M

Mr._Clark

Audioholic Field Marshall
You'd have to admit that the biorx preprint does not disprove the hypothesis that pangolins look like giant artichokes.
 
Swerd

Swerd

Audioholic Warlord
What is the bivalent booster?
The original mRNA vaccines, made by Pfizer and Moderna, were tested in 2020 and put into use starting in December 2020 and January 2021. The mRNA in both of them contained the coding sequence of the SARS-CoV-2 virus spike protein as it was first sequenced in 2019.

The bivalent booster vaccine contains two spike protein coding sequences – the original 2019 version (same as above) plus sequences from last year's Omicron BA.4 and BA.5 variants. There are now educated guesses about how well it should work, but we'll find out for certain this next winter.

I got mine nearly 2 weeks ago. At the same time, I also got this year's flu vaccine in the other shoulder.

I wouldn't wait to get the bivalent booster. November and December, the Thanksgiving and Christmas holidays, have often been when viral diseases get widely spread. If you get the booster now, you will have allowed the roughly 2 weeks needed by your immune system to fully react to the booster before those holidays begin.
 
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Swerd

Swerd

Audioholic Warlord
You'd have to admit that the biorx preprint does not disprove the hypothesis that pangolins look like giant artichokes.
That biorx preprint is an article that has been submitted to a scientific journal for publication. It has not yet received peer review nor has it been approved for publication. Essentially, if it's neatly typed, it can appear as a pre-print.

If, after review, it does get approved for publication, the journal might very well require some wording changes to the conclusions. After reading it, I thought it's conclusions were worded too strongly. It claimed that endonuclease cleavage site indicates a synthetic origin. I think it should be changed to suggests that a synthetic origin might be possible.

To justify the use of the word "indicates" the paper would have to present data to demonstrate (or be consistent with, at the very least) that a synthetic origin actually happened. No such data was presented. What the authors did present only suggests that a synthetic origin cannot be ruled out.

In other words, I'm not impressed. We already knew that 3 years ago.
 
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Swerd

Swerd

Audioholic Warlord
This is a follow up to my previous post (Post #8,243) …

Today, I read an article in the Washington Post, that got me riled up.
Senate Republican staffers have produced a report laying out their argument that the “most likely” origin of the coronavirus pandemic was some kind of “research-related incident” in China. It cited safety lapses in laboratories there and arguing that there are evidentiary gaps in published scientific research that points to a natural origin from animals sold at a market in Wuhan.

The report, while not a formal scientific document, represents a possible template for a future investigatory hearing in Congress if Republicans gain control of the House or Senate — or both — following the midterm elections. The so-called “lab leak” theory is a talking point for some Republicans seeking office, and Sen. Rand Paul (R-Ky.) has promised hearings if his party wins the Senate.

The 35-page “interim” report released Thursday comes from Sen. Richard Burr (R-N.C.) and Republican staffers on the Senate Health, Education, Labor and Pensions Committee, which has been probing the origin of the virus.
I want to emphasize two points:
  1. The GOP report is is not a formal scientific document. It's entirely political.
  2. The report ignored two recent publications (published back to back in the same issue of the highly respected journal Science) that presented sharply different conclusions – that the Huanan Seafood Market was the site of the outbreak.
The report’s conclusions diverge sharply from those of two peer-reviewed studies published in the journal Science this summer that presented the case for the Huanan Seafood Market as the epicenter of the outbreak. One study found a geographical bull’s eye on the market among early cases of the disease that came to be called covid-19. The other study presented an analysis of two early strains of the virus suggesting that there were two and maybe many more distinct spillovers of the virus from animals sold at the market.
https://www.science.org/doi/10.1126/science.abp8715

https://www.science.org/doi/10.1126/science.abp8337

Both of these articles presented a strong case favoring the market origin. But the authors do not know which animals were infected or where they came from – because no animals at the market were tested before the market was closed and cleaned.

The GOP report stated that “Critical corroborating evidence of a natural zoonotic spillover is missing. While the absence of evidence is not itself evidence, the lack of corroborating evidence of a zoonotic spillover or spillovers, three years into the pandemic, is highly problematic."

Michael Worobey, a professor at the University of Arizona who co-authored both studies published in Science, said the new GOP report “gets the science completely wrong.”

