FDA Panel to Review Checkpoint Inhibitors Greenlit Under Accelerated Approval

 The fate of three cancer immunotherapies that had been authorized under the U.S. Food and Drug Administration’s Accelerated Approval pathway will be determined next week following failures in confirmatory trials.

The FDA’s Oncologic Drugs Advisory Committee will review products approved under the pathway for breast, urothelial, gastric, and hepatocellular cancers. Specifically, the advisory committee will discuss Merck’s Keytruda (pembrolizumab), Bristol Myers Squibb’s Opdivo (nivolumab), and Roche’s Tecentriq (atezolizumab). Each of these checkpoint inhibitors had been approved under the accelerated pathway, but required confirmatory trials. Keytruda was approved for gastric or gastroesophageal junction adenocarcinoma, hepatocellular carcinoma, and urothelial carcinoma. Opdivo was approved as a single agent treatment for hepatocellular carcinoma and Tecentriq was approved in triple-negative breast cancer and urothelial carcinoma.

“We are committed to ensuring the integrity of the accelerated approval program, which is designed to bring safe and effective drugs to patients with unmet medical needs as quickly as possible. The program allows the FDA to approve a drug or biologic product intended to treat a serious or life-threatening condition based on an outcome that can be measured earlier than survival that demonstrates a meaningful advantage over available therapies. However, when confirmatory trials do not confirm clinical benefit, a reevaluation must be performed to determine if the approval should be withdrawn,” the committee said in a statement.

The meeting has been called after these checkpoint inhibitors have been withdrawn for use in other indications over the past five months. Most recently, Merck withdrew Keytruda for use as a treatment in patients diagnosed with metastatic small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy and at least one other previous line of therapy. Keytruda was first approved for this indication in 2019, but in January of this year, the company reported the confirmatory Phase III study, KEYNOTE-604, only met one of the dual primary endpoints. In that study, Keytruda met the endpoint for progression-free survival, but did not reach statistical significance for the other primary endpoint of overall survival. The company withdrew Keytruda in this indication after announcing the confirmatory trial results.

AstraZeneca and Roche have also pulled some of their oncology drugs following confirmatory trial failures. In February, AstraZeneca pulled the use of its checkpoint inhibitor Imfinizi in bladder cancer following a post-approval confirmatory trial failure. The FDA first authorized Imfinzi for this indication in 2017. However, AstraZeneca pulled the plug after the Phase III DANUBE study missed the mark of improving overall survival in patients with advanced bladder cancer who have previously been treated with platinum-containing chemotherapy.

Two weeks after AstraZeneca pulled Imfinizi, Roche also pulled Tecentriq in bladder cancer. The Swiss pharma giant pulled Tecentriq for use in prior-platinum treated metastatic urothelial carcinoma (mUC) after failing to meet its confirmatory goals. Tecentriq was first authorized for this indication in 2016. Hints to this failure were first seen in 2017 when Tecentriq failed to hit the mark in a Phase III bladder cancer study as a second-line treatment.

In late December 2020, BMS withdrew Opdivo as a treatment for patients with small-cell lung cancer (SCLC) whose disease has progressed after platinum-based chemotherapy and at least one other line of therapy. Like the other checkpoint inhibitors, Opdivo failed to live up to expectations in this indication. When Opdivo was approved for this setting in 2018, it was the first new drug for this indication in 20 years.

The FDA’s Accelerated Approval Program allows people with difficult-to-treat cancers to receive certain new therapies earlier. However, part of the conditions for accelerated approval includes post-marketing requirements that confirm the safety and efficacy of the treatment. Over the past few months, the FDA has been running an industry-wide evaluation of its accelerated approvals with a focus on determining which have not met post-marketing requirements. The FDA’s Oncology Center of Excellence called the advisory meeting to evaluate the accelerated approvals in oncology for drugs whose confirmatory trials failed to confirm clinical benefit. Over the course of multiple meetings held April 27-29, the committee will discuss each drug and determine the continued approval in these indications and if additional trials will be required, the FDA said.

https://www.biospace.com/article/fda-advisory-committee-to-review-checkpoint-inhibitors-greenlit-under-accelerated-approval/

FDA to scrutinize unproven cancer drugs after 10-year gap

 Each year the U.S. approves dozens of new uses for cancer drugs based on early signs that they can shrink or slow the spread of tumors.

