Stéphane Bancel, Moderna CEO (Endpoints JPM20/Jeff Rumans)

Mod­er­na's flu da­ta of­fer a clear les­son: mR­NA is­n't mag­ic

Last fall, as their Covid-19 vac­cine crossed the fin­ish line, Mod­er­na un­veiled plans to take its new­ly proven mR­NA plat­form and use it to ef­fec­tive­ly change how the world blocks hu­man­i­ty’s most per­sis­tent vi­ral foes.

In ad­di­tion to their pre-ex­ist­ing vac­cine pro­grams, ex­ec­u­tives an­nounced new ones for flu, where vac­cines have chron­i­cal­ly un­der­per­formed, and HIV, which has elud­ed every in­oc­u­la­tion ef­fort over near­ly 40 years. In flu, the oth­er mR­NA vac­cine com­pa­nies — BioN­Tech (with Pfiz­er), Trans­late Bio (un­der Sanofi), and Cure­Vac (with GSK) — all had sim­i­lar am­bi­tions, hop­ing to make shots that were as high as 80% ef­fec­tive.

Fri­day morn­ing, though, cast doubt on those lofty hopes. Mod­er­na be­came the first com­pa­ny to re­lease da­ta on an mR­NA flu can­di­date, and they looked, well, fine.

The com­pa­ny showed the shot could suc­cess­ful­ly in­duce an­ti­bod­ies against the four fam­i­lies of flu virus­es that cur­rent killed virus and pro­tein-based vac­cines do. But noth­ing in the ear­ly da­ta sug­gest­ed it was any bet­ter at in­duc­ing those an­ti­bod­ies, ex­perts said.

Ef­fec­tive­ly, the com­pa­ny re­pro­duced the same old shot in fan­cy new clothes.

“It’s just as good as what we have right now,” said Pe­ter Palese, who stud­ies flu and flu vac­cines at the Ic­ahn School of Med­i­cine. “But I don’t think what we have seen so far is break­ing new ter­ri­to­ry or re­al­ly open­ing up a com­plete­ly new tech­nol­o­gy.”

Or, as his col­league Flo­ri­an Kram­mer put it on twit­ter: “mR­NA is not a sil­ver bul­let.”

An mR­NA ver­sion of the ex­ist­ing flu shots could still be use­ful and of­fer a cou­ple ad­van­tages, but they al­so come with their own of­ten over-looked short­com­ings. Chief among them is the shot’s re­ac­to­genic­i­ty — i.e., its ten­den­cy to cause sig­nif­i­cant headaches, fever and oth­er un­pleas­ant side ef­fects in the days af­ter in­oc­u­la­tion.

Mod­er­na’s da­ta showed that, like its Covid-19 vac­cine, its flu shot caused more ad­verse re­ac­tions than pro­tein-based or live virus vac­cine. On a con­fer­ence call, an­a­lysts ar­gued that could stand in the way of Mod­er­na’s greater am­bi­tion of build­ing a sin­gle sea­son­al shot that com­bines flu, RSV and Covid-19 vac­cine — a vi­sion that’s on­ly fea­si­ble with mR­NA.

If just the flu and coro­n­avirus shot each trig­gered such side ef­fects on their own, SVB Leerink’s Mani Foroohar not­ed, how re­ac­to­genic would they be com­bined?

Pe­ter Palese

But just an mR­NA flu shot alone could pose safe­ty ques­tions, Palese said. The lipid nanopar­ti­cles that car­ry the mR­NA to cells al­so act as an ad­ju­vant, stim­u­lat­ing the in­nate im­mune sys­tem. That boosts the pro­tec­tion peo­ple re­ceive, but it could have long-term ef­fects if giv­en an­nu­al­ly.

The flu vac­cines most peo­ple cur­rent­ly re­ceive are not ad­ju­vant­ed. Gen­er­al­ly, on­ly those over 65 re­ceive an ad­ju­vant­ed flu vac­cine such as Flu­zone.

“I think there has been pro­vi­sion­al­ly a re­luc­tance to use ad­ju­vants for vac­cines against in­fluen­za, be­cause one doesn’t want to give an ad­ju­vant every year, con­tin­u­ous­ly for 60 or 70 years of some­one’s life,” he said.

