Abbott (NYSE: ABT) today announced that the U.S. Centers for Medicare & Medicaid Services (CMS) revised its National Coverage Determination (NCD) to expand coverage for transcatheter edge-to-edge repair (TEER), also referred to as transcatheter mitral valve repair (TMVr), to include patients with secondary (or functional) mitral regurgitation (MR) resulting from heart failure. The decision significantly increases the number of people eligible for insurance coverage for mitral valve repair with MitraClip, enabling broader access to the device. As the first and only TEER device approved by the U.S. Food and Drug Administration (FDA) and reimbursed by Medicare for primary mitral regurgitation, physicians have increasingly relied on the therapy to improve survival and quality of life for their patients. Today's decision improves insurance coverage for people with secondary MR who need treatment with MitraClip.
Wednesday, January 20, 2021
Humanigen changes late-stage trial endpoints
On January 19, 2021, Humanigen, Inc. (the “Company”) provided an update on its ongoing Phase 3 clinical trial of lenzilumab in hospitalized patients with COVID-19. As of January 19, 2021, more than 500 patients have been enrolled in the trial.
In response to the rapidly evolving therapeutic landscape, the primary endpoint of the trial has been changed to ventilator-free survival through day 28, previously one of several secondary endpoints. Time to recovery will be one of several secondary endpoints. The Company believes this change in the primary endpoint represents a more meaningful endpoint for patients, health-care providers, and payors given the current standard of care for hospitalized and hypoxic COVID-19 patients. The protocol and statistical analysis plan for the Phase 3 trial have been updated to reflect these changes. These changes have been reviewed and discussed with FDA and are expected to be posted to clinicaltrials.gov (NCT04351152). The Company remains blinded to the results of this ongoing trial.
Tuesday, January 19, 2021
New COVID Strain Reportedly Emerging Within Brazilian Amazon
As warnings about the hyper-infectious COVID strains first isolated in the UK and South Africa ring out across the US, Europe and, well, the rest of the world, too, at this point, authorities in Brazil fear they may have a new strain on their hands that's more infectious, and deadlier, than anything the world has seen previously.
According to a report published by Brazilian outlet Universo Online, a surge in cases and deaths, particularly among younger patients, in the hard-hit Amazonian city of Manaus (situated in northwestern Brazil, on the banks of the River Negro) has drawn the attention of health professionals working on the front lines of the pandemic in the hard-hit Latin American powerhouse.
Several officials with direct knowledge of the situation told UOL that a new "variant" - a mutated strain of the virus - may be responsible for harsher symptoms, and quicker onset times.
Publix COVID-19 vaccinations expanding to 3 more Florida counties
Three more counties in Florida will be added to the list of those offering COVID-19 vaccinations through Publix.
Publix locations in Palm Beach County, Martin County and Monroe County will begin administering the COVID-19 vaccine.
All 67 Publix stores in Palm Beach County will receive doses of the vaccine.
During a later news conference on Tuesday, Governor DeSantis said announced the addition of Lee County and Charlotte County stores that will offer the vaccine.
Below is a list of all counties offering vaccinations through Publix pharmacies:
- Bay County
- Citrus County
- Collier County
- Charlotte County
- Escambia County
- Flagler County
- Hernando County
- Lee County
- Marion County
- Martin County
- Monroe County
- Okaloosa County
- Palm Beach County
- Santa Rosa County
- St. Johns County
- Volusia County
- Walton County
The governor said, as of right now, there are close to 700,000 seniors in Florida that have received at least their first dose of the COVID-19 vaccine.
To make an appointment for a vaccine at Publix once more become available, click here.
Memory B Cells, Infection, and Vaccination
By Derek Lowe
This new article, I have to say, is rather reassuring about the human immune response to the coronavirus. It’s from a large team centered at Rockefeller University in New York, and it examines 87 people who have previously been infected. We’ve seen many studies of antibody titers and the like over time, but this is going to a deeper level and looking at the actual memory B cells. Those, you may well recall or already know, are the ones that persist and stay on guard should the same antigens reappear. They can go on for decades as an inbuilt surveillance system, ready to expand and start the antibody production process again if a similar immunologic threat shows up again.
