In­side the quixot­ic 30-year quest that gave us the Covid-19 treat­ments, vac­cines and could un­lock vac­ci­nol­o­gy’s new holy grail

John Mas­co­la, Amer­i­ca’s soft-spo­ken, no-non­sense chief vac­ci­nol­o­gist, spent 2020 on the fourth floor of the Vac­cine Re­search Cen­ter in Bethes­da, MD, pri­mar­i­ly work­ing on three projects. There’s a de­cent chance one of them has al­ready been in­ject­ed in your arm — twice. An­oth­er was in­fused in­to hun­dreds of thou­sands of Covid-19 pa­tients, po­ten­tial­ly pro­tect­ing them from hos­pi­tal­iza­tion.

And the third is a sci­en­tif­ic codex that has be­dev­iled Mas­co­la, his col­leagues, and re­searchers around the world for the bet­ter part of three decades.

Be­fore Covid-19, the largest and longest-run­ning mys­tery in in­fec­tious dis­ease was how to build a vac­cine against HIV, the fa­mous­ly eva­sive virus that has claimed the lives of 36 mil­lion peo­ple since the 1980s. With­in a year of the nov­el coro­n­avirus’ dis­cov­ery, two vac­cines were al­ready avail­able and shown to be 95% ef­fec­tive. Thir­ty-eight years af­ter HIV’s dis­cov­ery, you could fill en­cy­clo­pe­dias with all sci­en­tists have learned about the pathogen, but it’s hard to say whether or not we’re any clos­er to a vac­cine.

Part of that dis­par­i­ty has to do with the coro­n­avirus’ com­par­a­tive sim­plic­i­ty — “this is a stu­pid easy virus to vac­ci­nate against,” as the im­mu­nol­o­gist Michael Farzan put it last year. HIV is, by any de­f­i­n­i­tion, the hard­est.

But part of it al­so has to do with all the tools re­searchers de­vel­oped try­ing to in­oc­u­late against HIV. Con­front­ed by a mi­cro­bial en­e­my more cun­ning than any hu­man­i­ty had ever en­coun­tered, the world’s lead­ing re­searchers were forced to go back to the draw­ing board. Cross­ing dis­ci­plines and con­ti­nents, they came up with new tools to un­der­stand both virus­es and the im­mune sys­tem and new ways of turn­ing that knowl­edge in­to walls and weapons against any pathogen, how­ev­er stu­pid or in­ge­nious it may be.

Those same re­searchers jumped out in the win­ter of 2020 to study the coro­n­avirus, un­leash­ing tools honed on a far more cun­ning foe. Mas­co­la, who had spent thir­ty years on HIV vac­cine de­vel­op­ment, most no­tably launched the ef­fort to find the first an­ti­body treat­ment, lat­er mar­ket­ed by Eli Lil­ly. Leg­endary AIDS re­searcher David Ho worked on his own an­ti­body treat­ment and con­duct­ed cru­cial stud­ies to see whether these ther­a­pies were evad­ing the virus.

“HIV was such a chal­leng­ing virus that we had to come up with new­er and new­er tech­nolo­gies,” said Neal Padte, Ho’s long­time col­lab­o­ra­tor. “So when SARS-CoV-2 broke out, we had a tool­box ready.”

The tim­ing — if this can ever be said of a pan­dem­ic — was for­tu­itous. Be­fore Covid-19, Mas­co­la and oth­ers re­searchers were fi­nal­ly near­ing, well, some­thing. It’s not quite a vac­cine, though it may yet lead to one. In­stead, it could turn in­to one of the best con­so­la­tion prizes in the his­to­ry of med­i­cine, a byprod­uct of the vac­cine hunt that may ul­ti­mate­ly prove near­ly as use­ful: a set of ul­tra-rare, Y-shaped mol­e­cules that, at least in an­i­mals, could neu­tral­ize most strains of HIV, po­ten­tial­ly pro­tect­ing at-risk peo­ple for months or a year and of­fer­ing a path to new treat­ments.

The sto­ry of how re­searchers ar­rived at these so-called broad­ly neu­tral­iz­ing an­ti­bod­ies over the last 30 years is one of the hid­den sto­ries of every­thing that went right about Amer­i­ca’s pan­dem­ic re­sponse, the silent en­gine be­hind the vac­cine and, par­tic­u­lar­ly, the most ef­fec­tive treat­ments: an­ti­body ther­a­pies from Vir, Re­gen­eron, and Eli Lil­ly.

It may al­so be the sto­ry of how the US pre­vents in­fec­tious dis­ease broad­ly in the fu­ture. For the first time, HIV vac­cines based on Mas­co­la’s re­search are en­ter­ing hu­mans. And while prospects for suc­cess re­main cloudy, he and his col­lab­o­ra­tors’ work may yet prove key to re­spond­ing to a broad suite of pathogens and achiev­ing one of vi­rol­o­gy’s new holy grails — a vac­cine and a treat­ment to pre­vent a coro­n­avirus out­break from ever re­cur­ring.

“HIV is the most vari­able virus there is out there, so if you can deal with HIV, you can deal with any­thing,” said Den­nis Bur­ton, a Scripps re­searcher com­mon­ly re­gard­ed as the fa­ther of the HIV an­ti­body field. “It has pushed re­searchers to the lim­it.”

The or­ga­nized hunt for a broad­ly neu­tral­iz­ing HIV an­ti­body be­gan in earnest 20 years ago, af­ter the In­ter­na­tion­al AIDS Vac­cine Ini­tia­tive, a non-prof­it found­ed in 1996 by the Rock­e­feller Foun­da­tion, hired a lanky and bushy-haired ex-pro­fes­sor named Wayne Koff as head of re­search. Like Mon­cef Slaoui in Op­er­a­tion Warp Speed, Koff was tasked with col­lat­ing and ex­pand­ing the pipeline of HIV vac­cines. Ex­cept Koff had mil­lions in­stead of bil­lions to spend on a prob­lem that — af­fect­ing pri­mar­i­ly gay men, peo­ple in the de­vel­op­ing world and IV drug users — rich na­tions and com­pa­nies ad­dressed with far less ur­gency.

