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Monday, March 15, 2021

SARS-CoV-2 hijacks two key metabolic pathways to rapidly replicate in host cells

 When SARS-CoV-2, the virus that causes COVID-19, infects a human cell, it quickly begins to replicate by seizing the cell's existing metabolic machinery. The infected cells churn out thousands of viral genomes and proteins while halting the production of their own resources. Researchers from Brigham and Women's Hospital, Massachusetts General Hospital (MGH), and the Broad Institute, studying cultured cells shortly after infecting them with the virus, now have more insight into the metabolic pathways co-opted by the virus. The findings, published in Nature Communications, highlight the potential therapeutic benefit of drugs such as methotrexate, which inhibit folate and one-carbon metabolic pathways appropriated by the virus.

"One of the things we're lacking in this pandemic is a pill that can be taken orally, as a prophylactic agent, before someone is hospitalized or even before they're infected," said corresponding author Benjamin Gewurz, MD, Ph.D., of the Division of Infectious Diseases. "Monoclonal antibodies have a lot of promise but need to be given intravenously. Blocking the metabolism pathways that viruses rely on to replicate could be a new strategy for treating patients at an early timepoint."

To identify which  to target, the researchers obtained samples of the  and cultivated them in a highly protected facility called a BSL-3 laboratory, located at the Broad Institute. They then paired up with the laboratory of co-senior author Vamsi Mootha, MD, of MGH, to apply mass spectrometry approaches to identify the resources being consumed and produced by  and . They studied the infected  at an "eclipse point," eight hours after infection, when the virus has begun manufacturing its RNA and proteins but has not yet exerted a serious effect on host cell growth and survival.

In analyzing the  and thousands of chemical metabolites produced by the cells, the researchers observed that infected cells had depleted stores of glucose and folate. They demonstrated that the SARS-CoV-2 virus diverts  from glucose production to the assembly of purine bases, which are necessary for creating large amounts of viral RNA. Additionally, they found that the 1-carbon pathway used to metabolize folate was hyperactive, thus supplying the virus with more carbon groups for making bases for DNA and RNA.

Drugs that inhibit folate metabolism, like methotrexate, are often used to treat autoimmune conditions like arthritis and could be therapeutic candidates for COVID-19. Methotrexate is currently being assessed as a treatment for the inflammation that accompanies more advanced COVID-19 infections, but the researchers suggest that it could also be beneficial early on. Their study also found that it could offer a synergistic effect when administered with the anti-viral drug remdesivir. Methotrexate's immune-suppressing properties could make its proper administration as a prophylactic challenging, however. Researchers would need to determine how to maximize the drug's antiviral effects without significantly compromising a patient's natural immune response.

Still, Gewurz points out that oral antivirals are an important addition to an arsenal of therapies for COVID-19, serving both as an immediate treatment for infection as well as a defense against new variants and other coronaviruses.

"We're hoping that, ultimately, we can find a way of preventing viruses from using cells' metabolism pathways to replicate themselves because that could limit the ability of viruses to evolve resistance," Gewurz said. "We're starting to see new viral variants, and we're hoping that we can stay ahead of that—treating patients before the virus has the chance to make copies of itself that could become resistant to antibodies."

More information: Yuchen Zhang et al, SARS-CoV-2 hijacks folate and one-carbon metabolism for viral replication, Nature Communications (2021). DOI: 10.1038/s41467-021-21903-z

https://medicalxpress.com/news/2021-03-sars-cov-hijacks-key-metabolic-pathways.html

How well do COVID vaccines protect after organ transplant?

 A new study raised questions about how well COVID-19 vaccines protect organ transplant recipients—and what precautions people with suppressed immune systems should take after the shots.

Vaccines rev up the immune system to recognize the virus, something that's harder to do if someone's immune cells aren't in good working order. Transplant recipients take powerful immune-suppressing drugs to prevent organ rejection, which also increases their risk from the coronavirus—but excluded them from vaccine studies.

Specialists say the shots appear safe for  and any protection is better than none. But how much protection do they get?

On Monday, researchers at Johns Hopkins University reported a first attempt to find out. They tested 436 people who had received new organs in recent years and were getting the Pfizer or Moderna vaccines. A few weeks after the first dose, 17% of the transplant recipients had developed antibodies against the coronavirus, said Dr. Dorry Segev, a Hopkins transplant surgeon who co-authored the study.

