Friday, April 16, 2021

Your Evening Audio...Peek-A-Boo

AllTheWorldsA
CoverVille


Just in case you all didn't know by now, I'm a sucker for covers.

Especially acoustical covers. 

So, because of this obsession the algorithm now follows me around with them and this week it through up a most excellent version of Daniel Johnston's 'Peek-A-Boo' by Phoebe Bridgers.

I think it's fair to surmise that both Ms. Bridgers and Mr. Johnston, who passed away recently, have been/were saddled with the descriptor 'genius kid' at various times in their lives.

Anyway, this song, I think, is about what happens when a genius kid decides that the only way forward for them is an an artist.

Here's my shot at it...



______
As anyone who has spent anytime around here at all knows, I'm no artist, but I'm surrounded by them...And it's a wonderful thing indeed.


.

Tuesday, April 13, 2021

The Rare And Serious Adverse Blood Clotting Events Temporally Linked To The Johnson & Johnson COVID-19 Vaccine.



On the weekend (see post-script), we noted that blood clotting events have been noted in a small number of people after they received the Johnson & Johnson vaccine.

This has led to a call for a pause of the vaccine's use in the United States while the American Center for Disease Control's 'Advisory Committee on Immunization Practices' reviews the data (they are scheduled to meet tomorrow/Wednesday).

As Helen Branswell, who is an excellent science journalist, reports in STAT News, the events identified so far are very rare. However, they are also very serious and appear to be similar those that have occurred rarely after administration of the AstraZeneca vaccine:

Federal authorities on Tuesday recommended that states stop using Johnson & Johnson’s Covid-19 vaccine while an investigation is conducted into six serious cases of clotting problems — one of which was fatal — that were reported among women who received the vaccine.

The blood clots are similar to those reported by several European countries after use of AstraZeneca’s Covid-19 vaccine. And they are similar to an event that occurred during Johnson & Johnson’s U.S.-based clinical trial, an event that led to a temporary pause in that trial last fall. That case involved a man in his 20s, STAT reported at the time.

The clotting problem appears to be quite rare. As of Monday, more than 6.8 million doses of the Johnson & Johnson vaccine had been administered in this country...

{snip}

...The blood clots reported in the six cases are known as cerebral venous sinus thrombosis (CVST); in all cases, the clots were seen in combination with low levels of blood platelets, a condition known as thrombocytopenia. All occurred among women between the ages of 18 and 48, the statement from the CDC and FDA said, and symptoms occurred between six and 13 days after vaccination...



Clearly, this is an abundance of caution issueand the pause appears completely reasonable at this time. While the incidence rate is lower for the J&J vaccine than with the AZ vaccine at the moment, that could change with increase surveillance.

If the post-J&J vaccine events truly are the same as those post-AZ innoculation they will hopefully become increasingly diagnosable and treatable, as has been suggested by recently published findings in the New England Journal of Medicine (see Update IV at top of the post).


****

So, what might be causing the problem here?

Originally, some folks speculated that the AZ vaccine issue might be occurring because the spike protein produced by that vaccine was not in the 'locked' conformation which could lead to bits of the protein being released and an initiating a rare adverse immunological response. However, the J&J vaccine produces the 'locked' form of the spike protein, as do the mRNA vaccines for which these types of clotting events have not been reported. Thus, the unlocked spike protein hypothesis has fallen from favour.

Another hypothesis is that the problem might, at least in part, be caused by the adenoviral vehicle that is used to deliver both the J&J and AZ vaccines, but not the mRNA vaccines, to our cells. If that turns out to be the case this could also be problematic for the Russian Sputnik and the CanSino vaccines as well as they, too, are in the adenoviral vaccine 'class'. Helen Branswell reports on that as well:

...The concern over Johnson & Johnson’s vaccine is raising questions about whether there is what’s known as a “class effect” — a problem one would expect to see with all vaccines made in the way the J&J and AstraZeneca vaccines are made. The Sputnik V vaccine, made by Russia’s Gamaleya Research Institute and the vaccine made by CanSino, a Chinese manufacturer, are made in the same way as the Johnson & Johnson and AstraZeneca vaccines.

The four vaccines use modified adenoviruses — viruses that cause colds — to deliver instructions to human cells to make the SARS-CoV-2 spike protein, the exterior proteins that allow SARS-2 viruses to attach to and invade cells. Those vaccine-induced spike proteins teach the immune system to look out for and defend against SARS-2 viruses.