Wayne Koff

By then, the world’s hopes for an HIV vac­cine had al­ready been de­flat­ed re­peat­ed­ly. When French re­searchers first iso­lat­ed the virus in 1983, sci­en­tists at Mer­ck and a Uni­ver­si­ty of San Fran­cis­co spin­out called Ch­i­ron were near­ing com­ple­tion of the he­pati­tis B vac­cine. It was a land­mark mo­ment in vac­ci­nol­o­gy. The first vac­cine to use re­com­bi­nant DNA tech­nol­o­gy, its suc­cess in­spired the same en­thu­si­asm that mR­NA has to­day. HIV, it seemed, was just a mat­ter of time.

“We ac­tu­al­ly thought it was go­ing to be easy to make vac­cines for all vi­ral dis­eases,” said Nan­cy Haig­wood, who worked for Ch­i­ron at the time. “But then HIV turned out to have quite a few num­ber of tricks up its sleeves.”

Vir­tu­al­ly all ear­ly con­structs failed in the lab or in an­i­mals, a phe­nom­e­non with which Koff was well-ac­quaint­ed. In 1990, as head of vac­cine re­search at the NIH, he hailed how new dis­cov­er­ies “cracked open the door” to a shot. By 1993, work­ing to build his own vac­cine at a biotech, he ac­knowl­edged that most of the can­di­dates that had cap­tured the world’s at­ten­tion had failed ba­sic lab tests.

Mas­co­la at a brief­ing with An­tho­ny Fau­ci and Pres­i­dent Trump on March 3, as the na­tion’s top physi­cians scram­bled to ad­dress the new virus. Mas­co­la at the time was al­ready de­vel­op­ing an an­ti­body treat­ment for the new virus. (Pho­to by Bren­dan Smi­alows­ki / AFP) (Pho­to by BREN­DAN SMI­ALOWS­KI/AFP via Get­ty Im­ages)

Click on the im­age to see the full-sized ver­sion

Koff was os­ten­si­bly hired to get more can­di­dates in­to hu­man tri­als around the world, as the US would do ef­fec­tive­ly for Covid-19. But he soon be­lieved that was the wrong task.

First, he de­cid­ed, re­searchers would have to fig­ure out what pro­tec­tion from HIV even looked like, lit­er­al­ly. He in­vit­ed 11 top sci­en­tists to a pair of meet­ings in Am­s­ter­dam and New York to hash out a plan.

“We re­al­ized very, very quick­ly that HIV vac­cine de­vel­op­ment wasn’t a prod­uct de­vel­op­ment prob­lem. It was a dis­cov­ery prob­lem,” said Koff, who now runs a non-prof­it ded­i­cat­ed to study­ing vac­cine im­munol­o­gy. “If Covid-19 had the en­ve­lope pro­tein that HIV does, we still wouldn’t have a vac­cine to­day.”

A spher­i­cal shield around the virus, the en­ve­lope is one of HIV’s most pow­er­ful weapons. To un­der­stand just how de­vi­ous it is, a con­trast with Covid-19 is in­struc­tive.

An­ti­bod­ies have been the he­roes of Covid-19 im­mu­ni­ty. Swarm­ing through your blood­stream are 10 bil­lion B cells, each car­ry­ing a slight­ly dif­fer­ent an­ti­body on its sur­face. These amaz­ing­ly eclec­tic Y-shaped mol­e­cules, pro­duced by ran­dom shuf­fling of DNA, act first like an army of sen­tinels. When one latch­es on­to a for­eign pro­tein, it starts mak­ing copies of it­self and spit­ting out thou­sands of an­ti­bod­ies per sec­ond. Ide­al­ly, these an­ti­bod­ies latch on­to a part of the virus and in­ter­fere with its abil­i­ty to in­fect cells, a process called neu­tral­iza­tion.

When SARS-CoV-2 en­ters the body, it makes lit­tle at­tempt to hide its spike pro­tein — that now fa­mous grap­pling hook — and, for all the con­cerns about vari­ants, it can’t read­i­ly change the spike’s struc­ture. With­in 7 days, most pa­tients are teem­ing with neu­tral­iz­ing an­ti­bod­ies that can glom on­to the spike and pre­vent it from hi­jack­ing cells, one of the rea­sons most peo­ple clear the in­fec­tion so quick­ly.

Give some­one a vac­cine en­cod­ing for the spike pro­tein and with­in two weeks, they’ll have swarms of neu­tral­iz­ing an­ti­bod­ies cours­ing through their blood, an army wait­ing to fire.

“The RBD — the no­to­ri­ous RBD — is just sit­ting there like a tar­get that says ‘hit me,'” said John Moore, an HIV re­searcher at Cor­nell Uni­ver­si­ty, re­fer­ring to the re­cep­tor-bind­ing do­main that sits atop the spike. “And the equiv­a­lent on the HIV en­ve­lope just does not ex­ist.”

The HIV’s en­ve­lope makes sure the virus doesn’t fall prey to the same fate. First, it’s stud­ded with a for­est of gly­cans, vi­brat­ing sug­ars that form a de­fen­sive canopy around the virus. The big­ger prob­lem, though, is that the en­ve­lope can mu­tate so rapid­ly that even if the im­mune sys­tem finds an an­ti­body that neu­tral­izes some strains, oth­er strains with­in the same per­son will evolve their way around it. The an­ti­body will be­come use­less.

The first HIV vac­cine ever de­signed, a con­struct Genen­tech first put in­to hu­mans in 1987, elicit­ed plen­ty of an­ti­bod­ies in vol­un­teers. But not one of them ef­fec­tive­ly neu­tral­ized the virus.

“The virus al­ways wins,” said Bur­ton.

Well, al­most al­ways. Ear­ly on, re­searchers learned from study­ing the blood of pa­tients that a tiny sub­set of HIV pa­tients kept the virus in check. And that point­ed to­ward a so­lu­tion. If some­one could fig­ure out what was hap­pen­ing in those pa­tients — if they could iso­late one of those an­ti­bod­ies — then maybe they could re­verse en­gi­neer it: fig­ure out what it looked like, how it bound to and dis­rupt­ed the virus and de­sign vac­cines that could in­duce healthy peo­ple to pro­duce repli­cas.

