US hoping for two Covid-19 vaccines by end of November

Two American companies expect to apply for emergency approval for their COVID-19 vaccines by late November, welcome news as the US hits a third surge of its coronavirus epidemic and approaches its eight millionth case.

Pfizer said Friday it hopes to move ahead with its vaccine after safety data is available in the third week of November, a couple of weeks after the November 3 presidential election.

The announcement means the United States could have two vaccines ready by the end of the year, with Massachusetts biotech firm Moderna aiming for November 25 to seek authorization.

“So let me be clear, assuming positive data, Pfizer will apply for Emergency Authorization Use in the US soon after the safety milestone is achieved in the third week of November,” the company’s chairman and CEO Albert Bourla said in an open letter. The news lifted the company’s shares two percent in the US.

But experts warn that even when vaccines are approved, it will take many months until they are widely available.

In any case, they are unlikely to be a good substitute for mask wearing, social distancing and other recommended behavior to curb transmission because we don’t know how effective they will be.

Indoor gatherings in colder weather

After falling numbers throughout the summer, the country hit an inflection point in its coronavirus outbreak around the second week of September—with a new daily case average of more than 50,000 according to the latest figures, and the trajectory is upward.

With a shade under eight million confirmed infections and more than 217,000 deaths, America is the hardest-hit country in the world.

The US never came close to returning to its baseline after its first wave in spring, meaning the current spike can be more accurately termed a third surge.

Geographically, the major hotspots are in the Upper Midwest and parts of the Rocky Mountains in the west, while parts of the Northeast that were hit hard in spring are seeing their outbreaks starting to rekindle.

Harvard surgeon and health policy researcher Thomas Tsai told AFP there were multiple factors behind the rising cases—from under testing in the Midwest to authorities failing to monitor the reopening of bars and restaurants and dialing back when necessary.

What’s more, “from the contact tracing reports from various municipalities and states, the worry is that the spread is driven now, by indoor social gatherings in people’s homes,” he added, as the focus of social life shifts from public to private spaces in the colder weather.

One bright sign is that COVID-19 treatments have improved markedly, and since the cases are more spread out than before, hospitals aren’t being overwhelmed.

Widespread mask use might also mean that when people do get infected, they have less virus in their body which makes them less sick.

‘No magic bullet’

While vaccines are a crucial tool against the virus, experts have warned they can’t be a substitute for behavioral measures like masks and distancing.

“It’s welcome news that there will be one more thing that can help prevent COVID transmission,” said Priya Sampathkumar, an infectious disease doctor and professor at Mayo Clinic.

“But I think we need to be cautious and understand that a vaccine isn’t a magic bullet,” she added.

Pfizer and Moderna, both funded by the US government, launched Phase 3 of their clinical trials at the end of July, and both were producing their doses at the same time.

They aim to deliver tens of millions of doses in the US by the end of the year.

Both are “mRNA vaccines,” an experimental new platform that has never before been fully approved.

They both inject people with the genetic material necessary to grow the “spike protein” of SARS-CoV-2 inside their own cells, thus eliciting an immune response the body will remember when it encounters the real virus.

This effectively turns a person’s own body into a vaccine factory, avoiding the costly and difficult processes that more traditional vaccine production requires.

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Cell-type mapping used to identify cellular substrates that underlie two types of thirst

A team of researchers from the California Institute of Technology, Nankai University and the University of California, Berkeley, has found that the cellular substrates that underlie two types of thirst could be identified using a certain kind of cell-type mapping. In their paper published in the journal Nature, the group outlines their study of thirst and the way it is processed by the brain.

Prior research has shown that our brains process at least two main kinds of thirst: Osmotic and hypovolaemic. Osmotic thirst is what we feel when we need more water. Hypovolaemic thirst is what we feel when we need minerals and water to replenish blood supplies. The researchers note that this can be easily observed—when people are just thirsty, they will be satisfied with a glass of water. But when they have been working out, they need water with added minerals. This is because we lose minerals through sweat. In this new effort, the researchers wanted to learn more about how the brain processes both types of thirst.