Mod­er­na ex­ec­u­tives cau­tioned against mak­ing too sweep­ing of a com­par­i­son be­tween vac­cines be­fore re­sults came in from a head-to-head tri­al. And they point­ed to oth­er ar­eas ex­perts agree mR­NA could have an ad­van­tage.

For ex­am­ple, mR­NA can be made faster than tra­di­tion­al egg or cell-grown flu shots. In the­o­ry, that could give Mod­er­na and oth­er mR­NA com­pa­nies more time to make sure the flu strains in the vac­cine match the flu strains cir­cu­lat­ing in the fall, chip­ping away at a prob­lem that in some years can make the sea­son­al shot as lit­tle as 19% ef­fec­tive.

Stephen Hoge

How much they chip away will de­pend on how fast Mod­er­na can make the shot. Palese doubt­ed the ad­van­tage will be sig­nif­i­cant, but Mod­er­na pres­i­dent Stephen Hoge not­ed the com­pa­ny al­ready plans to man­u­fac­ture an Omi­cron-spe­cif­ic vari­ant in 100 days. To­day, by con­trast, of­fi­cials have to se­lect strains in Feb­ru­ary.

Ul­ti­mate­ly, though, the im­pact of Mod­er­na’s tech­nol­o­gy — or Trans­late’s or BioN­Tech’s — may come down to whether they can do more than just make mR­NA ver­sions of oth­er shots.

Those ef­forts present far greater tech­ni­cal chances but al­so far greater op­por­tu­ni­ty. The biotech said Fri­day it would now ad­vance a can­di­date that it de­signed sim­i­lar­ly to pro­posed “uni­ver­sal” flu vac­cines that can pro­tect against all strains, a long-sought holy grail that has had mixed re­sults in the clin­ic.

The com­pa­ny is al­so work­ing to ad­vance its pro­gram for an HIV vac­cine, the great­est prize in vac­ci­nol­o­gy for more than three decades. Louis Pick­er, an im­mu­nol­o­gist at Ore­gon Health and Sci­ence Uni­ver­si­ty fo­cused on HIV, cau­tioned any­one against get­ting their hopes up on it.

“At this point mR­NA vac­cine tech­nol­o­gy, by it­self, does very lit­tle to counter the ma­jor ob­sta­cles to HIV vac­cine ef­fi­ca­cy,” he said in an email.

But mR­NA can be very help­ful, he said. For the last 12 years, the HIV vac­cine field has been try­ing to build shots that can elic­it ul­tra-rare an­ti­bod­ies that can neu­tral­ize all of the many di­verse strains of HIV.

Hilde­gund Ertl

mR­NA, Pick­er said, is unique in al­low­ing re­searchers to quick­ly and it­er­a­tive­ly de­sign new con­structs and test them in hopes of even­tu­al­ly hit­ting on the right de­sign. Mod­er­na is now putting the first such blue­print in Phase I, though Pick­er is pret­ty con­fi­dent the first shot on goal is go­ing to miss.

“Re­al suc­cess is not a fore­gone con­clu­sion,” he said, “And if it hap­pens is quite a way off in the fu­ture.”

Oth­er re­searchers agree. Hilde­gund Ertl, who has worked on HIV vac­cines at the Wis­tar In­sti­tute, point­ed in an email to an NIH pa­per from this week study­ing Mod­er­na’s HIV shot in mon­keys. The mon­keys were giv­en the vac­cine and then ex­posed to HIV. Most weren’t in­fect­ed but those who were didn’t seem to sup­press the virus at all, sug­gest­ing a very poor re­sponse.

“I’m not hold­ing my breath,” Ertl said.

Forge Bi­o­log­ics’ cGMP Com­pli­ant and Com­mer­cial­ly Vi­able Be­spoke Affin­i­ty Chro­matog­ra­phy Plat­form

Forge Biologics has developed a bespoke affinity chromatography platform approach that factors in unique vector combinations to streamline development timelines and assist our clients in efficiently entering the clinic. By leveraging our experience with natural and novel serotypes and transgene conformations, we are able to accelerate affinity chromatography development by nearly 3-fold. Many downstream purification models are serotype-dependent, demanding unique and time-consuming development strategies for each AAV gene therapy product1. With the increasing demand to propel AAV gene therapies to market, platform purification methods that support commercial-scale manufacturing of high-quality vectors with excellent safety and efficacy profiles are essential.

Feng Zhang (Susan Walsh/AP Images)

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