Moderna and its partners in the federal government are just now gearing up for a late-stage COVID-19 vaccine trial set to launch later this month, but at the same time, the mRNA biotech is prepping a supply of doses for quick shipment if the shot gets an FDA go-ahead.
On a conference call detailing positive phase 1 data for mRNA-1273, the company’s COVID-19 vaccine, Moderna CEO Stéphane Bancel said the company has “already started to make commercial product at risk and will continue to do so every day, every week, every month.”
The company and its partners are working to produce millions of doses at three sites for the U.S. market, Bancel said. Moderna itself is turning out vaccine supplies for the U.S. market at its site in Massachusetts and in conjunction with partner Lonza, which is producing supplies in New Hampshire, Bancel said. Catalent will handle fill and finish duties in Indiana.
The company believes it can produce 500 million doses to 1 billion doses annually, and has set out to make enough product “to be able to vaccinate everybody in the U.S.,” Bancel said.
As for distribution, which poses its own challenges during a pandemic, Bancel said a partnership with the government would be “very important” under an emergency authorization from the FDA. The government, not a company, should prioritize early shipments and decide who gets the first vaccinations, he told analysts. Early on, Bancel expects “very tight supply,” while “traditional channels” of distribution would take over after some time.
Moderna late Tuesday posted phase 1 data showing the vaccine candidate elicited a “robust” immune response across all dose levels in all patients, with no serious side effects. With the results, the company is gearing up for a randomized phase 3 study in 30,000 participants set to launch later this month.
The new data, and phase 3 trial preparations, raised hopes that a vaccine could be available later this year or early next year, which is the stated goal of the United States’ Operation Warp Speed program.
Tricida (NASDAQ:TCDA) shares tank ~33% AH in reaction to the FDA notification regarding “deficiencies” regarding labeling and postmarketing requirements for veverimer for metabolic acidosis in chronic kidney disease patients. Though the notice doesn’t specify the deficiencies identified by the FDA.
Tricida says the notification doesn’t reflect a final decision, and it will work with the FDA to identify and seek to resolve deficiencies.
The company has no plans to modify/suspend its ongoing confirmatory postmarketing trial, VALOR-CKD.
Marketing application was filed in September last year.
The Lancet medical journal said on Wednesday it will publish keenly-awaited phase 1 clinical trial data on a potential COVID-19 vaccine being developed by Astrazeneca and Oxford University on Monday.
“We expect this paper, which is undergoing final editing and preparation, to be published on Monday, July 20, for immediate release,” a spokeswoman for the journal said.
London’s Telegraph reports that results from a Phase 1 clinical trial evaluating Oxford University’s COVID-19 vaccine candidate ChAdOx1 nCoV-19 [ADZ1222 by licensee AstraZeneca (NYSE:AZN)] in healthy volunteers showed that it triggered a “double defense” immune response against the SARS-CoV-2 virus.
Researchers noted that administration of the candidate produced both antibodies and killer T cells. The response, if confirmed, has significant implications for sustained immunity since antibodies may fade away within months while T cells remain in circulation for years.
It’s only a tiny change. At some point early in the pandemic, one of the 30,000 letters in the genome of SARS-CoV-2 changed from an A to a G. Today, that mutation, at position 23,403, has spread around the world. It is found in the vast majority of newly sequenced viruses and has become the center of a burning scientific question: Has the mutation become so common because it helps the virus spread faster? Or is it just coincidence?
More than 6 months into the pandemic, the virus’ potential to evolve in a nastier direction—or, if we’re lucky, become more benign—is unclear. In part that’s because it changes more slowly than most other viruses, giving virologists fewer mutations to study. But some virologists also raise an intriguing possibility: that SARS-CoV-2 was already well adapted to humans when it burst onto the world stage at the end of 2019, having quietly honed its ability to infect people beforehand.
On average, the coronavirus accumulates about two changes per month in its genome. Sequencing SARS-CoV-2 genomes helps researchers follow how the virus spreads. Most of the changes don’t affect how the virus behaves, but a few may change the disease’s transmissibility or severity.
One of the earliest candidates was the wholesale deletion of 382 base pairs in a gene called ORF8, whose function is unknown. First reported by Linfa Wang and others at the Duke-NUS Medical School in Singapore in a March preprint, the deletion has since been reported from Taiwan as well. A deletion in the same gene occurred early in the 2003 severe acute respiratory syndrome (SARS) outbreak, caused by a closely related coronavirus; lab experiments later showed that variant replicates less efficiently than its parent, suggesting the mutation may have slowed the SARS epidemic. Cell culture experiments suggest the mutation does not have the same benign effect in SARS-CoV-2, Wang says, “but there are indications that it may cause milder disease in patients.”