At the six-month check-in, the patients in this study were all PCR-negative for the virus – they were no longer infected. Still, 38 of them reported some persistent long-term effects from it (you really, really do not want to catch this if you can avoid it – for more on long-term effects, see this new paper). The more severe the acute infection was, the more likely people were to experience long-term problems. Over a six-month period after recovery from SARS-CoV2, the patients in this work did indeed show lowered antibody levels. The drop in antibody titers was not evenly distributed over the different types (antibodies against the Spike receptor-binding domain (RBD) or the nucleoprotein (N), and IgM for these versus IgA), but overall neutralizing antibody activity was down about five-fold at the six month point as compared to the after-one-month check. But that’s what happens with any infection: the immune system does not crank out high levels of specific antibodies forever. It settles back down to its watch-and-wait mode, and that’s where the memory B cells come in.
And looking at those B cells showed some interesting patterns. There were a variety of them at both the 1-month and 6-month points, but they changed over time. Some of the clonal lines that were present earlier had disappeared, while new ones had continued to show up. The distribution was different as well: at the earlier point, the most common B cell clones were a greater percentage of the whole than at the 6-month point, for example. The authors say: “We conclude that while the magnitude of the RBD-specific memory B cell compartment is conserved between 1.3 and 6.2 months after SARS-CoV-2 infection, there is significant clonal turnover and antibody sequence evolution, consistent with prolonged germinal center reactions.“
What’s that antibody evolution look like, then? The good news is that the ones from the six-month check showed both increased potency and an increased range of responses against various protein mutations. That includes many of the ones that are in the news these days, things like R346S, Q493R, and E484K. (As an aside, did anyone ever imagine that amino acid variant notation would creep into major news stories? Strange days). But while the one-month antibody samples were unable to recognize these and bind to them, the six-month ones were.
How does the immune system do this? It comes down to follicular dendritic cells (FDCs), a specialized cohort that displays antigens on their cell surface for an extended time in the “germinal centers” where B cells replicate. You’ll find them in lymph nodes, spleen, bone marrow, and other tissues (here’s a review article on the subject). They’re quite odd, with unusual cellular structures (very few visible organelles in their cytoplasm and an overall large, spread-out net-like structure). They secrete chemokine signals that attract B cells, allowing them to be exposed repeatedly over the long term to the antigens that they present on the FDC surfaces (which are technically in the form of “immune complexes” there).
In severe autoimmune disease, it appears that this process can go wrong and lead to FDCs and B-cells assembling in other parts of the body entirely as part of a sustained (and completely inappropriate) immune response. But when things are working as they’re supposed to, the reservoir of antigen in the FDCs and its continued presentation to the B cells allows for the generation and selection of new and improved antibodies, as seen in this study. We got this system via evolution, too, of course: the viruses that have been attacking us and our phylogenetic ancestors for hundreds of millions of years have always been mutating in real time, so having a system that keeps pace with them after an initial infection is a clear survival advantage. As always, the immune system inspires awe and a bit of terror as well.
What does this mean for people who are vaccinated, instead of getting their immune response by being really infected by the virus? As that last link mentions, “an efficient vaccine should maximize the deposition of immune complexes on FDCs“. You would expect the Spike protein produced in the body via the mRNA or viral vector vaccines to be handled in just this way, as well as the directly-introduced antigen proteins in a vaccine like Novavax is developing. The new paper being discussed also looks into the possibility of persistence of viral antigens in intestinal tissue, which was seen in some (but not all) of the patients studied, and would be expected to drive the evolution of IgA-type antibodies in particular. But overall, the key would be to make sure that the FDCs are displaying the Spike antigen the way that they should be.
How about the variations on the coronavirus that are out there right now? This has a bearing on some very real-time data from Ravi Gupta’s lab at Cambridge. There’s a manuscript that’s on the way to MedrXiv, but this pre-preprint stuff can be found on Twitter here and here. They’re looking at antibodies from the blood of people who were vaccinated three weeks ago, and seeing how these perform against the B.1.1.7 variant. In short, they still have neutralizing activity, but it’s generally lower (at least, in ten of the fifteen patients studied). Now, this doesn’t mean that the vaccine is ineffective in those people – the antibodies still do their job. But it does mean that as mutations continue to pile up, that escape of such a new variant of the coronavirus is not impossible.
