed laboratory tests using samples collected on site. USAMRIID hopes to eventually obtain viral isolates for medical countermeasure development and receive data on the performance of the diagnostic assays.
Other contributors to the work include the Department of Defense Joint Program Executive Office-Critical Reagents Program, the Defense Threat Reduction Agency Cooperative Biological Engagement Program and the DTRA Joint Science and Technology Office.
[...]
2015 Patent :
https://patents.justia.com/patent/20170274063
With : hDr. David Michael Hone (born 1960)
Aug 7, 2015 - THE GOVERNMENT OF THE UNITED STATES AS REPRESENTED BY THE SECRETARY OF THE ARMY
In this application is described a method for preparing nano-VLP composition, thereby permitting purification using chromatography and filtration. The nano-VLP composition has a more uniform size range of filovirus particles, roughly 230 nm diameter, allowing ease of manipulation of the composition, while retaining GP conformational integrity and the antigenic effectiveness of the vaccine. Additionally, the nano-VLP can be lyophilized without loss of nano-VLP structure, or GP immunogenicity. Lyophilized nano-VLP have greatly enhanced thermostability, allowing the creation of a filovirus nano-VLP vaccine without a cold chain requirement.
Bethany Halford / C&EN Boston / C&EN, 2016, 94 (8), pp 33–36February 22, 2016 / Source (this was paid content) - [HP00AH][GDrive]
NOTE - Article also here : [HP0077][GDrive]
Mentioned : Dr. Thomas Patrick Monath (born 1940) / Sina A Bavari (born 1959) / NewLink Genetics Corporation / Zika virus epidemic (2015-2016) / Dr. Hugh Alexander "H. Alex" Brown Jr. (born 1960) /
When the Pan American Health Organization put out an alert last May about the first confirmed cases of Zika virus infection in Brazil, the news barely registered. After all, compared with other mosquito-borne viruses, such as potentially life-threatening dengue and yellow fever, Zika seemed pretty harmless. Only 20% of people infected with Zika even become ill, and their symptoms tend to be mild—fever, rash, joint pain, and conjunctivitis.
But in January, nine months after the organization raised the alarm, doctors in Brazil reported a disturbing trend that coincided with Zika’s spread across the country. Since October 2015, more than 4,000 babies in Brazil had been born with abnormally small heads and brains—a rare condition known as microcephaly. Although further analysis lowered that figure by 462 cases, the sharp rise nonetheless has experts worried that Zika could be to blame. For comparison, Brazil reported just 147 cases of microcephaly in 2014.
Zika is also being blamed for an uptick in cases of Guillain-Barré syndrome, a potentially life-threatening disorder in which the body’s immune system attacks the central nervous system and causes paralysis. As with microcephaly, the evidence connecting Zika and Guillain-Barré is still circumstantial. Nevertheless, the link is strong enough for the World Health Organization to declare the Zika outbreak a public health emergency of international concern.
Margaret Chan, WHO’s director-general, said earlier this month that the virus is “spreading explosively” through the Americas, with cases of active virus transmission in at least 26 countries and territories in the Americas. Panic over the virus has prompted health officials in some countries to take the drastic measure of advising women to delay pregnancy for months or longer. In El Salvador, Deputy Health Minister Eduardo Espinoza asked women to avoid becoming pregnant until 2018.
With Zika making headlines for the past month, scientists have been scrambling to get a handle on the virus. Industry, government, and academic scientists have all announced efforts to develop and test treatments and vaccines. But the path ahead for these researchers is long and full of pitfalls. Even though Zika has been around for almost 70 years, surprisingly little is known about the virus and its basic biology. A PubMed search for “Zika virus” turns up mostly case studies.
What we do know is that Zika is a flavivirus, a member of the same family as dengue, yellow fever, and West Nile virus. Zika is primarily transmitted via bites from infected mosquitoes, but in recent weeks doctors have reported that the virus can be sexually transmitted as well.
It was first identified in a monkey in Uganda’s Zika forest in 1947, but only a handful of human Zika cases were reported until a 2007 outbreak in Micronesia’s Yap Island. An outbreak in French Polynesia followed six years later. Last November officials in that country reexamined the cases of microcephaly that followed the outbreak. Before the outbreak, about one case of microcephaly was reported each year. In 2014–15, officials found 17 cases of fetuses and infants with “central nervous system malformations,” which includes microcephaly.
As the case connecting Zika to serious health effects builds, the world would love a vaccine or treatment for the virus. But because so few have studied Zika, drug developers currently have few tools to work with. For example, there’s no commercially available, U.S. Food & Drug Administration-approved test to screen for Zika virus.
Tracking Zika in people is hard because it’s difficult to determine that they’re infected with Zika and not a related flavivirus or that they’re not infected with more than one virus, says Priscilla L. Yang, a flavivirus expert at Harvard Medical School. Simultaneous infection with Zika and another virus could cause health effects that haven’t been seen before.
Scientists can use polymerase-chain-reaction-based methods to distinguish Zika from other flaviviruses. But those tests are accurate only during the short window patients still have the virus in their system—about seven days after infection. By the time a patient has symptoms that warrant a visit to the doctor, the virus is no longer circulating in their bloodstream, Yang notes.
Another option is to look for antibodies against the virus. But Zika and dengue are closely enough related that antibodies to Zika also recognize dengue and vice versa. Making a definitive diagnosis based on antibodies is possible but becomes time-consuming and laborious, Yang says.
For scientists who have compounds that might be effective against Zika, actually testing them has been tough. “We have small molecules that seem to be broadly acting against dengue and West Nile virus,” Yang says. “We want to test them, but getting access to the live virus has been hard.” She’s heard that certain labs known to have the Zika virus have been bombarded with hundreds of requests from researchers.
Even if someone manages to access the live virus and can find a compound that kills it in cells, the researcher will hit another roadblock: To date, no one has published practical animal models of Zika virus to screen potential therapies against. Yang points to a paper from the 1970s in which scientists did an intracranial injection of Zika virus in newborn mice, but she notes that is a poor model because many small molecules can’t slip past the blood-brain barrier.
“We’re basically starting from scratch on this one, unfortunately,” says [Sina A Bavari (born 1959)], chief scientific officer (CSO) at the U.S. Army Medical Research Institute of Infectious Diseases. Bavari and colleagues are currently working with pharma companies to see if they have any compounds that inhibit Zika replication in cells.
They’re primarily interested in compounds that have passed the hurdles of Phase I or Phase II clinical trials but are sitting idle for business reasons. That’s because it can take upward of a year and a half just to get a new compound ready for Phase I. “My worry is that by the time we get something out the door, this outbreak will have already burned out,” Bavari says.
Scientists are also grappling with this question: If only 80% of people infected with Zika have symptoms, who would get the treatment? The most vulnerable patients are pregnant women, but Bavari points out, there’s a high bar when it comes to approving a medication that can be given to them. “They don’t even want to drink caffeine,” he says.
Other scientists are working to develop a vaccine against the Zika virus. Earlier this month President Barack Obama said he would ask Congress for $1.8 billion to combat Zika at home and abroad. Of those funds, $200 million would be used for vaccine development. The U.S. National Institute of Allergy & Infectious Diseases, Sanofi Pasteur, and [NewLink Genetics Corporation] are among the heavy hitters in the vaccine field who’ve said they’ll step up to the plate.
Even so, it could take three to five years before a vaccine is ready, experts say. [Dr. Thomas Patrick Monath (born 1940)], CSO of [NewLink Genetics Corporation]’s infectious disease division, led that firm’s efforts to develop an Ebola vaccine and was CSO at Acambis, where he worked on vaccines for dengue and yellow fever. Monath tells C&EN he thinks a large field trial of 10,000 to 20,000 people across multiple sites will be necessary to determine efficacy once a Zika vaccine is developed. “Only after those trials would you contemplate doing studies in pregnant women,” he says.
Monath also says because so many people who are infected with Zika never show any symptoms, it is more difficult to determine whether the vaccine has actually prevented infections. Still, he thinks a large enough trial should be conclusive.