“As the saying goes, when you mix science and politics, you get politics,” he said.

And that's my point too. Politicians who ignore science, do it at their own risk.

The authors of that pre-print (the subject of my previous post) will very likely get a letter from the editors of what ever journal they submitted it to, telling them their manuscript is rejected because it ignores those two papers published last July in Science.
 
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M

Mr._Clark

Audioholic Field Marshall
Got my Moderna bivalent booster today. So far, the only effect is a slightly sore shoulder.

If I may vent a little, I went to a local pharmacy that advertises "walk in boosters." Silly me, I thought this suggested at least a hint of "quick" might be involved. It turns out a more complete description would be "walk in, followed by waiting to get a form to fill out, followed by sitting and waiting, followed by more sitting and waiting, followed by more waiting . . ."

I noticed that a couple recent preprints suggested that the bivalent boosters didn't produce a better neutralizing antibody response than the original boosters (both produced a significant immune response).

>>>"There was no significant difference in neutralization of any SARS-CoV-2 variant tested between individuals who received a fourth monovalent vaccine and those who received a fourth dose of a bivalent vaccine," concluded one study, which has yet to be peer-reviewed, posted by the team led by Ho. . . .

Barouch said a phenomenon called immune imprinting may turn out to be the culprit for the disappointing immune response to the updated booster.

Immune imprinting, also known as "original antigenic sin," refers to the theory that the initial exposure people had to an earlier strain of the virus — either from infection or vaccination — may hinder the ability of the body to produce antibodies to new strains.<<<


Apparently the studies also did not show much of a boost in @Swerd's favorite immune cells:

>>>His team also measured another part of the immune response from T cells. Those were "not substantially" boosted by additional shots from either the bivalent or original formulations.

"We all talk about antibodies, the focus has been on antibodies, but there's two sides to the immune system: antibodies and T cells. And we believe that both are important for protection against severe disease," said Barouch.<<<

I'm curious if further studies confirm that immune imprinting is a significant issue. It looks like it's just a best guess right now that this might explain the results for the bivalent vaccines so far.
 
Swerd

Swerd

Audioholic Warlord
Got my Moderna bivalent booster today. So far, the only effect is a slightly sore shoulder.

If I may vent a little, I went to a local pharmacy that advertises "walk in boosters." Silly me, I thought this suggested at least a hint of "quick" might be involved. It turns out a more complete description would be "walk in, followed by waiting to get a form to fill out, followed by sitting and waiting, followed by more sitting and waiting, followed by more waiting . . ."

I noticed that a couple recent preprints suggested that the bivalent boosters didn't produce a better neutralizing antibody response than the original boosters (both produced a significant immune response).

>>>"There was no significant difference in neutralization of any SARS-CoV-2 variant tested between individuals who received a fourth monovalent vaccine and those who received a fourth dose of a bivalent vaccine," concluded one study, which has yet to be peer-reviewed, posted by the team led by Ho. . . .

Barouch said a phenomenon called immune imprinting may turn out to be the culprit for the disappointing immune response to the updated booster.

Immune imprinting, also known as "original antigenic sin," refers to the theory that the initial exposure people had to an earlier strain of the virus — either from infection or vaccination — may hinder the ability of the body to produce antibodies to new strains.<<<

Apparently the studies also did not show much of a boost in @Swerd's favorite immune cells:

>>>His team also measured another part of the immune response from T cells. Those were "not substantially" boosted by additional shots from either the bivalent or original formulations.

"We all talk about antibodies, the focus has been on antibodies, but there's two sides to the immune system: antibodies and T cells. And we believe that both are important for protection against severe disease," said Barouch.<<<

I'm curious if further studies confirm that immune imprinting is a significant issue. It looks like it's just a best guess right now that this might explain the results for the bivalent vaccines so far.
Those initial studies of the effectiveness of the bivalent Covid-19 vaccine have been limited, too limited to make any real conclusions. The only useful conclusion so far is that they are no worse than the original vaccine – in the short run. And they may or may not be any better.
  1. The studies I've read only tested for antibodies in plasma from immunized people, shortly after (a few weeks, maybe a month) they received the booster. If they mentioned T-cells, it was only to say they didn't test for that activity. Those T-cell assays may be underway now, but their results are not yet available. And I'm rather certain that they will not be done in enough immunized people to make statistically valid comparisons between antibody and killer T-cell activity.