Theories about the cause of the rare clotting issues hinge on the possibility that, in small numbers of people, the adenoviruses trigger an aberrant immune response. That, in turn, results in a rare combination of widespread clotting and low platelet counts...

{snip}

...“It’s a reasonable but unproven assumption that the J&J and AstraZeneca vaccine safety concerns are linked by being related to an immune response against an adenovirus component,” he (John Moore, an immunologist at Weill Cornell University) said. “So, FDA and scientists need time to better understand what is going on, which means a pause is the right course of action.”...


Having noted that, it is important to realize that at this point this is only an hypothesis at this time. Thus, there are no hard data yet to either support or refute it.

****

Here in British Columbia there has been a delay in delivering Johnson & Johnson vaccine but we are  currently offering the AstraZeneca vaccine for folks between 55-65 where the risk/reward ratio tips more heavily towards the latter than it does in younger people. 

Again, the science on what causes these rare adverse clotting events is not clear, but protocols for diagnosing and treating them are being developed and apparently the first case identified in Canada has been successfully treated.

Finally, to reiterate, these events have not been found in people that have received the mRNA vaccines from Pfizer and Moderna.


______
Update, Wed April 14th: Drug development guy Derek Lowe has an excellent overview of all this, including from a regulatory point of view....Here.



.

Saturday, April 10, 2021

You Have Not Heard This One Before...

TheEnemyOfYourViralEnemyIs
AlwaysYourFriendVille


And heckfire...

We even got the same lot on the same day!



(different pharmacies though - mine was at LD at 41st & Victoria)



________
Just a note that I've updated the eariler post about the rare and serious blood clotting events post-AZ vaccine inoculation to include the now published papers on one likely cause, and potential treatments, for the condition.
A group at Cambridge in the UK has put together a solid risk-reward analysis of getting the AZ vaccine... It tilts heavily towards the reward side with increasing age which, of course, is even more of a reason for semi-old folks like Mr. Wilkinson and myself to get this particular jab.
The European Medicines Agency is now investigating a still small number of reported blood clotting events that have been time-associated with Johnson & Johnson vaccine inoculation (scroll down)...Like the AstraZeneca vaccine this, too, is adenovirus-based (the mRNA vaccines from Pfizer and Moderna are not)...So...This is a subject you are likely to hear/read more about in the coming days, particularly given that the Sputnik and CanSino vaccines are also adenovirus-based...To be clear, however, at this point it is by no means certain that the adenoviral-delivery method is the, or even a, causal link to the rare, serious clotting events.



.

Wednesday, April 07, 2021

Europe Updates Its Findings On Rare, Serious Blood Clotting Events Associated With AstraZeneca COVID-19 Vaccination.


_______

Update Saturday April 10th: The paper, mentioned as a pre-print in a previous post, from the German group that originally described the issue has now been peer-reviewed and published in the New England Journal of Medicine...Here....A companion paper that comes, essentially, to the same conclusions from a Norwegian group is...Here.

_______

Pre-post note: If you would like to cut right to the chase and go to an excellent description of this rare, but serious, side effect to the AZ vaccine, as well as specific diagnosis and treatment protocols, please go directly to the Ontario Science Table's  outstanding 'Science Brief'.

_______

As we noted previously, the European Medicines Agency's safety committee (PRAC) has been assessing reports of rare serious clotting issues in people who have received the adenovirus-based AstraZeneca/Oxford COVID-19 vaccine.

The report is now out. It is very worth reading in its entirety.

Here are some highlights:

EMA’s safety committee (PRAC) has concluded today that unusual blood clots with low blood platelets should be listed as very rare side effects of Vaxzevria (formerly COVID-19 Vaccine AstraZeneca)...

{snip}

...So far, most of the cases reported have occurred in women under 60 years of age within 2 weeks of vaccination. Based on the currently available evidence, specific risk factors have not been confirmed...

{snip}

...The Committee carried out an in-depth review of 62 cases of cerebral venous sinus thrombosis and 24 cases of splanchnic vein thrombosis reported in the EU drug safety database (EudraVigilance) as of 22 March 2021, 18 of which were fatal.1 The cases came mainly from spontaneous reporting systems of the EEA and the UK, where around 25 million people had received the vaccine...