But. . .note that Gupta’s lab is (necessarily!) looking at the antibody profile of people who have been recently vaccinated. The paper I’m discussing today raises the strong possibility of continued B-cell and antibody evolution over a period of months, leading to a different set of antibodies that appears to be able to better deal with some of these mutations. It will be very interesting indeed to combine these two studies – clonal B cell changes and antibody evolution with activity against variants like B.1.1.7 – to see if this is indeed the case. It should be, but we’ll want to check!
https://blogs.sciencemag.org/pipeline/archives/2021/01/19/memory-b-cells-infection-and-vaccination
UnitedHealthcare launches new virtual primary care offering in 11 states
UnitedHealthcare is launching a new, virtual primary care option as part of an effort to expand access to local clinicians in its employer-sponsored plans.
Virtual primary care will be available to members in certain employer plans across 11 states, UnitedHealthcare said in an announcement. The insurer expects to expand the offering to additional states over the course of the year.
The goal, UnitedHealth said, is to make it easier for patients to establish and maintain an ongoing relationship with a primary care provider.
“The UnitedHealthcare Virtual Primary Care service and updated policy help expand the use of virtual care from delivering care to people who are sick, to now also focusing on preventing and detecting disease before it starts and, if needed, helping people more conveniently manage certain chronic conditions,” said Anne Docimo, M.D., chief medical officer at UnitedHealthcare," in a statement.
"As more people and care providers move to a digital-first mindset, UnitedHealthcare will continue to modernize our approach to health benefits and invest in new ways to use technology to help make it more convenient for our members to access primary care and other types of medical services," Docimo said.
Through the program, eligible members will be able to access a slew of primary care services with little or no cost sharing, UnitedHealthcare said. Available services include annual wellness visits, routine follow-ups and checkups for chronic conditions, lab tests and referrals to specialists.
For the duration of the COVID-19 public health emergency, cost sharing will be waived for all members seeking testing or treatment for the virus, including virtually, UnitedHealthcare said.
Recent survey data from UnitedHealthcare found a quarter of respondents would actually prefer a virtual relationship with their doctor compared to the more traditional in-person approach, the insurer said.
The new virtual primary care offering is available in Arizona, Colorado, Illinois, Maryland, North Carolina, Ohio, South Carolina, Texas, Virginia, Washington, D.C., and West Virginia.
What we now know — and don’t know — about coronavirus variants
The coronavirus variants are, in a word, confusing.
By now, you have likely heard about different variants that first raised trouble in the United Kingdom, South Africa, Brazil, and now maybe California — though the jury is very much out on whether that last one is cause for concern. To make a messy alphabet soup even more jumbled, these variants have unwieldy names, and they each contain mutations with unwieldy names of their own. The result is that people are left trying to differentiate among B.1.1.7 and N501Y and E484K and C-3PO.
Wait, sorry, that last one is from “Star Wars.”
The point is that all of this is difficult to keep track of, and it will only grow more confusing with more variants likely to turn up. “It’s becoming a mutation-of-the-week game,” said Stephen Goldstein, a coronavirologist at the University of Utah.
Below, STAT explains what’s known about the variants, why they’re getting so much attention, and what they mean for the trajectory of the pandemic.
Why are variants popping up now?
Well, they are and they aren’t.
SARS-CoV-2, the virus that causes Covid-19, has been mutating all along; that’s just what viruses do. Many of those mutations don’t change the virus substantively, and some might actually be detrimental to the virus, making that variant likely to die out.
But every so often, a mutation or combination of mutations will give rise to a new form of the virus with an evolutionary edge, like being able to infect cells better or spread faster. This new variant can outpace earlier iterations of the virus and become dominant.
Early on in the pandemic, a mutation known as D614G seems to have given the virus a boost in its infectiousness, and variants with the mutation became the most prevalent around the world.
Beyond the fact that the virus is constantly changing, there are other reasons why these “fitter” variants have started to emerge. In the early days of the pandemic, when just about all of us were vulnerable to Covid-19, any infectious variant had a pretty easy time circulating. But as more people in certain areas have become protected — either after an initial infection or vaccination — pressure on the virus has increased. A so-so spreader might no longer be able to find new hosts (that’s us) to infect, but variants with mutations that help them spread can still transmit, and can take off from there.
