Tal Zaks (Moderna via YouTube)

For two decades, a new vac­cine tech­nol­o­gy has been slow­ly ap­proach­ing prime time. Now, can it stop a pan­dem­ic?

Two months be­fore the out­break, Mod­er­na CMO Tal Zaks trav­eled from Cam­bridge, MA to Wash­ing­ton DC to meet with An­tho­ny Fau­ci and the lead­ers of the Na­tion­al In­sti­tutes of Health.

For two years, Mod­er­na had worked close­ly with NIH re­searchers to build a new kind of vac­cine for MERS, one of the dead­liest new virus­es to emerge in the 21st cen­tu­ry. The pro­gram was one test for a new tech­nol­o­gy de­signed to be faster, cheap­er and more pre­cise than the ways vac­cines had been made for over a cen­tu­ry. They had gath­ered ev­i­dence the tech­nol­o­gy could work in prin­ci­ple, and Fau­ci, the long­time head of the Na­tion­al In­sti­tute of Al­ler­gy and In­fec­tious Dis­eases and a long­time ad­vo­cate for bet­ter epi­dem­ic pre­pared­ness, want­ed to see if it, along with a cou­ple of oth­er ap­proach­es, could work in a worst-case sce­nario: A pan­dem­ic.

“[We were] try­ing to find a test case for how to demon­strate if our tech­nol­o­gy could rapid­ly pre­pare,” Zaks told End­points News.

Zaks and Fau­ci, of course, wouldn’t have to wait to de­vel­op a new test. By year’s end, an out­break in Chi­na would short cir­cuit the need for one and throw them in­to 24/7 work on a re­al-world emer­gency. They al­so weren’t the on­ly ones with new tech­nol­o­gy who saw a chance to help in a cri­sis.

An ocean away, Lidia Oost­vo­gels was still on va­ca­tion and re­lax­ing at her moth­er’s house in Bel­gium when her Face­book start­ed chang­ing. It was days af­ter Christ­mas and on most peo­ple’s feeds, the news that Chi­na had re­port­ed a nov­el virus to the World Health Or­ga­ni­za­tion blurred in­to the stream of hol­i­day sweaters and fir trees. But on Oost­vo­gels’s feed, full of vac­cine re­searchers and virus ex­perts, spec­u­la­tion boiled: There was a virus in Chi­na, some­thing con­tained to the coun­try, but “ex­ot­ic,” “weird,” and maybe hav­ing to do with an­i­mals. Maybe a coro­n­avirus.

Lidia Oost­vo­gels

“I was im­me­di­ate­ly think­ing like, ‘Hey, this is some­thing that if need­ed, we can play a role,'” Oost­vo­gels told End­points.

Oost­vo­gels is the in­fec­tious dis­ease chief for Cure­Vac. Along­side Mod­er­na, the Ger­man biotech has be­come one of the most high-pro­file com­pa­nies work­ing on a new kind of vac­cines made out of mR­NA, the same code our cells use to make pro­teins. It was a bold ap­proach, con­ceived decades ago in labs on both sides of the At­lantic, and in re­cent years re­searchers have shown the first da­ta sug­gest­ing it can work in hu­mans.

As much of Big Phar­ma sat out the ear­ly days of the epi­dem­ic, Cure­Vac and Mod­er­na rose to the cen­ter of an in­ter­na­tion­al ef­fort to build a vac­cine that could stop a virus that’s now in­fect­ed more than 70,000 peo­ple and killed more than 1,700. They were two of the four ef­forts backed by the Coali­tion for Epi­dem­ic Pre­pared­ness Ini­tia­tive, a glob­al fund launched three years ago to pre­vent a pan­dem­ic, and they raced to de­vel­op a vac­cine faster than any­one had be­fore.

“The promise, the po­ten­tial of mes­sen­ger RNA is very ex­cit­ing,” CEPI’s pro­grams and tech­nol­o­gy R&D chief Nick Jack­son told End­points.

But ex­perts, in­clud­ing Jack­son, cau­tion the tech hasn’t yet been proven. In fact, if the Covid-19 out­break reach­es the pan­dem­ic stage — and the fu­ture is very much still up in the air — our best hope of in­oc­u­la­tion will like­ly rest with a tech­nol­o­gy that has on­ly ever been test­ed in a few hun­dred healthy vol­un­teers. If Covid-19 pe­ters out like SARS and MERS, then Fau­ci will have had his test run; he’ll know if the world and this new sci­ence can re­spond.

“These tech­nolo­gies have not been put through Phase III,” Glax­o­SmithK­line CMO Thomas Breuing told End­points. “I have great hopes, I think it will rev­o­lu­tion­ize how vac­cines are pro­duced in the fu­ture, but it’s still ear­ly.”