But some scientists say the emphasis on vaccines is misplaced. “We just don’t know enough about Zika virus right now to run around and vaccinate people,” Bavari says. “Understanding the immunopathology and immunology behind it would be really prudent before starting a full vaccination program.”
Harvard’s Yang says developing a vaccine for every emerging virus is impractical. “Vaccines are, for the most part, specific. You have one virus, and you have one vaccine for it,” she explains. “I don’t think we’ll ever have the luxury of enough resources to get a vaccine against every single possible emerging virus or enough time to do it in a reactive way.”
One area that’s not getting as much attention, she says, is development of broadly acting antivirals that could keep a virus in check while the immune system fights it off. Classical antivirals go after a single viral enzyme, but viruses are quick to develop resistance to them. “If people could identify targets that have the potential to be effective against multiple viral pathogens, it could be game-changing,” Yang says.
[Dr. Hugh Alexander "H. Alex" Brown Jr. (born 1960)], a Vanderbilt University professor who works on antivirals, agrees. “There are so many viruses out there. We need to be working on a much more broad-spectrum approach to infectious disease,” he says. “If we can develop more tools to combat broad categories of viruses, I think we would be much better off than we are today.” [ Note - [Dr. Hugh Alexander "H. Alex" Brown Jr. (born 1960) passed July 25, 2017 ]
In the meantime, scientists agree that the research community needs to be more organized if it’s going to have a real shot at combating Zika. Yang thinks the first steps should be figuring out how to get the necessary reagents to the labs that need them and agreeing on standards so they can compare results and learn from each other’s work. “If you actually want to have some sort of impact, we all need to work together,” she says. In an encouraging sign, earlier this month, major scientific institutions and top research journals agreed to share data relevant to Zika virus.
Bavari agrees scientists need to be better at organizing their efforts, but he has doubts about the direction the community is taking. “The outbreak is moving so quickly that I am worried people will jump and we won’t do the correct research,” he says.
With a treatment or vaccine for Zika potentially years away, countries are relying on mosquito control to curb the virus’s spread. Aedes aegypti mosquitoes, which inhabit tropical and subtropical regions, have been named as the culprit in transmitting the virus.
But getting rid of Aedes aegypti is extremely difficult because the mosquitoes don’t seem to be affected by most spraying regimens, says Joseph M. Conlon, an entomologist and technical adviser to the American Mosquito Control Association. According to Conlon, Aedes aegypti feed during the day, but pesticides must be sprayed at dawn or dusk. Also, mosquitoes like to come indoors to feed. So, unless pesticides are sprayed inside homes, chances are good they’re not getting to the insects.
These mosquitoes are very small, and you can’t feel the bites. “Oftentimes you don’t even know you’ve been bitten,” Conlon says.
To get rid of the biting bugs, it’s critical to eliminate any standing water. “I’ve seen Aedes aegypti breeding in discarded soda bottle caps,” Conlon says. “They’re survivors.”
Despite Aedes aegypti’s survival skills, the mosquitoes actually have a fairly limited flight range of about 150 meters. That has made some scientists suspect that because Zika has spread so quickly, the more common Culex mosquito may be transmitting the virus as well. The theory is currently being investigated.
“If that is true, that brings this to a whole different level,” Conlon says. Culex mosquitoes have a much larger range, he notes, but they can usually be controlled through common mosquito abatement programs. ◾
On panel with Dr. Robert Wallace Malone (born 1959)
https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&ved=2ahUKEwi02rirj_j9AhWZF1kFHWvLDQg4ChAWegQIERAB&url=http%3A%2F%2Fwww.ip-watch.org%2Fweblog%2Fwp-content%2Fuploads%2F2016%2F03%2FWHO-Agenda-with-list-of-participants-of-the-RD-meeting.docx&usg=AOvVaw0KA56VaA5W3-c3bGL7Heju
Intellectual Property Watch
http://www.ip-watch.org › uploads › 2016/03
NOTE - By day of event, some of the presenters changed, as suggested in this summary : https://cdn.who.int/media/docs/default-source/blue-print/who-global-consultation-of-research-related-to-zika-virus-infection.pdf?sfvrsn=2e0731e0_1&download=true (March 10 2016 - https://www.who.int/publications/m/item/who-global-consultation-of-research-related-to-zika-virus-infection )
author - Mark Nunn
who-global-consultation-of-research-related-to-zika-virus-infection (1).pdf
No mention of Virginia Benassi in this document ...
Also there -
Dr. Duane J. Gubler (born 1939) / Dr. Eva Harris (born 1965) / Dr. Rick Arthur Bright (born 1966) /
Mar 8, 2016 — Sumathy Kandaswamy; Bharat Biotech. Joan Fusco; NewLink ... Robert Malone; Vaccines & Biotchenology. 10.30-11.00, Coffee break.
2016-03-07-09-who-agenda-with-list-of-participants-of-the-rd-meeting.doc
Author - MURGUE, Bernadette
2016-03-07-09-who-agenda-with-list-of-participants-of-the-rd-meeting-img-pg-1.jpg
2016-03-07-09-who-agenda-with-list-of-participants-of-the-rd-meeting-img-pg-3.jpg
Saved as PDF : [HW006R][GDrive]
AUTHORS : [Dr. Robert Wallace Malone (born 1959)]*1,2, [Veronica Soloveva (born 1966)] 3,4, [Dr. Sina A Bavari (born 1959)] 3,4
1. Atheric Pharmaceutical, LLC, Scottsville, VA, USA,
2. Class of 2016, Harvard Medical School Global Clinical Scholars Research Training Program, Boston, MA
3. United States Army Medical Research Institute of Infectious Diseases, Frederick, MD, USA.
4. United States Army Medical Research Institute of Infectious Diseases, Therapeutic Development Center, Frederick, MD, USA.
Purpose of the study: Antiviral agent development. Clinical care for Zika virus infection is supportive, and there are no prophylactic or therapeutic drugs, vaccines, or other biologicals licensed for use to prevent or treat Zika virus infection and disease. A Zika virus threat assessment and evaluation of medical countermeasure development options has been completed; re-purposing existing licensed drugs was identified as the most efficient strategy for rapid development of licensed medical countermeasures suitable for prevention, treatment, or containment of the pathogen (1,2).
Methods/summarized description of the project: Hypothesis-driven high throughput re-purposed drug screening. An iterative multi-step drug selection and screening algorithm was established; 1) drug targets involving inhibition of virus-host cell interactions were identified, 2) compounds with significant clinical pharmacokinetic and safety data (preferably including in pregnancy) which inhibit the pathways were selected, 3) selected pharmaceuticals were tested for inhibition of Zika virus infection and replication using multiple cell types and Zika viral isolates, 4) pharmaceuticals with single-digit micromolar to nanomolar IC50 and CC50/IC50 ratios consistent with anti-viral specificity were selected for subsequent development as prophylactic and therapeutic anti-Zika drug candidates.
Results: Re-purposed licensed drugs with anti-Zika activity which are safe for use in pregnancy. Three general mechanisms of action (including autophagy inhibition) have been identified and corresponding compounds have been screened. Multiple re-purposed drugs have been identified which meet selection criteria for subsequent development.
Conclusion: Hypothesis-driven high throughput re-purposed drug selection can expedite identification of emerging infectious disease medical countermeasure candidates. A summary of the pathways targeted, drugs identified and viral inhibition results obtained will be presented.
Discussion: Zika infection of the recipient host requires viral envelope protein binding and particle uptake into susceptible cells, is mediated by specific receptors which include DC-SIGN, AXL, Tyro3, and TIM-1, and triggers transcriptional activation of Toll-like receptor 3 (TLR3), RIG-I, MDA5, interferon stimulated genes including OAS2, ISG15, and MX1, and beta interferon (4). Primarily infected cells include skin fibroblasts, epidermal keratinocytes, and skin dendritic cells. Zika virus subsequently exploits autophagy to facilitate uptake and replication8, and pharmacologic manipulation of Zika infected cells with 3-Methyladenine (3-MA), an inhibitor of autophagosome formation, strongly reduces viral copy numbers in infected fibroblasts (3). Based on prior murine studies involving Zika virus inoculation in mouse brain (5), autophagy of Zika virus has been postulated as playing a key role in the pathogenesis of Zika-associated primary microcephaly (6). Pharmacological mechanisms of currently licensed 4-Aminoquinoline anti-malarial drugs include inhibition of autophagy and broad-spectrum cathepsin B-mediated inhibition of viruses which require endosomal acidification (7).
