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Saturday, September 8, 2018

Synthetic DNA vaccine effective against influenza A virus subtype


Currently available vaccines for the prevention of seasonal influenza virus infection have limited ability to induce immunity against diverse H3N2 viruses, an influenza A subtype that has led to high morbidity and mortality in recent years.
Now, Wistar scientists have engineered a synthetic DNA vaccine shown to produce broad immune responses against these H3N2 viruses. Study results were published online in the journal Human Gene Therapy.
The recent severe influenza seasons in 2013/2014, 2014/2015 and 2017/2018 can be directly attributed to H3N2. Commercial vaccine efficacy against H3N2 in 2017/2018 was low and contributed to a greater rate of pneumonia and influenza-associated deaths.
“Current vaccine design and manufacturing to meet the antigenic diversity of H3N2 viruses is challenging, and with another flu season approaching there remains a pressing need for new vaccine approaches for influenza,” said lead researcher David B. Weiner, Ph.D., executive vice president and director of the Vaccine & Immunotherapy Center at The Wistar Institute, and W.W. Smith Charitable Trust Professor in Cancer Research. “There is also a need for improvements in rapid selection and deployment against newly emergent viral strains and synthetic DNA vaccines represent an important tool to reach this goal.”
To overcome the antigenic diversity of H3N2 viruses, Weiner and colleagues used H3N2 strains from 1968 to the present retrieved from the Influenza Research Database to generate four synthetic common sequences of the hemagglutinin antigen (HA), a protein present on the viral surface. These micro-consensus sequences were used to generate four DNA vaccines that were co-mixed to create a cocktail vaccine labeled pH3HA. The scientists administered the vaccine or placebo to mice and a booster vaccine two weeks later. Two weeks after the booster injection, they inoculated them with two representative influenza viruses.
Sarah Elliot, Ph.D., a senior postdoctoral fellow in the Weiner Lab, and colleagues monitored clinical signs, body weight and survival for two weeks after infection. All mice immunized with the synthetic DNA vaccine developed broad, robust antibody responses against HA and effective cellular immune responses including CD4 and CD8 T cell responses.
They were protected against lethal influenza A infection from two different challenge H3N2 viruses. Vaccination with pH3HA induced robust antibodies against the 1968 pandemic H3N2 as well as contemporary H3N2 strains that were components of commercially available vaccines from 2015/2016 and 2017/2018.
Compared with those who received placebo, immunized mice survived intranasal virus challenge with 10 times the median lethal dose; the placebo group succumbed to infection within six days of exposure to the challenge virus.
“The pH3HA vaccine represents a unique micro-consensus approach to producing immune responses to antigenically related — yet diverse, seasonal influenza A H3N2 viruses,” Weiner said. “The overarching goals of this approach are to limit the number of vaccine reformulations that can be deployed to protect against novel H3N2 viruses.”
Story Source:
Materials provided by The Wistar Institute. Note: Content may be edited for style and length.
Journal Reference:
  1. Sarah Elliott, Amelia A. Keaton, Jacqueline D. Chu, Charles C. Reed, Bradley Garman, Ami Patel, Jian Yan, Kate E Broderick, David Weiner. A Synthetic Micro-Consensus DNA Vaccine Generates Comprehensive Influenza-A H3N2 Immunity and Protects Mice Against Lethal Challenge by Multiple H3N2 Viruses. Human Gene Therapy, 2018; DOI: 10.1089/hum.2018.102
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Perrigo Gets Final FDA OK, Plans Launch for Store Brand OTC Imodium Equivalent


Perrigo Company plc (NYSE; TASE: PRGO) today announced that it has received final approval from the U.S. Food & Drug administration for the store brand over-the-counter (OTC) equivalent of Imodium®Multi-Symptom Relief (loperamide hydrochloride and simethicone tablets, 2 mg/125 mg). This product will be packaged and marketed as store brands or retailer ‘own label’ brands and will provide consumers with a high-quality, value alternative to the national brand. Perrigo is finalizing plans to launch its wholly owned store brand loperamide hydrochloride and simethicone tablets, 2 mg/125 mg, in the fourth quarter of 2018.

