Canada, US are easing pandemic border-crossing restrictions

 Pandemic restrictions on travel between Canada and the U.S. began to loosen Monday for some Canadians, and Prime Minister Justin Trudeau said plans to totally reopen the border would be announced over the next few weeks.

Canadian citizens and permanent residents who have had a full dose of a coronavirus vaccine approved for use in Canada can skip a 14-day quarantine that has been a requirement since March 2020. Eligible air travelers also no longer have to spend their first three days in the country at a government-approved hotel.

Restrictions barring all non-essential trips between Canada and the United States, including tourism, will remain in place until at least July 21.

Trudeau said the easing of the rules marks a "big step″ toward re-opening the border.

"We're very hopeful that we're going to see new steps on reopening announced in the coming weeks," he said at a news conference in Sault Ste. Marie, Ontario. "We're going to make sure that we're not seeing a resurgence of COVID-19 cases because nobody wants to go back to further restrictions, after having done so much and sacrificed so much to get to this point."

Julia Dunn, who landed at Toronto's Pearson International Airport from the United States while on her way to Halifax, said she was glad the restrictions had eased.

"It's very freeing being able to get home to family without having to spend those two weeks alone,″ she said.

Dunn, who is originally from Cape Breton but now lives in Houston, said she booked her trip to Canada after learning about the planned easing of quarantine rules a few weeks ago.

Trudeau said he understands how eager people are to see the border reopen but noted that the pandemic continues and "things aren't normal yet."

"Nobody wants us to move too fast and have to reimpose restrictions as case numbers rise like we're seeing elsewhere in the world,″ he said. ``We need to do this right."

https://medicalxpress.com/news/2021-07-canada-easing-pandemic-border-crossing-restrictions.html

Inhaled COVID-19 vaccine prevents disease and transmission in animals

 In a new study assessing the potential of a single-dose, intranasal COVID-19 vaccine, a team from the University of Iowa and the University of Georgia found that the vaccine fully protects mice against lethal COVID-19 infection. The vaccine also blocks animal-to-animal transmission of the virus. The findings were published July 2 in the journal Science Advances.

"The currently available vaccines against COVID-19 are very successful, but the majority of the world's population is still unvaccinated and there is a critical need for more vaccines that are easy to use and effective at stopping disease and transmission," says Paul McCray, MD, professor of pediatrics-pulmonary medicine, and microbiology and immunology at the UI Carver College of Medicine, and co-leader of the study. "If this new COVID-19 vaccine proves effective in people, it may help block SARS-CoV-2 transmission and help control the COVID-19 pandemic."

Unlike traditional vaccines that require an injection, this vaccine is administered through a nasal spray similar to those commonly used to vaccinate against influenza. The vaccine used in the study only requires a single dose and it may be stored at normal refrigerator temperatures for up to at least three months. Because it is given intranasally, the vaccine may also be easier to administer, especially for those who have a fear of needles.

"We have been developing this vaccine platform for more than 20 years, and we began working on new vaccine formulations to combat COVID-19 during the early days of the pandemic," says Biao He, Ph.D., a professor in the University of Georgia's Department of Infectious Diseases in the College of Veterinary Medicine and co-leader of the study. "Our preclinical data show that this vaccine not only protects against infection, but also significantly reduces the chances of transmission."

The experimental vaccine uses a harmless parainfluenza virus 5 (PIV5) to deliver the SARS-CoV-2 spike protein into cells where it prompts an immune response that protects against COVID-19 infection. PIV5 is related to common cold viruses and easily infects different mammals, including humans, without causing significant disease. The research team has previously shown that this vaccine platform can completely protect experimental animals from another dangerous coronavirus disease called Middle Eastern Respiratory Syndrome (MERS).

The inhaled PIV5 vaccine developed by the team targets mucosal cells that line the nasal passages and airways. These cells are the main entry point for most SARS-CoV-2 infections and the site of early virus replication. Virus produced in these cells can invade deeper into the lungs and other organs in the body, which can lead to more severe disease. In addition, virus made in these cells can be easily shed through exhalation allowing transmission from one infected person to others.

The study showed that the vaccine produced a localized immune response, involving antibodies and cellular immunity, that completely protected mice from fatal doses of SARS-CoV-2. The vaccine also prevented infection and disease in ferrets and, importantly, appeared to block transmission of COVID-19 from infected ferrets to their unprotected and uninfected cage-mates.