Segev acknowledged transplant recipients may fare better after the needed second dose—he'll also check that—but prior studies show the first shot is enough to kickstart antibody production in just about everybody with a well-functioning .

Of most concern, people whose transplant medications include a type called an anti-metabolite were far less likely to respond to the shot than those who don't require that kind of drug, the team reported in the Journal of the American Medical Association.

The findings come after the U.S. Centers for Disease Control and Prevention said fully vaccinated people can relax some, but not all, of the masking and distancing precautions against the coronavirus.

Segev called on CDC to consider a more nuanced message.

"From what we know, transplant patients cannot assume that they are safe after being vaccinated," Segev said. They may need post-vaccination blood tests to be sure, he added.

The CDC didn't immediately comment.

Dr. David Mulligan, Yale University's chief of transplant surgery and immunology, said Monday's report is a disappointment but not a surprise, because people with weak immune systems don't respond as well to other vaccines.

Some transplant groups, including the American Society of Transplantation, already have issued cautions about that.

Yale's Mulligan urged patients to check in with their transplant center for advice. Those waiting for a life-saving organ transplant might be able to get vaccinated first. He said some people who've already had a  might be good candidates to temporarily cut back on certain immune-suppressing drugs. And the immune-compromised should be sure to get both  doses for the best chance at protection.

"Our patients are already calling" for advice, Mulligan said. "Until you've had your antibodies checked and you know, boy, I've got a vigorous immune response—or we've got better data," the immune-compromised shouldn't let down their guard against the virus.


Explore further

Study indicates COVID-19 vaccines are safe for organ transplant patients
https://medicalxpress.com/news/2021-03-covid-vaccines-transplant.html

White House billion-dollar campaign aimed at convincing every American to get vaccinated

 The White House will soon unveil a wide-reaching public relations campaign aimed at boosting vaccine confidence and uptake across the U.S., Biden administration aides told STAT.

This television, radio, and digital advertising blitz, set to kick off within weeks, will focus on Americans outright skeptical of vaccines’ safety or effectiveness as well as those who are potentially more willing to seek a Covid-19 immunization but don’t yet know where, when, or how. Specifically, the campaign will target three groups in which access, apathy, or outright skepticism may pose a barrier to vaccinations: young people, people of color, and conservatives, according to a Biden aide. Congress and the administration have set aside over $1.5 billion for the effort.

The effort highlights a looming and underappreciated public health challenge: Though millions of Americans are currently clamoring to receive a Covid-19 vaccine, in a few short months, or even weeks, the opposite may be true. Instead of scrambling to manufacture doses, the government may soon be scrambling to find arms willing to receive them.

While the administration Covid response advisers organizing the effort are broadly optimistic, they and many public health experts fear that without winning buy-in from a critical, final slice of the population, the effort could fall short of its goal: effectively ending the country’s coronavirus crisis.

“I’m worried about the 15% of Americans who say they will not take the vaccine,” said Sten Vermund, the dean of the Yale School of Public Health. “And about 8% or 9% of Americans say, ‘I will take it if they make me, if my job forces me to.’ So that’s about 23% or 24%, and that’s flirting with the level we need to get to herd immunity.”

The rollout fulfills one of Biden’s first promises in office. He pledged on Jan. 21 to kick off an “unprecedented vaccination public health campaign” aimed at convincing every American adult to seek a Covid-19 immunization.

As for the specific content, administration officials said they were mindful that appeals directly from President Biden or Anthony Fauci are not likely to sway vaccine-hesitant people. As a result, they are expected to recruit both celebrities and trusted local officials to advance the pro-vaccine message.

Dorit Reiss, a law professor at the University of California, Hastings, whose research focuses on vaccine policy and ethics, explained why Biden and his lieutenants may not always be the best suited to spread the word.

“Messaging from the Biden administration might not be where conservative communities would look for guidance,” she said. “It’s community leaders that you want to get on board, and it might be better for the federal government to provide funding for a variety of willing community leaders to address those communities instead.”

To that point, the plan includes a major emphasis on community-level messaging: Federal officials have already allocated more than $500 million for local efforts to recruit local leaders and community organizations to encourage vaccine uptake and ensure racial equity in the vaccine distribution effort.

On a national level, White House officials declined to share details of what form many of the ads will take, or, in particular, whose voices they’ll highlight. But in a hint of the strategy, top administration officials have been already deployed to spread the word. Vice President Kamala Harris, the first Black and South Asian woman elected to the White House, has spent much of the past three weeks conducting in-person outreach, TV appearances, and radio interviews, in many cases geared specifically toward boosting vaccine uptake in Black communities.