“The first ob­ser­va­tion was that the nat­ur­al im­mune re­sponse to HIV in some peo­ple – some peo­ple — was much bet­ter than any­thing we could get with the vac­cine,” Mas­co­la said. “So then the ques­tion was pret­ty ob­vi­ous: What’s in these peo­ple’s serum?”

Fish­ing in­di­vid­ual — some­times called mon­o­clon­al — an­ti­bod­ies out of serum, the yel­low soup left over when you dump all the blood cells out of blood, wasn’t easy then. The orig­i­nal method, pi­o­neered in 1976, in­volved tak­ing a B cell from a mouse and fus­ing it with a can­cer cell to cre­ate an im­mor­tal, an­ti­body-pump­ing hy­brid cell.

It was No­bel Prize-win­ning stuff, spark­ing hopes for drugs for all sorts of dis­eases. But, like many things in med­i­cine, it worked best with mice. “And it turned out that it’s a lot more dif­fi­cult to get hu­man mon­o­clon­al an­ti­bod­ies,” Bur­ton said.

Bur­ton at his lab in San Diego at 2008, as he and and IAVI neared their first break­through

Bur­ton, who at 69 has a full head of gray-white hair, a quick laugh, and still plays foot­ball (the British kind) once per week, made his name by de­vel­op­ing a new ap­proach while on sab­bat­i­cal at Scripps in 1989. At the time, Richard Lern­er’s lab there was rac­ing with a Cam­bridge group to iso­late the DNA of an an­ti­body and grow it in bac­te­ria.

When he ar­rived from a Swedish uni­ver­si­ty, they were try­ing to grow just a por­tion of the an­ti­body, but it wouldn’t form. Bur­ton sug­gest­ed to the grad­u­ate stu­dent lead­ing the project that they grow the whole thing.

“And un­be­liev­ably, when I looked back on it, he lis­tened to me straight off and said ‘right,'” Bur­ton said. A few Fri­days lat­er, Bur­ton went down­stairs to find his pho­to­plates glow­ing black, sig­ni­fy­ing the lab-grown an­ti­bod­ies were bind­ing to their tar­get. They cracked a bot­tle of cham­pagne that Bur­ton still keeps on his shelf to­day: “It just opened up the whole an­ti­body field.”

Bur­ton stayed at Scripps, en­ticed by the sci­ence and the San Diego sun. Im­me­di­ate­ly, he start­ed us­ing his new tech­nol­o­gy on HIV, be­liev­ing it held a path to a vac­cine.

It was an un­pop­u­lar opin­ion. At the time, most lead­ers — 90%, he es­ti­mates — in the nascent HIV vac­cine field fo­cused on T cells. Many doubt­ed that a broad­ly neu­tral­iz­ing an­ti­body could ever be found, and Bur­ton had trou­ble just se­cur­ing mon­keys for his stud­ies.

But in 1994, he iso­lat­ed an an­ti­body called B12 that neu­tral­ized two vast­ly dif­fer­ent strains and pro­tect­ed mon­keys from ex­po­sure to those spe­cif­ic virus­es. It proved his idea was pos­si­ble, but ul­ti­mate­ly the an­ti­body “wasn’t all that broad and wasn’t all that po­tent,” Koff said. Most virus­es es­caped. The tech­nol­o­gy was still too prim­i­tive.

“I mean it was re­al­ly, re­al­ly dif­fi­cult,” said James Crowe, who runs a lab at Van­der­bilt and in­vent­ed the Covid-19 an­ti­bod­ies As­traZeneca is now de­vel­op­ing. “It was a mir­a­cle if you could make one an­ti­body in a year.”

Af­ter the meet­ings in Am­s­ter­dam and New York, IAVI and the NIH es­tab­lished the Neu­tral­iz­ing An­ti­body Con­sor­tium in 2002 to try to ac­cel­er­ate the hunt. They brought to­geth­er re­searchers from four dif­fer­ent labs, a num­ber that even­tu­al­ly grew to 18, com­bin­ing im­mu­nol­o­gists, vi­rol­o­gists and struc­tur­al bi­ol­o­gists. They tried to es­tab­lish new stan­dard pro­ce­dures for iso­lat­ing an­ti­bod­ies, test­ing their neu­tral­iz­ing abil­i­ty, com­par­ing them to oth­er an­ti­bod­ies and turn­ing the best ones in­to vac­cines.

A rare ex­am­ple of sci­ence with­out ego, the con­sor­tium ef­fec­tive­ly cen­tered around sep­a­rate ef­forts at Scripps and the Vac­cine Re­search Cen­ter. Mas­co­la, a Bethes­da na­tive, was deputy chief of the cen­ter at the time. He ar­rived in 1999 af­ter a post-med school stint at the Wal­ter Reed Army In­sti­tute of Re­search an­a­lyz­ing the virus and why some of the first vac­cines had failed, where he came to some of the same con­clu­sions about the im­por­tance of an­ti­bod­ies as Bur­ton.

“He’s very col­lab­o­ra­tive,” Bur­ton said. “Not the type to be in­volved in a dirty race.”

The big break start­ed in 2006, when Koff and Bur­ton launched “Pro­to­col G.” So few pa­tients made an­ti­bod­ies that neu­tral­ized HIV that to find them, sci­en­tists would have to look around the world. Over the next 3 years, Koff teamed with lo­cal med­ical cen­ters to col­lect an­ti­body sam­ples from 1,800 HIV pa­tients across the globe, large­ly in Africa.

They se­lect­ed for those who had been in­fect­ed for at least three years, yet hadn’t be­come sick. The body tends to make the best an­ti­bod­ies af­ter pro­longed ex­po­sure to the virus be­cause the im­mune sys­tem evolves with the in­vad­er, se­lect­ing over time for the best de­fend­ers — a fact that would even­tu­al­ly throw a wrench in Bur­ton and Mas­co­la’s vac­cine ef­forts.

