Re­searchers move clos­er to de­ci­pher­ing blood clots from As­traZeneca, J&J's Covid-19 vac­cines

Re­searchers may be near­ing an an­swer for the mys­te­ri­ous and life-threat­en­ing blood clots that ap­peared on very rare oc­ca­sions in peo­ple who re­ceived the J&J or As­traZeneca Covid-19 vac­cine.

The new work builds on an ear­ly hy­poth­e­sis re­searchers in Nor­way put for­ward last spring, when the cas­es first cropped up. They pro­posed the events were sim­i­lar to blood clots that can oc­cur in a small sub­set of pa­tients who re­ceive he­parin, one of the most com­mon­ly used blood thin­ners.

In those pa­tients, he­parin binds to a pro­tein float­ing in the blood called platelet fac­tor 4, or PF4, to form a com­plex. The body rec­og­nizes that com­plex as for­eign and be­gins mak­ing an­ti­bod­ies against PF4, trig­ger­ing a cas­cade of events. The Nor­we­gian re­searchers’ smok­ing gun? Peo­ple who took the J&J or As­traZeneca vac­cine and then suf­fered life-threat­en­ing blood clots al­so test pos­i­tive for an­ti-PF4 an­ti­bod­ies, just as pa­tients with he­parin-in­duced clots do.

But that still left a raft of ques­tions. Most no­tably: What about these vac­cines are caus­ing pa­tients to make an­ti­bod­ies against PF4, a com­plete­ly un­re­lat­ed pro­tein?

New work from the Mayo Clin­ic, Ari­zona State Uni­ver­si­ty and Cardiff Uni­ver­si­ty, pub­lished this week in Sci­ence, points to an an­swer, as well as po­ten­tial ways of build­ing new vac­cines with­out the same is­sue.

Alexan­der Bak­er

Af­ter re­ports of the blood clots emerged, Alexan­der Bak­er, a re­searcher at Mayo who fo­cus­es on en­gi­neer­ing virus­es for ther­a­pies and vac­cines, de­cid­ed to take a clos­er look at the As­traZeneca vac­cine’s struc­ture. Both J&J and As­traZeneca are vi­ral-vec­tor vac­cines. In each case, de­vel­op­ers took dif­fer­ent ver­sions of a com­mon cold virus called ade­n­ovirus, neutered them so they can’t repli­cate or cause symp­toms like a nor­mal virus, and used them as car­ri­er pi­geons to de­liv­er the in­struc­tions for our cells to pro­duce coro­n­avirus spike pro­tein.

“It seemed rea­son­able that there was some kind of in­ter­ac­tion be­tween the vac­cine and [PF4],” Bak­er told End­points News. “But it had not been shown ro­bust­ly.”

So Bak­er and his col­lab­o­ra­tors used a tech­nique called cryo-elec­tron mi­croscopy to look at the As­traZeneca vac­cine at an un­prece­dent­ed­ly close scale. They froze the virus to ul­tra-cool tem­per­a­tures — less than -180 de­grees Cel­sius — and fired elec­trons at dif­fer­ent an­gles to get an im­age of it from dif­fer­ent van­tage points.

Struc­ture of As­traZeneca vac­cine re­con­struct­ed from Cryo-Em

Click on the im­age to see the full-sized ver­sion

Ab­hishek Sing­haroy

They then stitched those dif­fer­ent snap­shots to con­struct a 3D im­age of the virus’ soc­cer ball-shaped out­er shell. With help from Ab­hishek Sing­haroy, a struc­tur­al bi­ol­o­gist at ASU, they de­ter­mined the atom-by-atom break­down with­in the shell.

Us­ing com­put­er sim­u­la­tions, they mod­eled how that shell would in­ter­act in wa­ter with a PF4 an­ti­body. Sure enough, it was “reg­u­lar­ly form­ing in­ter­ac­tions with the PF4 an­ti­body,” Bak­er said.

At that point, the groups put the work out as a pre-print, at­tract­ing the at­ten­tion of As­traZeneca ex­ec­u­tives, who were al­so try­ing to de­ci­pher the mys­te­ri­ous con­di­tion set off by their vac­cine. With the com­pa­ny’s help, Bak­er was able to run a study on a mi­cro-chip to prove out their com­put­er sim­u­la­tion.

Es­sen­tial­ly, they strapped the virus to the chip and flowed so­lu­tion con­tain­ing a PF4 pro­tein over it. Sure enough, the PF4 latched on­to the virus, al­beit not too tight­ly.

“It has mod­er­ate bind­ing affin­i­ty, which is to say it ain’t that strong, but it ain’t that weak,” Bak­er said.

That sug­gests the virus hasn’t evolved to tar­get PF4. In­stead, there’s a trag­ic ac­ci­den­tal align­ment be­tween the shape of the pro­teins on the virus and the shape of the hu­man pro­tein.