Convincing Americans that the current vaccines are safe and effective, experts say, could make the difference between a country with widespread immunity and one in which the disease continues to spread, albeit more slowly.

It is already clear that the White House is not deploying a one-message-fits-all strategy. Marcella Nunez-Smith, the Yale physician-researcher advising Biden on health equity, appeared last month on The Shade Room, an online outlet geared toward Black viewers, and Anthony Fauci, the top government infectious diseases researcher, has conducted interviews with several Spanish-language news and entertainment outlets. 

The administration has even deployed Francis Collins, the longtime director of the National Institutes of Health, to address one of the demographics that early surveys show is most likely to decline a Covid-19 vaccination: white, conservative, evangelical Christians. (According to a recent Marist poll, the three most vaccine-hesitant demographics are supporters of former President Donald Trump, Republicans, and white evangelical Christians, at 47%, 41%, and 38% likely to decline a vaccine, respectively.) 

A devout Christian himself, Collins cast the vaccines as a gift from God in an interview with the Christian Broadcasting Network, and stressed that the Catholic Church has endorsed the use of Johnson & Johnson’s vaccine despite its use of a cell line that originated from an abortion procedure decades ago. 

The White House’s announcement of the PR blitz will come just days after it decreed that by May 1, all state and local governments would be required to make all American adults eligible to sign up for vaccine appointments. The U.S. is currently administering over 2 million doses daily. Just over 10% of the population is fully vaccinated, and roughly 20% has received at least one vaccine dose.

But even as the vaccine rollout continues, some experts have fretted that when it comes to the PR campaign, there’s no time to waste. 

“I think President Biden is right that by May, there will be enough vaccines for anyone who wants them, and we’ll start looking to people who don’t,” Reiss said. “I don’t think we can wait. It’s not that long.” 

In recent weeks, White House aides including Nunez-Smith and Cameron Webb, another physician advising Biden’s pandemic response on equity issues, have workshopped the plan with the Department of Health and Human Services, the Centers for Disease Control and Prevention, and local community leaders.

“I’ve been hosting roundtables with key constituencies to make sure that we get that effort right,” Nunez-Smith said during a press briefing last week. “We’re building relationships with trusted messengers, all over the country, to make sure they have the best information possible to share with their communities.”

Congress and the administration have pledged major resources for the effort.

Much of the project’s funding comes from the sweeping $1.9 trillion Covid-19 relief bill Biden signed last week.

The administration has also already pledged over $500 million in additional funds to address vaccine uptake, health literacy, and equity in the vaccine distribution, including $250 million to fund local health literacy projects and another $255 million for the CDC to fund local government efforts to focus on equity and confidence in underserved communities.

Upon taking power in January, the administration also inherited a third funding stream meant for Covid-19 mitigation and prevention efforts: a $250 million contract that the Trump administration inked with the Virginia-based PR firm Fors Marsh months ago. That campaign, which began under President Trump and has continued under the Biden administration, has helped to fund Spanish-language radio commercials, ads in newspapers serving the Black community, and other Covid-19 mitigation outreach work.

Taken together, federal efforts to promote vaccine uptake total nearly $2 billion.

The Biden administration will also have backup from the nonprofit world. It’s working with the Ad Council, a nonprofit agency that has partnered with the government on PSAs meant to reduce drug and tobacco use, on a $50 million campaign meant to sell Americans on vaccine safety and effectiveness. The Creative Coalition, another nonprofit, has also won buy-in from a collection of celebrities, corporate executives, and prominent public health figures for its own vaccine-focused campaign.

Those campaigns have largely relied on the same strategies foreshadowed by Biden aides. Much of the Ad Council’s early effort, which consists of TV commercials, radio and print ads, and digital messaging, has stayed away from celebrities but nonetheless focused on Black and Spanish-speaking communities.

At a virtual kickoff dinner for the Creative Coalition campaign, meanwhile, Rochelle Walensky, the CDC director, said it would seek to “harness the power of influencers in building vaccine confidence.” Fauci called celebrities’ ability to build vaccine trust “extraordinary.”

In light of recent data, however, public health experts and Biden officials acknowledge that messaging to white conservatives — in other words, those least likely to view the new administration as credible — might pose the biggest hurdle to achieving true, population-wide immunity.