  2. To address the question of Immune Imprinting, large clinical trials would have to test immunizations with the bivalent vaccine(s) among several different populations of people who all share the same prior immunizations and history of prior Covid-19 infections. Such a study would require 2 or more arms, where each arm consists of people with common histories of prior immunizations or virus exposure, but different from the histories of people on other arms. Each arm would have to be large enough to allow valid statistical comparisons with the other arms. This won't be easy, and I doubt if it's being done on a large enough scale. Until it's done, immune imprinting is limited to hand-waving theoretical descriptions. Barouch, a respected immunologist at Harvard Med School, knows how to talk about this without over-interpreting the results. He also knows how to talk about this while side-stepping any differences between reliably tested clinical results and theories that are probably true but not yet demonstrated to be true.
Since the pandemic began early in 2020, we have seen that the popular press cannot reliably report about these kinds of scientific uncertainties.
 
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mtrycrafts

mtrycrafts

Seriously, I have no life.
...
Since the pandemic began early in 2020, we have seen that the popular press cannot reliably report about these kinds of scientific uncertainties.
In general, people don't like uncertainties. ;) :D
And some like to gamble like my oldest.
 
M

Mr._Clark

Audioholic Field Marshall
Got my Moderna bivalent booster today. So far, the only effect is a slightly sore shoulder.
Got the booster Friday, had a headache Saturday morning that lingered all day. Everything seems normal today.
 
M

Mr._Clark

Audioholic Field Marshall
Eric Topol has a cautiously optimistic view of the BQ.1.1 variant. Although it seems to evade immunity in lab testing, so far it has not lead to a wave of hospitalizations in France where it is widespread.

>>>And despite the BQ.1.1 wave in France , new Covid hospitalizations were on the decline throughout, as you can see below. The worry about this highly immune evasive variant with such troublesome multiple mutations beyond BA.5 has not played out as even a significant wave of new cases, no less severe Covid. . . . This uncoupling of lab assays of immune escape vs a benign clinical outlook is the first we have seen in the pandemic. Previously, substantial increments in immune evasion were associated with significant new waves, such as the Beta variant wave in South Africa, the Gamma variant in South America, or the different Omicron lineages throughout the world. . . .<<<

He states that the bivalent booster is effective against the variants, but it is underutilized here in the U.S.:

>>>Of course, there are still reasons for concern. The US hospitalizations for Covid have not gotten below 25,000 for several months and now they are ticking up a bit, especially in people age 70+ (lower graph). That’s occurring without a BQ.1.1 effect giving a relatively high baseline to build from. . . . That’s where the bivalent booster, which has been grossly under-utilized, needs to kick in. We’ve learned, as I reviewed in recent daily updates, that the bivalent BA.5 booster helps protect against BQ.1.1 and BA.2.75.2, another potentially troublesome variant here (at lower levels) in the US. Only ~15% of people age 50 and older, the group with most to gain from the bivalent booster, have yet received it.<<< (emphasis added)

 
M

Mr._Clark

Audioholic Field Marshall
As I understand it, this paper identifies a spike protein that is present in all betacoronaviruses and a corresponding neutralizing antibody.

It's not clear to me how significant this is. My best guess is that testing would be required to determine how effective a vaccine based on this antibody would be in the "real world."

@Swerd would you be willing to weigh in on this?

>>>The characteristics of antibodies that
broadly neutralize coronaviruses are
poorly understood. Here, Dacon et al.
identify a class of stem helix-specific
monoclonal antibodies from COVID-19
convalescent donors that neutralize
diverse betacoronaviruses, use an
IGHV1-46/IGKV3-20 gene signature, and
bind in a conserved manner to the spike
protein.<<<

1667917716873.png


 
Swerd

Swerd

Audioholic Warlord
In response to @Mr._Clark

Thanks for posting the link to PDF copy of the paper. I think that format is easier to read.

On a quick read, that paper is good. I can't quibble with what it actually says. Papers published by Cell and it's various sub-journals are almost always very good.