All those donors posed a prob­lem: How do you screen them? On­ly pa­tients whose sera could neu­tral­ize nu­mer­ous dis­parate HIV strains would be use­ful, so you would need to match dozens of virus­es with thou­sands of sam­ples. “And that’s when we start­ed us­ing ro­bot­ics,” Bur­ton said.

They en­list­ed a di­ag­nos­tics com­pa­ny called Mono­gram to throw hun­dreds of sera sam­ples against tens of virus­es at once. It worked. In an ini­tial study, about 1% of the 1,234 donors screened were iden­ti­fied as “elite neu­tral­iz­ers.” Some­thing in their blood had out­wit­ted HIV.

Koff and Bur­ton didn’t have a plan for how they could turn those elite neu­tral­iz­er sam­ples in­to an­ti­bod­ies, but the gold rush for an­ti­bod­ies in can­cer — pow­er­ful new drugs like Her­ceptin and rit­ux­imab — had brought star­tups with new tech­nolo­gies in­to the fray. Bur­ton called a biotech in Seat­tle called Spal­tudaq, told them they should be work­ing on HIV in­stead of can­cer and of­fered them half a mil­lion dol­lars for each sam­ple they screened.

Spal­tudaq took 30,000 B cells iso­lat­ed from one of the neu­tral­iz­ers and turned them in­to so-called su­per­natants, putting each in­to an in­di­vid­ual well and stim­u­lat­ing them to pump out pools of an­ti­bod­ies. Test­ing each pool against a pan­el of virus­es, they found two could neu­tral­ize most.

Back at Scripps, a pro­lif­ic new grad­u­ate stu­dent named Lau­ra Walk­er dropped every­thing and be­gan study­ing how the two an­ti­bod­ies bound to the virus, hop­ing it could di­rect the path to a vac­cine. The pa­per ap­peared in Sci­ence in 2009, point­ing to the first two pow­er­ful an­ti­bod­ies against HIV.

”Lau­ra just ran with it,” Koff said.

The break­through be­gan to rekin­dle in­ter­est in HIV an­ti­bod­ies, a shift that ac­cel­er­at­ed that De­cem­ber with a find­ing out of Thai­land. A vac­cine tri­al there had once again failed. But un­like pre­vi­ous tri­als, a small sub­set, 30%, ap­peared to have been pro­tect­ed for a year and their serum seemed to con­tain an­ti­bod­ies.

“Every­one was caught by sur­prise,” said Mo­ham­mad Sa­ja­di, an HIV re­searcher at Uni­ver­si­ty of Mary­land. “And that re­al­ly opened [things] up, put the fo­cus back on an­ti­body.”

Every­thing was click­ing. In Bethes­da, the Vac­cine Re­search Cen­ter was al­so near­ing a dis­cov­ery us­ing a slight­ly dif­fer­ent ap­proach. Rather than sep­a­rat­ing and an­a­lyz­ing all the B cells from a pa­tient, re­searchers took those B cells and pooled them to­geth­er. Then they took one part of the HIV en­ve­lope they knew was vul­ner­a­ble — in many cas­es, a pro­tein that the NIH’s struc­tur­al bi­ol­o­gists had iden­ti­fied— and used it as a fish­ing hook for the best an­ti­bod­ies.

In 2010, they found one that could neu­tral­ize 90% of the virus­es thrown at it. Mas­co­la pre­sent­ed the re­sults to his col­leagues in a con­fer­ence room on the fourth floor, show­ing a col­or-cod­ed ta­ble rep­re­sent­ing how well each of sev­er­al an­ti­bod­ies could neu­tral­ize 190 strains of HIV. Green meant it bare­ly bound, red meant a po­ten­tial drug.

Near­ly all of the rows for the an­ti­body, called VRC01, were bright red.

“It was re­al­ly un­prece­dent­ed,” said Gary Nabel, the di­rec­tor of the Vac­cine Re­search Cen­ter at the time. It forced him to think about his life’s work dif­fer­ent­ly. “The first thought that popped in my mind was, wait a minute, do we have it back­ward?”

VRC01 re-en­er­gized and re­shaped the course of HIV vac­cines. Long­time skep­tics of Bur­ton’s ap­proach dove in­to an­ti­body work. Bur­ton, Mas­co­la and oth­ers iden­ti­fied hun­dreds more neu­tral­iz­ing an­ti­bod­ies and set about de­sign­ing vac­cines based on the parts of the virus­es to which those an­ti­bod­ies.

“There was tremen­dous ex­cite­ment,” said Shelly Karuna, an HIV re­searcher at Fred Hutch.

Nabel and Mas­co­la, though, won­dered if in­stead of re­verse-en­gi­neer­ing a vac­cine, they could just man­u­fac­ture large dos­es of the an­ti­body and in­fuse them in­to pa­tients. The an­ti­bod­ies wouldn’t last for­ev­er and they wouldn’t be cheap (an­ti­bod­ies cost or­ders of mag­ni­tude more per dose to pro­duce than vac­cines) but they might pro­tect peo­ple for a while and of­fer a stop­gap un­til a vac­cine be­came avail­able.

A mod­el of the VRC01 an­ti­body. The pur­ple re­gions latch on to the part of the en­ve­lope HIV us­es to en­ter im­mune cells.

The strat­e­gy had been tried be­fore, most no­tably with an ap­proved drug to pro­tect at-risk kids from res­pi­ra­to­ry syn­cy­tial virus. In HIV, it had the po­ten­tial to not on­ly pre­vent but al­so treat — on the back of each an­ti­body is a bea­con that might sig­nal the im­mune sys­tem to clear HIV-in­fect­ed cells, some­thing that could be es­sen­tial for an even­tu­al cure.

There were risks, though, to de­vel­op­ing VRC01. In­dus­try wasn’t much in­ter­est­ed be­cause the sci­ence re­mained too spec­u­la­tive and most com­pa­nies weren’t in­ter­est­ed in in­fec­tious dis­ease, mean­ing the cen­ter would have to some­how make the an­ti­body it­self. And they knew some strains would still be im­per­vi­ous to VRC01 — should they wait for one bet­ter to come along?