But how often do those initial results translate into longer, healthier lives for patients?

That seemingly simple question is one of the thorniest debates in medicine. It spills into public view Tuesday as the Food and Drug Administration convenes the first meeting in a decade to consider clawing back approvals from several cancer drugs that have failed to show they extend or improve life.

The agency says it has used innovative research shortcuts to speed up the availability of medicines for desperately ill patients. But many researchers say it has failed to crack down on medications that don’t deliver on their early promise, leaving a glut of expensive, unproven cancer drugs on the market.

“Doctors are using these drugs and patients are receiving them with all their toxicities and without knowing whether they actually doing anything,” said Dr. Ezekiel Emanuel, a cancer specialist and bioethicist at the University of Pennsylvania. “We should not be in a situation where we’re endlessly uncertain.”

The three-day meeting on drugs from Merck, Roche and Bristol-Myers Squibb is part of an industrywide review triggered by an “unprecedented level of drug development” in recent years, according to FDA officials. The agency has only held three similar meetings in its history, the last one in 2011.

The U.S. spends more per person on prescription drugs than any other nation, and spending on cancer drugs has more than doubled since 2013 to over $60 billion annually, according to the data firm IQVIA. New medications typically cost $90,000 to $300,000 a year. And those prices have risen much faster than patient survival.

The FDA is prohibited from considering cost, but it is supposed to keep ineffective drugs off the market.

“This is finally a referendum, a small court, where we can ask whether we are we better off for spending all this money,” said Dr. Vinay Prasad, a cancer specialist at University of California, San Francisco and longtime critic of FDA’s approach. “And for many of these drugs, the answer looks like ‘no’”

The FDA will hear presentations from the drugmakers and seek advice from a panel of cancer experts. Agency leaders stated in a recent op-ed that the discussion is important because a failed study “does not necessarily mean that the drug is ineffective.”

FDA makes the final decision on whether to pull approvals, but there are signs the agency may be ready for a tougher approach.

Earlier this year, four drugmakers “voluntarily” pulled approvals for several types of lung and bladder cancers after “consulting” with FDA. Each drug had failed to extend survival after initially winning FDA approval based on measures like tumor shrinkage.

The removal of four cancer approvals in quick succession is unprecedented. Several former FDA directors said at a recent conference that it showed the agency’s so-called accelerated approval program is “healthy.”

But the sheer rarity of such withdrawals undercuts that view.

In 1992, Congress gave the FDA the ability to accelerate drug approvals based on preliminary study data, responding to protests from HIV patients and activists over the slow pace of drug development. The program was embraced by the industry for giving many drugs a faster, cheaper path to market.

As originally conceived, these quicker approvals functioned like a contract: If the drugs weren’t shown to help patients live longer or better lives in follow-up studies, the approvals would be revoked.

That’s rarely happened. Of 155 expedited cancer approvals, 10 have been withdrawn, almost always voluntarily by the manufacturer. The FDA has used its authority to revoke an accelerated cancer approval only once. That long, ugly experience still looms large over the agency’s oversight of cancer drugs.

It took the FDA more than a year to finally pull the breast cancer approval from Roche’s blockbuster drug Avastin. The agency was besieged by calls from cancer patients and libertarian groups to keep the approval, despite clear evidence that it didn’t extend life and caused dangerous side effects.

The drugs under review this week — Merck’s Keytruda, Roche’s Tecentriq and Bristol Myers Squibb’s Opdivo — are part of a recent wave of “immunotherapies” that help the body’s defense system recognize and attack cancer. The blockbuster drugs have shown life-extending gains against deadly forms of skin and lung cancer. But they’ve also racked up several dozen approvals in other diseases, including forms of bladder, throat and liver cancer that are the focus of the meeting.