But it does focus only on the antibody-mediated arm of immunity. The authors looked only at the various antibodies they identified in plasma from previously infected patients. In their search, they looked at all antibody epitopes (targets), not just those that bind to the Spike protein's receptor binding domain (RBD). The majority of those antibodies were non-neutralizing and bound to the K814 residue of the Spike protein.

Note: K814 is an amino acid residue located at a poorly characterized site just N-terminal to the S20 cleavage site and fusion peptide region, and is part of loop that extends to the side of the spike protein (Figure 2B). It is not part of the RBD. This residue has also been recently identified as a target of two other SARS-CoV-2 S2-specific mAbs, suggesting that this is a common recognition site (Chen et al., 2021).​

However, 11 antibodies targeted the conserved stem helix in the Spike protein's S2 subunit and cross-neutralized betacoronaviruses from different subgenera, highlighting the importance of this site as a target of neutralizing antibodies in conjunction with reports from previous studies.

The authors say the target of those 11 antibodies may be more important to focus on for future vaccines and therapeutic monoclonal antibodies.

All of that looks good. But it ignores a good half of the immune response against SARS-CoV-2, the T-cell response. What targets do the various Killer T-cells focus on in previous infected patients? Are they similar to the targets the antibodies focus on, or are they different?
 
M

Mr._Clark

Audioholic Field Marshall
In response to @Mr._Clark

Thanks for posting the link to PDF copy of the paper. I think that format is easier to read.

On a quick read, that paper is good. I can't quibble with what it actually says. Papers published by Cell and it's various sub-journals are almost always very good.

But it does focus only on the antibody-mediated arm of immunity. The authors looked only at the various antibodies they identified in plasma from previously infected patients. In their search, they looked at all antibody epitopes (targets), not just those that bind to the Spike protein's receptor binding domain (RBD). The majority of those antibodies were non-neutralizing and bound to the K814 residue of the Spike protein.

Note: K814 is an amino acid residue located at a poorly characterized site just N-terminal to the S20 cleavage site and fusion peptide region, and is part of loop that extends to the side of the spike protein (Figure 2B). It is not part of the RBD. This residue has also been recently identified as a target of two other SARS-CoV-2 S2-specific mAbs, suggesting that this is a common recognition site (Chen et al., 2021).​

However, 11 antibodies targeted the conserved stem helix in the Spike protein's S2 subunit and cross-neutralized betacoronaviruses from different subgenera, highlighting the importance of this site as a target of neutralizing antibodies in conjunction with reports from previous studies.

The authors say the target of those 11 antibodies may be more important to focus on for future vaccines and therapeutic monoclonal antibodies.

All of that looks good. But it ignores a good half of the immune response against SARS-CoV-2, the T-cell response. What targets do the various Killer T-cells focus on in previous infected patients? Are they similar to the targets the antibodies focus on, or are they different?
Thanks. I wondered about the T-cell response.

Based on my (extremely) rudimentary google-based research, it appears to me that T cells "recognize" (not sure of the proper word) specific peptides on the surface of infected cells rather than proteins on the virus itself, and there's therefore probably no way to know for sure without further studies if a vaccine based on this conserved section of the helix protein would result in an effective T cell response? In other words, if I'm following this, it appears to me that there's no way to know for sure based on the results of the paper if the conserved spike protein would result in peptides on the surfaces of infected cells that would be recognized by T cells?

>>>Antigen recognition by T cells
. . . T cells can detect the presence of an intracellular pathogen because infected cells display on their surface peptide fragments derived from the pathogen's proteins. These foreign peptides are delivered to the cell surface by specialized host-cell glycoproteins. . . .

3-11. A T-cell receptor recognizes antigen in the form of a complex of a foreign peptide bound to an MHC molecule
Antigen recognition by T-cell receptors clearly differs from recognition by B-cell receptors and antibodies. Antigen recognition by B cells involves direct binding of immunoglobulin to the intact antigen and, as discussed in Section 3-8, antibodies typically bind to the surface of protein antigens, contacting amino acids that are discontinuous in the primary structure but are brought together in the folded protein. T cells, on the other hand, were found to respond to short contiguous amino acid sequences in proteins. These sequences were often buried within the native structure of the protein and thus could not be recognized directly by T-cell receptors unless some unfolding of the protein antigen and its ‘processing’ into peptide fragments had occurred (Fig. 3.14).