But they de­cid­ed — af­ter meet­ings with No­bel win­ner David Bal­ti­more, renowned vac­ci­nol­o­gist Stan­ley Plotkin, and oth­er ad­vi­sors — that they need­ed to at least test the con­cept.

“We knew that a vac­cine that could in­duce these an­ti­bod­ies was a long way off,” Mas­co­la said.

And as the months went by, they gained new rea­sons for putting the an­ti­body in­to peo­ple. The an­ti­body hunt was sup­posed to point them to a vac­cine, but it quick­ly point­ed to just how hard a vac­cine would be. The first con­structs Bur­ton, Mas­co­la and oth­ers built based off their prized an­ti­bod­ies failed to pro­duce those same an­ti­bod­ies in an­i­mals.

Broad­ly neu­tral­iz­ing an­ti­bod­ies for HIV, it turned out, were strange mol­e­cules. Many of them bound to both the virus and that vi­brat­ing gly­can for­est, some­thing few an­ti­bod­ies do. They had long loops rarely found in oth­er an­ti­bod­ies. Their ge­net­ic code con­tained weird in­ser­tions and dele­tions.

In hind­sight, the strange­ness may not have been sur­pris­ing. Af­ter all, these an­ti­bod­ies are dis­tant out­liers, a tiny frac­tal of the tens of thou­sands of B cells iso­lat­ed from just 1% of HIV pa­tients. They were the prod­ucts of an im­mune sys­tem evolv­ing over years liv­ing with the virus, se­lect­ing for the best an­ti­bod­ies over and over again as the virus tried to evade each in­no­va­tion.

But it meant that HIV re­searchers would have to in­vent a new strat­e­gy. They would have to some­how fig­ure out a way of coax­ing a healthy im­mune sys­tem down that same path these rare pa­tients had fol­lowed, some­thing that no one re­al­ly knew had to do.

“Log­i­cal­ly, it should work,” Bur­ton said. “What we didn’t an­tic­i­pate at the time was how long that path would be.”

VRC01 would be the best way for­ward for a while.

VRC01 would soon of­fer its own dis­ap­point­ments. Mas­co­la set up the Vac­cine Re­searcher Cen­ter’s 2,000-liter biore­ac­tor to churn out kilo­gram af­ter kilo­gram of an­ti­body — far more ma­te­r­i­al than the cen­ter had ever pro­duced — and NIH and US Army labs set up a se­ries of tri­als in healthy vol­un­teers and then HIV in­fect­ed pa­tients.

Trevor Crow­ell, hired as a new physi­cian at the US Mil­i­tary HIV Re­search Pro­gram in 2014, re­mem­bered fly­ing out to Thai­land for in­tense five-day trips to set up a tri­al there on HIV pa­tients. The study would take vol­un­teers off their med­ica­tion to test whether VRC01 could keep the virus sup­pressed on its own.

In the­o­ry, the tri­al was blind­ed and place­bo-con­trolled, but back in Vir­ginia, the re­sults be­came clear rather quick­ly. Crow­ell got an email every time a vol­un­teer had their virus re­bound and had to go back on meds. The up­dates came in swift­ly.

“It was dis­ap­point­ing,” Crow­ell said, though he not­ed one pa­tient on VRC01 did keep the virus sup­pressed for 40 weeks, which he called “a glim­mer of hope.”

A pair of stud­ies from the NIH and the AIDS Clin­i­cal Tri­al Group reached the same con­clu­sion. By the time the nov­el coro­n­avirus rolled around, on­ly one ma­jor tri­al was left: a 4,500-per­son study to con­clu­sive­ly test whether the an­ti­body could pre­vent re­mis­sion.

VRC01 may have neu­tral­ized 90% of virus­es, but prac­ti­cal­ly, with the lev­els of an­ti­body you could in­fuse in peo­ple, it pro­tect­ed against a far low­er per­cent­age of strains world­wide.

It “was an awak­en­ing,” said Katharine Bar, a Uni­ver­si­ty of Penn­syl­va­nia re­searcher who led two of the stud­ies.

Yet even as a vac­cine or treat­ment for HIV re­ced­ed fur­ther in­to the dis­tance, the Neu­tral­iz­ing An­ti­body Con­sor­tium’s work be­gan pop­ping up against oth­er virus­es.

In 2013, Ja­son McLel­lan, a struc­tur­al bi­ol­o­gist who worked with the Vac­cine Re­search Cen­ter on iden­ti­fy­ing how Mas­co­la’s an­ti­bod­ies bound to HIV, left the NIH to start his own lab at the Uni­ver­si­ty of Texas at Austin. He reached out to Pe­ter Kwong, the chief struc­ture bi­ol­o­gist on the HIV project, and Bar­ney Gra­ham, Mas­co­la’s deputy, to try an­oth­er spin on the con­cepts the con­sor­tium was strug­gling to ap­ply.

“To me, it was un­clear clear whether these con­cepts … weren’t work­ing be­cause they were bad ideas, or be­cause HIV was just a re­al­ly hard virus to make a vac­cine for,” McLel­lan said. “So my idea was: Why don’t we ap­ply these prin­ci­ples to a more tractable virus?”

The most ob­vi­ous case was RSV, the sec­ond-lead­ing killer of small chil­dren in the world af­ter malar­ia. Vac­cines for RSV were an in­fa­mous fail­ure; one can­di­date in the 1960s ac­tu­al­ly turned out to en­hance the dis­ease. But sci­en­tists had found an an­ti­body, mar­ket­ed as Synagis, that could pro­tect the high­est risk chil­dren from in­fec­tion. Pro­tec­tion had to be pos­si­ble some­how.

A vac­cine made by re­verse en­gi­neer­ing VRC01, now in de­vel­op­ment with Mod­er­na

Click on the im­age to see the full-sized ver­sion

McLel­lan took Synagis and a cou­ple oth­er neu­tral­iz­ing an­ti­bod­ies and stud­ied how they bound to the fu­sion pro­tein, RSV’s equiv­a­lent of a spike pro­tein. When RSV reach­es a cell, it changes the pro­tein’s shape for en­try. McLel­lan dis­cov­ered that the an­ti­bod­ies bound on­ly to the pre-fu­sion form of the virus, not the post-fu­sion struc­ture that every­one had been mak­ing.