Studies by all three companies have shown negative or inconclusive results.

Even if all six uses under review are withdrawn, the drugs will stay on the market because they are approved for many other indications. And that may not change care much for patients. Dr. Shilpa Gupta of the Cleveland Clinic notes FDA approved five immunotherapy drugs for bladder cancer between 2016 and 2017 — including two under review.

“Did we really need all five of those drugs?” she asked.

Accelerated approval is technically reserved for drugs that fill an “unmet need.” But today roughly a third of all cancer drugs reach the market through the pathway, including many drugs approved for overlapping uses.

After years of studies criticizing the FDA’s oversight of the program — including by government inspectors — agency scientists have begun pushing back.

In a 2018 study, FDA staffers deemed the program a success, noting only 5% of accelerated cancer approvals had ever been withdrawn and 55% had been “verified” by follow-up studies.

But when Harvard researchers dug into that claim, they found that only about 20% of cancer drugs had actually been shown to extend lives. In most cases, the FDA had allowed drugmakers to confirm their drugs’ worth by conducting a second study of a preliminary measure, such as tumor shrinkage or delayed tumor growth.

In some cancers, shrinking or slowing tumor growth is proven to benefit patients. But in many cases that link hasn’t been established.

“Having a smaller cancer that kills you, rather than a bigger cancer, is no consolation because you’re still dead,” said Emanuel.

https://apnews.com/article/us-news-health-science-business-government-and-politics-019790c439dfd39a11868ede5d55b6e6

Modi says India shaken by coronavirus 'storm', U.S. readies help

 Prime Minister Narendra Modi urged all citizens to be vaccinated and exercise caution, saying the "storm" of infections had shaken India, as the country set a new global record of the most number of COVID-19 infections in a day.

The United States said it was deeply concerned by the massive surge in coronavirus cases in India and would rapidly send aid.

The number of cases surged by 349,691 in the past 24 hours, the fourth straight day of record peaks. Hospitals in Delhi and across the country are turning away patients after running out of medical oxygen and beds.

"We were confident, our spirits were up after successfully tackling the first wave, but this storm has shaken the nation," Modi said in a radio address.

His government has faced criticism that it let its guard down earlier this year, allowed big religious and political gatherings to take place when India's cases fell to below 10,000 a day and did not plan for boosted healthcare systems.

Hospitals and doctors have put out urgent notices saying they are unable to cope with the rush of patients.

Outside a Sikh temple in Ghaziabad city on the outskirts of Delhi, the street resembled an emergency ward of a hospital, but crammed with cars carrying COVID-19 patients gasping for breath as they were hooked up to hand held oxygen tanks.

Elsewhere, people were arranging stretchers and oxygen cylinders outside hospitals as they desperately pleaded for authorities to take patients in, Reuters photographers said.

"Every day, it the same situation, we are left with two hours of oxygen, we only get assurances from the authorities," one doctor said on television.

Delhi's Chief Minister Arvind Kejriwal extended a lockdown in the capital that had been due to end on Monday for a week. COVID-19 is killing one person every four minutes in the city.

Epidemiologists and virologists say more infectious variants of the virus, including an Indian one known as B.1.6.1.7, have fuelled the ferocious surge.

Doctors at New Delhi's All India Institute of Medical Sciences have found that one patient is now infecting up to nine in 10 contacts, compared with up to four last year.

DEATHS SOAR

India, a country of 1.3 billion people, has recorded a total of 16.96 million infections and 192,311 coronavirus deaths, after 2,767 more died overnight, health ministry data showed.

In the last month alone, daily cases have gone up eight times and deaths by 10 times. Health experts say the death count is probably far higher.

"Our hearts go out to the Indian people in the midst of the horrific COVID-19 outbreak," U.S. Secretary of State Anthony Blinken said on Twitter.

"We are working closely with our partners in the Indian government, and we will rapidly deploy additional support to the people of India and India's health care heroes."

