AstraZeneca/Oxford Calculations

By Derek Lowe

We have a lot of vaccine news to catch up on! First up is the latest on the possible clotting side effects seen with Oxford/AstraZeneca. This is looking more and more likely to be a rare-but-real effect, and I’m not happy that it’s holding up. I had hoped at first that this was a false signal, but as more data have come in, that possibility is fading. The EMA and others have been coming around to this view, and the question now is what to do about vaccine-induced immune thrombotic thrombocytopenia (VITT). Kai Kupferschmidt and Gretchen Vogel have an excellent overview on this here. As with all public health measures and all drug treatments, there’s a risk/benefit calculation at the heart of this matter. I gather from my email and messages that not everyone is reconciled to those, and while I sympathize – it would be a lot easier if we didn’t have to – I can only reiterate that it’s the only way to go. “You can’t put a price on a human life” is the saying, but while you may well not be able to put a price on yours or on the lives of your loved ones, that statement’s force dissolves when you have to consider millions of people.

Still not convinced? Try an unpleasant thought experiment, then, a sort of vaccination trolley problem: how many people should die of Covid-19 in order to keep one person from dying from a vaccine-induced thrombosis? There are all sorts of calculations imbedded in the answer – coronavirus incidence rates and fatality rates overall and in different cohorts, those same incidence and fatality rates for VITT across those different groups, the estimated effectiveness of the AZ/Oxford vaccine under current conditions in those populations, its availability (and availability versus other vaccine alternatives) and how many people you’re hoping to vaccinate in general with these supplies, the current state of coronavirus spread in the population that you’re looking at, and more. Complicating some of these (or making the comparisons starker, anyway) is the observation that thrombotic events also seem to be more common among people who are infected with coronavirus! You can obviously turn the dials on these numbers to get any answer you want by making enough assumptions. But a pretty solid one number to start with is that fatalities and serious complications from the coronavirus are more likely in older patients, and that tilts the scale towards them getting any vaccine rather than none. With that in mind, German authorities are saying that that AZ/Oxford vaccine should only be used in patients over 60. France puts the cutoff at 55, and the UK at 30 – other countries are all making their own calls, but the EMA itself is not making any recommendations like this (or not yet).

Why wasn’t this picked up in the clinical trials? Numbers, again. The thrombosis risk is still tough to estimate well, but might be roughly around 1 in 100,000. That means that in a clinical trial that doses some 20,000 people, you are simply not going to pick up this signal. No one has ever run a controlled trial (for a vaccine or for anything else) large enough to get good statistics on an incidence rate like that. You’re simply not going to see it, until you get out into a much larger population, which means after approval. That may not be fun to think about, but it’s been the case with every drug that has ever been approved. AstraZeneca and Oxford have made mistakes in the testing and rollout of this vaccine, but this problem isn’t on that list.

And to get all cold and clinical about it again, a one-per-hundred-thousand death rate can mean different things. It would be completely unacceptable for a drug that reduced common cold duration by two days, or one that cut down on the amount of hair growing out of your ears. But if you had a drug that was really effective against glioblastoma, pancreatic cancer, full-blast Huntington’s chorea or other such diseases, patients and families would be beating a path to your door, whooping and waving and shouting for joy and hardly giving that death rate a second glance. After all, nearly everyone with those conditions is going to die sooner rather than later and in relentlessly increasing pain and disability, so why not?

The calculation is nowhere near as stark for the coronavirus, of course, and the calculation is correspondingly harder to make, as detailed above. As we get more data, things will surely adjust. For example, it seems for now that women may be at greater risk than men – if this is true, then you could adjust in that direction. It may be that people with existing antibodies towards the PF4 protein are at greater risk, too, and that would be worth knowing about as well. More important questions that we don’t have answers to yet include whether this is a general adenovirus-vector effect or not. You could imagine that going either way. The Oxford/AZ vaccine uses a chimpanzee-derived adenovirus, whereas J&J uses a less-common human one (and the Gamaleya “Sputnik-V” vaccine from Russia uses that one and the more common adenovirus-5 in its two doses). There could be some protein-binding event that’s unique to the ChAdOx platform, or it could be more or less common across the other adenoviruses. There have been a few scattered reports of what may be VITT symptoms among people who have been vaccinated with the J&J shot, but the situation is far from clear.