With some tricky struc­tur­al bi­ol­o­gy tech­niques al­so bor­rowed from HIV, they swapped some amino acids to cre­ate a sta­ble ver­sion of the post-fu­sion pro­tein. Overnight, it be­came one of the world’s lead­ing can­di­dates for RSV.

McLel­lan then used the pro­tein to en­gi­neer new an­ti­bod­ies for the virus, in­clud­ing nir­se­vimab, which As­traZeneca li­censed and is now prepar­ing to launch as the new stan­dard-of-care for RSV.

“I don’t think we have to be em­bar­rassed about the progress be­cause it’s amaz­ing,” Crowe said, pre­dict­ing McLel­lan’s RSV vac­cine can­di­date will be ap­proved. “And all these oth­er fields are ben­e­fit­ing.”

Nabel and An­tho­ny Fau­ci pro­posed ap­ply­ing the same ap­proach to de­vel­op a uni­ver­sal vac­cine for the flu, an­oth­er high­ly vari­able virus. A vac­cine rough­ly based on their blue­print re­cent­ly showed promis­ing ef­fects in Phase I.

For Bur­ton, the iso­la­tion of HIV neu­tral­iz­ing an­ti­bod­ies “lays down a mark­er” for what’s pos­si­ble: If you can find an an­ti­body to HIV, you can find one to any­thing.

And in 2016, Mas­co­la did. Team­ing with a Swiss start­up called Hum­abs that had de­vel­oped a more ad­vanced form of the NIH’s B cell sort­ing tech­nol­o­gy, the agency iden­ti­fied a sin­gle neu­tral­iz­ing an­ti­body against Ebo­la. Af­ter the virus re­turned to the Con­go in 2018, it proved to be one of the first two ef­fec­tive treat­ments for the dead­ly virus, bring­ing sur­vival rates to near­ly 90% when giv­en ear­ly in in­fec­tion.

Mean­while, McLel­lan start­ed ap­ply­ing what he learned from RSV to a nov­el coro­n­avirus out­break in the Mid­dle East called MERS. He fig­ured out that, with a sim­i­lar amino acid swap, he could make a sta­ble ver­sion of the virus’ spike pro­tein for the first time. It would be cru­cial for a vac­cine, which Gra­ham want­ed to de­sign just in case an­oth­er coro­n­avirus broke out again.

When Mas­co­la learned of a new virus cir­cu­lat­ing in Wuhan, Chi­na, he walked up­stairs to a col­lab­o­ra­tor’s of­fice and start­ed plan­ning. This “could be the cul­mi­na­tion of a life’s work,” he lat­er told Wired.

Since 2009, oth­er com­pa­nies and re­searchers had ex­pand­ed on the tech­niques they used to de­vel­op VRC01. One, a lit­tle-known but well-con­nect­ed Van­cou­ver biotech called Ab­Cellera, de­vel­oped a mi­croflu­idic chip that could sort mil­lions of B cells with­in days. In 2018, DARPA, the de­fense agency be­hind weath­er satel­lites and the in­ter­net, gave the com­pa­ny a $30 mil­lion con­tract for a pi­lot project to test whether it could de­vel­op an an­ti­body against a virus in 60 days.

In mid-Jan­u­ary, af­ter the first case struck the US, Mas­co­la and Gra­ham called CEO Carl Hansen and sug­gest­ed they ditch the pi­lot and start on Covid-19. Ab­Cellera had the ad­vanced plat­form, but it would need Mas­co­la’s in­fec­tious dis­ease ex­per­tise.  “He im­me­di­ate­ly agreed,” Mas­co­la said of Hansen.

Call­ing hos­pi­tals and clin­i­cians to ob­tain the prop­er eth­i­cal re­views, Mas­co­la man­aged to get a blood sam­ple from the first US pa­tient, a man in Seat­tle, and shipped it off to Van­cou­ver. Over three days, Ab­Cellera screened 5 mil­lion cells, found 500 an­ti­bod­ies against the spike pro­tein, whit­tled those to 175, and sent the se­quences over to the NIH.

Every­one knew iso­lat­ing a neu­tral­iz­ing an­ti­body for Covid-19 would be eas­i­er than iso­lat­ing one for HIV, but do­ing it so quick­ly posed its own prob­lems. In HIV, re­searchers had sought out thou­sands of blood sam­ples from the tiny sliv­er of pa­tients who were best at at­tack­ing the virus. For the first Covid-19 an­ti­body, Mas­co­la had one sam­ple, from a man cho­sen by fate to be first.

“We must have looked at over 100 an­ti­bod­ies,” Mas­co­la said. “And on­ly one of them was good.”

Fu­ture sam­ples from oth­er donors would prove more po­tent. But they didn’t have those then, and with Eli Lil­ly agree­ing to come on as a part­ner, they be­gan de­vel­op what would lat­er be known as bam­lanivimab. Al­though it would even­tu­al­ly be pulled out of cir­cu­la­tion be­cause it wasn’t ef­fec­tive against virus vari­ants, ear­ly da­ta showed it re­duced the risk of hos­pi­tal­iza­tion in pa­tients ex­posed to the orig­i­nal virus. Near­ly 800,000 dos­es were shipped across the coun­try.

Mod­er­na, Pfiz­er and J&J all used McLel­lan’s mod­i­fi­ca­tions in their vac­cines. Oth­er an­ti­bod­ies, from Re­gen­eron and Vir, which bought Hum­abs in 2017, al­so re­lied on sim­i­lar tech­nol­o­gy to what was used to find VRC01. The NIH used the knowl­edge and in­fra­struc­ture it gained from the then-on­go­ing VRC01 pre­ven­tion study to get those quick­ly through clin­i­cal tri­als. Even the an­i­mal mod­els used to ver­i­fy the an­ti­bod­ies re­lied on HIV work, Shelly Karuna said.

It was an “un­ex­pect­ed ben­e­fit,” she said. “All of these years of ef­fort and HIV mon­o­clon­al an­ti­bod­ies have come to fruition.”