The first vac­cines were crude things; folk med­i­cines strapped to the en­gine of an in­dus­tri­al rev­o­lu­tion. For cen­turies, moth­ers rubbed small­pox in­to the arms of their kids to in­oc­u­late them. An Eng­lish doc­tor learned what farm­ers knew, that milk­maids didn’t get small­pox, and tried in­ject­ing cow­pox in­to kids in­stead of the hu­man ver­sion. Amer­i­can Home Prod­ucts, lat­er known as Wyeth, even­tu­al­ly used a fac­to­ry to mass-pro­duce his serum. The last US out­break was in 1902.

Ad­vance­ment came rapid­ly. Louis Pas­teur traced in­fec­tions to virus­es and bac­te­ria and showed how those mi­crobes could be at­ten­u­at­ed, or weak­ened, and then in­ject­ed in­to hu­mans to pre­vent an in­fec­tion:  Soon ra­bies, an­thrax and measles could be stopped. Lat­er sci­en­tists learned how to give pa­tients just a few parts of a mi­crobe, rather than a liv­ing one, and have the body still build an im­mune de­fense. Ty­phoid, bubon­ic plague and, most fa­mous­ly, po­lio were new­ly pre­ventable.

And then at some point in the lat­ter half of the 20th cen­tu­ry, some­thing changed. De­vel­op­ment, at least in how vac­cines were built, halt­ed.

Kizzmekia Cor­bett

“The gen­er­al way we make vac­cines has not changed in decades,” Kizzmekia Cor­bett, the sci­en­tif­ic lead at the NIH’s vac­cine lab, told End­points.

It’s not that re­searchers stopped dis­cov­er­ing new ways of pre­vent­ing in­fec­tion. GSK poured mil­lions in­to virus-like par­ti­cles — a near-repli­ca of a virus but with­out ge­net­ic code — and J&J spent heav­i­ly on ade­n­ovirus­es, a be­nign mi­crobe that can be en­gi­neered to car­ry pro­teins from the dan­ger­ous one. But few of the vac­cine can­di­dates made it through the clin­ic.

“I’m not ac­tu­al­ly sure why that is,” Har­vard vi­rol­o­gist and epi­demi­ol­o­gist Michael Joseph Mi­na told End­points. “It could be be­cause the vast ma­jor­i­ty of pathogens we want to vac­ci­nate against, we al­ready have vac­cines for. They were years in the mak­ing but they now ex­ist.”

That’s good news for hu­man­i­ty. By some es­ti­mates, peo­ple in de­vel­oped coun­tries live over 3 decades longer on av­er­age be­cause of these vac­cines. But it leaves ques­tions as to how quick­ly coun­tries could re­spond in emer­gency sit­u­a­tions, such as a nov­el virus out­break. The old meth­ods take longer. It took re­searchers over a year to come up with vac­cine can­di­dates for the SARS out­break in 2003. Even a new kind of the fa­mil­iar flu virus, like the H1n1 out­break in 2009, presents prob­lems. Many com­pa­nies still use eggs to grow the virus­es need­ed for flu vac­cines, an idea pi­o­neered in the 1960s.

“First you have to get the eggs from chick­ens,” Mi­na said. “I mean, like, re­al­ly?”

In the 1990s, as the ear­li­est forms of gene se­quenc­ing and gene edit­ing be­came fea­si­ble, a new idea emerged that promised to re­think the en­tire field: DNA vac­cines. The ear­li­er forms of vac­cines tried to get virus pro­teins harm­less­ly in­to the body, where im­mune cells would then learn to rec­og­nize them and build de­fens­es to neu­tral­ize them. But what if in­stead of virus­es or virus pro­teins, you gave pa­tients on­ly the ge­net­ic code for the virus pro­teins? A per­son’s cells would take up the DNA and make the virus’s pro­teins, and then the body’s im­mune cells would see and build de­fens­es against them, as they would from an at­ten­u­at­ed virus. You could build vac­cines faster and code for anti­gens that had been dif­fi­cult to cre­ate by oth­er means.

Af­ter a mouse pa­per in 1993, an NIH of­fi­cial said: “this tech­nique has con­cep­tu­al­ly raised the field of vac­cine re­search to an­oth­er lev­el.”

In the years since, how­ev­er, those ef­forts have strug­gled to take off and may have been eclipsed by an­oth­er tech­nol­o­gy. As re­cent­ly as the last ma­jor glob­al epi­dem­ic, Zi­ka in 2016, DNA tech­nol­o­gy was at the cen­ter of the hunt for a vac­cine. Now Mod­er­na is work­ing in lock­step with NIH and Cure­Vac has its own fund­ed ef­fort. Their rise has caught the eye of Joseph Kim, CEO of In­ovio, the DNA-based vac­cine biotech that got a Zi­ka can­di­date in­to the clin­ic in 2016 and is now de­vel­op­ing a Covid-19 can­di­date.