CRITICISM OF UNITED STATES

The United States has faced criticism in India for its export controls on raw materials for vaccines put in place via the Defense Production Act and an associated export embargo in February.

The Serum Institute of India (SII), the world’s biggest vaccine maker, this month urged President Joe Biden to lift the block on exports of raw materials that is hurting its production of AstraZeneca shots.

Others such as U.S. Congressman Raja Krishnamoorthi urged the Biden administration to release unused vaccines to India.

"When people in India and elsewhere desperately need help, we can't let vaccines sit in a warehouse, we need to get them where they'll save lives," he said.

German Chancellor Angela Merkel expressed her "sympathy on the terrible suffering" that the pandemic had brought to India, her chief spokesman Steffen Seibert said in a statement.

"Germany stands in solidarity with India and is urgently preparing a mission of support."

The surge in India is expected to peak in mid-May with the daily count of infections reaching half a million, the Indian Express said, citing an internal government assessment.

The newspaper said V.K. Paul, a COVID-19 task force leader, made the presentation during a meeting with Modi and state chief ministers and said the health infrastructure in heavily populated states is not adequate to cope.

https://www.marketscreener.com/quote/stock/ASTRAZENECA-PLC-4000930/news/AstraZeneca-nbsp-PM-Modi-says-India-shaken-by-coronavirus-storm-U-S-readies-help-33062127/

UK officials close to deal to buy tens of millions more doses of Pfizer vaccine

 UK officials are close to finalising a deal to purchase tens of millions more doses of the Pfizer COVID-19 vaccine in time for a third booster dose to be given to the elderly this autumn, the Sunday Times reported https://bit.ly/3gDd8dd.

Government sources told the newspaper that they hope to roughly double the UK's original order of 40 million jabs.

If talks succeed, the extra stock may also be used for those in their 20s, who are to be offered an alternative to the AstraZeneca jab, the report added.

https://www.marketscreener.com/quote/stock/ASTRAZENECA-PLC-4000930/news/AstraZeneca-nbsp-UK-officials-close-to-deal-to-buy-tens-of-millions-more-doses-of-Pfizer-vaccine-33061992/

Covid-19 Vaccine's 1,500-Mile Journey Through India

 India is simultaneously battling the world's fastest-growing surge of infections and carrying out one of the most logistically complex vaccination campaigns. New Delhi has set a target of vaccinating 300 million of its more than 1.3 billion people by the fall.

Some of those doses will be transported hundreds of miles -- by truck, plane, scooter, boat and even on foot -- before being injected into the arms of people living in small, remote villages. Along the way, each dose must be tracked and kept chilled. The enormous challenge has become all the more urgent as infections have skyrocketed in recent weeks. Here is the story of one dose's 1,500-mile journey.

PUNE, India -- A half-milliliter dose of a vaccine developed by AstraZeneca PLC and the University of Oxford began its life here in a 1,500-liter metal tank, along with millions of others in batch number 4120Z017, months before it was approved for use.

The tank -- one of the bioreactors used to grow the cells to make vaccines -- produces millions of doses at a time. Bioreactors are the workhorses of the Serum Institute of India, the world's largest vaccine maker. The Institute started making and stockpiling doses as soon as it got the formula and tiny seed vial of material used to grow the vaccine from AstraZeneca in May.

PUNE: Born in a Bioreactor

From the bioreactor, the dose on Nov. 11 was put in a 10-dose vial that was then sealed with a stopper and stacked with millions of others on the giant purple-and-white shelves of a warehouse kept at around 40 degrees Fahrenheit.

After weeks in storage, the dose would travel 1,500 arduous miles to a remote village in the country's northeast before being injected into the shoulder of a schoolteacher, some 120 days after its emergence from the bioreactor -- another small victory in one of the world's most ambitious and logistically challenging vaccination campaigns.

The campaign has gained urgency as the coronavirus has surged in India, with daily new cases surpassing 300,000 last week. India is now regularly delivering more than 3.5 million doses a day, second only to China.