Imodium® Multi-Symptom Relief is indicated to relieve symptoms of diarrhea plus bloating, pressure and cramps, commonly referred to as gas. Retail sales for the last 12 months were approximately $62 million as measured by IRI.
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Bayer officials ‘vague on lawsuit strategy, despite liability’


It’s been nearly three weeks since the merger between Bayer AG and Monsanto officially began its integration, about two months since the deal closed and nearly two years since the planned deal was announced.
Despite that, newly appointed Bayer officials are vague on how they plan to handle the mountain of lawsuits inherited from Monsanto over pesticides such as glyphosate and dicamba.
These lawsuits have plagued Monsanto, most recently in an August 10 court decision that ordered the company to pay $289 million in damages.
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The nonprofit news outlet Midwest Center for Investigative Reporting provided this article to The Associated Press through a collaboration with Institute for Nonprofit News.
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But at the recent Farm Progress Show in Boone, Iowa, Brett Begemann, Bayer’s new chief operating officer and former Monsanto executive, was non-committal on the newly integrated company’s approach.
Begemann highlighted that the companies had only been together for a short time because of the mandate by the U.S. Department of Justice that disallowed the two companies from making any plans until August 16.
“We continue to learn, just like any company, from feedback from our customers.” He said. “We’ll continue to listen to that feedback, engage in that conversation, look at additional research, and move on from there.”
Of the recent verdict over glyphosate, Begemann said it doesn’t change the way the company plans to move forward.
“I would look at that as one case – doesn’t change 800 scientific studies, it doesn’t change 40 years of use, it doesn’t change the incredible value that products brought to agriculture and consumers worldwide. We’re thoroughly supportive of the product and will continue through the legal process that’s available to us,” said Begemann. “It’s a horrible and unfortunate situation with the plaintiff, Mr. Johnson. We have great sympathy for him and his family, but Roundup does not cause cancer.”
After the August 10 decision against Monsanto, Bayer’s stock prices dipped 10 percent. That doesn’t bode well for future litigation against the newly merged company.
While Roundup, the commercial name for the chemical glyphosate, is the subject of more than 8,000 lawsuits against Monsanto, dicamba has only been in use for soybeans for three years. But in that time, it’s attracted 37 lawsuits over damage to crops.
Dicamba has been hailed as Monsanto’s solution to weeds that have become resistant to glyphosate in recent years, wreaking havoc on soybean fields across the Midwest. But as effective as it was on weeds, dicamba also has the ability to damage soybeans, cotton, and specialty crops that are not genetically modified to withstand the chemical.
By July of last year, university weed scientists estimated more than 2.5 million acres of soybeans had been damaged by dicamba, according to Dr. Kevin Bradley, professor of plant sciences at University of Missouri. By the end of 2017, that estimate would jump to 3.6 million acres. One dispute over damage in Northern Arkansas led to a man’s murder.
As a result, the Environmental Protection Agency placed greater restrictions on the chemical in early 2018, and eight states added further safety measures and training requirements. Monsanto cautioned against the application of reactionary restrictions.
“We sympathize with any farmers experiencing crop injury, but the decision to ban dicamba in Arkansas was premature since the causes of any crop injury have not been fully investigated. While we do not sell dicamba products in Arkansas, we are concerned this abrupt decision in the middle of a growing season will negatively impact many farmers in Arkansas,” Monsanto said in a 2017 statement.
The company argues that any damage was due to a failure by operators to follow the extensive label, which outlines proper use of the chemical, and not the fault of the company.
But a lawsuit filed by the National Family Farm Coalition in the U.S. Court of Appeals for the 9th Circuit claims the EPA’s two-year approval of dicamba in 2016 was unlawful, stating Monsanto influenced the registration process and the EPA didn’t follow the Federal Insecticide, Fungicide and Rodenticide Act and the Endangered Species Act.
As of July 15, 2018, the number of investigations into dicamba-related damage has dropped to 605, compared to the 1,411 reported by the same time in 2017. Weed scientists estimate 1.1 million acres of soybeans have been injured. But this doesn’t include numbers from key soybean producing states like Iowa and Wisconsin.
These numbers show a marked improvement from the damage in 2017, which can be attributed to stronger restrictions from the EPA and states, better training from the chemical manufacturers, or the increased sale of dicamba-resistant crops.
In 2017, Monsanto sold 25 million acres worth of dicamba resistant soybeans. In 2018, that number was expected to double to 50 million. That’s more than half the 89.5 million acres of soybeans planted this year.
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Pfizer and CYTOO develop Duchenne target discovery platform