{snip}

...One plausible explanation for the combination of blood clots and low blood platelets is an immune response, leading to a condition similar to one seen sometimes in patients treated with heparin (heparin induced thrombocytopenia, HIT). The PRAC has requested new studies and amendments to ongoing ones to provide more information and will take any further actions necessary.

The PRAC stresses the importance of prompt specialist medical treatment. By recognising the signs of bloods clots and low blood platelets and treating them early, healthcare professionals can help those affected in their recovery and avoid complications.

Patients should seek medical assistance immediately if they have the following symptoms

  • shortness of breath
  • chest pain
  • swelling in your leg
  • persistent abdominal (belly) pain
  • neurological symptoms, including severe and persistent headaches or blurred vision
  • tiny blood spots under the skin beyond the site of injection

****

So, the findings are similar to those we discussed last week, based on initial findings in Germany and other European jurisdictions. One important new thing  is that there are now data from the UK to support this finding.

To reiterate, this is a  rare condition. Specifically, there have been 86 events reported out of  ~25 million vaccinated so far. Importantly, the condition is more common in women under the age of 60. A British medical oversight group has attempted to estimate the incidence rate in that specific group. They still find that it is a very rare event but emphasize that more data are required to be certain of the rate of adverse events.

As the EMA notes, it appears that the post-AZ vaccine events may be similar to a rare immunological response to heparin that causes inappropriate clotting inside the blood vessels. 

Unfortunately, at this time it is not possible to tell who will respond to the AZ vaccine in this way  (i.e. 'specific risk factors have not been confirmed'), other than it occurs most often in women under 60. However, a number of post-vaccination physical symptoms of concern have been identified that indicate the need for immediate medical intervention. The latter are outlined in the box above.

As we noted last week, a group in Germany with expertise in the field, including a rare heparin-induced clotting syndrome, has proposed a way to diagnose and treat the AZ vaccine-associated condition. At this time the European Medicine Agency's safety committee (the 'PRAC' quoted above) has asked for more study on this matter. However, the British Hematological Society has posted a 'Guidance on Management' protocol as has a similar German Society For The Study Of Thrombosis and Hemostasis as well as the Ontario Science Table. 

In the case of the Ontario Science Table, they have outlined concrete diagnosis and treatment protocols.  As noted at the top of the post, they also explain things well - it is very worth reading.

Here's hoping that we receive an update on this matter from our National Advisory Committee On Immunization so that Canadians can be confident that we are moving forward with all the best and most appropriate information and procedures possible.



_________
The BCCDC statement on the AZ Vaccine,
which is now being offered to folks 55-65 years of age, is....here....A handout on AZ vaccine aftercare is....here.


.

Monday, April 05, 2021

The SARS-CoV-2 Variants Of Concern.



The graphic above is from Eric Topol of the Scripps Research Institute in San Diego. He is a clinician researcher whose group published important work on asymptomatic spread of the SARS-CoV-2 virus and he has been following COVID-19 developments closely, including the latest on vaccines and variants of concern, including the three shown in the table. All of this is just by way of explaining Topol's bonafides to you. 

Below are some take aways/explanations, focusing on the receptor binding domain or 'RBD' of the 'spike' protein. Much of what I'm going to type can be gleaned from a very recently peer-reviewed and published paper from a group at Oxford in the top-ranked journal 'Cell' titled 'Antibody evasion by the P.1 strain of SARS-CoV-2':

How the variants arise: SARS-CoV-2, like all viruses that have RNA as their genetic material, has an error prone RNA polymerase. The latter is the enzyme that is required to make new genetic material/RNA. The errors lead to mutations in viral genes, including the gene for the spike (S) protein. This produces a viral variant and those mutations can change the 'code' for amino acids in numbered positions in the viral proteins. The mutation in the spike protein that is common to all three 'variants of concern' shown above, all of which are currently present in British Columbia, is the N501Y mutation. This means that 'asparagine' amino acid (code name 'N')  at position 501 in the spike protein has been changed to a 'tyrosine' (code name 'Y') which slightly changes the shape and electrostatic characteristics of the bit of the spike that binds to our cells (that 'receptor binding domain'/RBD again).