“It’s a healthy com­pe­ti­tion,” Kim, whose com­pa­ny al­so got a $9 mil­lion grant from CEPI to build a Covid-19 vac­cine, told End­points. “I don’t mind go­ing mano a mano.”

Tal­ent­ed, nerdy and brash, Katal­in Karikó liked to brag over the Xe­rox ma­chine at the Uni­ver­si­ty of Penn­syl­va­nia Med­ical School of­fices. She boast­ed the way you might at a bar: About her work on RNA, for in­stance, a field still in in­fan­cy. Or about her daugh­ter, who would be­come a two-time Gold Medal-win­ning Olympic row­er.

Ori­gin sto­ries are dan­ger­ous in sci­ence. Few break­throughs are as we re­mem­ber: Edi­son didn’t re­al­ly in­vent the light bulb and even Dar­win had his pre­de­ces­sors. Ideas swell on a con­tin­u­um, not in steps. But if mR­NA vac­cines be­gan any­where, they be­gan in two places: In Ger­many in 2000, when Cure­vac was found, and two years be­fore at Penn, when Karikó saw a new hire ap­proach­ing as she copied a jour­nal ar­ti­cle: im­mu­nol­o­gist Drew Weiss­man.

“So I wait­ed,” Karikó told End­points. Then she said to him, “You are a new guy, and you know what? I am Kate, I do RNA, I can do any­thing.”

Weiss­man was less in­tim­i­dat­ed than in­trigued. The two talked. Karikó had done her ear­ly RNA work on HIV and AIDS at the height of the epi­dem­ic, when she and oth­ers toyed with the idea of us­ing it to make “the per­fect vac­cine.” Weiss­man had come from Fau­ci’s NIH lab to Penn to build an an­tivi­ral pro­gram, but was strug­gling to use plas­mids — lit­tle cir­cles of DNA — to de­liv­er them.

“So I said, ‘Oh I can make RNA,’ and he said, ‘OK I will try it,'” Karikó said. “So that’s how it hap­pened.”

Drew Weiss­man and Katy Karikó

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Mes­sen­ger RNA of­ten gets cast as a side­kick to DNA, a couri­er who takes or­ders from its nu­cle­ic cousin and de­liv­ers them for the rest of the cell to ex­e­cute: Build this en­zyme, that ri­bo­some. But mes­sen­ger RNA al­so con­tains the code for every pro­tein, and in the­o­ry, you can use them, like DNA vac­cines, to hi­jack the cell’s ma­chin­ery and coax the body to make its own anti­gens.

The ad­van­tage of RNA, as the vac­cine world has come around to, is that you can sim­ply in­ject it in­to a cell and the ri­bo­somes float­ing in the cy­to­plasm will pick it up and start mak­ing the pro­teins. DNA vac­cines need to reach the nu­cle­us, where DNA is housed.

It’s “a lit­tle bit more dif­fi­cult from a mol­e­c­u­lar bi­ol­o­gy per­spec­tive com­pared to mR­NA,” said CEPI’s Nick Jack­son, who pre­vi­ous­ly worked on vac­cines for Sanofi and Pfiz­er.

There were many ques­tions, though: Could you make an RNA that was sta­ble? Could you de­liv­er it with­out caus­ing se­vere side ef­fects that had long de­terred oth­ers from try­ing to build such drugs? Af­ter a shot, would pa­tients be­come im­mune to the RNA it­self? Cure­Vac launched in 2000 af­ter a Ger­man sci­en­tist found in­ject­ing plain mR­NA led tis­sues to ex­press pro­teins, but for years it was the on­ly ma­jor com­pa­ny in the space; big phar­ma showed lit­tle in­ter­est.

“It was a ques­tion of who was brave enough,” Phillip Sharp, an MIT pro­fes­sor who won the 2016 No­bel Prize in Med­i­cine for his work on mes­sen­ger RNA and co-found­ed Al­ny­lam, told End­points. “To pic­ture it and to or­ga­nize it.”

Noubar Afeyan wasn’t try­ing to stop a pan­dem­ic when he start­ed build­ing a new com­pa­ny in 2010. The CEO of one of biotech’s largest VCs, then called Flag­ship Ven­tures, he was look­ing for a new way of mak­ing drugs. And, at a time when gene and cell ther­a­py looked in­fea­si­ble, he got a pitch from Der­rick Rossi, a Har­vard pro­fes­sor who worked on stem cells.