1. Malone RW, Homan J, Callahan MV, Glasspool-Malone J, Damodaran L, Schneider Ade B, Zimler R, Talton J, Cobb RR, Ruzic I, Smith-Gagen J, Janies D, Wilson J; Zika Response Working Group. Zika Virus: Medical Countermeasure Development Challenges. PLoS Negl Trop Dis. 2016 Mar 2;10(3):e0004530. doi: 10.1371/journal.pntd.0004530. PMID: 26934531
2. Longini IM Jr, Nizam A, Xu S, Ungchusak K, Hanshaoworakul W, Cummings DA, Halloran ME. Containing pandemic influenza at the source. Science. 2005 Aug 12;309(5737):1083-7. PMID: 16079251
3. Hamel R, Dejarnac O, Wichit S, Ekchariyawat P, Neyret A, Luplertlop N, et al. Biology of Zika Virus Infection in Human Skin Cells. J Virol. 2015; 89(17):8880–96. doi: 10.1128/JVI.00354-15 PMID: 26085147.
4. Carneiro LA, Travassos LH. Autophagy and viral diseases transmitted by Aedes aegypti and Aedesalbopictus. Microbes Infect. 2016. doi: 10.1016/j.micinf.2015.12.006 PMID: 26774331.
5. Bell TM, Field EJ, Narang HK. Zika virus infection of the central nervous system of mice. Arch Gesamte Virusforsch. 1971; 35(2):183–93. PMID: 5002906.
6. Tetro JA. Zika and microcephaly: Causation, correlation, or coincidence? Microbes Infect. 2016. doi: 10.1016/j.micinf.2015.12.010 PMID: 26774330.
7. Zilbermintz L, Leonardi W, Jeong SY, Sjodt M, McComb R, Ho CL, Retterer C, Gharaibeh D, Zamani R, Soloveva V, Bavari S, Levitin A, West J, Bradley KA, Clubb R3, Cohen SN, Gupta V, Martchenko M. Identification of agents effective against multiple toxins and viruses by host-oriented cell targeting. Sci Rep. 2015 Aug 27;5:13476. doi: 10.1038/srep13476. PMID: 26310922
A controversial leader is creating a culture of fear and is stifling cutting-edge research at the U.S. Army Medical Research Institute of Infectious Diseases, according to a newly released Army report.
The Army’s investigating officer urged that the leader, science director Sina Bavari, be removed from USAMRIID and re-assigned to a job without supervisory duties.
Bavari continues in the position, however, and there is no evidence the institute has acted on these recommendations.
At USAMRIID, Bavari oversees the majority of the Fort Detrick institute’s research departments, including staff members who work in immunology, genomics, bacteriology and virology.
The Army found in a 2015 investigation that since Bavari took that position in 2014, he has created an “environment of fear” at the prestigious lab.
“Workers are genuinely afraid for their jobs and scientific careers,” the investigating officer stated in the report. In June, The Frederick News-Post obtained a copy of the Army report through a Freedom of Information Act request.
The News-Post spoke to multiple sources, including current and former institute researchers, about the Army report. Those who declined to be named feared Bavari would fire them, damage their reputations as researchers, or both.
The Army’s investigation of Bavari did not find any illegal activity.
Bavari declined an interview with The News-Post, but issued a statement through a USAMRIID spokeswoman.
In the statement, he said he is honored to serve as science director and looks forward to “enabling USAMRIID’s expanded capabilities and increased collaborations.”
Statements from multiple current and former USAMRIID employees in the Army report showed that Bavari “fostered a negative or toxic leadership climate,” the investigating officer stated.
“There is a duality in Dr. Bavari’s tactics,” a former USAMRIID employee wrote in an email to The News-Post. “Those who are loyal and follow him unquestioningly are richly rewarded, while anyone who questions him or whom he otherwise perceives as a threat does not have a long future at USAMRIID, and will usually be made to suffer in the time that they are still there.”
The science director tarnished reputations, falsely accused employees of scientific misconduct and threatened them with termination, according to sworn statements in the Army investigation.
Many researchers at the institute work closely with toxins and biological agents such as anthrax and the Ebola virus in maximum-containment laboratories where protective, full-body suits are mandatory.
Henry Heine, who worked at USAMRIID from 1998 until 2010, said in an interview that Bavari was already working at the institute when Heine started there.
According to Caree Vander Linden, a spokeswoman for the institute, Bavari started at USAMRIID as a post-doctoral fellow in 1991.
Heine described Bavari as a “hot potato” who caused problems and was passed from one department to another before he became science director.
In a sworn statement provided for the Army investigation, a colonel said Bavari preferred to hire contractors, so he could terminate them for any reason.
Heine said Bavari took advantage of his ability to terminate contractors.
“When somebody would get into something that crossed him, or crossed something he was trying to do, they would disappear,” Heine said.
Heine is currently program director at the University of Florida’s Institute for Therapeutic Innovation. He did not work directly with Bavari while at USAMRIID, but felt familiar with the director’s modus operandi.
He said Bavari used other employees to further his own goals.
“He’s a consummate user,” Heine said.
Current and former USAMRIID employees have described Bavari as condescending, manipulative and disrespectful.
Some also described him as an ambitious, resourceful leader who has attracted diligent, loyal workers to his research team.
Travis Warren, a principal investigator at USAMRIID, noted that the Army investigator did not ask some of Bavari’s closest colleagues to provide statements for the Army investigation.
Warren said he has been one of Bavari’s right-hand workers since 2007.
“I regard him as the single most influential mentor in my career development,” he wrote in an email to The News-Post.
Bavari has high expectations and little tolerance for maintaining the status quo, Warren wrote.
“While he often voices strong opinions, I have never felt these viewpoints were presented in an antagonistic or authoritarian manner and have found him to be highly receptive and encouraging of countering viewpoints,” he wrote in an email.
Gustavo Palacios, director of the institute’s Center for Genome Sciences, also works closely with the science director.
The center houses cutting-edge equipment for genome sequencing, which help researchers gain insight into the genes of bacteria, viruses and potential biowarfare agents. According to Warren, Bavari led efforts to get the Center for Genome Sciences off the ground.
Bavari has a sense of purpose that is “inspirational,” Palacios said, and he challenges his staff to think outside the box.
Bavari said in a statement to the investigator that taking care of employees “is of paramount importance to me and is at the centerpiece of my management style.”
Palacios described Bavari as a “transformational” leader whose goal is to ensure that USAMRIID is constantly growing and operating as a first-class lab.
“That’s a very tall task, given the restrictions in funding and the continuous appearances of new natural challenges like Ebola and Zika, or the potential risks associated with bioterrorism acts,” Palacios wrote in an email to The News-Post.
Bavari received an honorary doctorate degree from the University of Nebraska this year for leading the institute’s efforts to fight the Ebola outbreak.
“Honorary degrees are awarded by the University of Nebraska to recognize those who have attained achievements of extraordinary and lasting distinction,” according to a press release from the school.
Palacios said institutions such as the World Health Organization and the Centers for Disease Control and Prevention also praised USAMRIID for its efforts during the Ebola outbreak.
“It means that the institute is moving in the right direction,” he wrote in an email to The News-Post. “Obviously that is not the sole result of Dr. Bavari’s work, but he has taken a leadership role at a crucial time.”
The Army started an investigation into Bavari last year, after a group of anonymous USAMRIID scientists submitted a letter to Army officials who oversee the institute.
Bavari, “while directing his own highly productive research program, is a detriment to the current and future state of medical research at USAMRIID and should be removed from this position,” the letter stated. “He is a person lacking in honesty, integrity and character, who in his short time as director has created a climate of distrust, intimidation, and fear of retribution.”
The letter writers called Bavari a “catastrophic threat” to the future of USAMRIID.
Some USAMRIID researchers commented to The News-Post that the frequent changes in command, in addition to the fact that their recently assigned commanders aren’t familiar with infectious disease research, have created a culture without checks or balances.