How the variants emerge/spread: The spike protein is critical for binding to our cells and getting the virus inside them via the RBD. Thus, when we make our own antibodies against the virus after we've been infected with it, or because we've seen the spike protein before due to vaccination, the ones we make against the RBD portion of the spike protein are the ones that can 'neutralize' the virus and prevent it from infecting our cells. Any mutation/amino acid change in the RBD that increases its ability bind our cells (i.e. could increase transmissibility) or decreases the ability of our antibodies to bind to the RBD (i.e. could cause immune evasion) will give the variant a selective advantage and so lead to its emergence and spread in a given locality/human population where community spread is occurring. When the variants 'take over' due to this advantage it can be a significant problem for public health-based control and vaccine efficacy as noted below.

The spike protein that all the (current) vaccines code for: They all code for the 'classic' spike protein coded for by the original Wuhan viral strain. Most of the vaccine-coded spike proteins have two changes (via 2 proline amino acid mutations/substitutions) that were engineered into them to 'lock' the protein into the configuration/shape that is normally found on the surface of the virus before it binds to cells. The two vaccines that do not have this 'lock' are the Oxford and Sputnik ones, and some researchers are now starting to think that this is why these vaccines aren't as good at producing neutralizing antibodies against some variant spike proteins.  Another thing worth knowing is that the mRNA vaccine makers are already at work making vaccine boosters based on the new varian forms of the spike proteins. Being able to do this quickly and efficiently is one of the advantages of the mRNA vaccine technology.

The B.117/UK variant: This one was first identified in the United Kingdom and, due to it's increased transmissibility, it very quickly spread and became the dominant form of the virus in the fall and early winter of 2020. It has a bunch of spike protein mutations but, as noted above, it also has that N501Y mutation that is common to the other two variants of concern and it is thought that this mutation increases transmissibility. This variant is also appears to be more lethal despite what it says in Topol's table above (about 1.6X). Luckily, it looks like all the current vaccines work reasonably well against this variant. This includes the AstraZeneca vaccine which has been the one that has been rolled out widely to good effect in the UK (for a comment on the rare, serious clotting disorder associated with taking this vaccine, see....here). According to the numbers we have so far, this is currently the most prevalent variant in British Columbia (scroll down). 

The P.1/Brazilian variant: In addition to the N501Y mutation seen in the UK variant, the P.1/Brazilian variant also has E484K (which is sometimes referred to as the 'eeek' mutant) and K417T mutations in the RBD that affect binding to cells and may also contribute to immune evasion. This is the variant that has been spreading rapidly in British Columbia recently, including at Whistler. P.1/Brazilian is also the variant where we have the least hard data. Topol's table states that the effect on transmissibility is not clear, but there is one non-peer reviewed report of an increase of greater than two fold which I assume is the one that local folks are basing their comments on in media reports. The lethality is also not clear, but there have been anecdotal reports that it is problematic in younger patients. 
    So, do the vaccines work against this variant? In a true clinical setting that is not clear as the data are not yet available, but in terms of making neutralizing antibodies it looks like there is reduced activity, but it is still there - the caveat here is that the mRNA vaccines look to be better than the AstraZeneca one (see Figure 7C/D). 

The B.1351/South African variant: It has very similar changes to the RBD as does the P.1 variant. The transmissibility and lethality changes are not clear. However, both the mRNA and Astra Zeneca vaccines least proficient at generating neutralizing antibodies against it (see the same Figure 7C/D). There are clinical data for this variant though. The mRNA vaccines work, but not as well against the 'classic' virus and a small scale, phase II clinical trial concluded that the AstraZeneca vaccine doesn't have much, if any, efficacy. This has caused a lot of concern but it is important to realize that they were only looking at mild-to-moderate disease as an endpoint (as opposed to severe disease, or worse) and the sample size was so small that the 95% confidence intervals were very wide (i.e. the statistical power was low). 
    Here in British Columbia, where we are now rolling out the AZ vaccine to folks 55-65 in a lot of locations (my appointment is on Thursday), one ray of hope on this front is that this variant is still at quite low numbers and it appears, assuming we are on top of things, to be increasing slowly compared to the other two variants.