The AstraZeneca vaccine wasn't approved for use in India until Jan. 2. The dose sat on the shelf for another week, until it was separated into an ice-pack-lined plastic-foam box containing about 1,000 vials and loaded onto an insulated truck.

From there it took a 30-minute drive to the Pune airport, one of millions of doses headed to different corners of the country. On the afternoon of Jan. 13, it was loaded into the cargo area of a regular passenger flight operated by India's largest airline, IndiGo, which has joined forces with the government to help deliver vaccines across the country. In Kolkata, it was transferred to another passenger flight operated by government airline Air India.

The dose was among the first deliveries in the country, leaving Pune days before India launched its nationwide vaccination program on Jan. 16. It stopped only briefly at Kolkata airport before moving on, but most of India's vaccines stop at regional distribution centers as part of the hub-and-spoke system it is using to reach across the country.

KOLKATA: Distribution Hub

The warehouse in the Central Family Welfare Stores in Kolkata, for example, which has been managing India's regular child vaccinations for years, takes care of Covid-19 vaccine deliveries for that state. On a recent Saturday, it was bustling as workers set up shipments across the state of West Bengal and tried to make way for the growing number of vaccines arriving every week.

India has given more than 130 million shots already and plans to vaccinate more than 300 million by fall. While in shots delivered it trails China and the U.S., India has set a higher target -- and in a country with a large percentage of people living near the poverty line and in rural areas.

"This is about reaching all of India. Nobody can be left behind," said Vivek Paul, one of the leaders of New Delhi's vaccination efforts. "We are looking at extinguishing the pandemic, not just controlling it."

After an overnight stay in Kolkata, the AstraZeneca dose was loaded onto another commercial flight for the 400-mile flight to one of India's remotest state capitals, Aizawl.

AIZAWL: Land of the Hill People

Aizawl is the capital of Mizoram ("land of the hill people," in the local language), a northeastern state wedged between Myanmar and Bangladesh. Over the centuries, its citizens have settled on the hills for protection. Now the winding ridges that make up the capital bristle with buildings like a little Hong Kong in the middle of a jungle. There is little level land anywhere -- even pigs are kept on hill-hugging bamboo platforms held up with stilts.

Of Mizoram's nearly 1.5 million people, many live in distant villages that are hard to reach. Trips between places less than 100 miles apart in a straight line can take 10 hours, often along narrow dirt roads that wind through the mountains. The state is rushing to provide shots before rainy season starts in June, making roads impassable.

"We have to finish as much as possible before the monsoon," said Eric Zomawai, the deputy director of the state's health department. "We get landslides and in spite of everything we have to manage."

The dose landed in Aizawl on Jan. 14 around noon. It was quickly packed into a smaller plastic-foam cooler with fresh ice packs and a credit-card-sized temperature monitor to ensure it stays between around 35 and 45 degrees for the next leg journey -- a long and winding eight-hour drive to the rural district headquarters of Lunglei.

There the dose had another long wait -- this time, for the distribution system to catch up with the supply. In the initial stages of the vaccination drive, there were technical glitches with the smartphone app-based system used to choose, notify and register people for vaccinations. Meanwhile, in parts of Mizoram and across India fewer people than expected were showing up for their shots.

NUNSURY: Shot in the Arm

After almost two months in a freezer used to store all sorts of vaccines, on March 11 dose it was packed into a small plastic-foam cooler equipped with a shoulder strap. A local health official slung it on her back, got on a scooter and drove it down to the Khawthlangtuipui River, which runs to the border between India and Bangladesh. She and four other health officials jumped in a long wooden boat to go downstream to the village of Nunsury.

Nunsury is little more than a riverside cluster of simple, single-story homes, some built of bricks, others of bamboo, most roofed with corrugated steel. Most citizens are fishermen or farmers. Around 10 of the oldest people in the village were the first to arrive at the makeshift vaccination center, set up in the village grade school. They all show their IDs and wait their turn.