And let’s not lose sight of all the ways in which this side effect is bad news. It has directly affected scores of people out of the millions vaccinated, of course. It has also thrown a number of national vaccination campaigns into turmoil, and that’s bad, too. One of the ways that’s happened is through making many people wonder about the safety of vaccination in general, and we certainly didn’t need a real reason for hesitancy thrown onto all the not-so-real ones. The AZ/Oxford vaccine was set to be widely used around the world, with huge numbers of doses being produced, so having this happen with it in particular complicates the timetable of vaccinating the whole planet. No, we didn’t need this at all.

https://blogs.sciencemag.org/pipeline/archives/2021/04/12/az-oxford-calculations

New way to starve brain tumors

 Scientists from Queen Mary University of London, funded by the charity Brain Tumour Research, have found a new way to starve cancerous brain tumour cells of energy in order to prevent further growth.

The pre-clinical research in human tissue samples, human cell lines and mice could lead to changes in the way that some children with medulloblastoma are treated in the future, if the findings are confirmed in human clinical trials.

Medulloblastoma is the most common high-grade brain tumour in children. Some 70 are diagnosed in the UK each year. Survival rate is 70 per cent for those whose tumour has not spread but it is almost always fatal in cases of recurrent tumour.

The research, published in the high impact journal Nature Communications, looks at inositol hexaphosphate (IP6), a naturally occurring compound present in almost all plants and animals, and showed how it inhibits medulloblastoma and can be combined with chemotherapy to kill tumour cells.

Lead researcher Professor Silvia Marino from the Brain Tumour Research Centre of Excellence at Queen Mary University of London said: "Medulloblastoma occurs in four distinct subgroups (WNT, SHH, G3 and G4). Despite our growing knowledge of the molecular differences between these subgroups, current options are surgery together with radiotherapy and/or chemotherapy for all patients. We desperately need to understand the key molecular events driving tumour growth in each subgroup to design new, less toxic, targeted treatments."

"G4 medulloblastoma is the least understood of all subgroups, despite being the most common and associated with poor prognosis. We have identified a novel way that this type of medulloblastoma is able to adapt its metabolism and grow uncontrollably. Significantly, we have also shown how this energy supply can be blocked. These exciting results bring hope of developing new targeted treatments for patients with this aggressive paediatric brain tumour."

Normal cells are able to switch specific genes on and off as required to control their growth. Known as epigenetics, this process can be disrupted in cancer, leading to over production of specific proteins that contribute to the development and growth of a tumour.

It is already known that epigenetic changes can contribute to the development of medulloblastoma. Furthermore, a protein involved in this process -- known as BMI1 -- is found in high levels in a broad range of cancers including brain tumours. In medulloblastoma, high levels of it are found in the G4 subgroup, where it sustains tumour growth.

Professor Marino's team has previously demonstrated that, alongside high levels of BMI1, G4 medulloblastoma cells also lack a protein called CHD7. This combination of changes, or signature, is thought to contribute to the development of G4 medulloblastoma.

Now the team has shown that high levels of BMI1 enable the cancer cells to adapt their metabolism and grow aggressively. This change can be reversed by treating the cells with inositol hexaphosphate (IP6). The team also showed that when IP6 was combined with chemotherapy -- in this case cisplatin -- they observed an increased ability to kill the tumour cells in mice.

Hugh Adams, Head of Stakeholder Relations at Brain Tumour Research said: "These very exciting results reveal a new way for epigenetics to control metabolism within tumour cells. Clinical trials are now required to test the ability of combining IP6 with chemotherapy to treat G4 medulloblastoma, offering promise to a particularly vulnerable group of patients.

"It is great news and brings some much-needed hope for the future. There is still some way to go but we hope that a clinical trial could be up and running in the near future.

"Brain tumours kill more children and adults under the age of 40 yet, historically, just 1% of the national cancer spend has been allocated to this devastating disease. Brain Tumour Research is determined to change this."

Peter Gardiner, from Aston Clinton, near Aylesbury, lost his 13-year-old son to medulloblastoma in November 2017. Next month, May marks six years since his diagnosis.

"I can only describe our experience as a long hell. Firstly, Ollie was diagnosed, then he went through surgery and extensive treatment. When we were told there were no further options for him in the UK, we crowdfunded £500,000 so he could have immunotherapy in Germany. It was our only hope and, sadly, it didn't work," he said.

Ollie's family generously donated £187,000 of the residue of their fundraising to Brain Tumour Research which is funding post-doctoral researcher Sara Badodi who works alongside Prof Marino.

Pete said: "We were overwhelmed by the support of friends, family and strangers who stood by us in our hour of need and came together to help us do the very best we could for our son. It means the world to think that, because of him and the love people showed to us, others might not have to go through what we did."