________
My usual disclaimer here is that, while I am a life scientist and a cell biologist, I am not a virus or vaccine expert...Thus, please understand, that I'm only trying to explain things that have been raised in media reports more fully based on what I can glean from the available scientific literature and the comments of true experts like Eric Topol mentioned above.
We here in B.C. have been lagging a bit with variant tracking but, as Andrea Woo reported in the Globe on the weekend, a group at St. Paul's led by Marc Romney has figured out how to speed that up - their actual paper is here....Here's hoping our PHO and the BCCDC adopt their methods so that we can get closer to real time variant tracking - it looks like it could really help keep us ahead of things, both from public health and vaccine implementation points of view.
Thanks again to all the readers who have sent helpful links to material to have a look at and consider.


.

Saturday, April 03, 2021

Will Saturday Nights Be Alright Without Randy?


WhatEverHappenedTo
UkeCoverFightingVille


The grant applications went in on Thursday and, after a couple of sleeps, my brain is starting to recover.

Neither grant had anything whatsoever to do with viruses or vaccines which is not the least bit surprising given that, as noted previously, neither of those subjects is my specialty.

However, given recent developments, especially here in Lotusland (i.e. British Columbia's Lower Mainland), I am doing my best to get up to speed with the latest on the SARS-Cov-2 viral variants of concern and vaccine responses to them. Hopefully, if I can make reasonable sense of the rapidly evolving literature, I'll be able to write a coherent post soon.

In the meantime, now that we know for sure that Randy's Vinyl Tap has been officially cancelled, I thought now might be the time to point interested readers (here's looking at you E.G.) to a complete archive of a similarly themed but, dare I suggest superior, radio show called 'Theme Time Radio Hour' that the almost octagenerian Bob Dylan put together a few years ago.

Weirdly, it's hard to find Dylan's complete series on podcasting apps (at least the ones I use). Surprisingly, however, all 100+ episodes have been archived somehow by fans and enthusiasts (as opposed to a megamediacorporatocracitic entity)...Here.

Talk to you all soon




______
Subheader?...It used to be a weekly thing 'round here.
Thanks to everyone who has sent me variant info...It's been helpful...I'm really doing my best to stay away from the finger pointing/hockey team stuff and stick to reading the most pertinent scientific publications, including an important recent one by a local group at St Paul's. 



.

Monday, March 29, 2021

The AZ Vaccine And The Rare But Serious Clotting Disorder.

TheCautionFlagIs
OutVille

_______

Update IV, Sat April 10th: The paper, mentioned as a pre-print in the original post, from the German group that originally described the issue has now been peer-reviewed and published in the New England Journal of Medicine...Here....A companion paper that comes, essentially, to the same conclusions from a Norwegian group is...Here.

Update III, Wed April 7th...The European Medicines Agency has provided an update, supported by data from the UK and concludes that this is a rare adverse event...We discuss this update...Here.

Update II, Wed Mar 31st...BC is now offering AZ Vaccine to folks 55-65 in the Lower Mainland due to the high rates of viral infection in the region...Announcement is here....Pharmacies to contact are here...I'm in the age group and will be getting the vaccine...The syndrome described below is  very rare and there is now a protocol to treat it if it does occur.

Update I, Tues March 30th, at bottom of post
______


On Saturday March 27th the top of the ladder journal Science published an information piece (i.e. not a primary data paper) on the rare but serious cases of blood clotting/thromboses with platelet problems in folks who have received the AstraZeneca COVID-19 vaccine. 

The piece was written by contributors Kai Kupferschmidt and Gretchen Vogel and it is good.

One of the issues is the differing incidence rates in various jurisdictions including...

The UK:

...The United Kingdom has officially reported only 5 cases—despite administering 11 million doses of the AstraZeneca vaccine...

Compared to, for example, Norway:

...Norway, which has administered the AstraZeneca vaccine to 130,000 people under 65, has reported five patients who had low platelets, hemorrhage, and widespread thromboses, three of whom died...


Why the difference?

Well, one possible explanation is the way the vaccine was initially used in continental Europe compared to the UK:

...So far, most cases have been observed in women under 65. But that could be because of the vaccinated population: Many countries initially used AstraZeneca only in people under 65 because early clinical trials included few older recipients. That meant the vaccine was used in priority groups such as health care workers and teachers, a majority of whom are women. In Norway, for example, 78% of the AstraZeneca doses went to women, says Sara Viksmoen Watle, chief physician at the Norway Institute of Public Health. The United Kingdom, however, used the vaccine first in older people, which may explain why fewer unusual clotting events have been spotted there...