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Successful MERS vaccine in mice may hold promise for COVID-19 vaccine

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More information: Dong An et al, Protection of K18-hACE2 mice and ferrets against SARS-CoV-2 challenge by a single-dose mucosal immunization with a parainfluenza virus 5–based COVID-19 vaccine, Science Advances (2021). DOI: 10.1126/sciadv.abi5246

https://medicalxpress.com/news/2021-07-inhaled-covid-vaccine-disease-transmission.html

How vaccine-induced immune thrombotic thrombocytopenia (VITT) happens

 A McMaster University team of researchers recently discovered how, exactly, the COVID-19 vaccines that use adenovirus vectors trigger a rare but sometimes fatal blood clotting reaction called vaccine-induced immune thrombotic thrombocytopenia or VITT.

The findings will put scientists on the path of finding a way to better diagnose and treat VITT, possibly prevent it and potentially make vaccines safer.

The researchers' article was fast-tracked for publication today by the journal Nature in its accelerated article preview because of the importance of the research.

"Our work also answers important questions about the connection between antibodies and clotting," said Ishac Nazy, principal investigator and corresponding author of the study. He added it will have both diagnostic and therapeutic implications.

Nazy is the scientific director of the McMaster Platelet Immunology Laboratory and an associate professor of medicine for the Michael G. DeGroote School of Medicine at McMaster.

The COVID-19 vaccines using adenoviral vectors, such as those from AstraZeneca and Johnson and Johnson, are associated with the VITT clotting disorder caused by unusual antibodies to blood platelets that are triggered by the vaccine.

The study shows, at a molecular level, how those unusual antibodies stick to components from blood platelets causing them to trigger clot formation.

"The antibodies stick to the platelet protein called platelet factor 4 (PF4) in a very unique and specific orientation, which allows them to align with other antibodies and platelets in the precise formation that leads to a self-perpetuating vicious cycle of clotting events," said Nazy.

"These disease-causing aggregates quickly activate platelets, creating a highly intense clotting environment in patients," he added.

The dangerous reaction to the adenovirus vector vaccines has been found to occur in one in 60,000 of people receiving the vaccine in Canada.

"The intention of our study was to better understand how the severe clots which characterize VITT develop," said Donald Arnold, study co-investigator and co-medical director of the McMaster Platelet Immunology Laboratory.

"A basic principle of medical care is to understand how the disorder happens and, in doing so, develop better treatments."

John Kelton, co-investigator of the study and co-medical director of the McMaster Platelet Immunology Laboratory, added: "We believe that this study is important because it clarifies how the clotting ensues, and because we have been able to identify the molecules involved.

"The next step is to develop a rapid diagnostic and accurate test to diagnose VITT. Our major interest is now to move upstream from how the clots happen to preventing them from occurring."

Current rapid tests yield false-negative results, and testing relies on more time-consuming tests to confirm VITT. This study now explains why the rapid tests frequently fail and allows for new strategies to improve diagnostic testing.

The investigators altered the molecular composition of the PF4 protein and, using this technology, were able to identify the binding region on the protein.

The research team included Angela Huynh, a research scientist in the McMaster Platelet Immunology Laboratory, and Mercy Daka, a graduate student of McMaster's Department of Biochemistry and Biomedical Sciences.

The researchers thanked the agencies supporting the research, including the Public Health Agency of Canada, the Canadian Institutes of Health Research (CIHR), and the Ontario Ministry of Health.

Story Source:

Materials provided by McMaster University. Note: Content may be edited for style and length.

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Journal Reference:

1. Angela Huynh, John G Kelton, Donald M Arnold, Mercy Daka, Ishac Nazy. Antibody epitopes in vaccine-induced immune thrombotic thrombocytopenia. Nature, 2021; DOI: 10.1038/s41586-021-03744-4

https://www.sciencedaily.com/releases/2021/07/210707112432.htm

Tuning the immune system may enhance vaccines and ease disease

 Immunologists at St. Jude Children's Research Hospital have identified a biological pathway that selectively controls how key immune cells, called T follicular helper cells, mature into functional components of the immune system.

The finding offers the promise of developing drugs to activate the metabolic pathway to enhance the effectiveness of vaccines, including those that protect against COVID-19. Such medications could stimulate the immune system to respond more vigorously following immunization to produce more antibodies against a virus or bacterium.

The work also lays the foundation for drugs that dial down the pathway to alleviate autoimmune diseases such as lupus. In such disorders, an overactive immune system produces antibodies that attack the body's own tissues.

Led by Hongbo Chi, Ph.D. of the Department of Immunology, the researchers published their findings today in Nature.

Regulating the adaptive immune response

Chi and colleagues identified a metabolic control pathway that selectively regulates the development of specialized immune cells in the adaptive immune system. These cells are called T follicular helper cells.

The adaptive immune system is so named because when the body is infected by viruses or bacteria, it learns to target and attack them. T follicular helper cells activate the component of the adaptive immune system called humoral immunity. While humoral immunity attacks invaders circulating outside cells largely via the generation of antibodies, the other adaptive immune system component, cellular immunity, targets invaders inside infected cells.