Establishing age has been a big problem. Until May, the vaccine is being offered only to people at least 45 years old, but in the far corners of Mizoram, official birth certificates weren't given out until the 1980s, said Lalhnunmawii, a local medical officer who goes by one name.

"Some people here are illiterate, so their ages are just what they imagine," she said. "They don't know their exact ages."

The vaccine-distribution app that suffered glitches early in the campaign has a separate problem in this remote area: lack of connectivity. Health workers have to keep records on paper and transfer them when they are back in an area with a network. In some districts of Mizoram, cellular networks are so scarce that it is a full-time job for people to drive hours to a spot where they can update the database.

The vial containing the dose was pulled from the cooler and marked with the time and date: "9:20 11/3/21." Once opened, a vial has to be used within four hours.

Teacher Sulochana Chakma was among the first 10 people in line for shots. Before the injection, health workers told her that if she feels any side effects, she should notify a government hospital.

With false vaccine scare stories circulating around the country via WhatsApp messages, state officials have stressed the importance of not spreading rumors and fear. One small group in Mizoram was even claiming using the vaccine was un-Christian, a big problem in the Christian majority state.

After getting her shot in the arm, Ms. Chakma waited quietly for 30 minutes, sitting a safe distance from others on well-worn wooden benches built for small children.

She hadn't been notified to show up for her shot by text, as the government had originally planned. The system was scrapped after proving unreliable. Instead, older people were called by a loudspeaker atop a tower, which is usually used to notify villagers in an emergency.

"Yesterday they announced in the afternoon time, then again in the evening and then again in the morning," she said. "It's free and from the government, so we are happy to get it."

https://www.marketscreener.com/quote/stock/ASTRAZENECA-PLC-4000930/news/A-Covid-19-Vaccine-s-1-500-Mile-Journey-Through-India-33062639/

Ocugen On Track to Bring Bharat Biotech's COVAXIN to US Market With Strong Data

 Ocugen’s plan to bring a COVID-19 vaccine developed by India-based Bharat Biotech later this year remains on track following an interim analysis of Phase III data that shows the vaccine demonstrated a 78% efficacy against mild to moderate infection and 100% efficacy against severe COVID-19.

This is the second interim analysis of the COVAXIN vaccine candidate. In the second analysis, the vaccine's efficacy against mild to moderate infection slipped a little from 81% revealed in the first interim analysis. Ocugen and Bharat Biotech have been working together since December to develop COVAXIN, an advanced stage whole-virion inactivated vaccine. COVAXIN, a two-dose vaccine, has already received authorization in India for people ages 12 and above.

Shankar Musunuri, chairman and chief executive officer of Pennsylvania-based Ocugen, said they continue to be excited about the “compelling second interim results” of the Bharat Biotech study. 

“We believe that COVAXIN can help change the course of this pandemic by preventing severe COVID-19 disease including hospitalizations by 100% as well as significantly limit the spread of asymptomatic COVID-19 infections based on efficacy shown to date. We are dedicated to being a part of the solution to save lives from COVID-19 by bringing COVAXIN to the U.S. market,” Musunuri said in a statement.

The second interim analysis is based on recording more than 87 symptomatic cases of COVID-19 among the trial of 25,800 patients. Due to the recent surge of COVID-19 in India, 127 symptomatic cases were recorded, which resulted in the estimate of vaccine efficacy of 78% against mild, moderate, and severe COVID-19 disease. 

Cases of COVID-19 are surging in India mainly due to the number of large gatherings related to recent religious festivals and political assemblies. Just today, India reported more than 332,000 new cases of COVID-19. According to CNBC, India has posted the highest number of daily cases for several days. 

The Phase III trial will be continuing to its pre-planned conclusion, Ocugen said. The efficacy against asymptomatic COVID-19 infection was 70%, based on a subgroup of approximately 8,000 participants who visited the clinical trial site each month for an RT-PCR test.

In March, Musunuri said the company was planning to meet with the U.S. Food and Drug Administration to press for Emergency Use Authorization of COVAXIN based on the interim data. In the latest announcement, there was no mention of a potential meeting with the regulatory agency. 

