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Wednesday, March 11, 2020

‘Flattening the curve’ may be the world’s best bet to slow the coronavirus

For many countries staring down fast-rising coronavirus case counts, the race is on to “flatten the curve.”
The United States and other countries, experts say, are likely to be hit by tsunamis of Covid-19 cases in the coming weeks without aggressive public health responses. But by taking certain steps — canceling large public gatherings, for instance, and encouraging some people to restrict their contact with others — governments have a shot at stamping out new chains of transmission, while also trying to mitigate the damage of the spread that isn’t under control.
The epidemic curve, a statistical chart used to visualize when and at what speed new cases are reported, could be flattened, rather than being allowed to rise exponentially.
“If you look at the curves of outbreaks, they go big peaks, and then come down. What we need to do is flatten that down,” Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, told reporters Tuesday. “That would have less people infected. That would ultimately have less deaths. You do that by trying to interfere with the natural flow of the outbreak.”
The notion that the curve of this outbreak could be flattened began to gain credence after China took the extraordinary step of locking down tens of millions of people days in advance of the Lunar New Year, to prevent the virus from spreading around the country from Wuhan, the city where the outbreak appears to have started. Many experts at the time said it would have been impossible to slow a rapidly transmitting respiratory infection by effectively shutting down enormous cities — and possibly counterproductive.

But the quarantines, unprecedented in modern times, appear to have prevented explosive outbreaks from occurring in cities outside of Hubei province, where Wuhan is located.
Since then, spread of the virus in China has slowed to a trickle; the country reported only 19 cases on Monday. And South Korea, which has had the third largest outbreak outside of China, also appears to be beating back transmission through aggressive actions. But other places, notably Italy and Iran, are struggling.
For weeks, a debate has raged about whether the virus could be “contained” — an approach the WHO has been exhorting countries to focus on — or whether it made more sense to simply try to lessen the virus’ blow, an approach known as “mitigation.”
That argument has been counterproductive, Mike Ryan, the head of the WHO’s health emergencies program, said Monday.
“I think we’ve had this unfortunate emergence of camps around the containment camp, the mitigation camp — different groups presenting and championing their view of the world. And frankly speaking, it’s not helpful,” Ryan told reporters.
Caitlin Rivers, an assistant professor of epidemiology at the Johns Hopkins Center for Health Security, said any lessening of spread will help health systems remain functional.
“Even if we are not headed to zero transmission, any cases that we can prevent and any transmission that we can avoid are going to have enormous impact,” she said. “Not only on the individuals who end up not getting sick but all of the people that they would have ended up infecting. … And so the more that we can minimize it, the better.”
On any normal day, health systems in the United States typically run close to capacity. If a hospital is overwhelmed by Covid-19 cases, patients will have a lower chance of surviving than they would if they became ill when the hospital’s patient load was more manageable. People in car crashes, people with cancer, pregnant women who have complications during delivery — all those people risk getting a lesser caliber of care when a hospital is trying to cope with the chaos of an outbreak.
“I think the whole notion of flattening the curve is to slow things down so that this doesn’t hit us like a brick wall,” said Michael Mina, associate medical director of clinical microbiology at Boston’s Brigham and Women’s Hospital. “It’s really all borne out of the risk of our health care infrastructure pulling apart at the seams if the virus spreads too quickly and too many people start showing up at the emergency room at any given time.”
Countries and regions that have been badly hit by the virus report hospitals that are utterly swamped by the influx of sick people struggling to breathe.
Alessandro Vespignani, director of the Network Science Institute at Northeastern University, is gravely worried about what he’s hearing from contacts in Italy, where people initially played down the outbreak as “a kind of flu,” he said. Hospitals in the north of the country, which the virus first took root, are filled beyond capacity, he said, and may soon face the nightmarish dilemma of having to decide who to try to save.
“This was what was really keeping me up at night, to unfortunately see Italy approaching that point,” Vespignani said, adding that now that the country has effectively followed China’s example and put its population on lockdown, “hopefully this will work.”
Vespignani, along with colleagues, published a recent modeling study in Science that showed travel restrictions — which the United States has adopted to a degree — only slow spread when combined with public health interventions and individual behavioral change. He’s not convinced that people in the United States comprehend what’s coming.
“I think people are not yet fully understanding the scale of this outbreak and how dangerous it is to downplay,” he said.
Mina agreed: “Without a very clear signal coming from our government at the national level, it’s really just like a small trickle as people start to recognize that this is happening.”
Rivers and colleagues from Harvard’s T.H. Chan School of Public Health have looked at what U.S. hospitals might endure if Wuhan-scale spread occurred in this country. Their analysis, posted on a preprint server in advance of peer review, came to a chilling conclusion.
“If a Wuhan-like outbreak were to take place in a U.S. city, even with strong social distancing and contact tracing protocols as strict as the Wuhan lockdown, hospitalization and ICU needs from COVID-19 patients alone may exceed current capacity,” they wrote. “We don’t want to go that route,” Rivers told STAT. “So it’s the top priority right now that we bend the curve.”
As of Tuesday, the Centers for Disease Control and Prevention said there had been 647 cases and 25 deaths in the country. A website maintained by Johns Hopkins University — which is considered the go-to website for Covid-19 statistics — scrapes data from a variety of sources. It suggested late Tuesday afternoon that there had been 808 cases in the U.S. and 28 deaths. Most in the deaths have been in the Seattle area.
But the reality is that with state and local laboratories in the country still getting up to speed with how to test for this infection, the full extent of spread is not known.
Without that kind of data, public officials have been loath to take the types of measures that would help to flatten the country’s epidemic curve. Those measures include banning concerts, sporting events, and other mass gatherings, closing movie theaters, telling people who can telecommute to work from home, and potentially closing schools. (The jury is still out on how much school closures would help slow spread.)
“I think that in terms of the decision-makers, we are in a place right now where we don’t have the data we wish we had in order to inform these decisions,” Rivers said. “So what I think we’re seeing is decision-makers struggling to pull the trigger on these really big, impactful decisions without having a clear sense of the current status.”
“But we know from pandemic planning and previous experiences that the sooner we implement these measures, the more effective that they are,” she said.
Mina said the lack of evidence of widespread transmission in the country may be making people feel any aggressive step right now may be an overreaction. But this is precisely the time when public health measures of this sort can have an impact, he said.
“We are all wondering if our actions are melodramatic. And we’re feeling silly,” he said, noting people still feel self-conscious bumping elbows instead of shaking hands.
“But this is the problem, that people aren’t recognizing that we are at this moment and we can make a decision right now to flatten this curve by … being OK with wondering if we’re being melodramatic,” he said.
“Should we be canceling classes? Should we be canceling our flights? Should we not be shaking hands? All of these things are things that I want the public to keep wondering if we should be doing this. Because the moment we’re no longer wondering whether we should be doing it, it’s too late,” Mina said. “That means that we know we should be doing it. And that is a bad place to be.”
Why ‘flattening the curve’ may be the world’s best bet to slow the coronavirus