Fort Detrick installation commander Maj. Gen. Brian Lein and Army Surgeon General Lt. Gen. Patricia Horoho, who received the letter from the anonymous USAMRIID scientists, have since left their positions.
Army spokespeople who took media inquiries for Lein were unable to reach him for comment the week before he ended his two-year assignment at Fort Detrick. Lein’s last day as commander of the installation was July 28.
The Department of the Army generally assigns the U.S. Army Medical Research and Materiel Command, or USAMRMC, and Fort Detrick a new commander every two or three years.
Fort Detrick’s installation commander traditionally has a dual role as commander of USAMRMC, which manages USAMRIID.
USAMRIID has its own commander, Col. Thomas Bundt, who is also serving a two- to three-year assignment.
Bundt’s spokespeople did not respond to a request for comment about the Army investigation.
In the investigation, current and former USAMRIID researchers told the Army’s investigating officer that Bavari maintains a large research program that seems to be funded “at the expense of other projects,” according to the report.
Warren said Bavari has had a positive effect on USAMRIID’s research portfolio.
“I have personally observed multiple research programs move from an early discovery phase program to advanced development status due in large part to Dr. Bavari’s dedication to USAMRIID’s mission,” Warren wrote in an email.
But the fact that Bavari has a research program at all creates a conflict of interest, the anonymous USAMRIID researchers wrote in their letter.
“It is impossible for the Science Director to have [his or her] own research program and maintain independent judgment in an ethically responsible way,” the researchers wrote.
Hood College biology professor Ann Boyd teaches ethics and sits on the Institutional Review Board for the USAMRMC. The board reviews study proposals from USAMRIID and USAMRMC researchers to ensure that human subjects are treated ethically in experiments.
Directors who conduct research are not necessarily wrong to do so, Boyd said, but those who act in their own self-interest may display a lack of leadership.
“The problem with [a conflict of interest] in research is that it erodes trust,” she said.
Connie Dudley, director of graduate programs in science at Mount St. Mary’s University, said Bavari’s position as director and researcher leaves an “open door” for conflicts.
“It would certainly be a reasonable conclusion that a conflict of interest exists, if indeed this person had the ability to make programmatic changes that would benefit them,” she said.
Bavari told the investigating officer that he does not believe having his own research program creates a conflict of interest.
“In order to be an effective Science Director and to have the respect of other scientists, I feel the need to maintain a good scientific reputation in the field,” he said.
As a researcher, he said he can better relate to the challenges his staff faces.
Heine said that as a director, it can be difficult to be engaged with scientists if you don’t have some of your own research to refer to, but that is a difficult line to walk.
“In an environment where you have a very limited and restricted amount of funding, the temptation is to take care of yourself first, and that’s exactly what I think happened,” he said.
But, Warren said Bavari has intentionally reduced his role in programs to allow colleagues to step up.
“He intentionally empowers individuals like myself to assume greater responsibilities, while remaining available to advise or assist with challenges that may arise,” he wrote in an email.
The Army investigator determined that Bavari uses his power and authority to limit researchers from submitting grant proposals and getting funding from the [Defense Threat Reduction Agency], a Department of Defense agency that is a major USAMRIID funder.
The agency declined to comment.
“It would be inappropriate for the [Defense Threat Reduction Agency] to comment on an USAMRIID matter or employee,” agency spokesman Ron Lovas wrote in an email.
Bavari opted to submit a limited number of proposals to the agency, which were subject to his approval, instead of allowing researchers to submit their own proposals.
That may have kept researchers from securing funding to support their own staff and goals, according to the Army report.
In Bavari’s response to the Army investigation, he argued that his approach eliminated a process that created internal competition and replaced it with team collaboration.
“To ensure that the collective wisdom of USAMRIID’s outstanding scientists are fully applied to solutions for the Warfighter, I am slowly changing the way in which we work with [Defense Threat Reduction Agency],” he said.
Some USAMRIID employees who provided sworn statements for the Army investigation also were concerned about Bavari’s relationship with the nonprofit Geneva Foundation.
The foundation supports innovative medical research and works with military researchers as they create proposals for federal or other funding.
A dozen principal investigators at USAMRIID are supported by the Geneva Foundation. The foundation also employs 30 research team members at the institute.
The Army investigator asserted that the science director used his relationship with the Geneva Foundation to “bank” funding from pharmaceutical companies to achieve his own research goals without letting USAMRIID know about the funds.
That’s not how the Geneva Foundation works, President Elise Huszar said.
The foundation does not award funding; it works with researchers during the proposal stage and after funding has been awarded from another source, such as the federal government.
“We’re not a grant-making body; we don’t have a cache of money that we make discriminately to different people,” Huszar said.threat
Huszar said the foundation typically works closely with USAMRIID’s business office to make sure financial awards are reported according to Geneva’s requirements.
“There shouldn’t be any awards that USAMRIID doesn’t know about,” she said.
Huszar found multiple problems with the Army’s report.
“Geneva’s experience with Dr. Bavari did not equate with the report that was provided,” she said.
The Army’s findings will not affect Bavari’s relationship with the Geneva Foundation, Huszar said, unless USAMRIID decides to restrict his proposals.
The Army investigator recommended removing Bavari from USAMRIID and re-assigning him to a job without supervisory duties.
The investigator also recommended the following:
Changing the science director position to minimize the possibility of a conflict of interest between that person and the institute’s research
Auditing funding from nongovernmental sources
Requiring detailed reporting of that funding
Extending commanders’ assignments from two to three years to reduce the impact of turnover
Requiring commanders to have subject matter expertise in the research their organizations conduct.
Vander Linden confirmed that Bavari continues to hold the position of science director at the institute, but could not comment whether the institute had acted on the investigator’s recommendations.
Current employees who spoke to The News-Post said they have not seen any indications that the institute has done so.
Officially, the institute itself was unable to comment on the report.
“Laws such as the Privacy Act severely restrict what can be discussed related to these matters,” Vander Linden wrote in an email. “Therefore, we are unable to comment further.”
