May 8, 2021

Coronavirus Variants Part 1: New York City

Today I wanted to review what we know about the NYC Variant and other variants found in NYC.  Very little genomic sequencing was done in the US prior to February 2021.  Since then NYC surveys approximately 1100 viruses per week from samples obtained and sequenced in labs here - a very exhaustive process.  I follow the weekly reports to see what variants are circulating, and today outline the variants as of 5.4.21 and review a report from MMWR (the CDC weekly bulletin) on the NYC Variant.  In the first genomic data reported (2.14.21) the NYC variant (B.1.126) accounted for 29% of the variants, the UK variant (B.1.1.7) was 7%, and other variants accounted for 0-1.2%.  Now the NYC variant was 36.7%, the UK variant was 41.5% and only the P.1 Brazilian variant was >1% at 3.6%.  The UK variant definitely increased demonstrating its increased transmissibility.  The NYC variant has increased, but it's trajectory is much slower than the UK variant.

NYC Variant:  There are two subgroups of the NYC Variant, which was originally isolated from an immune deficient patient in Manhattan.  Now the dominating subgroup of the circulating NYC variant is the one which contains the E424K "EEK" mutation - which is present in both the South African and Brazilian variants.  The CDC, after studying patients with either the NYC or UK variant concluded:

1.  The NYC variant does not cause more severe disease.  2.  It is not associated with breakthrough cases after vaccination.  3.  It does not cause more reinfections in patients who had Covid-19.  4.  71% of patients are symptomatic.  Much more testing and analysis is needed, but this is a good start. See  Below

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The next Blog Post, Part 2, will review data on variants in other countries:  There is data from Israel on the efficacy of the Pfizer vaccine against the UK and South African variants.  But there are also studies that are reported from Qatar and I will need to look at them before I can pass along the information. 

 

May 5, 2021

Covid Collage/Info #100: Grandma's Happiness!

You may have already heard that last Friday Pfizer submitted data to amend their EUA to vaccinate 12 to 15 year old children.  My happy dance means that 3 more of our grandchildren may be vaccinated and hopefully before they go to camp.  My 17 and 16 year old grandchildren were vaccinated already without any problems.  Determination of safety, tolerability and immunogenicity of vaccines is usually done systematically like this in younger and younger age groups. This group could take the 2 standard doses of Pfizer vaccine 3 weeks apart, but for younger children reduced doses will also have to be established and tested.  There will be 3 more age groups to be tested and Pfizer will also have to submit data from each randomized placebo-controlled trial.

There were 2,260 adolescents enrolled in this study - with or without a prior history of Covid-19.  Eighteen (18) cases of Covid-19 were seen in the placebo group vs 0 in the vaccinated group.  Neutralizing antibodies were tested and the immune response was even greater than that seen in 16-25 year old volunteers in the previous trial.  The vaccine was well tolerated, with side effects generally consistent with those in the 16-25 year old range. All of the participants in the trial will continue to be followed for a full 24 months, like the original Pfizer phase 3 trial.  The FDA and then the CDC independent scientific advisory board will hopefully approve the amendment quickly.   Then vaccinations can begin.  See Below  

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Pfizer also has an ongoing Phase 1/2/3 study in 3 decreasing age groups: Children 5-11 years, 2-5years, and 6 months to 2 years.  The 5-11 year old group began dosing last week and the 2-5 year old group will begin one week after that.  Moderna is also conducting similar trials.  In the last few weeks experts say that herd immunity will not be achieved in the US, and the next wave and clusters of cases will spread quickly in the susceptible groups.  With increased variant transmissibility, one susceptible population may now become children.  That is frightening to me.  This is my 100th collage and Covid-19 discussion since last Spring - and at some point I will have to decide when to return to warm weather outdoor sketching instead.