CDC developing serologic tests that may show full scope of US Covad-19 outbreak

The Centers for Disease Control and Prevention is developing tests that could provide public health officials crucial information about how broadly the coronavirus has spread in the United States, even among mild cases or people without symptoms, the agency’s director said Wednesday.
The serologic tests, which are different from the ones used to diagnose active infection, would allow researchers to test the blood of people who were not confirmed cases of Covid-19 in communities where the virus spread. They would be designed to look for signs that people have mounted an immune response after being exposed to the virus.
CDC Director Robert Redfield told Congress that the agency is working on two of these types of tests. “CDC has developed two serological tests that we’re evaluating right now so we can get an idea through surveillance what’s the extent of this outbreak, how many people really are infected,” he told a House panel. “That is being moved out now to do these extensive surveillance programs.”
Understanding the full scope of an outbreak would allow authorities to learn more about how the virus spreads. It would also provide a more accurate picture of the so-called infection fatality ratio, or, in layman’s terms, the percentage of cases that are fatal. The figure is arrived at by taking the number of deaths and dividing that by the number of cases, so if many thousands of cases are not accounted for, it can make a disease appear more lethal than it actually is.
Researchers in China and Singapore have also developed serologic tests and have initiated these types of studies, according to the World Health Organization. The agency has called on all countries with cases to conduct this kind of epidemiological work.
“These types of studies should be conducted now,” Maria Van Kerkhove, who heads WHO’s emerging diseases and zoonoses unit, recently told STAT. “This is one of the major things that needs to be done now. And everywhere. Not just in China. In the U.S., in Italy, in Iran — that would give us a better understanding of where this virus is and if we’re truly missing a large number of cases.”
She added: “Until we have population-based sero-surveys, we really don’t truly know.”
CDC developing serologic tests that could reveal full scope of U.S. coronavirus outbreak