REVIEW Broad-spectrum coronavirus antiviral drug discovery Allison L. Totura and Sina Bavari Division of Molecular and Translational Sciences, United States Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD, USA (NOTE - Allison Totura was the last graduate student of Dr. Ralph Steve Baric (born 1954) )
NOTE : GS-5734 ( Remdesivir ) is identified as most likely anti-viral to help
Broad-spectrum coronavirus antiviral drug discovery
Allison L. Totura ORCID Icon & Sina Bavari
Pages 397-412 | Received 16 Aug 2018, Accepted 07 Feb 2019, Published online: 08 Mar 2019
ABSTRACTIntroduction: The highly pathogenic coronaviruses severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) are lethal zoonotic viruses that have emerged into human populations these past 15 years. These coronaviruses are associated with novel respiratory syndromes that spread from person-to-person via close contact, resulting in high morbidity and mortality caused by the progression to Acute Respiratory Distress Syndrome (ARDS).Areas covered: The risks of re-emergence of SARS-CoV from bat reservoir hosts, the persistence of MERS-CoV circulation, and the potential for future emergence of novel coronaviruses indicate antiviral drug discovery will require activity against multiple coronaviruses. In this review, approaches that antagonize viral nonstructural proteins, neutralize structural proteins, or modulate essential host elements of viral infection with varying levels of efficacy in models of highly pathogenic coronavirus disease are discussed.Expert opinion: Treatment of SARS and MERS in outbreak settings has focused on therapeutics with general antiviral activity and good safety profiles rather than efficacy data provided by cellular, rodent, or nonhuman primate models of highly pathogenic coronavirus infection. Based on lessons learned from SARS and MERS outbreaks, lack of drugs capable of pan-coronavirus antiviral activity increases the vulnerability of public health systems to a highly pathogenic coronavirus pandemic.1. Introduction
Outbreaks of severe acute respiratory syndrome (SARS, 2002–2004 [1,2]) and Middle East respiratory syndrome (MERS, 2012-current [3]) in the last two decades are a significant threat to global public health. SARS and MERS represent a new class of public health concern that may continue to emerge into human populations: respiratory syndromes caused by coronaviruses (CoVs) that are transmitted from person-to-person via close contact, resulting in high morbidity and mortality in infected individuals. Although SARS and MERS initially present as mild, influenza-like illnesses with fever, dyspnea, and cough, progression to more severe symptoms is characterized by an atypical interstitial pneumonia and diffuse alveolar damage. Both SARS-CoV and MERS-CoV are capable of causing acute respiratory distress syndrome (ARDS), the most severe form of acute lung injury where alveolar inflammation, pneumonia, and hypoxic lung conditions lead to respiratory failure, multiple organ disease, and death in 50% of ARDS patients [4]. The total confirmed number of patients infected with highly pathogenic CoVs is relatively low (approximately 10,000 cases of both SARS and MERS since 2002), but CoVs are of particular concern due to high case fatality rates, lack of proven therapeutics, as well as the demonstrated ability of these pathogens to seed outbreaks that rapidly cross geographic and geopolitical borders into other countries and continents [5,6].2. In vitro systems for pan-coronavirus drug discovery
3. In vivo systems for pan-coronavirus drug discovery
Based on the results from in vitro screening methods, potential new pan-coronavirus drugs that successfully target HCoVs require additional evaluation in animal species that model viral infection on an organismal scale. Due to urgent public health need for effective treatments against SARS-CoV and MERS-CoV, development of animal models of CoV infection emphasized these pathogens [58,59]. Reproducible models of highly pathogenic coronavirus infection in common laboratory animal species have utility not only in development and testing of pan-coronavirus drugs, but also in elucidating mechanisms of viral replication or disease pathogenesis. Desirable qualities for animal models of SARS-CoV and MERS-CoV include recapitulation of severe disease symptoms seen in SARS and MERS patients, and lethality caused by fulminant viral infection of the lung as indicated by high viral titers, inflammatory infiltrates, and aberrant cell signaling programs. Although therapeutic efficacy against viral transmission is essential to disrupting SARS or MERS outbreaks, current animal model development has focused on disease resulting from relevant infection routes (i.e. intranasal) over directly developing models of CoVs transmission.4. Pan-coronavirus antivirals
Pan-coronavirus antivirals must target viral or host factors that are i) highly conserved among known CoVs, ii) essential to viral replication or viral pathogenesis by known CoVs, and iii) likely to be conserved and essential in emerging CoVs. Inhibiting highly conserved mechanisms involved in the coronavirus lifecycle is likely to result in a reduction of viral titers, alteration of host responses, and/or amelioration of disease signs. SARS-CoV and MERS-CoV are known threats to global health, but other novel coronaviruses may emerge in the future complicating drug design if antiviral targets are too specific to known viral strains. Unlike with influenza viruses, specific antiviral drugs like oseltamivir and zanamivir targeting coronaviruses are not yet available, but several promising candidates have been recently described in the literature. The most conserved proteins among CoVs are nonstructural proteins (nsps) involved in essential functions of the viral lifecycle. The structural proteins that make up the virion are less conserved than nsps, and accessory proteins are only functionally conserved among very closely related viruses (Figure 2). In addition to potential lack of conservation between known and emerging HCoVs, targeting viral proteins can be problematic for drug discovery due to viral escape by mutation. Alternatively, antivirals that target conserved host factors utilized during the viral life cycle may also be potential pan-coronavirus antiviral therapeutics, but have the disadvantage of potential off-target effects.As an example of coronavirus virion (A) and genome (B) structure, a schematic of MERS-CoV (GenBank JX869059) is provided. Virions exist as enveloped viral particles, with the Spike (S), Membrane (M), and Envelope (E) proteins decorating the outside of the membrane. Coronaviruses in genogroup 2a have an additional structural protein hemagglutinin esterase (HE), which has been omitted from this discussion. Inside of the virion, the Nucleocapsid (N) protein encapsidates the viral genome. The viral genome is composed of + sense, single-stranded RNA. At the 5ʹ end of the genome, a single polyprotein open reading frame encodes the more highly conserved nonstructural proteins (ORF1a, ORF1b). At the 3ʹ end of the genome, the functionally conserved structural proteins that make up the virion are interspersed with virus-specific accessory proteins (ORF3, ORF4a, ORF4b, ORF5, and ORF 8b). Accessory proteins are conserved between very closely related viruses like BatCoV-HKU4, BatCoV-HKU5, and MERS-CoV. There is no conservation of accessory proteins between known HCoVs.5. Expert opinion
Article Highlights
March 27, 2020 | A version of this story appeared in Volume 98, Issue 13 /by Lisa M. Jarvis , with reporting by Bethany Halford / Source saved as PDF : [HP00AF][GDrive]
Mentioned : Sina A Bavari (born 1959) / Dr. Mark Randall Denison (born 1956) /
Gilead's antiviral remdesivir is being tested in multiple late-stage studies in China and the US to treat COVID-19.
In the coming weeks, the world will get a sense of whether Gilead Sciences’ [Remdesivir], an antiviral developed for Ebola, is useful against the novel coronavirus. With the coronavirus pandemic spiraling—during the week of March 23, worldwide infections crossed 500,000 and deaths shot towards 25,000—initial results emerging from several late-stage studies will be under the microscope.
But infectious disease experts on the front lines warn that the data are unlikely to clearly answer the question of whether remdesivir works in COVID-19, the respiratory illness caused by the SARS-CoV-2 virus. Those first tests are in the sickest, hardest-to-treat, patients. Moreover, antivirals don’t have a great track record at taking down coronaviruses, which can be a little more sophisticated than your average RNA virus.
Still, some industry watchers hope the studies signal enough success to convince the US Food and Drug Administration to approve Gilead’s experimental drug.
When a new infectious disease threatens the world, researchers’ first move is to look for any existing therapies that might work against it. As Sina Bavari of Edge Bioinnovation Consulting and Management puts it, when you’re really hungry, you’d rather take a lasagna out of the freezer than make one from scratch. Bavari previously spent many years as chief scientific officer at the US Army Medical Research Institute of Infectious Diseases.
As the coronavirus began to spread, one of the first compounds to be pulled from the freezer was remdesivir. Discovered by Gilead and the Army institute during the 2014 Ebola outbreak in West Africa, the RNA polymerase inhibitor seemed like a sound choice. Although it turned out not to work in Ebola—a failure many blame on how late in the progression of the disease it was given—studies in both healthy and infected people showed the drug is fairly safe.
And researchers point to solid science for why remdesivir might still work against COVID-19.
The SARS-CoV-2 genome is made up of a string of nucleotides that, during replication, are reconstructed, one by one, by the viral polymerase. The RNA-dependent RNA polymerase is a good drug target because it is “almost exclusively associated with the virus,” says University of Wisconsin–Madison virologist Andy Mehle. Polymerase inhibitors will be highly specific for infected cells, sparing healthy ones.
Enter remdesivir, which acts like a mimic for adenosine—one of the nucleotides in that string.
The virus is tricked into incorporating the active form of the drug into its genome, preventing it from making more copies of itself. The mechanism by which remdesivir does that is still unclear, but “polymerase inhibitors primarily work by causing mutations of the genome, or by blocking polymerase function,” Mehle says.
Although Gilead developed remdesivir for Ebola, which belongs to a different family of viruses than SARS-CoV-2, the “viral machinery has elements in common,” Erica Ollmann Saphire, a virus expert at the La Jolla Institute for Immunology, said in an email. Those common elements include polymerases, meaning that for any “safe, bioavailable and manufacturable molecule, the only remaining question is will it work against this other virus,” she said.
While remdesivir was being tested in people with Ebola, several academic and government groups were exploring its potential to take down other viruses, including the coronaviruses that cause SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome). They showed in both lab experiments and animal studies that remdesivir could treat infections and prevent them altogether—what scientists call prophylaxis.
In fact, remdesivir is one of only two highly effective compounds to come out of six years of screening against coronaviruses, says [Dr. Mark Randall Denison (born 1956)], a coronavirus expert and director of the Division of Infectious Diseases at Vanderbilt University Medical Center. Denison has collaborated with labs at the University of North Carolina and elsewhere to find small molecules that keep coronaviruses from replicating—and still work if the virus mutates. The other effective compound, EIDD-2801, was discovered by Emory University chemists and recently licensed to Ridgeback Biotherapeutics.