It al­so helps re­con­struct a plau­si­ble sto­ry for how the clot­ting events oc­cur. The As­traZeneca or J&J shot is in­ject­ed in­to the mus­cle in your shoul­der. Then, one of two things hap­pens: Ei­ther it goes in­to the blood­stream be­cause it ac­ci­den­tal­ly nicks a vein (as most shots do), or the body drains the virus from your mus­cle in­to your lym­phat­ic sys­tem, which drains and cir­cu­lates cer­tain flu­id around the body.

In ei­ther event, the virus is then ex­posed to PF4, which is al­ways cir­cu­lat­ing at low lev­els but is even more present in in­flamed en­vi­ron­ments, such as di­rect­ly af­ter a vac­ci­na­tion. The virus binds to PF4 and then drags the hu­man pro­tein on its jour­ney through the body to the lymph nodes, the hub of the im­mune sys­tem.

Re­searchers have shown that a very small sub­set of pa­tients has, for what­ev­er rea­son, pre-ex­ist­ing B cells that can make an­ti­bod­ies against PF4. Once the virus drags it in­to the lymph nodes, the B cells start churn­ing out those an­ti­bod­ies.

Be­cause an­ti­bod­ies have two arms that can each bind to dif­fer­ent PF4 pro­teins, you end up “group­ing to­geth­er clus­ters of PF4,” Bak­er said. “And when this hap­pens, it can over­ac­ti­vate platelets. And from that point, platelets be­come ac­ti­vat­ed and do what they’re sup­posed to do — you start form­ing clots.”

The prob­lem is that the clots are form­ing in the ab­sence of a wound or the “prop­er en­vi­ron­ment,” he said.

For­tu­nate­ly, their work points to a pos­si­ble so­lu­tion. The virus’ soc­cer ball shell is stud­ded with lit­tle pro­tein loops that in­ter­act with oth­er pro­teins. If re­searchers can pin down ex­act­ly how they bind to PF4, they might be able to swap out amino acids to pro­duce a virus that’s still func­tion­al for vac­cines but can’t bind to PF4 or cause blood clots.

In the mean­time, though, these vac­cines are still safe and ef­fec­tive, Bak­er not­ed. And the risk of blood clots from Covid-19 — along with all the oth­er risks the dis­ease brings — far out­strips the risk from the shot.

“So you’re much bet­ter off get­ting your vac­cine,” he said.

UP­DAT­ED: In a fresh dis­ap­point­ment, Am­gen spot­lights a ma­jor safe­ty is­sue with KRAS com­bo

Amgen had hoped that its latest study matching its landmark KRAS G12C drug Lumakras with checkpoint inhibitors would open up its treatment horizons and expand its commercial potential. Instead, the combo spurred safety issues that blunted efficacy and forced the pharma giant to alter course on its treatment strategy, once again disappointing analysts who have been tracking the drug’s faltering sales and limited therapeutic reach.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 147,200+ biopharma pros reading Endpoints daily — and it's free.

Ad­dress­ing the ‘Ca­pac­i­ty Crunch’ with a Scal­able Plat­form Process Ap­proach

The field of gene therapy has been diligently moving forward over the past several decades to bring potentially life-saving treatments to patients with genetic diseases. In addition to two approved adeno-associated viral (AAV) gene therapies, there are more than 250 AAV gene therapies in various clinical trial stages.1 AAV vectors remain the most frequently used vector for delivering therapeutic transgenes to target tissues due to their demonstrated and lasting clinical efficacy and extensive safety track record. As AAV therapies advance through clinical trials and into commercialization, many biotech companies are turning to contract development and manufacturing organizations (CDMOs) to prepare their programs for late-stage clinical and commercial scale manufacturing. Given the scope and scale of the manufacturing needs that will accompany regulatory approvals for these assets, CDMOs continue to expand their capacity to meet the needs of increasing prevalent patient populations. However, despite rapid growth, projected gene therapy manufacturing demands still outpace the collective capacity of the CDMO industry.

A $5B Pfiz­er buy­out? Am­gen, Gilead head­line M&A Thurs­day; Al­ny­lam's AT­TR sweep; An­drew Lo's rare dis­ease quest; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

One of the cool things about adding EndpointsPharma to the daily roster is that my colleagues can now dedicate time to tracking quarterly updates and tuning into calls with Big Pharma companies. Check out their dispatch from the Q2 earnings below.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 147,200+ biopharma pros reading Endpoints daily — and it's free.

Albert Bourla, Pfizer CEO (Laurent Gillieron/Keystone via AP)

Break­ing: Pfiz­er in hot pur­suit of a $5B buy­out of Glob­al Blood Ther­a­peu­tics — re­port

Pfizer CEO Albert Bourla has vowed to leave no stone unturned in the search for new biotech deals, and the BD team is not letting him down.