NIH official: Big gatherings should be canceled due to coronavirus outbreak

Tony Fauci, the nation’s top infectious disease researcher, escalated his tone regarding the novel coronavirus outbreak during a congressional hearing Wednesday, suggesting that large gatherings across the country should be cancelled.
“The bottom line: It is going to get worse,” Fauci told lawmakers.
The remarks, during a hearing before the House Committee on Oversight and Government Reform, represented perhaps the sharpest advisory yet from a federal official regarding shifts Americans should prepare to make in their day-to-day lives.
“We would recommend that there not be large crowds,” Fauci said. “If that means not having any people in the audience where the NBA plays, so be it. But as a public health official, anything that has large crowds is something that would give a risk to spread.”
Fauci’s advisory follows a wave of major event cancellations. Sen. Bernie Sanders (I-Vt.) and former vice president Joe Biden each cancelled presidential campaign rallies in Cleveland on Tuesday on the advice of Ohio’s governor. Save for a mid-size event in Milwaukee next week, President Trump has not scheduled campaign rallies in the coming week. And in Southern California, the major music festivals Stagecoach and Coachella announced they would postpone the events until October.
Sports leagues have also hatched contingency plans. The Golden State Warriors have continued to stage basketball games at their San Francisco arena despite advice from public health officials there. Major League Baseball’s Seattle Mariners, whose season begins in two weeks, could also be forced to relocate games, The Athletic, a sports journalism website, reported.
In a press briefing Tuesday night, Fauci suggested Americans should consider reconfiguring their lives more broadly in an effort to prevent new exposures to the  coronavirus and the respiratory disease it causes, known as Covid-19.
“As a nation, we can’t be doing the kinds of things we were doing a few months ago,” he said. “It doesn’t matter if you’re in a state that has no cases or one case — you have to start taking seriously what you can do now, if and when the infections will come. And they will come. Sorry to say, sad to say, they will.”
At various points during the hearing, Fauci also appeared to contradict some of President Trump’s messaging surrounding the coronavirus.
“Nothing is shut down, life & the economy go on,” Trump tweeted on Monday, referencing annual influenza outbreaks. “At this moment there are 546 confirmed cases of CoronaVirus,with 22 deaths. Think about that!” Trump also said recently that he was  “shocked” to learn the flu kills tens of thousands of Americans each year.
Fauci, however, stressed that in his estimation, Covid-19 poses a dramatically greater risk to individuals who contract it than the flu does.
“The seasonal flu that we deal with every year has a mortality of 0.1%,” he said at the hearing. “The stated mortality, overall, of [the coronavirus], when you look at all the data including China, is about 3%.”
Fauci estimated that true mortality rate, given the number of cases that do not result in serious symptoms, as “somewhere around 1%, which means it is 10 times more lethal than the seasonal flu,” he said. “I think that’s something that people can get their arms around and understand.”
Fauci also expressed regret that the Trump administration had not moved to replace pandemic response staffers on the National Security Council who resigned or were fired. Trump has been criticized for firing and not replacing Tom Bossert, who served as the NSC’s homeland security advisor in 2018 and whose role included pandemic preparedness efforts.
Asked about the move, Fauci declined to directly criticize the Trump administration.
“I wouldn’t necessarily characterize it as a mistake,” Fauci said. “I was saying we worked very well with that office. It would be nice if that office was still there.”
NIH official suggests large gatherings should be canceled due to coronavirus outbreak

Parallax Health up 13% on planned coronavirus test

Thinly traded nano cap Parallax Health Sciences (OTCPK:PRLX +13%) is, yet another, would-be player in the mad dash for a rapid screening test for COVID-19.
Today, it announced that subsidiary Parallax Diagnostics intends to in-license and develop monoclonal and polyclonal antibodies for such a test based on its VT-1000 immunoassay platform. Available resources appear to be an issue since it is seeking partners to accelerate the development.
Test-related tickers: Aytu BioScience (AYTU -17.3%), Co-Diagnostics (CODX +63.6%), Thermo Fisher Scientific (TMO -4.7%), Abbott (ABT -3.8%), Roche (OTCQX:RHHBY N/A), Chembio Diagnostics (CEMI -1.3%), Becton, Dickinson (BDX -2.7%), Luminex (LMNX -2.9%)
https://seekingalpha.com/news/3550582-parallax-health-up-13-on-planned-coronavirus-test