“We’ve reached a point one year on and in certain parts of the world where the density of natural immunity is sufficient so that the variants that have got a fitness advantage … are more likely to emerge and spread,” said Wendy Barclay, the head of infectious diseases at Imperial College London.
From the time SARS-2 got on people’s radars in late 2019, it was already quite well-suited to infecting humans, even compared to SARS and MERS, the other coronaviruses that have caused health emergencies in recent decades. But that’s not to say that SARS-2 didn’t have room to improve.
“Compared to SARS or MERS, it was already quite capable, but that doesn’t mean that it couldn’t become more capable,” said Kristian Andersen, an infectious diseases expert at Scripps Research Institute. “And that’s what we’re observing now.”
The variant that first appeared in the U.K. — and perhaps others as well — is a bit of a special situation. Most people who have an acute case of Covid-19 will vanquish the virus after a relatively short period of time. But it’s thought that this variant, dubbed B.1.1.7, came from a person who was immunocompromised and had a rare chronic case, essentially providing an incubator for the virus to accrue mutations as it replicated for weeks or months in that person’s body. The virus, the hypothesis goes, then spread from that person to others.
If the virus is changing all the time, why are these variants setting off alarms?
For now, let’s focus on the variants that emerged first in the U.K., South Africa, and Brazil. (There are at least two variants in Brazil scientists are keeping an eye on). These have the most evidence of greater transmissibility or some other characteristic that might be cause for concern. And, what’s more, they share some of the same mutations despite arising independently. To scientists, that’s a clue that the mutations might confer some evolutionary advantage.
When scientists assess the impact of a new viral variant, they consider at least three factors: disease severity, protection, and transmissibility.
For now, none of the variants seems to change how sick people get with Covid-19.
Answering the question of whether people with existing immunity to SARS-2 are still protected — and whether the vaccines still work — is a bit more complicated. Scientists are testing vaccines against the mutations and variants, and results should be available in the coming weeks. But many experts have a fairly optimistic outlook on the vaccine question. The vaccines generate a multipronged immune response that recognizes and targets different parts of the virus; changes caused by one mutation likely won’t make the virus invisible to protective antibodies generated by immunizations. And even if a mutation reduces the vaccines’ effectiveness a bit, the shots have been shown to be so powerful that they should work just fine even if their potency is taken down a notch.
Eventually, scientists think, the virus will accumulate the right combination of mutations to warrant updating the vaccines, a not-that-difficult process for vaccine makers. But it doesn’t appear we’re at that point now (though plenty of studies are ongoing, and some are more anxious than others).
There are some concerns about people becoming more vulnerable to reinfection with the new variants. In lab experiments, one of the mutations present in the variants identified in South Africa and Brazil, called E484K, has helped the virus evade the antibodies generated after an initial infection in some people.
On Monday, scientists in South Africa reported that antibodies from some people infected during the country’s first wave failed to recognize the newer variant spreading there now; they didn’t have results yet about its impact on vaccine-elicited antibodies. Separately, in Brazil, surging cases in a region that had already been hit hard by the virus raised worries that a different variant, called P.1, is able to sneak past existing protection and infect people again. (More on that in a second.)
When it comes to transmissibility, it seems that these variants do spread more easily — though there are wide-ranging estimates for just how much more infectious they are.
What does a more transmissible virus mean?
Because a more transmissible variant can infect more people more quickly, it leads to more cases overall without mitigation efforts. Even if people individually aren’t likely to get sicker, the result is that there will be more hospitalizations and deaths. (One caveat: Widespread vaccinations could prevent some of those.)
Faster-spreading viruses also require a greater proportion of a population to be protected for herd immunity to be achieved. Vaccine campaigns will have to reach even more people.
That also means that more contagious variants can spread in communities that, even if they hadn’t hit herd immunity, had enough immune people to blunt the circulation of SARS-2.
The arrival of more transmissible variants is “bad news, because that means some places that had already started to see protective effects become vulnerable again,” said Caitlin Rivers, an infectious diseases epidemiologist at the Johns Hopkins Center for Health Security.