Weak evidence of a moderate effect
The mutation at position 23,403 has drawn the most attention—in part because it changed the virus’ spike, the protein on its surface that attaches to human cells. The mutation changed the amino acid at position 614 of the spike from an aspartic acid (abbreviated D) to a glycine (G), which is why it’s called G614.
In a Cell paper this month, Bette Korber and colleagues at Los Alamos National Laboratory showed that G614 has become more common in almost every nation and region they looked at, whereas D614 is virtually gone (see graphic, below). That might be a sign that it’s outcompeted by G614, but it could also be a coincidence. “Any one mutation may rise to very high frequency across the world, just because of random chance,” says Kristian Andersen, a computational biologist at Scripps Research. “This happens all the time.”
Comparing the spread of different viral variants carrying the two mutations could reveal a difference. The United Kingdom’s COVID-19 Genomics Consortium has sequenced 30,000 SARS-CoV-2 genomes, allowing scientists to compare how fast 43 lineages carrying the G614 mutation and 20 with D614 spread. They estimated that the former grew 1.22 times faster than the latter—but the statistical significance was low. “Evidence for a difference is weak and if it does exist, the estimated effect is moderate,” says evolutionary biologist Andrew Rambaut of the University of Edinburgh.
Researchers have also turned to cell culture experiments. When Korber’s group engineered so-called viruslike particles to carry one spike protein or the other, the G614 variant appeared to be more efficient at entering cells. Jeremy Luban of the University of Massachusetts Medical School, who has found the same thing, explains that G614 causes a slight change in the shape of the spike, apparently making it easier for the protein to undergo the structural changes that cause the membranes of the virus and the cell to fuse. “Our data looks like it’s somewhere between three and 10 times more infectious,” Luban says. “That’s a pretty enormous effect.”
That does not mean the mutation has an effect in the real world, says virologist Emma Hodcroft of the University of Basel. In the past, she notes, “We have cases where we really thought that we had evidence for a mutation that was changing viral behavior and as more evidence came, it didn’t seem to be the case.” An increased ability to infect a laboratory cell line may not translate to the billions of diverse cells in a human body, adds Angela Rasmussen, a virologist at Columbia University: “Humans aren’t Vero cells.”
Animal experiments are another way to probe the effects of G614. One option, virologist Marion Koopmans of Erasmus Medical Center (EMC) says, would be to infect ferrets with it and D614 and look for differences in how much virus they shed. But infections in ferrets only last about 1 week, Koopmans notes. “The effect would have to be very big to show up in an experiment like that.”
Another idea is to expose uninfected ferrets to animals carrying either of the two variants and see how well they transmit. An uncontrolled transmission experiment has already taken place on Dutch mink farms, where the new coronavirus jumped from humans to minks at least five separate times. Twice it was the D614 variant, and three times G614, Koopmans says. She hopes data from the outbreaks could show whether either one spread faster and wider than the other. But the experiment doesn’t have the rigor of a lab study, she concedes. “We have a natural experiment here. The study design is not optimal.”
Whether G614 is more transmissible or not, it has become the dominant strain and the world is living with it, Rambaut says. Most recent estimates of the virus reproduction number—which denotes how well it spreads—are already based mostly on the mutant strain. “What we don’t know is whether D614 would have been different,“ Rambaut says.
Why so little evolution?
The attention lavished on G614 may obscure a bigger question, however: With the virus having spread to at least 11 million people worldwide, why aren’t more mutations that affect its behavior emerging?
Perhaps there’s just little selection pressure on the virus as it races through millions of immunologically naïve people, scientists say. That could change with the advent of vaccines or new therapies, forcing the virus to evolve. But it could also indicate that the virus has been with people longer than we know, and was spreading before the first known cases in Wuhan, China, in December 2019. “The evolution of this virus to become a human pathogen may have already happened and we missed it,” Rasmussen says.
Wang thinks a version of the virus may have circulated earlier in humans in southern Asia, perhaps flying under the radar because it didn’t cause severe disease. “If it happens in a small or remote village, even with some people dying, nobody is going to know there’s a spillover,” Wang says. The virus could then have infected an animal that was brought to Wuhan and started the pandemic.
At Dutch mink farms, after all, the virus jumped not just from humans to animals, but also back from animals to humans, Wang says. “If that can happen in the Netherlands, surely it can happen in a village in Thailand, or in Yunnan province in southern China.”
Well, I was writing just the other day about what we don’t know about the T-cell response to coronavirus infection, and as of today we know quite a bit more. And from what I can see, we have encouraging news, mixed with some things that we’re going to need to keep an eye on.