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Story Source:

Materials provided by Queen Mary University of London. Note: Content may be edited for style and length.

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Journal Reference:

1. Sara Badodi, Nicola Pomella, Xinyu Zhang, Gabriel Rosser, John Whittingham, Maria Victoria Niklison-Chirou, Yau Mun Lim, Sebastian Brandner, Gillian Morrison, Steven M. Pollard, Christopher D. Bennett, Steven C. Clifford, Andrew Peet, M. Albert Basson, Silvia Marino. Inositol treatment inhibits medulloblastoma through suppression of epigenetic-driven metabolic adaptation. Nature Communications, 2021; 12 (1) DOI: 10.1038/s41467-021-22379-7

https://www.sciencedaily.com/releases/2021/04/210412084523.htm

New Haven preparing week-long COVID vaccination clinic for city’s high school students

 Good news for New Haven high schoolers: the city is preparing a COVID-19 vaccination clinic at Career High School for next week.

High schoolers returned to the classroom for hybrid learning just this week after more than a year of remote learning. Now, the city’s health director says they’ll begin the process of bringing the vaccine right to students.

New Haven’s Health Director Maritza Bond says the vaccine clinic will begin at Career High School starting the week of April 12. She says hundreds of doses of Pfizer vaccines are on order specifically for Elm City high school students.

“The data tells us that the increase of rates among adolescent and young adults is prevalent for those age groups,” Bond explained. “So the fact that we are able to now vaccinate around the same time that the school is opening, is really exciting.”

Students age 16 and up can sign up to get vaccinated now that Gov. Ned Lamont has opened eligibility to all residents 16 and up.

“The Pfizer vaccine is approved for 16 and up and so we made a request for the vaccine to be available for teens for that particular week,” Bond said.

The week-long clinic will be held April 12-16, the same week as Spring Break for Elm City students. Dir. Bond says they have enough capacity to vaccinate between 400-500 students a day.

Adding an extra layer of protection for students in the classroom. New Haven school officials are on board with the plan.

Dr. Iline Tracey, superintendent of New Haven Public Schools said, “Especially for the high school teachers, they will feel much safer that they are vaccinated, and their students are vaccinated.”

Restoring a sense of normalcy for kids during a tumultuous year.

“We’re hoping that parents come,” Bond said. “If they don’t have an appointment, they can come with their child and get vaccinated.”

New Haven’s Health Department says you can call them to sign up for the clinic at  (203) 946-6999.

https://www.wtnh.com/news/connecticut/new-haven/new-haven-preparing-covid-vaccination-clinic-at-career-high-school-for-all-of-citys-high-school-students/

L.A. opens up COVID-19 vaccine appointments for everyone age 16 and up

 Los Angeles has opened COVID-19 vaccine appointments to people age 16 and older.

On the city’s website for COVID-19 vaccine registration, operated by Carbon Health, there is now an option to book an appointment for people 16 and older at city-run vaccination sites.

People who are seeking shots at city-run vaccination sites must provide valid identification and be a resident of Los Angeles County. City-run sites are open from Tuesday through Saturday.

“We are excited to open vaccination appointments for Angelenos 16 and older,” Mayor Eric Garcetti said in a statement. “We continue to receive a limited supply of vaccines, and when we receive greater supply in the weeks ahead, the city will be ready to administer even more vaccines quickly and safely.”

Only one vaccine — manufactured by Pfizer — has been authorized for use by those age 16 and 17.

The updated website offers appointments for everyone 16 and older as early as Tuesday — two days earlier than Thursday, when California formally opens vaccinations to all residents in this age range. Currently, the statewide criteria say that only people 50 and older, those with underlying health conditions, and workers in certain specified essential job sectors are eligible for the vaccine.

But many local jurisdictions have moved faster than the state in allowing everyone age 16 and above to get the vaccine.

The city of Long Beach, the UC Davis Health system in the Sacramento area, and the counties of Riverside, San Bernardino, Kern, Fresno, Contra Costa, Butte, Shasta and Nevada have opened up vaccines to those ages 16 and older; Yuba and Sutter counties have made shots available to all adults.

Orange County and San Francisco are allowing people 16 and older living in hard-hit ZIP Codes to get vaccinated.

https://www.latimes.com/california/story/2021-04-10/l-a-opens-up-covid-19-vaccine-appointments-for-everyone-aged-16-and-up

Variants could lead to more COVID-19 cases in children: Duke doctor

 Now that Pfizer has applied for emergency authorization for its COVID-19 vaccine in children ages 12 to 15, we could see shots available for that age group by the fall.