In their experiments, the researchers sought to discover whether a metabolic control pathway existed that modified the T follicular helper cells to activate them. When such cells are activated, they help antibody-producing cells, called B cells, to mature and to generate infection-fighting antibodies.

Discovering a key pathway

To discover a possible control pathway, Chi and his colleagues used genetic techniques to delete in the T cells multiple enzymes known to be elements of such metabolic control pathways. Then, the scientists introduced the deletion-engineered T cells into mice followed by infection with a virus and tested whether the T cells lacking the enzyme were functional.

Their experiments revealed that one metabolic control pathway, called the CDP-ethanolamine pathway, selectively regulated the T follicular helper cells.

"This finding was a big surprise," Chi said. "First of all, this pathway was considered to have a housekeeping function leading to the production of building blocks for the cell membrane. But we discovered that it has a major signaling function. And secondly, we were surprised that this pathway -- and not other parallel pathways of this type -- was the only one involved in regulating T follicular helper cells."

As a complementary method to determine if the pathway selectively regulated the T follicular helper cells, the researchers deleted each of the key enzymes they identified in the CDP-ethanolamine pathway. They found that deletion of these enzymes, but not those of other parallel regulatory pathways, selectively impaired development of the T follicular helper cells, but not overall immune function.

Importantly, said Chi, those key enzymes could be targets for drugs that either enhance or inhibit the pathway, and thus the activity of the T cells.

"We are now exploring whether we can enhance the effectiveness of vaccines by using drugs that activate the pathway, to help these T cells mobilize the immune system to generate antibodies in response to a vaccine," he said.

"On the other hand, to treat autoimmune disease, we're interested in developing new ways to inhibit this pathway," he said. "This approach is promising because we know that such activation or inhibition is highly selective for T follicular helper cells and would not affect other immune functions."

The researchers are also delving into the structural mechanisms by which the enzymes work -- insights that could offer such drug targets, Chi said.

Story Source:

Materials provided by St. Jude Children's Research Hospital. Note: Content may be edited for style and length.

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Journal Reference:

1. Guotong Fu, Clifford S. Guy, Nicole M. Chapman, Gustavo Palacios, Jun Wei, Peipei Zhou, Lingyun Long, Yong-Dong Wang, Chenxi Qian, Yogesh Dhungana, Hongling Huang, Anil KC, Hao Shi, Sherri Rankin, Scott A. Brown, Amanda Johnson, Randall Wakefield, Camenzind G. Robinson, Xueyan Liu, Anthony Sheyn, Jiyang Yu, Suzanne Jackowski, Hongbo Chi. Metabolic control of TFH cells and humoral immunity by phosphatidylethanolamine. Nature, 2021; DOI: 10.1038/s41586-021-03692-z

https://www.sciencedaily.com/releases/2021/07/210707140704.htm

Stem cells can use same method as plants and insects to protect against viruses

 Researchers at the Francis Crick Institute have found a vital mechanism, previously thought to have disappeared as mammals evolved, that helps protect mammalian stem cells from RNA viruses such as SARS-CoV-2 and Zika virus. The scientists suggest this could one day be exploited in the development of new antiviral treatments.

On infecting a host, a virus enters cells in order to replicate. For most cells in mammals the first line of protection are proteins, called interferons. Stem cells, however, lack the ability to trigger an interferon response and there has been uncertainty about how they protect themselves.

In their study, published in Science today (8 July) the scientists analysed genetic material from mouse stem cells and found it contains instructions to build a protein, named antiviral Dicer (aviD), which cuts up viral RNA and so prevents RNA viruses from replicating. This form of protection is called RNA interference, which is the method also used by cells in plants and invertebrates.

Caetano Reis e Sousa, author and group leader of the Immunobiology Laboratory at the Crick says, "It's fascinating to learn how stem cells protect themselves against RNA viruses. The fact this protection is also what plants and invertebrates use suggests it might be something that goes far back in mammalian history, right up to when the evolutionary tree spilt. For some reason, while all mammalian cells possess the innate ability to trigger this process, it seems to only be relied upon by stem cells.

"By learning more about this process, and uncovering the secrets of our immune system we are hoping to open up new possibilities for drug development as we strive to harness our body's natural ability to fight infection."

In laboratory experiments which exposed engineered human cells to SARS-CoV-2, the virus infected three times fewer stem cells when aviD was present in the cells compared to when the researchers removed this protein.