Here’s a post from May on a paper in Cellthat looked at T cell responses in recovering SARS CoV-2 patients and compared them to reports of people who had been infected with “original SARS” back in 2003, and to people who had never encountered either. It also has some background on T cells in general, which might be useful if you don’t have that info right at the top of your brain’s queue. That’s the paper that showed that the T-cell response to this virus is less “Spike-o-centric” than it was to SARS. It also showed that there are, in fact, people who have both CD4+ and CD8+ T cells that recognize protein antigens from the new coronavirus even though they have never been exposed to SARS, MERS, or the new virus. The paper speculated that this might be due to cross-reactivity with proteins from the “common cold” coronaviruses”, and raised the possibility that there might be a part of the population that has at least some existing protection against the current pandemic.
Now comes a new paper in press at Nature. It confirms that convalescent patients from the current epidemic show T-cell responses (mostly CD4+ but some CD8+ as well) to various epitopes of the N (nucleocapsid) protein, which the earlier paper had identified as one of the main antigens as well (along with the Spike and M proteins, among others, with differences between the CD4+ and CD8+ responses as well). Turning to patients who had caught SARS back in 2003 and recovered, it is already known (and worried about) that their antibody responses faded within two or three years. But this paper shows that these patients still have (17 years later!) a robust T-cell response to the original SARS coronavirus’s N protein, which extends an earlier report of such responses going out to 11 years. This new work finds that these cross-react with the new SARS CoV-2 N protein as well. This makes one think, as many have been wondering, that T-cell driven immunity is perhaps the way to reconcile the apparent paradox between (1) antibody responses that seem to be dropping week by week in convalescent patients but (2) few (if any) reliable reports of actual re-infection. That would be good news indeed.
And turning to patients who have never been exposed to either SARS or the latest SARS CoV-2, this new work confirms that there are people who nonetheless have T cells that are reactive to protein antigens from the new virus. As in the earlier paper, these cells have a different pattern of reactivity compared to people who have recovered from the current pandemic (which also serves to confirm that they truly have not been infected this time around). Recognition of the nsp7 and nsp13 proteins is prominent, as well as the N protein. And when they looked at that nsp7 response, it turns out that the T cells are recognizing particular protein regions that have low homology to those found in the “common cold” coronaviruses – but do have very high homology to various animal coronaviruses.
Very interesting indeed! That would argue that there has been past zoonotic coronavirus transmission in humans, unknown viruses that apparently did not lead to serious disease, which have provided some people with a level of T-cell based protection to the current pandemic. This could potentially help to resolve another gap in our knowledge, as mentioned in that recent post: when antibody surveys come back saying that (say) 95% of a given population does not appear to have been exposed to the current virus, does that mean that all 95% of them are vulnerable – or not? I’ll reiterate the point of that post here: antibody profiling (while very important) is not the whole story, and we need to know what we’re missing.
There are still major gaps in our knowledge: how many people have such unknown-coronavirus-induced T-cells? How protective are they? How long-lasting is the T-cell response in people who have been infected with the current SARS CoV-2 virus, and how protective is it in the declining-antibody situation that seems to be common? What sorts of T cell responses will be induced by the various vaccine candidates? We just don’t know yet. But we’re going to find out.
AbbVie Inc ABBV 1.58% shares popped Tuesday after researchers found that the large-cap pharma’s cholesterol-lowering drug Tricor could work against SARS-CoV2, the virus that causes COVID-19.
What Happened: Researchers at Israel’s Hebrew University and the Mount Sinai Medical Center in New York said FDA-approved Tricor could potentially downgrade COVID-19’s severity into “nothing worse than a common cold,” Israeli media reported.
Tricor impairs the replicating potential of the new coronavirus or even could eradicate it, the reports said, citing Hebrew University professor Ya’acov Nahmias and Sinai’s Dr. Benjamin tenOever.
How Tricor Acts: Following three months of in vitro, or lab, studies and a review of eight already approved drugs, the researchers found that Tricor burns fat, causing the virus to disappear with merely five days of treatment.
SARS-Co-V2 was found to impede with the carbohydrate metabolism, leading to the accumulation of fat inside the lung cells, which in turn provides a conducive environment for the thriving of the virus.
Tricor’s fat-burning mechanism comes in handy to make the environment inclement for the virus, leading to its eventual elimination, studies found.
What’s Next? The researchers are advancing the drug into animal studies in the U.S. With the safety of Tricor already proved, they hope to fast track clinical studies both in the U.S. and Israel within the next couple of weeks.