Musunuri said COVAXIN will be an essential tool to help the nation continue its vaccination efforts against COVID-19. There are three vaccines authorized for use in the United States, two mRNA vaccines developed by Pfizer and BioNTech and Moderna, and a Johnson & Johnson vaccine. The vaccine developed by Johnson & Johnson is currently paused in the United States while health authorities investigate cases of clotting in a handful of the seven million people who have received the preventative medication.

Bruce Forrest, a member of Ocugen’s vaccine scientific advisory board, touted the safety and efficacy of the COVAXIN drug. He said those results are “remarkable” due to the presence of multiple variants of COVID-19 that were present during the Phase III study conducted by Bharat Biotech.

“This vaccine is based on a proven technology platform and the company plans to consider clinical development in special populations such as children,” Forrest said in a statement.

https://www.biospace.com/article/with-new-data-ocugen-moves-closer-to-seeking-eua-in-the-u-s-for-india-developed-covid-19-vaccine-/

Do preservative and stray proteins cause rare COVID-19 vaccine side effect?

 Researchers in Germany and Canada have added provocative new details to their proposal for how the COVID-19 vaccine made by AstraZeneca might be causing an unusual clotting disorder in a small number of recipients. The mechanism, involving stray human proteins and a preservative in the vaccine, remains speculative. And it is not clear whether their hypothesis explains similar reactions observed in recipients of the COVID-19 vaccine made by Johnson & Johnson (J&J).

The new data are “interesting but not a smoking gun by any means” for the group’s hypothesis, says Gowthami Arepally, a hematologist at the Duke University School of Medicine who is working as an external consultant with AstraZeneca on the issue. But figuring out what in a COVID-19 vaccine might start the sometimes fatal combination of blood clotting and low platelets is crucial for developing better treatments for the side effect and possibly for understanding who might be most at risk, says Paul Offit, a vaccine researcher at the Children’s Hospital of Philadelphia (CHOP). It could also be vital for modifying vaccines so they don’t kick-start the reaction, which researchers are calling vaccine-induced immune thrombotic thrombocytopenia (VITT).

Vaccine regulators are struggling to balance the small risk of VITT versus the clear need to immunize people against the pandemic virus SARS-CoV-2. The European Medicines Agency (EMA) declared on Tuesday that the COVID-19 protection of the J&J vaccine significantly outweighs the danger of the rare side effect and recommended its use, with an addition to the warning label that alerts doctors and recipients to the clotting problem. That advice, which matches EMA’s verdict on the AstraZeneca vaccine, cleared the way for vaccinations with the J&J shots to begin across Europe.

Both J&J and AstraZeneca use modified adenoviruses to deliver and express the spike protein gene of SARS-CoV-2. But new data posted Tuesday in a preprint on Research Square show that doses of the AstraZeneca vaccine also contain significant amounts of protein from human cells—presumably from the human cell line used to grow the virus during the manufacturing process. The preprint’s authors, some whom were among the first to identify the VITT side effect, propose that these proteins, together with another component of the vaccine called ethylenediaminetetraacetic acid (EDTA), may set off a dangerous response by the immune system in some vaccine recipients.

EDTA is used in some vaccines as a preservative, but it is also known to make blood vessels a bit leaky, says Andreas Greinacher, an expert on clotting at the University of Greifswald who led the study. He said he was suprised at the concentration the group found in the AstraZeneca vaccine samples they examined: 100 micromoles, which is much higher than amounts listed for other common vaccines.

The group showed that in a mouse model, the vaccine did increase vascular leakage. Greinacher says this may make any free proteins in a vaccine dose more likely to encounter platelets, or thrombocytes, in a recipient’s bloodstream. Platelet factor 4 (PF4), a protein secreted by these thrombocytes, could then form complexes with the residual human proteins and other components of the vaccine, thanks to its strong positive charge. Indeed, when the researchers added PF4 to the vaccine in the lab, large complexes formed. Greinacher notes that other vaccines contain human proteins, but the amount—between 70 and 80 micrograms per milliliter (mcg/mL) in the four batches they tested—was “surprisingly high,” he says. Other vaccines list amounts of 5 mcg/mL or less, although many do not specify an amount.