Figure 3.14. Differences in the recognition of hen egg-white lysozyme by immunoglobulins and T-cell receptors.
Figure 3.14
Differences in the recognition of hen egg-white lysozyme by immunoglobulins and T-cell receptors. Antibodies can be shown by X-ray crystallography to bind epitopes on the surface of proteins, as shown in panel a, where the epitopes for three antibodies (more...)<<<


Please humor me and pretend that was a good question if I'm way off track on this :)
 
Swerd

Swerd

Audioholic Warlord
Thanks. I wondered about the T-cell response.
… …
Please humor me and pretend that was a good question if I'm way off track on this :)
I'm simply glad that at least one reader here has learned to wonder about T-cell responses. But the reality, as I understand things, is not quite as you presented in that cut & paste job from the book you cited. I doubt if the book got it wrong. But unless you already understand more of the big picture, it would be easy to select excerpts and get very confused. I don't know of a good treatment of the complex subject of immunology, that is also short.

T-cells and antibodies recognize infectious viruses, bacteria, or other microorganisms by similar, but not identical, methods. Mature T-cells have cell surface proteins that are related to antibodies, but not identical to them. Both react to the intact coronavirus Spike protein they encounter without digesting it into small protein fragments.

The antibodies recognize and bind to infectious virus particles that float around in the blood. Produced in great quantity by other infected cells in the same host, these viruses spread the infection within the host. If the antibodies coat a virus particle with enough antibodies, they are said to neutralize the virus particles. These coated virus particles are eaten up by other immune cells, such as macrophages, because they are coated with those antibodies. In that sense, macrophages act as non-specific garbage collectors. The result is that the blood becomes cleared of circulating infectious virus particles.

The Killer T-cells don't bother with circulating infectious virus particles. They recognize and kill host cells that have been infected by the virus. These infected cells have been hijacked by virus particles, becoming factories to produce thousands more infectious virus particles, spreading the infection. These cells also have cell surface proteins called major histocompatability complex proteins (abbreviated as MHC, or sometimes HLA, which stands for human leukocyte antigens). The MHC proteins identify the host cells as coming from the same host organism as the T-cells themselves. MHC or HLA therefore identify the cells as "self" cells that also produce a foreign or "non-self" protein, the virus Spike protein. Once an activated T-cell contacts and recognizes an infected cell, the T-cell punches holes in the cell's membrane, causing it to die. T-cells can do this job many times over, while antibodies do their job only once because they get cleared away as garbage by the macrophages.

It is the mechanisms that lead to developing mature T-cells or B-cells (the cells that secrete antibody proteins) where partial digestion of a potential target protein, such as the Spike protein, takes place. The paragraphs you quoted from that book seem to confuse those separate events. Those processes themselves are also quite complex, and I won't go into them. I'll stick to the functions of mature T-cells vs. the functions of secreted antibodies, as produced by mature B-cells.
Based on my (extremely) rudimentary google-based research, it appears to me that T cells "recognize" (not sure of the proper word) specific peptides on the surface of infected cells rather than proteins on the virus itself, and there's therefore probably no way to know for sure without further studies if a vaccine based on this conserved section of the helix protein would result in an effective T cell response? In other words, if I'm following this, it appears to me that there's no way to know for sure based on the results of the paper if the conserved spike protein would result in peptides on the surfaces of infected cells that would be recognized by T cells?
Basically, you've got that right.

The only way we now have to assess whether a vaccine induces T-cell-based immunity vs. antibody-based immunity would be to measure them both in large numbers of infected people. The lab assays for neutralizing antibodies are quick & easy, lending them to be done on blood drawn from thousands of people. The assays for T-cell recognition are much more difficult, expensive, and much slower. At best, they can be done on dozens or maybe hundreds of people. If we want to address that question in large numbers of infected people, we are left with clinical evaluations of large numbers of infected people. Do these the clinical outcomes of all the patients correlate better with antibody or T-cell functions done in the lab with samples from some of those same patients?

I don't think there will be a clear cut answer. My bet is that you need both T-cell and antibody arms of the immune system.