Prior research has shown that circumventricular organs located in the lamina terminalis are the parts of the brain that process the two kinds of thirst, but how they do so has not been clear. To find out, the researchers used stimulus-to-cell type mapping which involved the use of single-cell RNA sequencing. The goal was to figure out which of the cellular components were involved with processing thirst types. They then forced test mice to experience either of the two types of thirst. That allowed them to see which cells were responding to which type of thirst. They also used optogenetics, in which the cells were engineered to respond to a light source. Shining a light on the cells then produced one kind of thirst or the other depending on how they had been engineered as evidenced by the water source the mice chose to use—one that was just water, or one that contained minerals, salt and sugar.

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Two existing drugs point to a potential new target against COVID-19

New lab-based studies show that two existing drugs, including one developed by a researcher at Harvard Medical School and Boston Children’s Hospital, inhibit SARS-CoV-2—the virus that causes COVID-19—from infecting human cells in a dish.

Both drugs, vacuolin-1 and apilimod, originally developed years ago, target a large enzyme called PIKfyve kinase.

Before this study, little was known about this enzyme’s role in COVID-19 infection. The work, which will need to be replicated in human trials, suggests a potential new target for COVID-19 therapies.

Findings were published Aug. 6 in PNAS.

“Our findings show that targeting this kinase through a small-molecule antiviral against SARS-CoV-2 may be an effective strategy to lessen the progression or seriousness of COVID-19,” said study co-senior author Tomas Kirchhausen, professor of cell biology in the Blavatnik Institute at HMS and professor of pediatrics at Boston Children’s.

Kirchhausen discovered vacuolin-1 16 years ago. Apilimod was developed by a company called LAM Therapeutics.

Ebola and beyond

When Kirchhausen first found vacuolin-1, he published a paper describing what it does in a variety of cell types.

Several years later, he began a long collaboration with HMS colleagues in the Center for Excellence in Translational Research focused on small molecules against emerging viruses.

They showed that vacuolin-1 and apilimod, which have a similar chemistry, were both effective inhibitors against the Ebola virus. They did not publish their results at the time.

When COVID-19 began to hit the U.S. hard in early March, Kirchhausen’s lab ramped down like many others in the country. Before turning out the lights, however, he remembered that the kinetics of cell entry of Ebola virus were similar to those of coronaviruses like SARS-CoV-2.

Kirchhausen reached out to co-senior author Sean Whelan, who had been part of the Center for Excellence team at HMS but had since moved to Washington University. The duo performed cell biology studies with SARS-CoV-2 virus in Whelan’s lab.

“Within a week, we knew apilimod worked extremely well in preventing SARS-CoV-2 infection in human cells in the lab,” says Kirchhausen, who initially published this discovery on the bioRxiv pre-print website in April 2020.

That pre-print also included a review of apilimod’s effectiveness against Ebola and SARS-CoV-2.

“We found that like apilimod, vacuolin-1 is a very strong inhibitor for viral infection in the lab,” said Kirchhausen.

In an unexpected coincidence, an unrelated group posted a paper showing that, in a screen of 12,000 clinical-stage or FDA-approved small molecules, apilimod was one of the best drugs for inhibiting SARS-CoV-2 virus replication. That paper has since been published in Nature.

Now in clinical trials

Apilimod’s parallel development ultimately landed with AI Therapeutics after it failed to show any benefit in phase I and II clinical trials for treatment of autoimmune conditions, its original purpose.

Although those trials were not successful, apilimod’s clinical testing in 700 healthy volunteers and patients showed it did not produce significant side effects even when given to patients for more than a year at high doses.

This spring, using some of the data from Kirchhausen’s bioRxiv paper as well as information from drug screens by others, AI Therapeutics received FDA approval to see whether apilimod reduces the seriousness of COVID-19.

In late July, AI Therapeutics announced a new randomized, double-blind, placebo-controlled study with apilimod, known as LAM-002 in the study. It will test apilimod’s safety, tolerability and efficacy in reducing the amount of virus in about 140 patients with confirmed early-onset COVID-19.

Looking forward, Kirchhausen hopes to identify other drugs to be given in addition to a PIKfyve kinase inhibitor.

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