In a tiny minority of people, Greinacher and his colleagues speculate, the combination of PF4 complexes and the strong inflammation triggered by the vaccine may turn on a specialized set of immune cells that can make antibodies to PF4. (This also happens in a similar clotting syndrome triggered by the blood thinner heparin. In that case, heparin forms the problematic complexes with PF4.) In an even smaller minority, the researchers say, the antibodies to PF4 are strong enough to fuel additional immune reactions in the blood that deplete platelets in the blood and cause potentially deadly clots to form in the brain, abdomen, or lungs.

Those PF4 antibodies can be useful if the body is fighting off severe infection—but they can get out of control, Greinacher says. “It’s like waking a sleeping dragon,” he says. “In most cases, we really want to keep the dragon sleeping, and the vaccine is like a guy coming into a cave and throwing stones at it.” An AstraZeneca spokesperson said the company could not comment directly on the preprint, but that they “continue to work to understand the individual cases, epidemiology, and possible mechanisms that could explain these rare events.”

Greinacher has asked J&J for doses of its vaccine so he can analyze its contents and see whether it might trigger the same cascade. The vaccine had not been used yet in Germany, which he says prevented him from using it in his initial experiments.

Offit notes that other vaccines are grown in cell culture and contain cellular debris, and it isn’t clear that AstraZeneca’s contains more or different remnants. EDTA may also not be needed to trigger VITT; J&J’s COVID-19 vaccine doesn’t include it, for instance. “Adenovirus has a notorious history of being a particularly inflammatory stimulating virus,” says Mortimer Poncz, a pediatric hematologist at CHOP. “Whether the EDTA is involved, I think, is the softest part of the whole story.”

Arepally agrees. “The virus itself, which has been given in such large amounts, is probably enough to cause an inflammatory response,” she says. Arepally suggests PF4 simply binds to the adenovirus—which could, in theory, be why the J&J vaccine produces the same side effect. She speculates that a few unlucky people “simply have higher levels of PF4 for some reason and that’s why they are forming these complexes when they get the vaccine.”

Poncz, on the other hand, isn’t convinced PF4 complexes are actually behind the clotting problems. The complexes may be innocent bystanders, he says, although he applauds Greinacher “for leading the field and providing thought-provoking and experiment-provoking questions.”

Rolf Marschalek, a molecular biologist at Goethe University Frankfurt, suspects that additional spike-related mechanisms may play a role once a vaccinated person’s cells start to make the viral protein, which happens in the same time frame as the clotting disorders appear, generally between 4 to 20 days following vaccination. These might then add to the PF4 antibody cascade which the Greifswald group describes, he says.

Even as the spotlight shines on the J&J and AstraZeneca vaccines, scrutiny is widening to two other COVID-19 vaccines that rely on adenovirus vectors: Sputnik V, developed by the Russian Gamaleya National Research Institute of Epidemiology and Microbiology, and another made by the Chinese company CanSino Biologics. CanSino CEO Yu Xuefeng told journalists the company is monitoring recipients more carefully after the clotting reports emerged. The Gamaleya Institute said in a press release there had been no reports of clotting disorders following its vaccine rollout it many countries, although it’s not clear how many people have received it so far.

Hungary is already using Sputnik V, and several other European countries are considering purchases, but EMA has not yet approved it for use. EMA Director Emer Cooke says the agency’s review of safety data for the vaccine “is at an early stage,” and it has not yet looked carefully at data regarding possible side effects. “But now that we are aware of [VITT], will make sure it’s part of the company’s responsibility to report any of these events.”

https://www.sciencemag.org/news/2021/04/do-preservative-and-stray-proteins-cause-rare-covid-19-vaccine-side-effect