 

May 1, 2021

Children Who Lost Parents and Deaths of HCW

I read two pandemic papers several weeks ago that made me very sad.  While we've all been alarmed at the number of deaths due to Covid-19 these two studies focused on the number of (1)  children who lost a parent and (2) deaths of health care workers.  I don't understand the modeling methods used in the first study, but it is published as a detailed research letter in JAMA Pediatrics, a reputable medical journal. They say that sudden parental death can be particularly traumatizing to children.  Their model demonstrates that from February 2020 to February 2021 there were 37,300 children aged 0-17 who lost at least one parent (9863 less than 9 years old).  Approximately 75% are non-Hispanic whites, the remainder non-Hispanic blacks.  We can only guess the types of trauma this causes in children and the support that will be needed for them.  I remember one family presented on MSNBC by Nicole Wallace in which both parents died, several days apart, leaving multiple young children.  See Below for Study on Health Care Workers

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Information about health care workers appeared in the Guardian based on data collected from mid-March 2020 to April 7, 2021.  More than 3600 health care workers died with 50% of them being less than 60 years.  A majority of deceased workers were people of color and more than a third were born out of the US.  A huge number of deaths occurred early in the pandemic, probably in part related to the difficulty getting PPE.  Most of the deaths were nurses and support staff, but also included physicians, pharmacists, first responders and hospital technicians.  Only about 25% of the people who died worked in hospitals.  Other people who died worked in places like residential facilities, outpatient clinics, hospices, and prisons etc.  Covid-19 is a deadly infection and I admire the physicians, nurses, respiratory therapists and other personnel so much. Since then scientists have developed very effective and safe vaccines and this is my plea to everyone reading this to please get vaccinated.  Dr. Michael Osterholm told everyone listening to his podcast from Thursday to get 2 people to agree to getting vaccinated. Please....

April 28, 2021

The J and J Vaccine PAUSE is Over - Happiness!

The J and J PAUSE is over after more vaccination data was collected, analyzed, and discussed at length at the CDC-ACIP meeting on April 23rd.  These clots are now called thrombosis with thrombocytopenia syndrome (TTS) and there are now a total of 15 well studied cases which means that this is a very rare adverse effect of the vaccine.  All of the cases were in women (13 in 18-49 years of age and 2 who were 50+).  Cerebral venous sinus thrombosis (CVST) occurred in 12 of the patients, the others had other large vein clots.  Nearly 8 million people were vaccinated with the J and J vaccine since it was approved making the risk of TTS 0.7-1.6 cases/million vaccinations.  There was a significant discussion of the benefit of the vaccine vs the risk and the ACIP independent advisory board of scientists then voted to lift the PAUSE.  Having an effective vaccine that only requires one dose and no special storage requirements means that many groups of people that are house bound, in shelters, in jails, or in rural areas or other countries will be able to be vaccinated.  

The types of clots that occurred after the vaccine occurs in other situations.  Patients who develop Covid-19 actually have a higher risk of developing the clots.  There is also a substantial risk of the same clots without either the vaccine or Covid-19:   

     CVST with Covid-19     5-6 cases/million 

     CVST 2 weeks after Covid-19 diagnosis  39 cases/million (hospitalized patients)

     CVST without known associated trigger  14.5-28.5/million US population per year   See Below

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The committee recommended that a Warning be added to the Vaccine Information.  Women who are 18-49 years old can elect to get one of the mRNA vaccines to reduce their risk.  Physicians will be provided with formation to make a prompt diagnosis when patients develop a severe headache, abdominal or leg pain, or shortness of breath.  A platelet count should be obtained and if <150,000 immediate treatment with intravenous IgG and a non-heparin anticoagulant should be started.  The diagnosis should be confirmed with a PF4 antibody assay, but treatment should begin before the results are obtained.  Physicians also need to be cautioned that patients should not be given heparin  or platelets This newly described clotting process appears to be an immune response to the vaccine and resembles a rare clotting disorder that occurs in patients being treated with heparin.  No other underlying risk factors were identified among the cases.   

April 24, 2021

Reasons to Avoid All COVID Infections

I have a guest contributor today - my son Jason - who is a Pediatric Hematologist-Oncologist.  He has a daily Instagram post with family photos of the day (for us I hope - to see our 2 grandchildren) and a paragraph about the pandemic.  This was his science paragraph from yesterday.