“When Magic Johnson said: ‘I have HIV, I got tested, and I am going to keep my family safe, I’m going to take antiretroviral drugs,’ we saw HIV testing rates go up the day after his announcement,” said Vermund, the Yale public health dean, who is advising the Creative Coalition effort. “It may take Donald Trump as a celebrity, saying, ‘I got the vaccine, I feel great.’ It may take a different kind of celebrity to reach the conspiracists and the anti-vax folks who are militant in that space.” (On Sunday, Fauci called for Trump to encourage his supporters to get vaccinated, calling such a message a potential “game-changer.”)

The messaging and public health experts behind the federal campaign and both nonprofit efforts have recognized, however, that their initiatives carry an inherent obstacle: Regardless of which community they’re addressing, a brief word from a celebrity or politician is unlikely to be effective on its own.

Part of the Creative Coalition’s mission, said the group’s CEO, Robin Bronk, is to recognize the ineffectiveness of simply parachuting into communities for a one-off celebrity cameo — a message she said the nonprofit and federal efforts would do well to bear in mind.

“We call it ‘red carpet-bagging,’ meaning that if you blow in and blow out for something, it’s not authentic, and it’s going to do more damage to the issue,” Bronk said. “Sometimes we don’t get involved in issues, particularly because getting the Hollywood community into it would do more harm than good. It’s not just throwing a celebrity up getting an arm jabbed — we have to be thoughtful.”

https://www.statnews.com/2021/03/15/white-house-unveil-a-wide-reaching-billion-dollar-campaign-convincing-every-american-to-get-vaccinated/

Mexico focuses vaccine loan request on U.S. stockpile of AstraZeneca doses

 Mexico has asked the United States to share doses of AstraZeneca's COVID-19 vaccine it has in stock, a senior diplomat said, following up on a request made by President Andres Manuel Lopez Obrador to his counterpart Joe Biden.

Deputy foreign minister for multilateral affairs Martha Delgado said that since the United States had not yet approved the AstraZeneca vaccine it would be a good candidate to offer to Mexico, which has started using it already.

"The possibility exists of being able to have access to some AstraZeneca batches they have," Delgado said in an interview with Reuters late last week, saying Mexico had made the request in diplomatic conversations since Lopez Obrador spoke to Biden on March 1.

"That vaccine is already authorized in Mexico, but doesn't have authorization at the moment in the United States," she said. "They could release it."

Lopez Obrador asked Biden for a vaccine "loan" during the virtual meeting, after Mexico's vaccine strategy was knocked off course by a delay in deliveries of the vaccine developed by Pfizer Inc and German partner BioNTech SE.

Delgado, who leads Mexico's diplomatic effort to get vaccine supplies, said the United States had not said whether it would meet the request for AstraZeneca and other vaccines, which she said included those from Moderna Inc and Novavax Inc . The Novavax shot also is not yet authorized in the United States.

A U.S. official, who asked not to be named, said the United States had not agreed to loans or distributions of AstraZeneca vaccines at this time. The person said the United States was not currently in a position to share doses but had already committed to doing so once the supply issue is dealt with domestically.

The U.S. State Department referred inquiries to the Mexican government and vaccine companies. The White House did not immediately respond to requests for comment.

A top U.S. health official told Reuters on Monday that AstraZeneca's vaccine could be authorized by U.S. regulators in about a month.

The request for AstraZeneca doses is notable because the British-developed drug is the backbone of Mexico's vaccine strategy, under a shared production deal with Argentina in which Mexico is due to bottle the doses for Latin America.

'MEXICO WILL NEVER FORGET'

Delays in the Mexican regulatory process mean the first doses will now not be shipped until the first week of May, Delgado said. Originally, the hope was for production by March, which had already slipped into April.

Delgado said Mexican diplomats also had to overcome delays in delivery of laboratory filters essential for vaccine production from U.S. drugmaker Merck & Co. That situation has not affected the production timeline, she said.

Under the deal with Argentina, the vaccine is produced in bulk in the South American country and shipped to Mexico for bottling. Two shipments of 6 million doses each were sent in January and early February.

Last month, Spanish newspaper El Pais reported that delays at the Mexican laboratory, Liomont, led the Argentine manufacturer to divert the equivalent of 12.8 million doses of vaccine material to a U.S. AstraZeneca bottler.

Delgado said she was not aware of such a diversion, adding that a new shipment from Argentina was due to arrive in Mexico "very soon."