So, can this problem be dealt with?

Well, there is a group in Germany led by a researcher named Andreas Greinacher that is calling the syndrome 'vaccine-induced prothrombotic immune thrombocytopenia' (VPIT). They think that VIPIT has similarities to another rare condition called 'heparin-induced thrmobmocytopenia' (HIT) that is caused when the body makes its own antibodies against a complex of the blood thinner heparin and a factor called PF4  that causes massive platelet activation and thus clotting. Greinacher says that VPIT can be diagnosed and treated in a manner similar to the way that HIT is dealt with:

...Greinacher agrees on the need for more data. But he says it's crucial to alert doctors to the potential complication. When recognized in time, HIT can be treated with immunoglobulins—nonspecific antibodies from blood donors—that help put the brakes on platelet activation. Non-heparin blood thinners can help dissolve the clots. VIPIT should be treated in a similar way, he says. In at least one case, Greinacher says, a doctor sought the group’s advice and the patient recovered...


The work of the German group has not yet been peer-reviewed, but they have placed the data on a public pre-print server so that it can be scrutinized by experts in the field. And, at the very least, the British Society for Hematology and the German Society for the Study of Thombosis and Hemostasis (of which Dr. Greinarcher is a member) are taking the matter very seriously and issuing guidelines for monitoring and potentially treating the issue. In addition, the European Medicines Agency is having a very close look at all the data and it is expected to report on the matter next week (Apr 6-9th). 

Given all this a number of jurisdictions have put age restrictions on the AZ vaccine:

...Many countries are, for now, accepting the risk that the AstraZeneca may carry, but several have restricted its use to people who are at the highest risk of dying from COVID-19: those aged 55 or older in France, 65 or older in Sweden and Finland, and 70 or older in Iceland...


It would appear that Canada's decision to do the same, despite the fact that no cases this disorder have yet been detected after the administration of 300,000 doses of the AZ vaccine nationally, is, at least for the moment, a prudent one, particularly given that we have other vaccines at hand.



______
The National Advisory Committee on Immunization (NACI) recommendation and rationale is...Here.
The Ontario Science Table's COVID-19 Response website also has an excellent primer on VPIT....Here.
Apologies for being mostly offline as this and the variant growth has been unfolding locally but it's grant writing season for me which has curtailed my reading on all things COVID somewhat for the last couple of weeks or so.
Update, Tues Mar 30th: Kai Kupferschmidt, one of the co-authors of the piece quoted above, reports on Germany's updated numbers... 2.7 million AZ vaccine doses administered, 31 cases of cerebral venous thromboses (29 in women age 20-63), 19 with thrombocytopenia...This is likely a considerably higher rate than would be seen in the population.


.

Wednesday, March 24, 2021

And So It Begins...

OhWoeAre
TheeVille



Following up on the good Mr. O'Toole's inability to yank the base toward a faux center last weekend, the self-proclaimed head trainer has grabbed hold of the leash and is attempting to lead the pack back to an old familiar kennel...



______
Tip O' The Toque
to Alison of Creekside.

.

Saturday, March 20, 2021

Erin O'Toole Learns That The Conservative Party Of Canada Is Full Of Conservatives.

RunRunRunRunRunRun
AwayVille


Mr. O'Toole, the man who would like Canadians to believe that he and his will meet them 'in the middle' during the next federal election campaign, made his case to the CPC faithful at their convention earlier today as reported by John Paul Tasker of the CBC:

...O'Toole told delegates the party "cannot ignore the reality of climate change" and that the debate "is over."

"We must also recognize that Canadians expect us to have a real plan for the environment. We need to boldly reclaim the environment as an area where Conservatives are leaders," he said.

O'Toole also said he doesn't want Conservative candidates to be branded as "climate change deniers" in the next election campaign...



A few hours later a majority of the faithful told O'Toole where to go:

...Conservative delegates at the party's policy convention have voted to reject adding green-friendly statements to the policy book — including a line that would have stated the party believes "climate change is real" and is "willing to act."...

{snip}

...Delegates issued a rebuke to climate-minded Conservatives and rejected the policy shift by a margin of 54 per cent to 46...



This could get interesting.



______
SubHeader Earworm rising?....This.


.

Thursday, March 18, 2021