"A terrific study was published today in Nature (one of the pre-eminent scientific research journals) that details the very health care issues faced by people who get even mild cases of COVID.  The study looked at non-hospitalized VA patients, comparing over 73,000 who were diagnosed with COVID to nearly 5 million who were seen for non-COVID reasons.  And the top line result is that in the 6 months following their diagnoses. the COVID patients had an increased risk of death, respiratory disease and failure, clotting disorders, neurocognitive disorders, diabetes and hypertension, among a number of other conditions.  In addition, those who had COVID used more pain medications (both opioid and non-opioid), antidepressants, and cardiac medications.  More Below

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All in all, it is sobering, because it is a real-world look at what people might face if they get COVID (even mild or asymptomatic).  And it is a massive wake-up call about the importance of doing everything we can do to avoid getting COVID - mild or severe, there's a very real chance that you'll spend months or more dealing with the consequences.  So keep wearing your mask around others and indoors, get vaccinated, and help those in your life make good choices and get their vaccine appointments.  We can do this! "

 

April 21, 2021

Breakthrough Covid Cases: What is the Denominater?

We know the efficacy of the mRNA Vaccines from Phase 3 trials, and now we can look at Breakthrough Cases to assess "real world" effectiveness.  A breakthrough case is defined as a Covid-19 positive patient who developed Covid-19 more than 2 weeks after their 2nd vaccine dose or single dose of J and J vaccine.  This week the CDC published data on 5,814 breakthrough cases  collected from Dec. 14 - April 13.  These infections are expected to occur because no vaccine is 100% effective.  But in science it is always important to know the denominator!    As of April 13th 75 million people were vaccinated in the US, but how many of them had 2 doses and were more than 2 weeks out from their final dose.  The CDC relies on State reporting systems for breakthrough cases and only 43 States reported cases.  Of the cases reported, we don't know how many  of them had a sample for genomic sequencing for variants.  The data is probably underestimated and not helping to determine true incidence and protection against variants due to incomplete reporting and lack of original samples to identify variants that are spreading.

The cases were from 43 States, 45% were 6O years or older, 65% were women, and 34% were asymptomatic making it hard to know how the cases were even identified.  Three hundred and ninety-six patients were hospitalized, and 74 died.  From now on the CDC will modify their "breakthrough case" surveillance to those patients who are hospitalized or die - in order to get the most important information.  See Below  

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Another recent report to illustrate the value of the denominator: 6 women who received the J and J vaccine, 6-13 days before, developed CVST (cerebral vein sinus thrombosis) with thrombocytopenia (low platelets).  One patient died and only 2 already left the hospital.  All of the patients had a positive platelet factor 4 (PF4) test to detect the autoantibody that may be causing these clots/low platelets.  Approximately 6.8 million doses of J and J vaccine had been administered to date in the US (risk 1:1 million).  But is the denominator really 6,800,000 or half that to determine the risks in those vaccinated within the month before the diagnosis of the clots, or only in the women vaccinated during that time period?  Each time we decrease the denominator the risk increases. Then to confuse the science even more, there is also a risk of CVST in Covid-19 patients because CVST occurs in unvaccinated Covid-19 patients as well.  Will the Risk vs Benefit ratio of the J and J vaccine be enough to continue using it?  The CDC ACIP Committee will meet again on Friday.

April 17, 2021

Vaccine-Induced Thrombotic Thrombocytopenia

Evaluating a Headache After Vaccination with J and J and AstraZeneca Vaccines:  The rare clotting adverse event after vaccination with one of the two adenovirus viral vaccine vaccines is now being called vaccine-induced thrombotic thrombocytopenia (VITT).  I am a retired hematologist and have evaluated many patients with blood clots - venous and arterial - and in general the development of a cerebral venous sinus thrombosis (CVST) in very rare.  But the US Vaccine Adverse Effect Reporting System (VAERS) for monitoring vaccine safety demonstrated 6 cases, all associated with low platelets. This combination resembles a heparin side effect known as Heparin-Induced Thrombocytopenia (HIT) - in which patients on heparin develop antibodies to a complex known as heparin-PF4 (platelet factor 4).  I spent the first 15-20 years, after my training, in a lab purifying, characterizing, and then measuring PF4. Since then a test has been developed to measure the heparin-PF4 antibodies in patients with HIT.  Now these tests are found to also be positive in patients with VITT following the J and J and AstraZeneca vaccines, even though none received heparin 

Some Risk Factors for any Clots: OCP, pregnancy, malignancy, smoking, immobility, inherited disorders.  

Risk Factors for CVST: J and J Vaccine: 1 per million;  Covid-19 4-20 per 100,000; pregnancy 10-20 per 100,000 deliveries; oral contraceptives 2.7-40 per 100,000 people, and General Population: 3-15 per million per year.