Der­rick Rossi

“We had done an­i­mal stud­ies show­ing mR­NA could ex­press lit­er­al­ly hun­dreds of pro­teins,” Rossi told End­points, de­scrib­ing his pre­sen­ta­tion.

The word “vac­cine” nev­er ap­peared in Rossi’s slides. He had a grand goal, ex­plain­ing how, by ex­press­ing any pro­tein, these nu­cleotides could be turned in­to a treat­ment for a vast ar­ray of ill­ness­es. Afeyan bit.

“We were in­ter­est­ed in pa­tients be­ing their own pro­tein fac­to­ries,” Afeyan told End­points.

(Rossi said his work was par­tial­ly in­spired by Karikó and Weiss­man’s, which Mod­er­na would ul­ti­mate­ly li­cense for $74 mil­lion, al­though Afeyan said they didn’t use them.)

For three years of stealth mode, those who knew Rossi or his work spec­u­lat­ed it was a stem cell com­pa­ny.

Then Mod­er­na launched and it wasn’t brave; it was au­da­cious. In a cou­ple of years, it grew to the most valu­able pri­vate biotech in the world. It had over 100 pro­grams, was es­ti­mat­ed to hold $1.5 bil­lion in cash re­serves, and spoke bold­ly about chang­ing how drugs were made.

Mes­sen­ger RNA isn’t on­ly valu­able for stop­ping in­fec­tious dis­eases like coro­n­avirus. Its nim­ble­ness and pre­ci­sion make it a good medi­um for po­ten­tial HIV and uni­ver­sal flu vac­cines, and the same prin­ci­ples could be ap­plied to make an­ti­body drugs. They were ide­al forms of can­cer vac­cines — an old idea re­searchers had long strug­gled to make work — be­cause you could se­quence a pa­tient’s tu­mor and ed­it a vac­cine to build pre­cise anti­gens against it. Rare ge­net­ic dis­eases in which pa­tients are miss­ing or have a mistyped gene could be treat­ed by bits of mR­NA that told the cells to build work­ing copies of the pro­tein.

Cure­Vac al­so rec­og­nized the po­ten­tial, as did BioN­Tech, which qui­et­ly launched with sim­i­lar mR­NA aims in 2008 and now em­ploys Karikó as a se­nior vice pres­i­dent. (BioN­Tech qui­et­ly an­nounced in an SEC fil­ing that they were in­ves­ti­gat­ing Covid-19 vac­cines, but de­clined to com­ment fur­ther on the ef­fort.)

Those ap­pli­ca­tions, though, took time. Mod­er­na wasn’t sure how to ad­min­is­ter mul­ti­ple dos­es with­out the cells be­com­ing re­sis­tant to RNA, or how to get it in­to all cell types. Skep­tics ques­tioned Mod­er­na’s me­te­oric val­u­a­tion as da­ta failed to ap­pear. They grew loud­er as some top sci­en­tists left the com­pa­ny.

It was al­so Flag­ship’s long-run­ning strat­e­gy to de­vel­op tech step-by-step, Afeyan said.

“We mapped out the space and ba­si­cal­ly asked, what was the min­i­mal thing we could do?” Afeyan, who serves as chair­man of Mod­er­na, said.

Noubar Afeyan, Flag­ship CEO

Well-un­der­stood — just ex­press enough of one pro­tein — and re­quir­ing on­ly a sin­gle dose, vac­cines pro­vid­ed an easy test. In 2016, Mod­er­na an­nounced two vac­cine tri­als. Then an op­por­tu­ni­ty arose in cri­sis. As the Zi­ka virus out­break con­tin­ued to spread across South and Cen­tral Amer­i­ca in 2016, Mod­er­na be­gan hunt­ing for a vac­cine. They teamed with the Bill & Melin­da Gates Foun­da­tion and the NIH. The re­sult was a vac­cine can­di­date still go­ing through tri­als and Mod­er­na’s first peer-re­viewed pub­li­ca­tion, the first in sev­er­al swaths of da­ta that have qui­et­ed crit­i­cism around the com­pa­ny.

“Mod­er­na is the most se­ri­ous biotech ef­fort” for mR­NA vac­cines, Sharp said. “Ba­si­cal­ly when Mod­er­na start­ed was when mR­NA vac­cines be­came re­al­ly dis­cussed.”

It al­so helped lead to an­oth­er NIH col­lab­o­ra­tion in 2017, on Mid­dle East Res­pi­ra­to­ry Syn­drome, a close cousin of Covid-19. CEPI was found­ed the same year. Then, this past Sep­tem­ber, Mod­er­na re­leased re­sults from a Phase I tri­al on CMV. Four months lat­er, Cure­Vac an­nounced re­sults from its ra­bies tri­al.