Vaccine trials in younger children began recently, but it will likely be longer before they can get vaccinated.

CBS 17 asked an expert in pediatric infectious diseases what risks younger children face as COVID-19 variants become more widespread.

As more children go back to the classroom and get ready for summer activities, doctors say it’s important to keep COVID-19 precautions in mind.

“The good thing is, we know masking still works,” noted Dr. Ibukun Kalu, an assistant professor of pediatric infectious diseases at Duke.

While she says the number of coronavirus cases in North Carolina children is lower than the post-holiday surge, other parts of country and the world are seeing more cases in children. Many of those are caused by COVID-19 variants, like the B.1.17. variant that originated in the U.K.

“What I’ve seen, especially from UK data, suggests that this virus is more transmissible across all age groups,” said Kalu.

CBS 17 asked if children infected with variants generally experience mild illness — like we often saw with the original strain of COVID — or whether they are experiencing more severe illness.

“Unfortunately, we have seen some increased reporting of severe illness with initial infection,” Dr. Kalu replied. “Some early reports from India, where they are seeing higher spread as well as variants, have suggested that we can see infections that are more severe in children or young adults.”

Dr. Kalu says it’s important to remember that masks and distancing can help protect children, and so could vaccines – even though the children, themselves, aren’t eligible yet.

“The more people who already can get a vaccine that actually do get vaccinated will help us in reducing spread and so we could potentially create that larger bubble effect around kids,” she said. “If they are not exposed to COVID-19, they will not spread it or get infected.”

https://www.cbs17.com/news/local-news/durham-county-news/variants-could-lead-to-more-covid-19-cases-in-children-duke-doctor-says/

Texas Doctors Notice Uptrend in Children Testing Positive for COVID-19

 The number of Texans who have received at least one dose of the COVID-19 vaccine has climbed to about 37%, according to Texas Health and Human Services.

Doctors said that's an encouraging number and urged more people to get vaccinated. But there's a light being focused on children under 17 as more kids continue to catch the virus.

"What we’ve consistently seen throughout this pandemic is that the 0-17-year-old age bracket actually has risen in proportionality the entire time to a high of almost 17% of all COVID-19 cases today and this month," Parkland Hospital Chief Medical Officer Dr. Joseph Chang said.

He said at the start of the pandemic, kids made up less than 2% of those who tested positive.

“Even though we know kids do OK with COVID-19, for the most part, that’s not all of them, some of them have some real complications, but actually more complicating than that is our young folks bring it home, not only to spread it with each other, but they spread it with the rest of the family," Chang said.

He said he thought extra curricular activities played a role.

“I think it’s really all the activities surrounding youth, whether that’s sports, choir any of those type of thing with kids gathering, and it’s not even so much the activity themselves, it’s all of the spectators that surround that," Chang said.

The Parkland-run vaccination site at Ellis Davis Field House is now open to anyone without an appointment. That's where 16-year-old Valeria Leon received her first dose of the vaccine alongside her mom.

“I think everybody should get the vaccine, you know," Leon said. "My family got it and everything seemed fine and everything seemed OK, so I’m getting it because I don’t want no COVID or anything.”

Sixteen-year-olds and 17-year-olds must have a parent or legal guardian with them to receive a vaccine. Immunization is not available for those 15 and younger.

“Vaccines are now cleared for 16 and those older, please get your teenagers vaccinated," Chang said. "We’re coming closer to when the vaccines will be approved for 12 and older and when that’s the case, I’m going to encourage everyone 12 and older to get the vaccine. This is the way out, this is how we protect each other. It is safe. It is effective.”

Ellis Davis Field House, at 9191 S. Polk St., began to offer vaccines without an appointment last week.

Those without an appointment can get a shot between 11 a.m. and 4 p.m. Monday through Saturday. The site is closed on Sunday.

People can still register in advance. For more information visit, Parkland Hospital's COVID-19 resource.

https://www.nbcdfw.com/news/coronavirus/doctors-notice-upward-trend-in-children-testing-positive-for-covid-19/2602644/

What happened to US COVID-19 testing?

 As more Americans get vaccinated, the urgency to get a COVID-19 test is steadily declining despite the Biden administration promising there would be a "wartime undertaking" to increase access, with billions of dollars in investment from U.S. manufacturing companies to develop new COVID-19 tests.

The U.S. has continued a downward trend, with a 30% decrease in the number of daily COVID-19 tests, according to the Johns Hopkins University Coronavirus Resource Center. The U.S. now conducts just over 1 million tests a day after hitting its peak for the year so far on Jan. 15 with 2.3 million tests.