CYTOO has entered into a research and option agreement with Pfizer to develop a target discovery platform for Duchenne Muscular Dystrophy (DMD), through modifying CYTOOs existing MyoScreen platform.
DMD is a rare and life-threatening genetic disorder that affects children approximately 1 in 3500 to 5000 boys and families. It is caused by mutations in the dystrophin gene that results in progressive muscle degeneration and weakness.
By the early teens, most individuals with DMD have lost the ability to walk unassisted and their heart and respiratory muscles have also weakened. Individuals with DMD usually die from cardiomyopathy and respiratory failure in their second decade of life.
CYTOO has developed a muscle-on-a-plate platform using patients primary cells, called MyoScreen. MyoScreen is an in vitro system in which skeletal muscle cells mimic the morphology, contractile and metabolic functions of human muscle in vivo and therefore allows analyses of the molecular mechanisms involved in such functions in health and disease.
Under the terms of the agreement, Pfizer and CYTOO will work together to develop and validate a target discovery platform using a DMD patient muscle-derived MyoScreen platform. The goal of the collaboration is to attempt to establish a robust in vitro system that may be used for a high throughput target identification screen.
Should such a system be developed, Pfizer will have an option to acquire a license for the use of the resulting platform for DMD target identification efforts.
Dr John Murphy, VP, Biology, Pfizers Rare Disease Research Unit, said: Although the genetic cause of DMD has been known for years, little is known about the molecular functions that are affected in DMD muscles. Pfizer is committed to early stage DMD research and target identification.
Luc Selig, CYTOOs CEO, said: Muscle dystrophies affect children severely, and we still dont know what happens in muscle. This is why we developed MyoScreen: to have a laboratory model of patient-derived muscle, to study and modulate muscle functions and to identify drug candidates that are specific to muscle function. Teaming with Pfizer on DMD means they have shown a great dedication to this project, and we are extremely motivated to succeed.
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Military $48 Million Federal Contract Awarded to Patterson Dental


Patterson Companies Inc. dba Patterson Dental, St. Paul, Minnesota, won a federal contract valued at up to $48 million from the Defense Logistics Agency for dental supplies and equipment.
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Nearly half of Americans pay no federal income tax


Wage growth has risen to a 9-year high. Unemployment remains at an 18-year low. Jobless claims haven’t been this low since 1969. And nearly half of Americans don’t owe a dime of federal income tax.
Approximately 76.4 million or 44.4% of Americans won’t pay any federal income tax in 2018, up from 72.6 million people or 43.2% in 2016 before President Trump’s Tax Cuts and Jobs Act, according to data released Thursday by the Tax Policy Center, a nonprofit joint venture by the Urban Institute and Brookings Institution, which are both Washington, D.C.-based think tanks. That’s below the 50% peak during the Great Recession. They still obviously pay sales tax, property taxes and other taxes.
“The large percentage of people who don’t owe federal income tax is a feature, not a bug, of the revenue code,” according to the Tax Policy Center. “By design, the federal income tax always has excluded a significant fraction of households through a combination of personal exemptions, the standard deduction, zero bracket amounts, and more recently, tax credits.”
These workers who won’t owe any federal income tax include single people, married couples filing jointly and married individuals not filing jointly, said Gary Burtless, a senior fellow at the Brookings Institution. For the most part, they don’t earn enough money. However, many people who work and who don’t owe any federal income taxes still give money to Uncle Sam, because money comes out of their paychecks for Social Security and Medicare, he said.
“Many low- and below-average-income families pay more in payroll taxes every year than they pay in federal income taxes,” Burtless said. “This means you have to be careful describing the federal tax liabilities of U.S. families. The U.S. individual income tax is quite progressive, with much heavier tax liabilities as we move up the income distribution and very low or even negative income tax liabilities at the bottom of the income distribution.”
“Either their taxable incomes are below the threshold at which the tax unit’s ’taxable income’ exceeds zero,” he said, “or the taxpayer qualifies for refundable tax credits — such as the Earned Income Credit and/or the Child Tax Credit — that are greater than the amount federal income tax owed, in which case the tax filer receives a tax refund or owes no federal income tax liability. Much more rarely, high-income taxpayers have adopted tax strategies that occasionally eliminate their federal income tax liability.”

All but the top 20% of American families pay more in payroll taxes than in federal income taxes, according to Treasury Department data, cited by the Pew Research Center. “After all federal taxes are factored in, the U.S. tax system as a whole is progressive, according to Pew. “The top 0.1% of families pay the equivalent of 39.2% and the bottom 20% have negative tax rates. That is, they get more money back from the government in the form of refundable tax credits than they pay in taxes.”
On the other hand, payroll taxes are mildly regressive, Burtless said. “Individual earners do not pay any additional Social Security payroll taxes on earnings above $127,200 per year (in 2018),” he said. “The implication is that federal taxes overall are progressive, but they are far less progressive than the federal individual income tax system viewed all by itself.”
“The tax reform passed in December 2017 will no doubt affect the number of people and families who pay no federal individual income taxes and who pay no net federal income and payroll taxes,” Burtless added. The Tax Policy Center estimates that roughly one-third of workers who pay no federal individual income taxes receive a net refundable credits that covers their payroll taxes, including their employer’s share.
“About 60% of those who pay no income tax will work and owe payroll taxes,” according to Roberton Williams, an associate at the Tax Policy Center. “Most of the other 40% are retirees whose income is too low to owe income tax …Refundable credits make it possible for some low-income households with workers to avoid paying income and payroll taxes. Even so, nearly three-quarters of Americans will end up paying at least one of those taxes this year.”
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How uncontrolled inflammation leads to brain cell loss