One reason so many compounds failed is that coronaviruses are a little smarter than other RNA viruses. They’re the only ones with a polymerase that can fix errors in their genomes, meaning they can spot and ignore the mimics that drug hunters typically design. [Dr. Mark Randall Denison (born 1956)]'s lab found that remdesivir, like EIDD-2801, can bypass that proofreading function.
Those studies, combined with the Ebola safety data, provided a rationale for trying the compound against the new coronavirus.
At the moment, five Phase III studies are testing the drug against COVID-19. Two began in China in early February—one in people with severe disease, the other in those with mild to moderate disease. One is a US National Institutes of Health–led study that started in February to test the drug in anyone hospitalized with evidence of lung involvement. And two are Gilead-led studies that started in March—one in severe disease and the other in moderate disease.
The first data should come from the studies in China, followed quickly by an initial report from Gilead. With so much pressure to find a COVID-19 treatment—even a modestly effective one—the results will be closely scrutinized. But many on the front lines caution that, even though the studies were carefully designed, the answers might not be clear cut.
“I don’t think the ongoing trials will tell us a lot,” says H. Clifford Lane, clinical director at the National Institutes of Allergy and Infectious Diseases, who is overseeing ongoing studies at the NIH, including its remdesivir study. “The studies might give us some hint, but I do think it will be important to get a study launched that focuses on early disease”—before it becomes severe.
A likely scenario is that several studies “don’t reach statistical significance but show a similar result, and that might be enough to say we should probably be using this,” Lane says. “It’s really hard to know what to do.”
Libby Hohmann, associate professor of medicine and infectious diseases at Massachusetts General Hospital, is similarly cautious. “It’s going to be a challenge to review the data because the protocol allows a wide range of illness into it,” says Hohmann, who leads the hospital’s participation in NIAID’s remdesivir trial. “Unless it’s sort of a home run, it may be difficult to parse at the get go.”
One issue is that the first studies to read out are the ones focused on the most severe cases, people whose disease might have progressed past the point of help by an antiviral.
“Everything we do in infectious disease is better treated when it’s early on and the bacterial or viral burden and the damage done is lesser,” Hohmann says. Doctors are realizing that COVID-19 is a two-phase illness, she says, that starts with upper respiratory symptoms that worsen after a week to two weeks. At some point during that period, patients “fall of a cliff,” Hohmann notes. “There’s a lot of data and speculation that it’s a kind of immunological phenomenon,” where certain people’s immune or inflammatory response goes awry.
So if those first data in severe or even moderate cases are unclear, it doesn’t necessarily mean the drug doesn’t work. Rather, it could just mean it isn’t being given early enough.
But even if patients are treated early, the benefits could be minimal, Lane warns. Consider, for example, the limitations of Tamiflu (oseltamivir), a common treatment for another virus, influenza. To have any effect, the drug must be taken within 48 hours of symptoms appearing. And even then, “the overall impact on clinical outcomes is not very dramatic,” Lane says. “We don’t have a lot of success in treating RNA viruses.”
In the ideal scenario where the trials do look good, caveats still abound. Ideally, doctors would deploy the drug either prophylactically or just after exposure, but before symptoms appear. Edge Bioinnovation’s Bavari calls it “something to give before you actually go to the hospital so you don’t end up in the hospital.”
But remdesivir can only be given intravenously, so “it’s not like we’re going to be able to give it to people with the sniffles out in the real world,” Hohmann says.
Nonetheless, her team has been trying to enroll people with a better chance of responding to the drug. Among the 16 patients her clinic has signed up so far, she’s emphasized younger people and those with mild to moderate disease—the ones with shortness of breath rather than those being intubated in the emergency room. “I think we will be able to tell if we’re making a difference in those people,” Hohmann adds.
Gilead says it has no plans to turn remdesivir into a pill. “Based on our understanding of remdesivir from preclinical studies, intravenous administration allows for the most stability and appropriate levels of the drug in the blood system,” a company spokesperson tells C&EN.
Another roadblock is manufacturing. Gilead’s spokesperson notes that “there are currently limited available clinical supplies of remdesivir, but we are working to increase our available supply as rapidly as possible.” For example, the firm is beginning in-house manufacturing of the drug, which had been made only by contract manufacturers. The biotech firm has also added new manufacturing partners around the world to enhance sourcing of everything from raw materials to the finished drug.
Despite the many caveats attached to remdesivir, stock analysts who cover Gilead say it has a reasonable chance of reaching the market. “No one expects it to be a magic bullet,” says Piper Sandler analyst Tyler Van Buren. “But if it works at all in a portion of patients, especially in severe ones, that is very meaningful.” If remdesivir can reduce the need for ventilators or time on supplemental oxygen, Van Buren argues, it could alleviate burden on the healthcare system.
While the FDA approval process typically takes 6–12 months, “this is an unprecedented, once-in-a-century situation,” Van Buren says. Gilead has been submitting as much data as possible to regulatory agencies to expedite approval, he notes. “If the data does look good, there will be tremendous pressure for FDA to make a decision within days.”
If that happens, could the world end some of the more extreme social distancing measures and start getting back to business? “I think it will depend on the level of efficacy,” NIAID’s Lane says. “The goal remains to prevent the spread of infection. While an effective therapy might have some effect, I doubt it would have a major impact.”
Even in the best-case scenario, where remdesivir moves the needle for patients in a meaningful way, successful deployment will require a health care workforce capable of administering it. Because of shortages of personal protective equipment (PPE) and other supplies, Mass General’s Hohmann says, conditions are already difficult—and the worst is yet to come.
“It’s just a challenge because the clinical workforce is overworked, nervous, worried about their own health, worried about the lack of PPE, and about the tsunami of patients that’s coming,” she says. “If we had all the PPE we need, such that nobody had to worry about going into the room of a patient with known disease, life would be a lot easier around here.”
In 2018, two researchers with the United States Army Medical Research Institute of Infectious Disease at Fort Detrick put forth an ominous warning that coronavirus represents a highly pathogenic and dangerous virus that has emerged in human populations over the past decade and a half. [Link to that research paper : [HP0029][GDrive] ]. Associated with novel respiratory syndromes, they move from person-to-person via close contact and can result in high morbidity and mortality caused by the progression to acute respiratory distress syndrome (ARDS). These two researchers were incredibly, and ominously, prescient.
New Coronaviruses Deadly
By 2018, Allison Totura and Sina Bavari, again researchers with Fort Detrick, discussed previous outbreaks involving SARS-CoV and MERS-CoV noting, “These coronaviruses may have the potential to cause devastating pandemics due to unique features in virus biology including rapid viral replication, broad host range, cross-species transmission, person-to-person transmission, person-to-person transmission, and lack of herd immunity in human populations.”
Although these first two outbreaks were contained by “diligent enforcement of public health measures” ominously they pointed to the threat of a “as-yet unknown BatCoV that causes severe disease in humans and makes antiviral therapeutics that broadly target coronaviruses a highly desirable commodity to ensure global public health.”
Instructing us back in 2018
Ms. Totura and Mr. Bavari essentially warned governments back in 2018 to start acting now when they noted that governments’ currently must “produce medical countermeasures that can protect vulnerable populations against known coronaviruses (SARS-CoV and MERS-CoV) but also could be effective against…novel highly pathogenic coronaviruses that may emerge from animal reservoir hosts.”
Predicting the Contagion
In an almost eerie threat, the researchers warned all that another coronavirus would come and although similar to SARS-CoV and MERS-CoV, this next pathogenic coronavirus could target “human populations with potentially disastrous consequences.” Although in 2018 the authors felt there was sufficient disease surveillance in place, they cautioned that a pandemic of the current magnitude could be forthcoming noting that “biological factors that increase cross-species transmission or facilitate person-to-person spread may lead to future coronavirus strains not capable of being contained by timely quarantine of infected individuals.”