As pressure for coronavirus vaccine grows, risks of accelerated tests debated

Drugmakers are working as quickly as possible to develop a vaccine to combat the rapidly spreading coronavirus that has infected more than 100,000 people worldwide.
Behind the scenes, scientists and medical experts are concerned that rushing a vaccine could end up worsening the infection in some patients rather than preventing it.
Studies have suggested that coronavirus vaccines carry the risk of what is known as vaccine enhancement, where instead of protecting against infection, the vaccine can actually make the disease worse when a vaccinated person is infected with the virus. The mechanism that causes that risk is not fully understood and is one of the stumbling blocks that has prevented the successful development of a coronavirus vaccine.
Normally, researchers would take months to test for the possibility of vaccine enhancement in animals. Given the urgency to stem the spread of the new coronavirus, some drugmakers are moving straight into small-scale human tests, without waiting for the completion of such animal tests.
“I understand the importance of accelerating timelines for vaccines in general, but from everything I know, this is not the vaccine to be doing it with,” Dr Peter Hotez, dean of the National School of Tropical Medicine at Baylor College of Medicine, told Reuters.
Hotez worked on development of a vaccine for SARS (Severe Acute Respiratory Syndrome), the coronavirus behind a major 2003 outbreak, and found that some vaccinated animals developed more severe disease compared with unvaccinated animals when they were exposed to the virus.
“There is a risk of immune enhancement,” said Hotez. “The way you reduce that risk is first you show it does not occur in laboratory animals.”
Hotez testified last week before the U.S. House Committee on Science, Space and Technology about the need for sustained funding for vaccine research. There remains no vaccine for any of the new coronaviruses that have caused outbreaks in the past 20 years.
At least for now, the world’s experts have concluded that accelerated testing is a risk worth taking.
At a specially convened World Health Organization (WHO) meeting in mid-February, designed to co-ordinate a global response to the new coronavirus, scientists representing government-funded research organizations and drugmakers around the world agreed that the threat was so great that vaccine developers should move quickly into human trials, before animal testing is completed, four people who attended the meeting told Reuters.
“You want to have a vaccine as quickly as possible,” Dr Marie-Paule Kieny, former assistant director-general at the WHO, who co-chaired the meeting, told Reuters. “You have to balance this with the risk that you impose on a very small number of people, and do all you can do to mitigate this risk as much as possible.”
The conclusion of that meeting, which was not open to media, has not been officially publicized by the WHO. It does not reflect any official position adopted by the WHO, a United Nations body whose job it is to help shape global health policy.
Regulatory oversight of drugmakers and medical research is in the hands of national regulators. The most powerful of those, the U.S. Food and Drug Administration (FDA), has signaled that it is in agreement with the consensus and will not stand in the way of accelerated testing schedules.
“When responding to an urgent public health situation such as novel coronavirus, we intend to exercise regulatory flexibility and consider all data relevant to a certain vaccine platform,” FDA spokeswoman Stephanie Caccomo said in a statement. The agency had no comment specifically on animal testing for vaccine enhancement.
Coronavirus vaccine developers are still required to conduct routine animal testing to make sure the vaccine itself is not toxic and is likely to help the immune system respond to the virus.

SEATTLE RISK

Some 20 coronavirus vaccine candidates are being developed by research institutes and drugmakers including America’s Johnson & Johnson and France’s Sanofi SA. The U.S. government has earmarked more than $3 billion for coronavirus treatments and vaccines.
Biotechnology company Moderna Inc, which is working with the U.S.-funded National Institutes of Health (NIH), is the closest to human testing, announcing plans to start a trial with 45 people in Seattle this month.
Testing for the specific risk of vaccine enhancement in animals will proceed simultaneously with human trials, the NIH told Reuters, which it said should establish whether it is safe to expose larger numbers of people to the vaccine. Moderna did not respond to requests for comment.
The plan is consistent with the WHO consensus and FDA requirements, said Dr Emily Erbelding, director of the Division of Microbiology and Infectious Diseases of the National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH. The trial is expected to take 14 months, a spokeswoman for the NIH said.
Dr Gregory Poland, a virologist and vaccine researcher with the Mayo Clinic in Rochester, Minnesota, expressed doubts about that approach. “This is important, but it has to be done in a way that reassures scientists and the public that these (vaccines) are not only efficacious, but safe,” he told Reuters.
Hotez said he was surprised human trials were going ahead. “If there is immune enhancement in laboratory animals vaccinated with the Moderna vaccine, that’s a showstopper,” he said.
U.S. immunotherapy company Inovio Pharmaceuticals Inc, which is developing a coronavirus vaccine in collaboration with a Chinese company, also expects to start human clinical trials in 30 U.S. volunteers in April rather than wait for animal studies on vaccine enhancement.
“The community as a whole weighed that and said we don’t want to delay the clinical process. We’ve been encouraged to go as rapidly as possible into Phase 1 studies,” Inovio Chief Executive Joseph Kim told Reuters.
The company plans to start human safety trials shortly thereafter in China and South Korea – two countries that have been hit hard by the virus. Kim said he expects to have an answer to the question of vaccine enhancement at some point this year.
The Moderna/NIH trial is enrolling patients at the Kaiser Permanente Washington Health Research Institute in Seattle. The choice of location, made several weeks ago, could prove to be problematic.
To reduce the risk to volunteers, scientists at the WHO meeting recommended that drugmakers restrict early clinical trials to small groups of healthy people and conduct them in places where the virus is not spreading, according to Kieny, who now works at French research institute Inserm. That lowers the chances that people who get the vaccine could encounter the virus and trigger a more severe reaction.
Since the location was chosen, the Seattle metro area has emerged as the epicenter of infections in the United States. Washington state has reported 162 coronavirus infections and 22 deaths, out of a total of 755 infections and 26 deaths in the country as of Tuesday, according to a tally by Johns Hopkins University.
Nevertheless, Moderna and the NIH plan to go ahead.
“We think there is no reason to have to change the site. If you change it, there might be community transmission in another site over the next couple of weeks,” Erbelding said. “Any risk of that to participants is very small. It would be manageable as the trial progresses. People are being observed very, very carefully.”