What’s happening in Brazil?
A recent study estimated that three-quarters of residents of the city of Manaus, Brazil had been infected by SARS-2 by October. The hope was that this level of protection might act as a buffer against more transmission. But last month, cases started rising in the city and its state of Amazonas, straining local health systems once again.
When researchers dug into the viral sequences, they found many cases involved a new variant, called P.1, as reported last week. (P.1. has also been identified in people who traveled from Brazil to Japan.) They warned the mutations it contained (including E484K) are “potentially associated with an increase in transmissibility or propensity for re-infection of individuals.”
Scientists suspect there are several potential factors at work in Manaus, which could be playing out together. They’re investigating.
Maybe P.1 is indeed able to evade some existing immune protection, leaving people more susceptible to reinfection. Scientists on Sunday confirmed a case of reinfection caused by P.1 in Amazonas.
Or perhaps P.1 is so transmissible that it can spread just fine even in communities with 75% protection.
Or what if some people in Amazonas who were infected months ago are just generally becoming susceptible again to any form of reinfection, regardless of variants? Though immune responses vary, it’s thought that most people who fend off the virus will have lasting protection for some time — but that it will wane. Already, some reinfections have been reported around the world, without the involvement of more transmissible variants. (It’s thought that reinfections with SARS-2 will generally be milder for most people than their initial case because they still have some immune memory to the virus, even if their systems couldn’t block infection entirely. Scientists will be looking out to see if that holds with different variants.)
What are scientists doing about all this?
Studying it from all angles. One line of inquiry is examining the effects of mutations in isolation and in concert with the other changes dotting the virus’ RNA genome. Essentially, a mutation on its own may not have much of an impact, but it can help a virus spread better or replicate faster if it’s paired with certain other mutations.
Scientists are also on the lookout for other potential variants of concern as they comb through sequencing data. But there’s a sense among some experts that new variants are being announced without much helpful information. Lots of mutations will be discovered; it can take some time to figure out what, if anything, each one means.
In California, for example, officials held a press conference Sunday to discuss the L452R variant, which has grown from accounting for 3.8% of samples sequenced in the state in the first half of December to 25.2% of sequences heading into January. “We do not know whether it’s more infectious yet,” UCSF virologist Charles Chiu said, though he added, “it is concerning that it may potentially be more infectious.”
Outside experts were quick to say that more evidence is needed before such a claim can be verified. The variant was first seen in California in May, and hovered at low levels while the state was at low levels of virus overall. Then, it started to increase as the state was suffering from major outbreaks. This can create the illusion that the variant — because it’s so much more prevalent — was perhaps driving the cases. But without more data, it’s just as likely the variant didn’t cause the wave, but simply “went along for the ride,” Goldstein said.
And what can I do about it?
Commit to the same precautions that have been recommended for months, experts say. Perhaps invest in a better mask than a fabric face covering. Get vaccinated when you can.
Public health authorities have been stressing that the new variants aren’t solely responsible for the raging epidemics happening around the world. The United States has never really had a handle on its epidemic, and the most recent surge in cases was driven not by a more transmissible iteration of the virus, but because of lax policies and a lack of precautions.
“It’s too easy to just lay the blame on the variant and say, it’s the virus that did it,” Mike Ryan, the head of the World Health Organization’s emergencies program, said Friday. “Unfortunately, it’s also what we didn’t do that did it, and we have to be able to accept our share individually and as communities, as governments, our share of the responsibility in this virus getting out of control, while recognizing the variants in the virus make it difficult.”
The emergence of the variants has given experts a new line of argument in their regular pleas that people and governments should do all they can to drive down transmission generally. Slowing spread can buy time for more people to get vaccinated before one of the more transmissible variants becomes dominant — which could happen in the United States as soon as March, a model released by the Centers for Disease Control and Prevention last week showed.
And the more the virus spreads, the higher likelihood that even fitter variants will emerge. Evolution is driven not only by the environment the virus finds itself in, but also, as Barclay put it, “the number of times you roll the dice.”
https://www.statnews.com/2021/01/19/coronavirus-variants-transmissibility-disease-reinfection/