Back to the Future
There are undoubtedly other researchers that identified future waves of potentially deadly new strains of novel coronavirus. This particular warning documented in 2018 was too close for comfort. Based on TrialSite News ongoing observations of the more successful reactions in select countries, it can be assumed that government agencies, researchers and health systems are accumulating considerable actional data for heightened response and readiness. First, we must get through the current crisis then we must be ready to protect ourselves worldwide.
Lead Research/Investigator
Allison Totura, ORISE postdoctoral research fellow, USAMRIID, US Army Medical Research Institute of Infectious Diseases
Sina Bavari, PhD, Chief Scientific Officer, Scientific Director US Army Medical Research Institute of infectious Diseases (USAMRIID)
2020-04-16-scientificamerican-com-heres-what-we-know-about-the-most-touted-drugs-tested-for-covid-191.pdf
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By Tanya Lewis on April 16, 2020
As the COVID-19 pandemic continues to claim lives around the world, there are no specific treatments for the disease beyond supportive care. Several drugs already prescribed for other illnesses have shown promise against the novel coronavirus in preclinical studies. And they are now being tested in clinical trials or given to patients on a compassionate-use basis. But experts warn that these medications have yet to prove effective in treating COVID-19 patients.
As of this writing, the virus has infected more than two million people worldwide and caused more than 130,000 deaths. A vaccine and new treatments could take years to fully develop, but the World Health Organization recently launched a large international trial called Solidarity to test four existing therapies. They are the closely related malaria drugs chloroquine and hydroxychloroquine; the antiviral medication remdesivir (originally developed to treat Ebola); the antiviral combination of lopinavir and ritonavir (used for HIV); and those two HIV drugs plus the anti-inflammatory small protein interferon beta. A number of separate clinical trials of these medications and others are underway in several countries, including the U.S.
The U.S. Food and Drug Administration has approved remdesivir for treating COVID-19 patients under the compassionate-use protocol (a designation that gives patients with life-threatening illnesses access to an experimental drug). And the agency has granted an emergency use authorization—which allows for otherwise unapproved drugs or uses during an emergency—for chloroquine and hydroxychloroquine.
“None of these therapies are proven,” says Stanley Perlman, a professor of microbiology and immunology at the University of Iowa. Only the results of randomized clinical trials can show whether they work, he adds.
Here is what scientists know so far about some of the most prominent drugs currently being tested as treatments for the potentially deadly infection.
CHLOROQUINE AND HYDROXYCHLOROQUINE
President Donald Trump has repeatedly touted the malaria drugs chloroquine and hydroxychloroquine as a treatment for COVID-19—despite a lack of clinical evidence that they work for the disease. The president’s comments set off a scramble among doctors and patients to obtain the drugs—which are frequently used to treat autoimmune diseases such as rheumatoid arthritis and lupus—and there is now a shortage of them in the U.S. Also, these substances can be dangerous in healthy people: a man in Arizona died after ingesting a fish-tank cleaner containing a type of chloroquine that is not approved for human use. On March 28 the FDA issued an emergency authorization for administering chloroquine or hydroxychloroquine to COVID-19 patients. The FDA subsequently cautioned, on April 24, that hydroxychloroquine and chloroquine, alone or with the antibiotic azithromycin, should not be used outside a hospital or clinical trial setting because of the risk of heart rhythm complications. Many experts say the widespread usage of these drugs is premature.
“The clinical support is very, very minimal,” says Maryam Keshtkar-Jahromi, an assistant professor of medicine at the Johns Hopkins University School of Medicine, who co-authored an article in the American Journal of Tropical Medicine and Hygiene calling for more randomized controlled trials of chloroquine and hydroxychloroquine. The drugs do “not show strong evidence at this point,” she adds.
A few preclinical studies have suggested these compounds could be effective at blocking infection with the novel coronavirus (officially called SARS-CoV-2), but there has been very little good evidence from clinical trials in patients with the illness it causes, COVID-19. A controversial small, nonrandomized trial of hydroxychloroquine combined with azithromycin in France suggested that COVID-19 patients given the treatment had less virus, compared with those who refused the drugs or those at another hospital who did not receive them. But experts have questioned the study’s validity, and the society that publishes the journal in which it appeared has issued a statement of concern about the results, according to Retraction Watch. On May 21 the same outlet reported that the authors have withdrawn the study from the preprint server medRxiv and that the Web site now says they did so “because of controversy about hydroxychloroquine and the retrospective nature of their study." (Scientific American reached out to the paper’s authors for comment but did not hear back from them.) A preprint study in China also claimed to show that hydroxychloroquine benefitted COVID-19 patients, but it had significant methodology problems, Keshtkar-Jahromi says. The issues included confounding variables, such as the fact that all of the subjects received other antiviral and antibacterial treatments.
Some scientists say the preclinical evidence is strong enough to support chloroquine’s use, however. “We know how it acts at the cellular level against the virus. We have preclinical proof,” says Andrea Cortegiani, an intensivist and researcher in the departments of anesthesia and intensive care and of surgical, oncological and oral sciences at the University of Palermo in Italy. “Second, it’s a cheap drug, available all over world,” adds Cortegiani, who is also a clinician at University Hospital “Paolo Giaccone” in Italy.
Chloroquine and hydroxychloroquine have been hypothesized to work against COVID-19 by changing the pH required for SARS-CoV-2 to replicate. Given their use in autoimmune disorders, these medications could also play a role in dampening the immune response to the virus—which can be deadly in some patients.
But these drugs’ cardiac toxicity is a concern, Keshtkar-Jahromi says. There have been some reports of myocarditis, or inflamed heart tissue, in people with COVID-19 who have not taken chloroquine or hydroxychloroquine. If patients receiving one of these medications die of heart complications—and are not in a clinical trial—doctors cannot know if the drug contributed to higher chance of death.
A drug that modulates the immune response could also make someone more vulnerable to other viral or bacterial infections. “It’s a double-edged sword,” says Sina Bavari, chief science officer and founder of Edge BioInnovation Consulting in Frederick, Md., who co-authored Keshtkar-Jahromi’s article in the American Journal of Tropical Medicine. Giving a drug to suppress the immune system has to be done with extreme care.
“We are not saying, ‘Don’t [prescribe chloroquine],’” Bavari says. “We are saying, ‘More data is needed to better understand how the drug works—if it works.’”
REMDESIVIR
This experimental antiviral drug was developed to treat Ebola, and it has been shown to be safe for use in humans. It is a broad-spectrum antiviral that blocks replication in several other coronaviruses, according to studies in mice and in cells grown in a lab. In addition to the WHO investigation, at least two trials in China and one in the U.S. are currently evaluating remdesivir in COVID-19 patients. Results for the Chinese trials are expected later this month.
“As of this moment, we don’t have data for remdesivir in human COVID-19 disease,” says Barry Zingman, a professor of medicine at Albert Einstein College of Medicine and clinical director of infectious diseases at Montefiore Health System’s Moses Campus. The two related institutions, both located in New York City, recently joined a nationwide clinical trial of the drug. “Our patients are randomized, so we don’t know who’s getting the drug or a placebo. [But] we have seen some patients do remarkably well,” Zingman says. Trial results are on track for publication sometime in the next six to eight weeks, he adds. Later, on April 29, Gilead Sciences, the company that manufactures remdesivir, announced that data from the phase III clinical trial of the drug were “positive” and that the study had “met its primary endpoint.” The data have not yet been released, but Gilead says it plans to submit them to a peer-reviewed journal in the coming weeks.
As Scientific American reported previously, remdesivir works by inhibiting an enzyme called an RNA-dependent RNA polymerase, which many RNA viruses—including SARS-CoV-2—use to replicate their genetic material. Timothy Sheahan of the University of North Carolina at Chapel Hill and his colleagues have shown the drug is effective against the coronaviruses that cause severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS), respectively, as well as some of the viruses behind the common cold. The team is currently in the process of testing the drug’s efficacy against SARS-CoV-2. A recent study of compassionate use of remdesivir in 53 severe COVID-19 patients found that 63 percent of those taking the drug improved, but it was not a randomized controlled trial.
“Remdesivir has some chance,” Perlman says. “If we can give [the drug] early in the disease course, it could work.” To know for sure, scientists must await the results of the ongoing clinical trials.