The scientists also grew mini brain organoids from mouse embryonic stem cells and found that, when infected with Zika virus, the organoids with aviD grew more quickly and less viral material was produced than in organoids without this protein. Similarly, when organoids were infected with SARS-CoV-2, there were fewer infected stem cells in the organoids with aviD.

Enzo Poirier, author and postdoc in the Immunobiology Laboratory at the Crick says, "Why stem cells use this different mechanism of defence remains a mystery. It might be that the interferon process would cause too much harm to stem cells, so mammals, including humans, have evolved to shield these precious cells from this damage. There is still a lot of uncertainty about how these cells are protected from viruses, which we're excited to explore further."

The researchers will continue this work, creating a mouse model which allows them to further study the effects and importance of aviD in mammalian stem cells.

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Story Source:

Materials provided by The Francis Crick Institute. Note: Content may be edited for style and length.

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Journal Reference:

1. Poirier, E.Z. et al. An isoform of Dicer protects mammalian stem cells against multiple RNA viruses. Science, 2021 DOI: 10.1126/science.abg2264

https://www.sciencedaily.com/releases/2021/07/210708143923.htm

How Many People Skipped Their Second COVID Shot?

 More than one in 10 people in the U.S. have missed their second dose of the COVID-19 vaccine, new data from the CDC showed. As the country begins to see a rise in coronavirus cases caused by the highly transmissible Delta variant, public health experts are urging Americans to complete the vaccination process.

Around 88% of people who were eligible for a second dose received it as of June 16, according to CDC data shared with CNN -- a decrease from the 92% completion rate seen earlier this year.

This adds up to nearly 15 million people who have not received their second shot -- which, for the Pfizer-BioNTech and Moderna vaccines is recommended 21 and 28 days, respectively, after the first dose. On top of that, 1.5% of people eligible for their second dose -- or 2 million people -- had not yet completed their vaccination series but were still within an "allowable interval" of 42 days between shots.

Early studies have found that the Delta variant does somewhat reduce the efficacy of vaccines, with one British study finding an overall 10% absolute reduction in vaccine effectiveness after both doses. Still, other studies have shown that getting the second dose can more than double the vaccine's efficacy; for example, a study by Public Health England found that the efficacy of the Pfizer vaccine jumped from 33% with the first dose to 88% with the second dose.

"It's clear how important the second dose is to secure the strongest possible protection against COVID-19 and its variants -- and I urge everyone to book in their jab when offered," said Matt Hancock, former U.K. health and social care secretary

Adults under the age of 30 were the most likely to miss their second dose, according to CNN's report; adults ages 30-39 were the next age group found to be more likely than average to miss their second shot.

This fact didn't come as a surprise to Leana Wen, MD, MSc, professor of health policy at George Washington University's Milken School of Public Health.

"This is an age group of many people who are working, who probably have many responsibilities when it comes to childcare and other factors in their lives," Wen told MedPage Today. "Getting a second dose of the vaccine may not be top of mind."

Like many other vaccines that require more than one dose, Wen said, there's always a drop-off to be expected between shots -- especially as COVID-19 stops being at the forefront of everyone's daily lives. But, in Wen's view, doctors might be able to play a crucial role in getting their patients fully vaccinated.

"If there's a patient who [doctors] are concerned will not return for that second dose, offer the Johnson & Johnson vaccine," Wen said. "One dose of the Johnson & Johnson vaccine is effective against COVID-19, including the Delta variant -- one dose of the mRNA vaccine is not."

According to the latest tally from the CDC, 55% of the U.S. population have received at least one dose of the COVID-19 vaccine, and 48% have been fully vaccinated. Among adults in the U.S., 67% of those over the age of 18 have received at least one dose, and 59% have been fully vaccinated.

https://www.medpagetoday.com/special-reports/exclusives/93498

FDA Approves, Expands Indication for Astellas-Seagen PADCEV for Urothelial Cancer

 Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") and Seagen Inc. (Nasdaq:SGEN) today announced the U.S. Food and Drug Administration (FDA) granted PADCEV® (enfortumab vedotin-ejfv) regular approval in the U.S., in addition to approving a new indication for adult patients with locally advanced or metastatic urothelial cancer who are ineligible for cisplatin-containing chemotherapy and have previously received one or more prior lines of therapy. Cisplatin-ineligible patients typically have limited treatment options and a poor prognosis.

In 2019, the FDA granted accelerated approval for PADCEV for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1/L1 inhibitor and a platinum-containing chemotherapy before (neoadjuvant) or after (adjuvant) surgery, or in a locally advanced or metastatic urothelial cancer setting. The conversion from accelerated approval to regular approval and the label expansion were based on two supplemental Biologics License Applications (sBLAs) reviewed under the Real-Time Oncology Review (RTOR) pilot program.

https://www.astellas.com/us/news/5661