Ea­ger to re­deem its Covid-19 vac­cine, As­traZeneca touts 82.4% ef­fi­ca­cy for 12-week dos­ing sched­ule — but will the FDA buy it?

As­traZeneca and Ox­ford say they now have clin­i­cal ev­i­dence that dos­ing their ade­n­ovirus-based Covid-19 vac­cine 12 weeks apart — a reg­i­men ap­proved by the UK, per­plex­ing many — can ac­tu­al­ly ren­der the shots more ef­fec­tive.

The da­ta will be key to As­traZeneca’s at­tempt to pull it­self back to the up­per ranks of the vac­cine hi­er­ar­chy, where it’s strug­gled as skep­tics poke holes in its ef­fi­ca­cy while pro­duc­tion de­lays trig­ger heat­ed dis­putes with the EU. But it re­mains to be seen what im­pact, if any, the analy­sis will have on the FDA’s think­ing and de­ci­sions re­gard­ing the vac­cine.

The new re­sults draw from the same Phase III study, con­duct­ed in the UK, Brazil and South Africa, whose in­ter­im da­ta ce­ment­ed the first au­tho­riza­tions of the vac­cine, but in­clude 332 cas­es of Covid-19 (com­pared to 131 at the ini­tial cut).

In­ves­ti­ga­tors wrote in a preprint on the Lancet:

In our study, vac­cine ef­fi­ca­cy was high­er, af­ter the sec­ond dose, in those with a longer prime-boost in­ter­val, reach­ing 82.4% in those with a dos­ing in­ter­val of 12 weeks or more. Point es­ti­mates of ef­fi­ca­cy were low­er with short­er dos­ing in­ter­vals, though it should be not­ed that there is some un­cer­tain­ty as con­fi­dence in­ter­vals over­lap. High­er bind­ing and neu­tral­is­ing an­ti­body titres were ob­served in sera at the longer prime-boost in­ter­val, sug­gest­ing that, as­sum­ing there is a re­la­tion­ship be­tween the hu­moral im­mune re­sponse and ef­fi­ca­cy, these may be true find­ings and not arte­facts of the da­ta.

In to­tal, 1293 par­tic­i­pants (out of 17,177 in­clud­ed for this analy­sis) were giv­en two full dos­es of the vac­cine 12 weeks apart.

If true, it con­firms ear­li­er sug­ges­tions by As­traZeneca ex­ecs — backed by some sci­en­tists — that the 12-week in­ter­val is the “win­ning for­mu­la” for get­ting ef­fi­ca­cy near the lev­els of the Pfiz­er/BioN­Tech or Mod­er­na vac­cines.

While there’s still some dis­tance be­tween 82.4% and 95% (as re­port­ed by the mR­NA play­ers), the dif­fer­ence is no­tably small­er than when in­ves­ti­ga­tors ob­served a 62% ef­fi­ca­cy for two full-dose reg­i­men, ad­min­is­tered 4 weeks apart.

Will it mat­ter out­side of the UK and the EU, where the au­thor­i­ties al­ready rec­om­mend the longer dose sched­ule?

Bio­phar­ma R&D chief Mene Pan­ga­los ad­mit­ted in a me­dia brief­ing Wednes­day morn­ing that the US Phase III tri­al, which he be­lieves the com­pa­ny needs to com­plete be­fore seek­ing an emer­gency use au­tho­riza­tion from the FDA, on­ly tests the 4-week dose in­ter­val. The la­bel and rec­om­mend­ed im­ple­men­ta­tion is a whole oth­er mat­ter.

“Ob­vi­ous­ly we do want the FDA and reg­u­la­tors to be in­formed by our da­ta on in­ter-dose in­ter­vals from our oth­er glob­al stud­ies,” he added.

In­ter­est­ing­ly, in­ves­ti­ga­tors pro­posed that the longer dos­ing sched­ule may be some­what re­spon­si­ble for the ear­ly sub­group analy­sis that found a low dose fol­lowed by a high dose — giv­en to around 8,000 vol­un­teers by er­ror — was much more ef­fec­tive, boost­ing ef­fi­ca­cy to 90%.

“This find­ing is con­firmed in the cur­rent analy­sis, but with fur­ther da­ta avail­able, we show that the en­hanced im­muno­genic­i­ty and ef­fi­ca­cy with this reg­i­men may be part­ly dri­ven by the longer dos­ing in­ter­val that was a fea­ture of this group, fur­ther sup­port­ing the ob­ser­va­tion of a re­la­tion­ship be­tween dose in­ter­val and ef­fi­ca­cy in the SD/SD group dis­cussed above and sup­port­ed by emer­gency use au­tho­ri­sa­tion,” they wrote, adding: “The SD/SD reg­i­men is pre­ferred op­er­a­tional­ly as it is more straight­for­ward to de­liv­er a vac­cine with one dosage, and be­cause there are more im­muno­genic­i­ty and ef­fi­ca­cy da­ta to sup­port its use.”

As­traZeneca has pre­vi­ous­ly said it would con­duct a new tri­al to test that reg­i­men, but they have now dropped that plan to fo­cus on the longer in­ter­val and next-gen­er­a­tion can­di­dates.

“Our am­bi­tion is to be ready for the next round of im­mu­niza­tions that may be nec­es­sary as we go in­to next win­ter,” he said. “That’s what we’re aim­ing for.”

Add that to the new­ly re­port­ed num­ber that the As­traZeneca vac­cine is 76% ef­fec­tive af­ter just one shot, and it’s al­so a boon for coun­tries that are scram­bling to put vac­cines in arms, giv­ing them more time to sort out the first dos­es for more peo­ple be­fore hav­ing to wor­ry about the sec­ond dose.

The com­pa­ny added that new da­ta con­firmed that its vac­cine could pre­vent hos­pi­tal­iza­tions or se­vere cas­es, reach­ing 100% pro­tec­tion if you start count­ing 10 days af­ter the first dose. In the same pe­ri­od, the con­trol group saw 22 such events.

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