The risk factors and incidence for development of CVST shows that the incidence for VITT is substantially less than the incidence in patients with Covid-19.  With the current data, the risk vs benefit ratio warrants continuation of J and J vaccinations, maybe to select age groups.  

 

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The CDC-FDA still have a PAUSE on J and J vaccinations - to carefully study any patients that may develop clots within 3 weeks after their vaccination that was before the pause.  Patients who develop severe headaches, abdominal pain, leg pain or shortness of breath should see a physician and have an evaluation - including a platelet count and a PF4 antibody test.  Under no circumstances should patients with clot, low platelets, and a positive PF4 test be treated with heparin - instead consult a hematologist for alternate treatments.   

April 14, 2021

Severe Headache, Blood Clots and Low Platelet Counts

Yesterday we learned that there would be a PAUSE in the administration of the Johnson and Johnson vaccine in order for the CDC and FDA to carefully review 6 cases of unusual blood clots associated with thrombocytopenia (decreased platelets).  The blood clot is in the veins of the brain (called central venous sinus thrombosis - CVST) or even more rarely in the veins in the abdomen.  The CDC and FDA together decided to PAUSE while they carefully studied these patients, one of whom died. The incidence of this type of clot in unvaccinated patients is 2-14 per million patients,  In this study there were 6 cases in almost 7 million J & J vaccinations in the US. or a risk of 1 per million.  What makes this CVST different is the severely decreased platelet count that occurs with it. 

Patients with CVST develop severe headaches, abdominal pain, leg pain, or shortness of breath and should consult a physician. This is not the flu-like headache seen 1-2 days after vaccination. The 6 women were between the ages of 18-48 and the onset of the thrombosis occurred 6-13 days after the vaccination.  A complete blood count should be done in addition to imaging studies to identify the clot and document the decreased platelet count.  Patients with venous clots are usually treated with heparin, but it is contraindicated in these patients - which is one of the reasons that the CDC and FDA wanted to PAUSE the vaccinations so physicians could be alerted to the possible diagnosis and correct treatment.  See Below

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Scientists want to see if they can identify any underlying risk factors, or specific patient groups that should not get the J&J vaccine.    Oral Contraceptive drugs did not seem to be the common factor.  At this time it appears as if this syndrome is due to the development of autoimmune antibodies, which activate the platelets and cause clotting.  These same types of clots, with thrombocytopenia, is also found after the AstraZeneca vaccines and groups of scientists here and abroad are already studying these events and changes in the coagulation system.  Note: both the J and J vaccine and Oxford-AstraZeneca vaccines use a harmless adenovirus to carry the spike protein DNA into cells so spike protein can be made and stimulate an immune response.  Pfizer and Moderna are messenger RNA vaccines - a different platform for vaccine production. 

April 10, 2021

Moderna Antibody Studies 6 Months After Vaccination

More Good News!  This week Moderna published antibody levels measured over 6 months after the 2nd dose in their Phase 1 trial and they were excellent and durable.  All of the tests were done at NIH-NIAID.  These were the volunteers that participated in the very first human studies.  Phase 1 clinical vaccine trials are done to assess safety and to establish a dose range that produces a good antibody response.  Now this small patient group has been observed and their antibody production measured regularly for just over 6 months from their vaccination.  In contrast, Phase 3 clinical vaccine studies assess the ability of vaccination to prevent symptomatic infection in vaccinated subjects compared to subjects given placebo - and then vaccine efficacy is calculated. 

In the current report antibody production to the "spike proteins" and the efficacy of the subjects serum to neutralize the virus was assessed serially by 3 different types of tests on 33 volunteers over a 6 month period.  There were 3 age groups tested: 18-55 years, 56-70 years, and 71+ years.  There was an excellent antibody response in all subjects and it remained high over 6 months in all age groups, although the amount of antibodies decreased with advancing age.  The antibody amounts that best correlate with vaccine efficacy are not currently known, but this patient cohort will continue to be monitored, and will even be given a booster dose to assess its effect on antibody production against the virus and the variants.   Even more good news: see below.

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Yesterday Pfizer submitted a request to the FDA to extend their EUA for approval of their vaccine for 12-15 year old children.   There were ~2000 children studied and there was an immune response in 100% of the children.  Antibody levels were even higher than in older groups. That means 3 more of our grandchildren will be eligible!

Shirley Parker Levine
New York City

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