The Wall Street Journal reported today that Pfizer is in the final stages of acquiring Global Blood Therapeutics for $5 billion. According to the Journal report, though, Pfizer is not the only buyer at the deal table and while the pharma giant may be close to clinching it, there are no guarantees it will continue.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 147,200+ biopharma pros reading Endpoints daily — and it's free.

Bob Bradway, Amgen CEO (Justin Kase Conder/AP Images for Amgen)

UP­DAT­ED: Am­gen chief Brad­way nabs a rare dis­ease play­er in $4B buy­out as the M&A tem­po ac­cel­er­ates

Amgen CEO Bob Bradway is bellying up to the M&A table today, scooping up the newly anointed commercial biotech ChemoCentryx $CCXI and its recently approved rare disease drug for $3.7 billion out of the cash stockpile. The deal comes in at $52 a share — a hefty increase over the $24.11 close yesterday.

Bradway and the Amgen team get a drug called Tavneos (avacopan) in the deal, a complement factor C5a inhibitor OK’d to treat anti-neutrophil cytoplasmic autoantibody (ANCA)-vasculitis, an autoimmune disease which can be lethal.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 147,200+ biopharma pros reading Endpoints daily — and it's free.

George Yancopoulos, Regeneron president and CSO (Brendan McDermid/Reuters/Alamy)

George Yan­copou­los says he's on the trail of the holy grail: ‘This could rep­re­sent the next break­through for im­munother­a­py’

Two of the most outspoken — and successful — drug developers in biotech say they’ve collected early-stage clinical data that are pointing them down the trail to the holy grail in cancer immunotherapy R&D.

While analysts largely busied themselves today with chronicling the ongoing success of Regeneron’s two big cash cows — Dupixent and Eylea — chief scientist George Yancopoulos and CEO Len Schleifer used the Q2 call to spotlight their early success with a combination of the “homegrown” PSMAxCD28 costimulatory bispecific antibody REGN5678 in combination with their PD-1 checkpoint Libtayo. The presentation comes just weeks after Regeneron completed a deal to gather all rights to the PD-1 that had been in Sanofi’s hands. And the two top execs are unstinting in their praise of the potential of a whole set of costimulatory pipeline projects which they say may finally deliver the long-awaited next-level approach to broadening the immunotherapy field of drugs.

Endpoints Premium

Premium subscription required

Unlock this article along with other benefits by subscribing to one of our paid plans.

(AP Photo/Richard Vogel, File)

US de­clares mon­key­pox a na­tion­al health emer­gency, as new drug­mak­ers con­sid­er en­ter­ing vac­cine race

Rising monkeypox cases have put the US on high alert as it announces a national health emergency, which grants the government more power in its response.

The news comes as Bavarian Nordic continues to fill orders for its Jynneos vaccine and other companies – including Moderna – consider jumping into the vaccine race. Meanwhile, the New York Times reports that the US has allowed around 20 million doses of smallpox vaccine in its stockpile to expire.

Vlad Coric, Biohaven CEO

Bio­haven touts surge in Nurtec sales ahead of Pfiz­er takeover

Forget buyer’s remorse, Pfizer is likely feeling pretty good about its $11.6 billion Biohaven takeover deal following reports of a 57% sales boost for migraine med Nurtec.

Biohaven reported in Q2 results on Friday that it’s cleared the necessary antitrust hurdles to move forward with the sale of its calcitonin gene-related peptide (CGRP) assets to Pfizer. However, because the company is “focused on workstreams related to the closing” of the deal, it did not host a call with analysts and investors.

Pharma ads are showing up on cooler screens at retail pharmacies, including Walgreens and CVS, under a new OptimizeRx deal (OptimizeRx)

Phar­ma brands chill in the phar­ma­cy re­tail aisle with new style ads on re­frig­er­a­tion screens

Want a prescription drug with that soda? While not directly possible, ads for pharma brands now running on beverage and snack cooler screens at pharmacy retailers may at least inspire customers to think about it.

OptimizeRx is hooking up with Cooler Screens media company to bring prescription drug advertising to refrigerator front doors at pharmacies including Walgreens, CVS and Kroger.

The “point of dispense” ads show a full-door image on the cooler doors when a shopper is 12 feet away, but shrinks down to a smaller banner-sized ad so that the refrigerator contents can be seen when a person gets closer. The doors — which have to be specially installed by Cooler Screens — can detect when a person is nearby, how long a person “dwells” in front of the ad and if they do or don’t open the door.

Endpoints News

Keep reading Endpoints with a free subscription

Unlock this story instantly and join 147,200+ biopharma pros reading Endpoints daily — and it's free.