By LAU­RAN NEER­GAARD-As­so­ci­at­ed Press

COVID-19 vac­ci­na­tions are at a crit­i­cal junc­ture as com­pa­nies test whether new ap­proach­es like com­bi­na­tion shots or nasal drops can keep up with a mu­tat­ing coro­n­avirus — even though it’s not clear if changes are need­ed.

Al­ready there’s pub­lic con­fu­sion about who should get a sec­ond boost­er now and who can wait. There’s al­so de­bate about whether pret­ty much every­one might need an ex­tra dose in the fall.

“I’m very con­cerned about boost­er fa­tigue” caus­ing a loss of con­fi­dence in vac­cines that still of­fer very strong pro­tec­tion against COVID-19’s worst out­comes, said Dr. Beth Bell of the Uni­ver­si­ty of Wash­ing­ton, an ad­vis­er to the U.S. Cen­ters for Dis­ease Con­trol and Pre­ven­tion.

De­spite suc­cess in pre­vent­ing se­ri­ous ill­ness and death, there’s grow­ing pres­sure to de­vel­op vac­cines bet­ter at fend­ing off milder in­fec­tions, too — as well as op­tions to counter scary vari­ants.

“We go through a fire drill it seems like every quar­ter, every three months or so” when an­oth­er mu­tant caus­es fran­tic tests to de­ter­mine if the shots are hold­ing, Pfiz­er vac­cine chief Kathrin Jansen told a re­cent meet­ing of the New York Acad­e­my of Sci­ences.

Yet seek­ing im­prove­ments for the next round of vac­ci­na­tions may seem like a lux­u­ry for U.S. fam­i­lies anx­ious to pro­tect their lit­tlest chil­dren — kids un­der 5 who are not yet el­i­gi­ble for a shot. Mod­er­na’s Dr. Jacque­line Miller told The As­so­ci­at­ed Press that its ap­pli­ca­tion to give two low-dose shots to the youngest chil­dren would be sub­mit­ted to the Food and Drug Ad­min­is­tra­tion “fair­ly soon.” Pfiz­er hasn’t yet re­port­ed da­ta on a third dose of its ex­tra-small shot for tots, af­ter two didn’t prove strong enough.

COM­BI­NA­TION SHOTS MAY BE NEXT

The orig­i­nal COVID-19 vac­cines re­main strong­ly pro­tec­tive against se­ri­ous ill­ness, hos­pi­tal­iza­tion and death, es­pe­cial­ly af­ter a boost­er dose, even against the most con­ta­gious vari­ants.

Up­dat­ing the vac­cine recipe to match the lat­est vari­ants is risky, be­cause the next mu­tant could be com­plete­ly un­re­lat­ed. So com­pa­nies are tak­ing a cue from the flu vac­cine, which of­fers pro­tec­tion against three or four dif­fer­ent strains in one shot every year.

Mod­er­na and Pfiz­er are test­ing 2-in-1 COVID-19 pro­tec­tion that they hope to of­fer this fall. Each “bi­va­lent” shot would mix the orig­i­nal, proven vac­cine with an omi­cron-tar­get­ed ver­sion.

Mod­er­na has a hint the ap­proach could work. It test­ed a com­bo shot that tar­get­ed the orig­i­nal ver­sion of the virus and an ear­li­er vari­ant named be­ta — and found vac­cine re­cip­i­ents de­vel­oped mod­est lev­els of an­ti­bod­ies ca­pa­ble of fight­ing not just be­ta but al­so new­er mu­tants like omi­cron. Mod­er­na now is test­ing its omi­cron-tar­get­ed bi­va­lent can­di­date.

But there’s a loom­ing dead­line. FDA’s Dr. Do­ran Fink said if any up­dat­ed shots are to be giv­en in the fall, the agency would have to de­cide on a recipe change by ear­ly sum­mer.

DON’T EX­PECT BOOST­ERS EVERY FEW MONTHS

For the av­er­age per­son, two dos­es of the Pfiz­er or Mod­er­na vac­cine plus one boost­er — a to­tal of three shots — “gets you set up” and ready for what may be­come an an­nu­al boost­er, said Dr. David Kim­ber­lin, a CDC ad­vis­er from the Uni­ver­si­ty of Al­aba­ma at Birm­ing­ham.

Af­ter that first boost­er, CDC da­ta sug­gests an ad­di­tion­al dose of­fers most peo­ple an in­cre­men­tal, tem­po­rary ben­e­fit.

Why the em­pha­sis on three shots? Vac­ci­na­tion trig­gers de­vel­op­ment of an­ti­bod­ies that can fend off coro­n­avirus in­fec­tion but nat­u­ral­ly wane over time. The next line of de­fense: Mem­o­ry cells that jump in­to ac­tion to make new virus-fight­ers if an in­fec­tion sneaks in. Rock­e­feller Uni­ver­si­ty re­searchers found those mem­o­ry cells be­come more po­tent and able to tar­get more di­verse ver­sions of the virus af­ter the third shot.

Even if some­one who’s vac­ci­nat­ed gets a mild in­fec­tion, thanks to those mem­o­ry cells “there’s still plen­ty of time to pro­tect you against se­vere ill­ness,” said Dr. Paul Of­fit of the Chil­dren’s Hos­pi­tal of Philadel­phia.

But some peo­ple — those with se­vere­ly weak­ened im­mune sys­tems — need more dos­es up-front for a bet­ter chance at pro­tec­tion.

And Amer­i­cans 50 and old­er are be­ing of­fered a sec­ond boost­er, fol­low­ing sim­i­lar de­ci­sions by Is­rael and oth­er coun­tries that of­fer the ex­tra shot to give old­er peo­ple a lit­tle more pro­tec­tion.

The CDC is de­vel­op­ing ad­vice to help those el­i­gi­ble de­cide whether to get an ex­tra shot now or wait. Among those who might want a sec­ond boost­er soon­er are the el­der­ly, peo­ple with health prob­lems that make them par­tic­u­lar­ly vul­ner­a­ble, or who are at high risk of ex­po­sure from work or trav­el.

COULD NASAL VAC­CINES BLOCK IN­FEC­TION?

It’s hard for a shot in the arm to form lots of virus-fight­ing an­ti­bod­ies in­side the nose where the coro­n­avirus latch­es on. But a nasal vac­cine might of­fer a new strat­e­gy to pre­vent in­fec­tions that dis­rupt peo­ple’s every­day lives even if they’re mild.

“When I think about what would make me get a sec­ond boost­er, I ac­tu­al­ly would want to pre­vent in­fec­tion,” said Dr. Grace Lee of Stan­ford Uni­ver­si­ty, who chairs CDC’s im­mu­niza­tion ad­vi­so­ry com­mit­tee. “I think we need to do bet­ter.”

Nasal vac­cines are tricky to de­vel­op and it’s not clear how quick­ly any could be­come avail­able. But sev­er­al are in clin­i­cal tri­als glob­al­ly. One in late-stage test­ing, man­u­fac­tured by In­dia’s Bharat Biotech, us­es a chim­panzee cold virus to de­liv­er a harm­less copy of the coro­n­avirus spike pro­tein to the lin­ing of the nose.

“I cer­tain­ly do not want to aban­don the suc­cess we have had” with COVID-19 shots, said Dr. Michael Di­a­mond of Wash­ing­ton Uni­ver­si­ty in St. Louis, who helped cre­ate the can­di­date that’s now li­censed to Bharat.

But “we’re go­ing to have a dif­fi­cult time stop­ping trans­mis­sion with the cur­rent sys­temic vac­cines,” Di­a­mond added. “We have all learned that.”