Caveat: I am vastly oversimplifying the details of an immune response. But I hope my answer makes it clear that expecting one arm of the immune system to work without the other arm acting is unrealistic. For example, the B-cells that must mature and produce large amounts of specific antibodies to an infectious virus can't do that without help and guidance from another population of T-cells, cleverly called Helper T-cells. These Helper T-cells recognize features on the virus particle and secrete cytokine proteins (interleukins) that signal immature B-cells to develop & mature, while paying attention to those non-self virus particles. The result is mature B-cells that secrete many thousands of antibody proteins. So antibody production can't take place without Helper T-cells. The Killer T-cells don't work without similar help.

I'll stop there.
 
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M

Mr._Clark

Audioholic Field Marshall
I realize that the great mask debates are largely behind us, but this article in the NEJM presents pretty strong evidence that masking requirements in schools reduced COVID cases:

>>>Conclusions
Among school districts in the greater Boston area, the lifting of masking requirements was associated with an additional 44.9 Covid-19 cases per 1000 students and staff during the 15 weeks after the statewide masking policy was rescinded.<<<

 
highfigh

highfigh

Audioholic Slumlord
You'd have to admit that the biorx preprint does not disprove the hypothesis that pangolins look like giant artichokes.
That conjures some odd image of a party where people call the Pangolin to them, so they can remove scales for dipping in some kind of sauce. Take a few, pat it on the head and send it to the other guests.

Or, Pangolin bowling-

1668094750570.png


Kind of looks like the FireFox logo.
 
GO-NAD!

GO-NAD!

Audioholic Spartan
I realize that the great mask debates are largely behind us, but this article in the NEJM presents pretty strong evidence that masking requirements in schools reduced COVID cases:

>>>Conclusions
Among school districts in the greater Boston area, the lifting of masking requirements was associated with an additional 44.9 Covid-19 cases per 1000 students and staff during the 15 weeks after the statewide masking policy was rescinded.<<<

I'm hearing more strident calls up here every day to re-institute masking protocols.
 
ryanosaur

ryanosaur

Audioholic Overlord
I decided it was more important to get boosted sooner than later so I have an appointment on the 18th for my bivalent upgrade. Still would love to see some more reports on the human trials, but risking another bout just isn't worth it.
 
D

Dude#1279435

Audioholic Ninja

In a startling revelation, a Washington Post analysis has found that more vaccinated people are now dying of the Covid disease and 58 per cent of coronavirus deaths in August in the US "were people who were vaccinated or boosted".

For the first time since the beginning of the pandemic in early 2020, a majority of Americans dying from Covid were at least partially vaccinated, according to the new analysis of federal and state data.

"In September 2021, vaccinated people made up just 23 per cent of coronavirus fatalities. In January and February this year, it was up to 42 per cent," the report mentioned.

The death among vaccinated people is increasing due to the waning efficacy of Covid vaccines and "increasingly contagious strains of the virus being spread to elderly and immunocompromised people" among those who have taken at least one vaccine dose.

"We can no longer say this is a pandemic of the unvaccinated," said Kaiser Family Foundation vice president Cynthia Cox, who conducted the analysis on behalf of the Washington Post.

Outgoing White House Chief Medical Adviser, Anthony Fauci has emphasised the safety and efficacy of the approved Covid vaccines in preventing severe illness and deaths, encouraging people to get vaccinated and boosted as soon as possible.

He said that coronavirus vaccine effectiveness wanes over time and the disease shouldn't be compared to other vaccine-treatable illnesses because of new emerging variants.

"My message, and my final message, maybe the final message I give you from this podium, is that please, for your own safety, for that of your family, get your updated Covid-19 shot as soon as you're eligible to protect yourself, your family and your community," Fauci said.

"I urge you to visit vaccine.gov to find a location where you can easily get an updated vaccine, and please do it as soon as possible."

Older people were always especially vulnerable and now make up a higher proportion of Covid fatalities than ever before in the pandemic, reports Scientific American.

Today in the US, about 335 people will die from Covid -- a disease for which there are highly effective vaccines, treatments and precautions, it added.

"Covid deaths among people age 65 and older more than doubled between April and July this year, rising by 125 per cent," according to the Kaiser Family Foundation.

The World Health Organization reported a nearly 90 per cent drop in recent Covid-19 deaths globally compared to nine months ago, but still urged vigilance against the pandemic as new variants continue to rise.

Overall, the WHO has reported 629 million cases and 6.5 million deaths linked to the pandemic.
 
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