In a study of inflammation mechanisms in the brain, researchers from the University of Bonn in Germany have identified how, as we get older, a vicious cycle of poorly regulated inflammatory responses leads to the loss of brain cells.
Recently, those researchers conducted a study that investigated the mechanisms that regulate inflammation in the brain, what happens when they stop working properly, and why that may happen.
The cannabinoid receptor type 1 (CB1), they say, plays an important role in processing the “rush” sensation produced by cannabis.
It also appears to be involved in the regulation of inflammatory reactions in the brain.
If CB1 receptors fail to respond, this contributes to the development of chronic inflammation, which can eventually lead to the loss of brain cells. So reports the study paper, now published in the journal Frontiers in Molecular Neuroscience.

‘Brake signals’ for inflammation

The researchers say that the immune response in the brain is mounted via microglial cells, a type of specialized immune cell found in the central nervous system, which includes the brain and the spinal chord.
Microglia work by responding to bacteria and clearing out malfunctioning nerve cells. At the same time, they send signals to recruit other types of immune cells and trigger inflammation when needed.
However, if unregulated, an inflammatory reaction in the brain can misguidedly attack and damage healthy brain tissue.
“We know that so-called endocannabinoids play an important role in this,” explains study co-author Dr. Andras Bilkei-Gorzo. “[Endocannabinoids],” he goes on, “are messenger substances produced by the body that act as a kind of brake signal: [t]hey prevent the inflammatory activity of the glial cells.”
These messenger substances act by binding to certain receptors, one of which is CB1. A second one is cannabinoid receptor type 2 (CB2).
Microglial cells have low levels of CB2, and even less, or no, CB1, the researchers explain. Still, these immune cells will react to endocannabinoids despite this lack.
“However, microglial cells have virtually no CB1 and very low level of CB2 receptors. They are therefore deaf on the CB1 ear. And yet they react to the corresponding brake signals — why this is the case, has been puzzling so far.”
Dr. Andras Bilkei-Gorzo

Neurons that ‘translate’ endocannabinoids

This is precisely the riddle that Dr. Bilkei-Gorzo and colleagues set out to solve in the current study. The investigation began with the observation that there is a certain group of neurons containing a large number of CB1 receptors.
The researchers worked with specially engineered mice, in which the CB1 receptors found in these neurons had been switched off.
Dr. Bilkei-Gorzo says, “The inflammatory activity of the microglial cells was permanently increased in these animals.” However, in mice with fully functioning CB1 receptors, inflammation was regulated as usual.
“Based on our results,” he says, “we assume that CB1 receptors on neurons control the activity of microglial cells.”
This has led the researchers to theorize that microglial cells do not communicate with other nerve cells directly. Instead, the scientists believe, microglial cells release endocannabinoids, and these bind to the CB1 receptors found in nearby neurons.
These neurons might be able to communicate with other nerve cells, and the immune response is thus indirectly regulated.
However, Dr. Bilkei-Gorzo and his team explain that with age, the production of endocannabinoids progressively decreases, leading to the improper regulation of immune responses and potentially to chronic inflammation.
“Since the neuronal CB1 receptors are no longer sufficiently activated, the glial cells are almost constantly in inflammatory mode,” says Dr. Bilkei-Gorzo.
“More regulatory neurons die as a result, so the immune response is less regulated and may become free-running,” he adds.

Can cannabis prevent brain aging?

The authors warn that, since the results were obtained in mice, they cannot yet be clearly extended to humans, and further research is needed to confirm that the same mechanisms apply.
Nevertheless, they are hopeful that, in the future, understanding these processes will mean that we will be able to develop drugs to act on them as necessary — particularly to prevent chronic inflammation.
Since the receptors activated to regulate inflammation are cannabinoid receptors, the team also suggests that cannabis may be a promising solution.
Tetrahydrocannabinol (THC), which is one of the main active substances in cannabis, is effective in activating CB1 — even when administered in low doses, the authors explain. This may help reduce inflammation and prevent the loss of brain cells.
Research conducted last year by the same scientists — alongside colleagues from other institutions across the world — also suggested that THC is able to restore cognitive function in the brains of aging mice, offering hope that the same may be possible for humans.
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