There had been im­prove­ments since Mod­er­na’s launch. Re­searchers knew bet­ter how to make a sta­ble mR­NA mol­e­cule and how to en­case it in lipid nanopar­ti­cles — in­fin­i­tes­i­mal­ly small balls of fat, to be slight­ly less than sci­en­tif­ic — in or­der to get it in­to the cell. The field had broad­ly switched over to a form of the vac­cine Karikó and Weiss­man helped pi­o­neer that doesn’t cause an in­nate im­mune re­sponse to the mol­e­cule. Build­ing per­son­al­ized can­cer vac­cines had al­so giv­en them ex­pe­ri­ence in de­sign­ing vac­cines rapid­ly.

The stud­ies were both small, de­signed to show safe­ty more than ef­fi­ca­cy, but they both point­ed one way: An mR­NA vac­cine could work.

“The tech­nol­o­gy is there,” Cure­Vac CEO Daniel Menichel­la told End­points.

mR­NA vac­cines are so­phis­ti­cat­ed things: An­cient bi­ol­o­gy tied to the 21st cen­tu­ry’s biotech rev­o­lu­tion. You be­gin with a virus’ ge­net­ic code, and if you have that, you can the­o­ret­i­cal­ly de­sign a can­di­date in hours.

There are prac­ti­cal con­straints on that, though, and as the new coro­n­avirus swelled from a wor­ry­ing sto­ry Tal Zaks read about in the Wall Street Jour­nal to an in­fec­tion that spilled through Chi­na and threat­ened to leak be­yond, the NIH–Mod­er­na re­sponse team found them­selves in a wait­ing game. For over two years, they had worked on build­ing a vac­cine for MERS, a coro­n­avirus that by all in­di­ca­tions was quite sim­i­lar to the new coro­n­avirus. They could use it as a tem­plate, quick­ly swap in ge­net­ic code from the new virus, and send it off to Mod­er­na for man­u­fac­tur­ing. But first, they need­ed that code.

The nov­el coro­n­avirus Covid-19 spread through Feb­ru­ary 18 (Ed­ward Park­er, The Vac­cine Cen­tre, Lon­don School of Hy­giene & Trop­i­cal Med­i­cine )

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“There’s on­ly so much you can do,” Kizzmekia Cor­bett, the NIH vac­cine re­searcher, said. “The anti­gen was es­sen­tial­ly de­signed in our head, all we need­ed was the se­quence from Chi­na.”

The se­quence ap­peared on a pub­lic data­base on Jan­u­ary 11, around two weeks af­ter the out­break be­came pub­lic knowl­edge. It was a sem­i­nal date for labs watch­ing the epi­dem­ic, in­clud­ing Mod­er­na and Cure­Vac.

The NIH lab took their MERS vac­cine and re­moved the ge­net­ic code for the ex­ist­ing crown-like spike pro­teins that give coro­n­avirus­es their name. Coro­n­avirus­es use these pro­teins to in­fect cells, mak­ing them promi­nent tar­gets for vac­cines. They sub­sti­tut­ed in code for the nov­el coro­n­avirus’s spike pro­teins and fired off the whole code in four days lat­er in an email to Mod­er­na.

In Mass­a­chu­setts, Mod­er­na start­ed mak­ing both the vac­cine and the re­search ma­te­ri­als need­ed to study it, in­clud­ing the reagents re­searchers need to test if it’s caus­ing an im­mune re­sponse, with aims of start­ing a clin­i­cal tri­al with­in 3 months of launch­ing the pro­gram, a goal set by the NIH. They’ve planned for rapid de­vel­op­ment be­fore, but nev­er had to ex­e­cute on this timescale.

“It’s a test of what we can do,” Zaks said.

Re­search on a po­ten­tial vac­cine be­gan short­ly af­ter Lidia Oost­vo­gels re­turned to Cure­Vac’s head­quar­ters in Tübin­gen, Ger­many, but the se­quence meant they could be­gin de­sign­ing their can­di­date. They or­dered plas­mid DNA, which is then in­duced to tran­scribe it­self on­to a strand of mR­NA to cre­ate the vac­cine. One re­searcher pulled out their own old MERS pro­gram from which they can build the virus. They worked more slow­ly than the NIH and Mod­er­na.

“If every­thing goes re­al­ly, very, very quick­ly and it’s like an easy one, it can be a ques­tion of a few weeks,” Oost­vo­gels said of find­ing a vac­cine can­di­date.

Ear­ly work done, re­searchers then gath­ered around a ta­ble to plan how fast they could re­spond: Good can­di­dates would be in the lab soon, they con­clud­ed, and pre­clin­i­cal test­ing would then take a few months.