EARLY WARNING SIGNS

Tragic lessons from other vaccines and prior work on coronaviruses have raised some warning flags for developers.
The best-known example occurred in a U.S. trial in the 1960s of a vaccine created by the NIH and licensed to Pfizer Inc to fight respiratory syncytial virus (RSV), which causes pneumonia in infants. The vast majority of babies who received the vaccine developed more severe disease, and two toddlers died. A more recent example occurred in the Philippines, where some 800,000 children were vaccinated with Sanofi’s dengue vaccine, Dengvaxia. Only afterward did the company learn that it could increase the risk of more severe disease in a small percentage of individuals.
Research, including that conducted by Hotez, has shown that coronaviruses in particular have the potential to produce this kind of response. But testing for the risk of vaccine enhancement is time-consuming because it requires scientists to breed mice that are genetically altered to respond to the virus like humans. Work on these and other animal models is just getting under way in several laboratories around the world.
Moderna, Inovio and several other vaccine developers are not waiting for that process to be completed and are planning to launch human trials in record time for a virus that was only discovered in December.
Both Moderna and Inovio say their vaccines are likely to have a lower risk of vaccine enhancement because they are made using newer technology that focuses on specific genes on the outer ‘spike’ portion of the virus. Coronavirus vaccines that caused vaccine enhancement were typically made using an inactivated version of the entire virus. Neither company has produced a licensed vaccine to date.
J&J said it is developing animal models to test for vaccine enhancement and hopes to have a vaccine candidate ready for human trials in October. A Sanofi spokeswoman said the company will examine this risk before testing the vaccine in clinical trials.
“People know how traumatic the RSV experience was,” said Dr Johan Van Hoof, global head of Janssen Vaccines, J&J’s vaccine unit. “When you see signals in animals like this, we should not ignore them.”
https://www.reuters.com/article/us-health-coronavirus-vaccines-insight/as-pressure-for-coronavirus-vaccine-mounts-scientists-debate-risks-of-accelerated-testing-idUSKBN20Y1GZ

Tiziana Life Sciences up on potential coronavirus treatment

Thinly traded nano cap Tiziana Life Sciences (NASDAQ:TLSA) is the latest coronavirus play. Shares are up on average volume in reaction to its announcement that candidate TZLS-501 may be a potential treatment for COVID-19 patients at risk of respiratory failure.
The company says it plans to administer TZLS-501, an interleukin 6 (IL-6)-inhibiting monoclonal antibody, using a proprietary formulation technology, adding that excess production of IL-6 is a key driver of chronic inflammation and is believed to play a key role in severe lung damage seen with COVID-19 infection and acute respiratory illness.
https://seekingalpha.com/news/3550476-tiziana-life-sciences-up-306-premarket-on-potential-coronavirus-treatment

Kamada up 4% on development of coronavirus treatment

Thinly traded micro cap Kamada Ltd. (KMDA +3.8%) is up on almost a 6x surge in volume, albeit on turnover of only 344K shares, in reaction to its announced plan to develop an immunoglobulin against the coronavirus causing the current outbreak.
The company will produce the IgG antibody product from plasma derived from donors who have recovered from coronavirus infection, including SARS-CoV-2.
It cautions that the product will be highly dependent on the availability of hyperimmune plasma and the regulatory pathway.
https://seekingalpha.com/news/3550554-kamada-up-4-on-development-of-coronavirus-treatment