A nurse in Cal­i­for­nia re­ceives an in­fu­sion of bam­lanivimab, a Covid-19 an­ti­body Mas­co­la co-de­vel­oped based off his HIV work (Ir­fan Khan / Los An­ge­les Times via Get­ty Im­ages)

Click on the im­age to see the full-sized ver­sion

The most di­rect ben­e­fit from the HIV field, though, could come in pre­vent­ing fu­ture pan­demics. Lau­ra Walk­er, who went to the an­ti­body spe­cial­ist com­pa­ny Adimab af­ter co-dis­cov­er­ing the first HIV broad­ly neu­tral­iz­ing an­ti­bod­ies, last year co-found­ed a new com­pa­ny called Ada­gio.

With a $300 mil­lion IPO this month, the com­pa­ny has now raised near­ly $800 mil­lion for an ap­proach that looks marked­ly sim­i­lar to what Walk­er and Bur­ton did in HIV: col­lect serum from nu­mer­ous donors and screen for a hand­ful of an­ti­bod­ies that can not on­ly neu­tral­ize one strain of coro­n­avirus, but vir­tu­al­ly all strains.

The goal is to de­vel­op a vari­ant-proof an­ti­body that could pro­tect against all SARS-like virus­es, giv­ing the world a po­tent treat­ment against this virus and any sim­i­lar virus that may one day spill over in­to hu­mans. A first can­di­date is now in clin­i­cal tri­als.

Bur­ton, mean­while, has been col­lect­ing sim­i­lar an­ti­bod­ies in his lab, but with a dif­fer­ent goal. As with HIV, he wants to re­verse en­gi­neer these uni­ver­sal coro­n­avirus an­ti­bod­ies in­to a uni­ver­sal coro­n­avirus vac­cine. He, along with top of­fi­cials at the NIH, have called for fund­ing for a mul­ti-bil­lion dol­lar ef­fort to do the same for all virus­es that have pan­dem­ic po­ten­tial.

Virus-fam­i­ly vac­cines have nev­er been made be­fore. In­oc­u­la­tions tend to be made for a spe­cif­ic virus — a Covid-19 shot won’t work well against SARS and it’ll be even worse against MERS. But it could prove the best weapon to pre­vent the pan­dem­ic. And Bur­ton’s HIV ap­proach — of find­ing the best an­ti­bod­ies and slow­ly coax­ing the im­mune sys­tem to make them — could be the best path.

“It’s all about get­ting a lev­el of con­trol you don’t usu­al­ly have. You’re not look­ing for any old an­ti­body, you’re look­ing for a pre­cise an­ti­body and for that you need a pre­cise vac­cine,” Bur­ton said. “That’s a lev­el of so­phis­ti­ca­tion we haven’t reached, but we have the tools to do that now. And we need to do that, be­cause the pathogens are ob­vi­ous­ly get­ting more so­phis­ti­cat­ed too.”

Last Jan­u­ary, as Covid-19 raged through the US, the re­sults from the last VRC01 tri­al came back. It was a fail­ure. Vol­un­teers on place­bo con­tract­ed HIV at the same rate as vol­un­teers who re­ceived an­ti­body.

“It was sober­ing,” said Mas­co­la. “A sin­gle an­ti­body wasn’t go­ing to be enough.”

Se­quenc­ing da­ta from in­fect­ed par­tic­i­pants showed VRC01 pro­tect­ed against a sub­set of strains, but it was go­ing to take broad­er and more po­tent an­ti­bod­ies to ac­tu­al­ly pre­vent in­fec­tion. Re­searchers are now test­ing those, bring­ing a com­bi­na­tion of an­ti­bod­ies in­to the clin­ic in hopes that hit­ting two spots on the virus will it make it hard­er for HIV to evade. Nabel, who left the NIH to be CSO of Sanofi from 2012 to 2018, even de­vel­oped a trispe­cif­ic an­ti­body to hit three spots. He is now de­vel­op­ing it as part of his new com­pa­ny Mod­eX.

Many of these an­ti­bod­ies have been en­gi­neered to stick around in the blood for six months or a year, po­ten­tial­ly pro­vid­ing long-term pro­tec­tion and an at­trac­tive al­ter­na­tive to the dai­ly pills that have long dom­i­nat­ed HIV pre­ven­tion. They might al­so be safer.

But those pills are al­ready known to be high­ly ef­fec­tive and com­pa­nies, in­clud­ing Mer­ck, Gilead and Glax­o­SmithK­line, are now mak­ing long-act­ing ver­sions, rais­ing ques­tions about where ex­act­ly an­ti­bod­ies can fit.

“They’re go­ing to have to com­pete in an en­vi­ron­ment right now where there’s very ef­fec­tive small mol­e­cule pre­ven­tion ap­proach­es,” Bar said.

A vac­cine seems an even longer way off, as ear­ly at­tempts to coax the im­mune sys­tem strug­gled. But Mas­co­la not­ed that VRC01 has al­ready changed the field.

The lead­ing can­di­date, de­signed by Bill Schief, Bur­ton’s col­league at Scripps, is de­signed to cre­ate what have be­come known as “VRC01-like an­ti­bod­ies.” There were promis­ing re­sults in a Phase I tri­al and now Mod­er­na, with some fan­fare, is mak­ing an mR­NA ver­sion.

Still, nei­ther Bur­ton nor Mas­co­la will tell you an HIV vac­cine is a few years away; there have been enough of those pre­dic­tions over the years. And yet, pleased as they are by the re­sults in coro­n­avirus and RSV, they’re not con­tent ei­ther.

“The lega­cy, the ear­ly suc­cess is go­ing to come with oth­er virus­es: Ebo­la, RSV, in­fluen­za coro­n­avirus,” Mas­co­la said. “But I think as sci­en­tists and pub­lic health of­fi­cials, you look at HIV as a pan­dem­ic. Yeah, you say, ‘Well, it’s hard­er and we haven’t fig­ured it out yet.’ But we’ve made some huge strides, and all the things we learned from coro­n­avirus and RSV and in­fluen­za ac­tu­al­ly teach you in the re­verse di­rec­tion.”