Daniel Menichel­la

They pre­sent­ed the plan to CEPI, who agreed to back it in full. Menichel­la, though, had al­ready giv­en a go-ahead. Since then, Cure­Vac has set­tled on two vac­cine can­di­dates. They are not dis­clos­ing how they work, al­though they said they have ways of at­tack­ing the coro­n­avirus out­side of the crown-like spike pro­teins. They have start­ed pro­duc­ing both for clin­i­cal test­ing, aim­ing to start a tri­al on the one that works best in ear­ly sum­mer, a cou­ple of months af­ter the NIH tar­get but far faster than a nor­mal vac­cine time­line.

“You can al­ways stop a pro­gram,” Menichel­la said. “But if it’s go­ing to be like this one has worked out, you want to get your­selves on it as quick­ly as you can.”

Last year, CEPI gave Cure­Vac a grant for up to $34 mil­lion for a sci-fi-es­que idea. Be­cause mR­NA nu­cleotides can es­sen­tial­ly be “print­ed,” re­searchers had flirt­ed with the idea of build­ing fa­cil­i­ties across the globe that could rapid­ly churn out a vac­cine in the event of a new virus, or with a dis­ease like the flu, re­spond to dif­fer­ent strains in dif­fer­ent re­gions by print­ing a vac­cine to match. Cure­Vac want­ed to build it.

It was a bold plan and al­though, like with Mod­er­na and Fau­ci’s pro­posed test, the out­break would pre-empt the tech­nol­o­gy, it got at one of the key ben­e­fits pub­lic health lead­ers see in mR­NA.

“It’s prob­a­bly go­ing to be very in­ex­pen­sive” to man­u­fac­ture, Drew Weiss­man, the mR­NA pi­o­neer, told End­points. “The Bill and Melin­da Gates Foun­da­tion said a glob­al vac­cine has to get down to $1.50. Few very vac­cines get down to that.”

Mod­er­na and Cure­Vac have each un­veiled new fa­cil­i­ties in the last cou­ple of years to make mR­NA vac­cines on an in­dus­tri­al scale for the first time. Cure­Vac us­es a form of mR­NA that trig­gers an im­mune re­sponse and al­lows the com­pa­ny to give dos­es as small as 1/1,000,000 of a gram and for its plant, they say, to churn out up to 1 mil­lion dos­es every two weeks.

Mod­er­na’s dos­es are much larg­er but they can still make their vac­cines in lots of less than 10 liters — a frac­tion of the thou­sands of liters re­quired to house the liv­ing cells that make at­ten­u­at­ed and in­ac­tive virus­es. A flu man­u­fac­tur­ing fa­cil­i­ty would re­quire a chick­en farm.

“Mod­er­na has man­u­fac­tur­ing down to a sci­ence,” Cor­bett said.

But those fa­cil­i­ties are built to build vac­cines for mil­lions of peo­ple. If the coro­n­avirus spreads as far and for as long as some ex­perts fear, it could re­quire hun­dreds of mil­lions or more vac­cines. Fau­ci has been all but beg­ging a Big Phar­ma to foot the bill, but it would be a mas­sive one. The in­dus­try has built it­self around the old mod­el and Zaks said a new fac­to­ry would have to be built.

In the mean­time, the Na­tion­al In­sti­tutes of Health is re­ly­ing on a com­pa­ny that has made batch­es of drugs for pre­clin­i­cal and Phase I suc­cess, and all but noth­ing be­yond.

“We’ve done it on a small scale re­peat­ed­ly. It’s quite dif­fer­ent to ac­tu­al­ly scale up,” Zaks said. “We have yet to il­lus­trate that and that re­quires time, and one of the things you don’t have in the set­ting of a pan­dem­ic is time.”

Michael Os­ter­holm knows a thing or two about pub­lic health crises. He di­rects the Cen­ter for In­fec­tious Dis­ease Re­sponse and Pre­ven­tion, ran the CDC for a part of the SARS out­break and serves on both the Na­tion­al Sci­ence Ad­vi­so­ry Board on Biose­cu­ri­ty and the World Eco­nom­ic Fo­rum Work­ing Group on Pan­demics. And he sees more ques­tions than an­swers in Mod­er­na and Cure­Vac’s pro­grams.

Michael Os­ter­holm

“I con­grat­u­late them for tak­ing on the ef­fort, but I cau­tion the world not to think this will have any im­pact on this par­tic­u­lar sit­u­a­tion,” Os­ter­holm told End­points. “It’s not. These are years off.”