A senior Argentine government official denied vaccine material was sent to the United States.

"There is no plan of sending them to other places. What did happen is that the U.S. was not exporting some goods that the Mexican lab needed to finish the process," the official said, requesting anonymity to speak freely.

The delays in U.S. and European vaccines have pushed Mexico toward deals with Russia and China.

China offered vaccines quickly, whereas Western countries had prioritized their own populations, leaving developing economies in the lurch, Delgado said.

She said the U.S. situation was understandable given the scale of the pandemic there, adding that the assistance from China would be long remembered.

"Mexico will never forget the countries that helped us," she said.

https://www.marketscreener.com/quote/stock/ASTRAZENECA-PLC-4000930/news/Mexico-focuses-vaccine-loan-request-on-U-S-stockpile-of-AstraZeneca-doses-32691376/

NYC keeping 24/7 vaccine centers open, despite state hours decreasing

 New York City will continue running its 24/7 vaccination sites, despite the state ending overnight vaccinations at the Javits Center last week.


The state was offering Johnson & Johnson shots overnight at the Javits Center when there was supply.

Supply decreased, and the site is back to its normal hours of 8 a.m. to 7 p.m.

"We have a couple of different things we have to achieve simultaneously. We've got to get the vaccines out to all communities, particularly the communities hardest hit. We've got to get the most grassroots," Mayor de Blasio said. "But the bottom line is the supply problem. If we had the supply, we'd be running a lot of places 24/7.

"We know that for essential workers, having hours early in the morning, late in the day and overnight, those are critically important as well to make sure people are able to access vaccination in a way that is convenient for them," Dr. David Chokshi said.

Mayor de Blasio said he's looking forward to getting vaccinated with the one dose Johnson & Johnson vaccine "very soon."

So far, more than 2.8 million New Yorkers have received their vaccine.

On Monday, the mayor announced a new initiative to reach homebound New Yorkers and those with disabilities so they will be able to vaccinated in their homes.

Also, for the first time in months, the daily COVID hospitalizations in New York City were below the threshold of 200 at 154.

But, the other indicators were still above their thresholds with daily positive cases at 3,123 and a 7-day positivity average of 6.16%.

Sunday marked one year since the first coronavirus death at a New York City hospital. Since then, nearly 30,000 New Yorkers have died.

Vaccine appointments available to all in Mississippi March 16

 All Mississippians will be eligible for COVID vaccine appointments beginning Tuesday, Mississippi Gov. Tate Reeves said Monday.

Reeves said almost 10,000 appointments would be available statewide over the next three weeks.

“Starting tomorrow, ALL new appointments will be open to ALL Mississippians. Get your shot friends – and let’s get back to normal!” Reeves wrote on Twitter.

Solid Biosciences Reports Efficacy and Safety Data from Duchenne Trial

  Interim data from six patients provide evidence of a potential benefit of SGT-001 in functional endpoints of North Star Ambulatory Assessments (NSAA), 6-minute walk test (6MWT), pulmonary function tests (PFTs), and clinically validated patient reported outcome measures (PROMs) -

- Patient 7, safely dosed with SGT-001, experienced transient and manageable adverse events, none of which were serious; six patients previously dosed showed no new drug-related safety findings 17-37 months post dosing; screening and enrollment of patients into IGNITE DMD continue -

- Presentations to follow at the 2021 Muscular Dystrophy Association (MDA) Virtual Clinical & Scientific Conference -

- Company to host conference call and webcast today at 4:30 PM ET to discuss clinical data and financial results -

Conference Call Today at 4:30 PM ET
Management will host a webcast and conference call to review the IGNITE DMD data and will take questions on this data and Solid’s financial results, today at 4:30 PM ET.

A live webcast of the call will be available on the Company's website at www.solidbio.com under the “News & Events” tab in the Investor Relations section, or by clicking here. Participants may also access the call, by dialing 866-763-0341 for domestic callers or 703-871-3818 for international callers, referencing conference ID# 1669808.

The archived webcast will be available for in the “News and Events” section of the Company's website.

https://www.globenewswire.com/news-release/2021/03/15/2193181/0/en/Solid-Biosciences-Reports-Efficacy-and-Safety-Data-from-the-Ongoing-IGNITE-DMD-Clinical-Trial-and-Resumption-of-Patient-Dosing-in-the-2E14-vg-kg-Cohort.html