One limitation with remdesivir is that it must be given intravenously, so patients can only get it in a hospital. Sheahan and his colleagues at Emory University have recently developed a related drug called EIDD-2801, which can be taken in pill form. Like remdesivir, the medication works as a nucleoside analogue, interfering with viral replication. It was effective at preventing SARS-Cov-2-infected lung cells from replicating in a lab dish and related viruses from doing so in mice.
RITONAVIR AND LOPINAVIR
The HIV drugs ritonavir and lopinavir (sold as a combination therapy by AbbVie under the brand name Kaletra) have been tested against COVID-19 in a few clinical trials. The initial data have not shown them to be effective, however. A study in the New England Journal of Medicine found they conferred no benefit beyond standard care.
The drug combination is what is known as a protease inhibitor, and it works by blocking an enzyme involved in viral replication. But its action is specific to HIV and so is unlikely to work for SARS-CoV-2, Perlman says. “If you have the key to a car, and you try to put it in your car, the odds of it working are one in a million,” he says. “Kaletra [targets] a completely different lock” than the one for COVID-19.
Nevertheless, the WHO trial includes a group of COVID-19 patients who will receive these drugs on their own—and another group that will receive them in combination with interferon beta, a small cell-signaling molecule used to treat multiple sclerosis. The molecule is a “massive orchestrator of immune response,” Perlman notes, so it must be used carefully. In mouse studies of the SARS and MERS coronaviruses, it halted the infections when administered early. When it was given later, he says, the mice died. Using a drug that activates the immune system could be helpful in the beginning of an infection, but giving it too late could be deadly.
IMMUNE SYSTEM INHIBITORS
Researchers are also considering a number of other therapies that tamp down the rampant immune response seen in severe COVID-19 cases. Such a flood of immune cells in the lungs—known as a cytokine storm—can lead to death. Many of the sickest patients have elevated levels of an inflammatory protein called interleukin-6 (IL-6). Research in China has suggested that Actemra (tocilizumab), an IL-6-blocking antibody drug made by Roche, shows promise against COVID-19. And Chinese authorities have recommended the drug in their treatment guidelines. Roche has since initiated a phase III randomized controlled clinical trial for the medication. In the U.S., Michelle Gong—chief of the division of critical care at Montefiore and Albert Einstein and director of critical care research at Montefiore—and her colleagues are among dozens of groups conducting a double-blind, placebo-controlled clinical trial of a related drug called sarilumab, which is already approved for treating rheumatoid arthritis. Sarilumab will only be given to the sickest individuals: to be part of the trial, patients must be hospitalized with COVID-19 and in severe or critical condition.
CONVALESCENT PLASMA
Another treatment approach involves injecting COVID-19 patients with blood plasma from people who have recovered from the illness. The FDA recently issued guidance on the investigational use of such “convalescent plasma,” which contains antibodies to the coronavirus, and clinical trials are underway.
Blood from disease survivors has been used as a treatment throughout history—from polio-infected horses in the 1930s to former Ebola patients in 2014. “There is a long-lasting rationale for the use of convalescent plasma against any infectious disease,” Cortegiani says. One problem, however, is that scientists do not know whether people develop strong immunity against SARS-CoV-2. And it is not easy to collect plasma containing enough antibodies, he adds. Another issue is the shortage of eligible donors. Some companies are looking into ways to produce these antibodies artificially. In the meantime, a number of hospitals are searching for volunteers to donate plasma.
None of the therapies described above have yet been proved to treat COVID-19. But some answers can be expected in the next few weeks and months as the results of clinical trials emerge. Until then, Cortegiani says, “we cannot say, ‘This drug is more promising than the other one.’ We can only say, ‘There is a rationale for it.’”
Editor’s Note (5/22/20): This article has been edited after posting to include an update concerning the withdrawal of a controversial preprint study of hydroxychloroquine. The text had previously been amended on April 29 to add a reference to an announcement of phase 3 trial results for remdesivir and on April 24 to include an update concerning an FDA warning about possible heart complications from hydroxychloroquine and chloroquine. And a correction of Maryam Keshtkar-Jahromi’s comments about her concerns with chloroquine and hydroxychloroquine was made on April 16.
Dr. Bavari is a lead decision maker and leader in global research and development of vaccines and therapeutics for deadly infectious diseases. Well-experienced in using and providing management on new and complex technologies, Dr. Bavari is adept at effectively translating scientific discovery into products, and has discovered and developed vaccines and therapeutics for multiple infectious diseases. Dr. Bavari has initiated and led programs at all stages of discovery and guided programs through critical decision points and into advanced development. Dr. Bavari has substantial experience in providing technical leadership and communicating policies and strategies to dynamic and highly matrixed environments. He has provided representation in both national and international settings and organizations.
Company NameUSAMRIID , US Army Medical Research Institute of Infectious Diseases
TitleChief Scientific Officer and Scientific Director
Dates EmployedSep 2014 – Sep 2019
Employment Duration5 yrs 1 mo
LocationFrederick, MD
TitleChief, Molecular and Translational Sciences
Dates EmployedJan 2011 – Sep 2014
Employment Duration3 yrs 9 mos
Principal Scientist, High Content Imaging, Quantitative Biosciences
Hanry M.Jackson Foundation for Advancement of Military Medicine; BCSAI, USAMRIID
As a lead of in vitro testing for anti-viral and anti-toxin discovery projects established collaborations on 80 projects (currently) with major pharmaceutical companies, biotech and academic organizations on the search for anti-viral therapies against major DoD viral threats and emerging pathogens including Filoviridae, Togaviridae, Bunyaviridae, Arenaviridae, Flaviviridae, Picornoviridae, Coronaviridae, Paramixaviridae ets.
Developed comprehensive phenotypic screening triage for efficient discovery of new active compounds and fast and evaluation of their potency and selectivity for using confocal imaging PE Opera platform.
Developed screening triage to search of inhibitors of Botulinum neurotoxin both whole enzyme and active side using Fluorescent Imaging and MSD technology platforms. Performed screening and hit to lead characterization for selected collections both inter- and extra-mural collaborations
On a daily bases coordinate work of screening group (7 people) applying high content imaging in antiviral drug discovery and supporting research lab of 1 PhD scientist (currently) for enzymatic in vitro testing.
Provide data analysis and data packages designed for rapid prioritization of potent and selective antiviral therapies for rapid transition into in vivo evaluation, report results for collaborators and financial agencies.see less
Accountable for project managing of three image based core platforms: PhenomicScreen, PhenomicID and Phenomic drug-target de-convolution. The Center comprises 20 people including 4 PhD-level scientists and 5 PhD students organized into three groups: Screening Technology, Discovery Biology and Image Mining.
As a Group Leader of Cellular Assay Development, organized, trained and supervised a group of 5 scientists working on cell-based assay development for Screening Sciences at Wyeth; coordinated the workflow for assay development and interacted with research group, HTS and automated cell culture group to deliver TS ready cell based assays.
Ran drug discovery projects for the Pharmaceutical Industry. Targets included GPCRs (neuroscience and inflammation), ion channels and transporters (inflammation, metabolic diseases, and neuroscience), kinases and receptors, cell signaling pathways, cellular enzymes (oncology). During 9 years I developed 52 fully characterized cell-based assays. Assays technologies included FLIPR-based, EFC DiscoverX , HTRF CisBio, MDS Transfluor, immuno-staining HCS technologies. I developed multiple assays for SAR, profiling and hit selection; 10 functional follow up HCS assays for PE Opera and Cellomics Array Scan VTI and additionally performed several low scale profiling and secondary screens.
Worked with HTS scientists on development and custom design of HSDM Thermo/duel FLIPR(tetra) Automated system (Reflected by publication in JALA, 2006 ). Evaluated and integrated (working with our HTS group, Thermo and PE) new technologies: first FLIPR-3-based assays, new fully automated platforms for FLIPR Tetra , PE Opera for first HCS project at Screening Sciences. Evaluated and integrated image-based technologies (PE/Evotec Opera confocal system, Cellomics Array ScanVTI, FCS Guava EasyCyte and Essen IncuCyte.see less