Fau­ci told Ax­ios on Tues­day Covid-19 was “at the brink” of glob­al pan­dem­ic. It may yet tail off come sum­mer, but pub­lic health of­fi­cials are grow­ing in­creas­ing­ly con­cerned it could linger for years, be­com­ing a reg­u­lar in­fec­tion, like the flu. And yet the ques­tions that plagued vac­cine de­vel­op­ment dur­ing the pre­vi­ous out­breaks are still present now, Os­ter­holm said.

Chief among those is man­u­fac­tur­ing, Os­ter­holm said. Com­pa­nies mo­bi­lized for past epi­demics, such as SARS, on­ly to be left foot­ing the bill when the virus was con­tained and their drugs were use­less. CEPI’s grants have curbed some of the bur­den for biotechs, but Fau­ci is still ask­ing phar­ma com­pa­nies to take a sev­er­al-hun­dred mil­lion dol­lar risk in part­ner­ing on a vac­cine.

It’s al­so not a giv­en that the vac­cines will work. Ex­perts cau­tion that mR­NA, while promis­ing, is large­ly untest­ed. That first Zi­ka vac­cine from Mod­er­na? It didn’t ac­tu­al­ly work once giv­en to hu­mans. They had to go back to the lab and make it stronger, and the re­sults from the new vac­cine are still forth­com­ing.

Asked how con­fi­dent peo­ple should be an mR­NA vac­cine will work, giv­en the ear­ly strug­gles the Zi­ka vac­cine faced, Zaks, though op­ti­mistic, said: “That’s a great ques­tion.”

Cure­Vac’s Menichel­la points to their re­cent ra­bies tri­al as proof their tech­nol­o­gy can work, but their first ra­bies at­tempt was far from per­fect: On­ly a frac­tion of pa­tients re­spond­ed and on­ly when giv­en with nee­dle-free de­vices.

Pe­ter Hotez

“We have to see if it works or not,” Pe­ter Hotez, a Bay­lor Col­lege of Med­i­cine im­mu­nol­o­gist who de­signed a vac­cine can­di­date for SARS and sees po­ten­tial in mR­NA, told End­points. “The prob­lem is not a sin­gle nu­cle­ic acid vac­cine has been ap­proved.”

Hotez and most of the ex­perts in­ter­viewed wish that gov­ern­ments would set up in­cen­tives to de­vel­op vac­cines even af­ter an epi­dem­ic. His SARS vac­cine sat in a freez­er for years, but had it gone through tri­als he said it could’ve been de­ployed when the out­break be­gan.

Cor­bett said if they had a gen­er­al coro­n­avirus vac­cine ap­proved, they could have quick­ly ad­just­ed it to work on Covid-19 and launched a tri­al. Now Mod­er­na and the NIH are push­ing in­to a Phase I tri­al with­out full pre­clin­i­cal test­ing. It’s not un­usu­al to short­en steps dur­ing out­breaks, but the time­line is par­tic­u­lar­ly ac­cel­er­at­ed.

“It is risky,” Zaks said, but worth the risk.

The NIH hasn’t said its plan for what would hap­pen af­ter a Phase I, but Cure­Vac and out­side ex­perts say the de­mands of pre­clin­i­cal test­ing and the time it takes to run the first and sub­se­quent tri­als mean the best es­ti­mates are a vac­cine avail­able af­ter 12 to 18 months — a vac­cine, es­sen­tial­ly not for an ear­ly out­break but for a worst-case sce­nario.

“If this be­comes the next pan­dem­ic, then we need be to able the pro­tect the pop­u­la­tion,” Oost­vo­gels said.

Still, Cor­bett sees hope in the speed with which they’ve been able to move thus far. A SARS vac­cine took 20 months to reach peo­ple and a MERS vac­cine took sev­er­al years.  Now, on the third coro­n­avirus out­break of the cen­tu­ry, ex­perts ex­pect mul­ti­ple vac­cines to be in hu­mans in less than than 6 months. If this is the test, they might be pass­ing.

“I don’t think I could’ve hoped for any­thing bet­ter,” she said. “I wake up and think we’re liv­ing in a dream.”

Sen. Ron Wyden (D-OR) (Francis Chung/E&E News/Politico via AP Images)

In­fla­tion re­bates in­com­ing: Wyden calls on CMS to move quick­ly as No­var­tis CEO pledges re­ver­sal

Senate Finance Chair Ron Wyden (D-OR) this week sent a letter to the head of the Centers for Medicare & Medicaid Services seeking an update on how and when new inflation-linked rebates will take effect for drugs that see major price spikes.

The newly signed Inflation Reduction Act requires manufacturers to pay a rebate to Medicare when they increase drug prices faster than the rate of inflation.