With roughly 20% of the U.S. population fully vaccinated against the coronavirus according to the Centers for Disease Control and Prevention, the nation still remains months away from vaccine availability being widespread in all regions of the country.

"Even if you take the really optimistic view that we're not missing anything right now, I just worry that we've lost that infrastructure," said Dr. Jennifer Nuzzo, lead epidemiologist for the Johns Hopkins Coronavirus Resource Center. "If we suddenly need to surge testing again, it's not clear to me how we would do it given that a number of the testing sites have turned over and are focused on vaccines."

COVID-19 testing has been a highly politicized issue from the pandemic's onset, with the first set of tests rolling out slowly and often highlighting a racial disparity within the U.S. health care system's infrastructure.

But now with the focus almost entirely on vaccinations and more states gradually starting to lift coronavirus restrictions, some medical experts see an immediate challenge in reversing the testing downturn.

"My assessment of what's going on out there is that COVID fatigue has had its influence on testing. There is a sense generally in the community that the proverbial light is getting brighter every day," said Dr. William Shaffner, a professor of infectious diseases at Vanderbilt University Medical Center. "That notion is out there in abundance, contrary to public health concerns, but I think it has contributed to a reduction in testing, which is unfortunate."

Testing still remains the surest way to track new infections with a continued nationwide increase in COVID-19 cases, and new, more contagious viral strains complicating the federal pandemic response.

The CDC recently declared the B.1.1.7 coronavirus strain, otherwise known as the U.K. variant, as the most predominant viral strain in the nation.

"We now have variants out there. And we need to know where the residual areas of viral spread are," said Shaffner. "The only way you can find that is to determine where the new cases are -- and you determine where the new cases are by testing."

The idea of consistent coronavirus testing as the U.S. vaccination rate increases seems to resonate more with the leaders of universities, school districts, private sector organizations and government agencies. Such organizations are rolling out spring pilot programs to explore how they might return students and employees to their buildings in greater number this fall.

The U.S. Food and Drug Administration partnered with Labcorp in March to implement a voluntary COVID-19 testing program for agency employees and contractors doing in-person work at government buildings or elsewhere.

Approximately 3,000 polymerase chain reaction, or PCR, tests a month are expected to be provided to FDA employees over the course of the program's year-long contract. Some FDA personnel inspect vaccine manufacturing facilities and food work places, making coronavirus testing a critical component of the agency's return to work.

The test -- the Pixel by Labcorp -- is designed for users taking a swab of their nostril and then sticking it into a solution. Users can expect test results within 48 hours after the lab processes that sample.

"This is adding one more way for them to access the test, it doesn't replace other opportunities to get tested where appropriate," said Dr. Brian Caveney, chief medical officer at Labcorp and president of Labcorp Diagnostics. "We don't have any idea how many of the tests will actually be used. It's just one of many purposes."

As U.S. companies and business grapple with how to implement effective testing regimes, the U.K. is taking their plan for rapid testing a step further, offering it to each of their citizens, at least twice a week.

In the U.S., the Biden administration laid out a $50 billion plan that would boost the nation's testing capacity through the increase of rapid antigen tests, testing centers, expand lab-test processing, provide uniform guidance for in-school COVID testing and establish a national pandemic testing board.

Ten billion dollars was allocated for testing in schools from the recently passed stimulus package aimed at helping districts confront the task of getting more children back into the classrooms safely.

The administration also announced a $230 million deal with Ellume, an Australian digital diagnostics company, to provide 8.5 million over-the-counter at-home tests. Ellume plans to produce 100,000 testing kits per month through July and ramp up to 19 million a month by the end of the year.

But despite the federal investment in testing and retail stores purchasing millions of rapid tests in bulk from U.S. test manufacturing companies, those efforts still haven't paid off with higher daily COVID testing numbers.

A Biden administration official, who spoke on condition of anonymity, told ABC News there has been no reduction in urgency regarding federal and state testing programs aimed at providing Americans greater access to COVID-19 testing.

The official also said the goal is now to ensure that Americans are aware and can easily access the various testing options available to them.

But still, some doctors and health care workers struggle to see how the Biden administration's ambitious plans for testing is meeting its promise with daily test numbers down.

"I haven't yet seen it realized on the ground, in the field," said Schaffner. "But any kind of structure and support one can give toward testing to stabilize that and to have people working in testing programs that are commuted over time is important so this is not a one-shot deal."

https://abcnews.go.com/Politics/us-vaccinations-increasing-happened-covid-19-testing/story