2023 Spot­light on the Fu­ture of Drug De­vel­op­ment for Small and Mid-Sized Biotechs

In the context of today’s global economic environment, there is an increasing need to work smarter, faster and leaner across all facets of the life sciences industry.  This is particularly true for small and mid-sized biotech companies, many of which are facing declining valuations and competing for increasingly limited funding to propel their science forward.  It is important to recognize that within this framework, many of these smaller companies already find themselves resource-challenged to design and manage clinical studies themselves because they don’t have large teams or in-house experts in navigating the various aspects of the drug development journey. This can be particularly challenging for the most complex and difficult to treat diseases where no previous pathway exists and patients are urgently awaiting breakthroughs.

Spe­cial re­port 2022: Meet 20 women blaz­ing trails in bio­phar­ma R&D

When you run a special report for a fourth year, it can start feeling a little bit like a ritual. You go through the motions — in our case opening up nominations for top women in biopharma R&D and reviewing more than 500 entries — you make your choices of inclusion and exclusion. You host a ceremony.

But then things happen that remind you why you do it in the first place. Perhaps a Supreme Court rules to overturn the constitutional right to abortion and a group of women biotech leaders makes it clear they strongly dissent; perhaps new data on gender diversity in the industry come out that look all too similar to the old ones, suggesting women are still dramatically underrepresented at the top; perhaps protests and conflicts around the world put in stark terms the struggles that many women still face in earning the most basic recognition.

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Kristen Hege, Bristol Myers Squibb SVP, early clinical development, oncology/hematology and cell therapy (Illustration: Assistant Editor Kathy Wong for Endpoints News)

Q&A: Bris­tol My­er­s' Kris­ten Hege on cell ther­a­py, can­cer pa­tients and men­tor­ing the next gen­er­a­tion

Kristen Hege leads Bristol Myers Squibb’s early oncology discovery program carrying on from the same work at Celgene, which was acquired by BMS in 2019. She’s known for her early work in CAR-T, having pioneered the first CAR-T cell trial for solid tumors more than 25 years ago.

However, the eminent physician-scientist is more than just a drug developer mastermind. She’s also a practicing physician, mother to two young women, an avid backpacker and intersecting all those interests — a champion of young women and people of color in STEM and life sciences.

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Gossamer Bio CEO Faheem Hasnain at Endpoints' #BIO22 panel (J.T. MacMillan Photography for Endpoints News)

Gos­samer’s Fa­heem Has­nain de­fends a round of pos­i­tive PAH da­ta as a clear win. But can these PhII re­sults stand up to scruti­ny?

Gossamer Bio $GOSS posted a statistically significant improvement for its primary endpoint in the key Phase II TORREY trial for lead drug seralutinib on Tuesday morning. But CEO Faheem Hasnain has some explaining to do on the important secondary of the crucial six-minute walk distance test — which will be the primary endpoint in Phase III — as the data on both endpoints fell short of expectations, missing one analyst’s bar on even modest success.

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Prometheus moves to raise cash hours af­ter PhII da­ta leads to stock surge

After releasing better-than-anticipated data on two mid-stage studies Wednesday morning, Prometheus Biosciences’ CEO said the company would “take some time to assess” its next financing options.

It only needed about seven hours. Wednesday afternoon after the market closed, the biotech announced it would seek $250 million through an equity offering as the company looks to edge out anti-TL1A competitor Pfizer and its new partner Roivant.

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Piper Trelstad, head of CMC, Bill & Melinda Gates Medical Research Institute

Q&A with Gates leader: Women tak­ing on more roles in phar­ma man­u­fac­tur­ing, but still work to do

More and more women are driving innovation and taking leadership roles in biotech – as evidenced today in the release of Endpoints News’ list of the top 20 women in the R&D world – but those gains are beginning to extend across pharma sectors.

In pharma manufacturing in the US today, around 46% of all roles are occupied by women, according to the US Bureau of Labor Statistics for 2021. And according to a Bloomberg report, women’s roles across manufacturing roles had a massive boost after the start of the pandemic.

Phar­ma rep­u­ta­tion re­tains 'halo' even as pan­dem­ic me­dia cov­er­age re­cedes — sur­vey

The Covid-19 halo effect on the pharma industry is continuing, according to a new global study from Ipsos. The annual survey for the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) finds considerable goodwill from consumers across measures of trust, cooperation with governments, and advancing research and drug development.

“Despite the pandemic in many countries no longer being the top of mind concern generally – although it does remain the top concern as a health issue – the industry’s reputation has remained positive,” said Ipsos research director Thomas Fife-Schaw.

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FDA commissioner Robert Califf (Jose Luis Magana/AP Images)

FDA pulls On­copep­tides' Pepax­to in­di­ca­tion, open­ing the door for dan­gling ac­cel­er­at­ed ap­proval en­force­ment

In a move all but ensured after an overwhelmingly negative adcomm vote this September, the FDA is yanking Oncopeptides’ dangling accelerated approval. And there may be more to come.

In recent months, US regulators have honed in on reforming the accelerated approval pathway and preventing drugmakers from continuing to sell their medicines in the event of a confirmatory study flop. The moves come after commissioner Rob Califf has called for companies to do more to produce post-marketing evidence quickly earlier this year.

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Mark McKenna, Prometheus Biosciences chairman & CEO

With clear PhII win in IBD, Prometheus thwarts Pfiz­er com­par­isons as it fol­lows Hu­mi­ra 'play­book'

Prometheus Biosciences reported a clear Phase II win in two inflammatory bowel disease conditions in a clinical development race with Pfizer, planting the biotech’s flag in a field of antibodies attempting to go against black box-cornered JAK inhibitors and AbbVie’s Humira.

Shares $RXDX have soared since the summer — a small dip last week notwithstanding when rival Pfizer teamed up with Roivant on a new company for their competing anti-TL1A monoclonal antibody. And they skyrocketed once again Wednesday morning, climbing from $36 apiece to more than $100 on the back of two Phase II studies: one placebo-controlled in ulcerative colitis and the other an open-label trial in patients with Crohn’s disease.

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