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Ma­gen­ta halts stem cell work and may sell it­self fol­low­ing pa­tient death, clin­i­cal hold

Magenta Therapeutics said it is halting work on its stem cell transplant drug pipeline and may sell itself, a week after the company reported the death of a patient in an early stage trial of its antibody-drug conjugate.

The Cambridge, MA-based company said it will conduct a “review of strategic alternatives,” and that could include an “acquisition, merger, business combination, or other transaction.”

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How to use ex­ter­nal con­trols: FDA spells out think­ing in new draft guid­ance

The use of real-world evidence to inform the FDA’s decision-making continues apace, with the agency releasing new draft guidance yesterday on how sponsors can compare outcomes of trial participants receiving a test treatment with outcomes in a group of people external to the trial.

The practice of externally controlled trials is common, particularly in oncology or other difficult areas where it’s not ethical or feasible to use internal controls.

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The Big Phar­ma axe: Mer­ck cuts chikun­gun­ya vax, Bris­tol My­ers drops Cy­tomX-part­nered pro­gram, and more

As fourth quarter earnings come in, Big Pharmas are disclosing changes to their pipelines during their investor calls, and sometimes more quietly in presentation appendices.

Merck dropped its chikungunya vaccine candidate, which completed a Phase II study. Merck acquired the vaccine through its purchase of Themis Bioscience in 2020. In developing a vaccine for chikungunya, a mosquito-borne virus, Valneva is the frontrunner, as it submitted its vaccine to the FDA at the end of December.

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Goldfinch Bio CEO Tony Johnson (L) and Karuna Therapeutics CEO Bill Meury

Karuna li­cens­es Goldfinch as­sets to com­pete with Boehringer In­gel­heim in neu­ro­science

Karuna Therapeutics is looking to compete with Boehringer Ingelheim on depression and anxiety with a new license to Goldfinch Bio’s assets, starting with $15 million to the shuttered biotech.

Karuna steps into an arena already being tested by Boehringer in multiple Phase II studies — the two are targeting transient receptor potential canonical 4 and 5, or TRPC4/5, which is thought to have a role in neuroscience indications. Goldfinch’s asset went through a Phase II in kidney diseases, but Karuna’s sights are set on mood and anxiety disorders for now.

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Teresa Graham, incoming Roche Pharmaceuticals CEO

In­com­ing Roche CEO builds out his top team, tap­ping Genen­tech vet to lead phar­ma di­vi­sion

Roche announced another leadership shuffle Thursday morning – the head of global product strategy, Teresa Graham, will take over as CEO of Roche Pharmaceuticals in March while the company’s corporate executive committee will make a spot for Levi Garraway, CMO and executive VP of global product development.

Thomas Schinecker will take over the top spot as Roche group CEO in March, leaving his spot as head of diagnostics.

Roche's headquarters in Basel, Switzerland (Kyle LaHucik for Endpoints News)

Roche ditch­es fi­nal PhI­II for can­cer hope­ful, re­ports set­back for key drug in $1.4B buy­out

Over the past few years, Roche has released news about its AKT inhibitor ipatasertib in drips — most of them negative. The drug yielded mixed data in a key prostate cancer trial, Phase III flops in triple-negative breast cancer forced the pharma giant to pull the plug there, and in mid-2022 Roche trimmed two more early-stage indications in prostate cancer after completing the trials.

Now, the last piece of the program is gone.

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Trodelvy notch­es a win in most com­mon form of breast can­cer

Following a promise last year to go “big and fast in breast cancer,” Gilead has secured a win for Trodelvy in the most common form.

The drug was approved to treat HR-positive, HER2-negative breast cancer patients who’ve already received endocrine-based therapy and at least two other systemic therapies for metastatic cancer, Gilead announced on Friday.

Trodelvy won its first indication in metastatic triple-negative breast cancer back in 2020, and has since added urothelial cancer to the list. HR-positive HER2-negative breast cancer accounts for roughly 70% of new breast cancer cases worldwide per year, according to senior VP of oncology clinical development Bill Grossman, and many patients develop resistance to endocrine-based therapies or worsen on chemotherapy.

Sanofi scraps PhI­II tri­al for Prin­cip­ia drug af­ter re­view­ing com­pe­ti­tion

Months after the FDA placed Phase III trials of Sanofi’s BTK inhibitor on hold, the company is winding down one of the studies.

Sanofi reported in its Q4 earnings that the URSA study “was discontinued after careful evaluation of the emerging competitive treatment landscape in” myasthenia gravis, a rare disease that causes muscle weakness.

The Phase III, placebo-controlled trial was testing tolebrutinib in patients with the moderate-to-severe form of the disease. It started in late 2021, according to records on clinicaltrials.gov, and was originally designed to recruit 154 participants who were receiving the standard of care.

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