Are challenge trials an ethical way to find a vaccine?

More than 30 pos­si­ble coro­n­avirus vac­cines are in clin­i­cal tri­als world­wide in a bid to squeeze tra­di­tion­al time­lines and roll out a vac­ci­na­tion pro­gramme in the next six to twelve months. But there are calls to speed up the process fur­ther through the use of con­tro­ver­sial human chal­lenge tri­als where vol­un­teers are giv­en an exper­i­men­tal vac­cine, then delib­er­ate­ly exposed to the virus.

Despite real safe­ty risks and eth­i­cal con­cerns, there is a bur­geon­ing appetite for these tri­als. More than 36,000 peo­ple from more than 160 coun­tries have expressed a will­ing­ness to take part with 1 Day Soon­er, an organ­i­sa­tion that sup­ports COVID-19 chal­lenge tri­als.

The organ­i­sa­tion pub­lished an open let­ter in July, urg­ing prepa­ra­tion of such tri­als, which was signed by more than 150 aca­d­e­mics and experts, includ­ing 15 Nobel lau­re­ates.

But the search for a vac­cine suf­fered a tem­po­rary set­back in ear­ly-Sep­tem­ber when an Oxford Uni­ver­si­ty tri­al with British drug­mak­er AstraZeneca was paused after a vol­un­teer suf­fered a pos­si­ble seri­ous adverse reac­tion, illus­trat­ing the risks involved even with­out delib­er­ate expo­sure to COVID-19.

Abie Rohrig, direc­tor of com­mu­ni­ca­tions at 1 Day Soon­er and chal­lenge tri­al vol­un­teer, says his desire to take part is for the good of humankind. “Since I am at a very low risk of death and hos­pi­tal­i­sa­tion from COVID-19, I am more than will­ing to take on the risk so that old­er and immuno­com­pro­mised pop­u­la­tions can stay safe,” the 20 year old says.

Human challenge trials could save lives or take them

Chal­lenge tri­als have been used in the past to test vac­cines against flu, typhoid, cholera and malar­ia. They can speed vac­cine devel­op­ment when low lev­els of virus cir­cu­lat­ing in the pop­u­la­tion make deter­min­ing nor­mal vac­cine effi­ca­cy dif­fi­cult. They can also com­pare the effi­ca­cy of dif­fer­ent vac­cines, high­light­ing which can­di­dates should be advanced, as well as pro­vid­ing impor­tant insights into the virus, dis­ease pro­gres­sion and immu­ni­ty.

A coro­n­avirus vac­cine would ben­e­fit from all this, par­tic­u­lar­ly if chal­lenged in the low-risk group of healthy 18 to 30 year olds, where fatal infec­tion rates are esti­mat­ed to be 0.03 per cent. But, unlike malar­ia and typhoid, COVID-19 has no suf­fi­cient res­cue treat­ment should tri­al vol­un­teers get sick and the SARS-CoV­‑2 virus is still poor­ly under­stood.

The first peer-reviewed paper call­ing for coro­n­avirus chal­lenge tri­als was pub­lished online in March in The Jour­nal of Infec­tious Dis­eases. Pro­fes­sor Nir Eyal, a senior bioethi­cist and direc­tor of Rut­gers University’s Cen­ter for Pop­u­la­tion-Lev­el Bioethics in the Unit­ed States, was the lead author and now a mem­ber of the 1 Day Soon­er advi­so­ry board.

He says there are risks to vol­un­teers, but chal­lenge tri­als should be sup­port­ed. “We don’t need chal­lenge tri­als to beat COVID. We need them to beat it faster,” he says. “Faster means avert­ing thou­sands of deaths per day.”

The risk too high and the reward uncertain

But the World Health Orga­ni­za­tion remains unde­cid­ed and oth­er aca­d­e­mics claim now is not the time. Dr Gre­go­ry Poland, direc­tor of the Vac­cine Research Group at the US-based Mayo Clin­ic, believes the claims about sav­ing lives are false argu­ments. Even if a chal­lenge tri­al was con­duct­ed today, he says, peo­ple would not be pro­tect­ed with a coro­n­avirus vac­cine tomor­row. It could take months just to find the appro­pri­ate strain and dose for these tri­als, eras­ing the speed advan­tage.

There is also no guar­an­tee the results of chal­lenge tri­als in low-risk healthy young adults would be applic­a­ble to the elder­ly or those with under­ly­ing con­di­tions. “To me, it’s uneth­i­cal to chal­lenge some­body and we’re in the mid­dle of mul­ti­ple, large phase-three vac­cine tri­als, so I do not see the ben­e­fit com­pared with the risk,” says Poland.

Dr Michael Jarvis, asso­ciate pro­fes­sor in immunol­o­gy and virol­o­gy at the Uni­ver­si­ty of Ply­mouth, takes a sim­i­lar stance. “A bad expe­ri­ence at the ear­ly stages of the vac­cine devel­op­ment path­way could real­ly impact accep­tance of an effi­ca­cious COVID vac­cine by the pub­lic,” he says. “I think this is a legit­i­mate rea­son to wait.”

Supporting challenge trials can be controversial

Yet we are get­ting clos­er to COVID-19 chal­lenge tri­als. Both US and Euro­pean reg­u­la­tors say they will con­sid­er pro­pos­als, and phar­ma­ceu­ti­cal com­pa­ny John­son & John­son says it is “eval­u­at­ing the poten­tial ben­e­fit of human chal­lenge tri­als”. The US Nation­al Insti­tute of Health also recent­ly announced the deci­sion to explore the pos­si­bil­i­ty of, and pre­pare for, human chal­lenge tri­als.

Mean­while, the Oxford Uni­ver­si­ty group devel­op­ing the fron­trun­ner coro­n­avirus vac­cine is under­stood to be review­ing the tech­ni­cal aspects of how these stud­ies could be under­tak­en.

A cross-nation­al sur­vey of almost 6,000 peo­ple con­duct­ed by Eyal and col­leagues in July found 75 per cent pre­ferred sci­en­tists to con­duct chal­lenge tri­als over stan­dard tri­als, even as respon­dents acknowl­edged the risks. The results may help remove a road­block to their imple­men­ta­tion. It could also open the door for more wide­spread use in infec­tious dis­eases and future pan­demics, espe­cial­ly in the absence of res­cue treat­ments.

The prob­lem though, says Eyal, is peo­ple are cagey about their sup­port. “Nobody wants to be first, lest the pub­lic and elec­torates pun­ish them for it,” he says.

Can we afford to wait longer for a vaccine?

But we may have no choice. Offi­cials in Amer­i­ca have already said chal­lenge tri­als might be need­ed if nat­ur­al infec­tions decline and stan­dard stud­ies can’t deter­mine effi­ca­cy. Ana Nicholls, health­care ana­lyst and man­ag­ing edi­tor of the Indus­try Brief­ing at The Econ­o­mist Intel­li­gence Unit, agrees this is a con­cern. “Some vac­cine devel­op­ers have had to chase cas­es around the world to set up and con­duct tri­als. Some ear­ly tri­als were aban­doned alto­geth­er,” she says.

If we want a vac­cine now or for a future pan­dem­ic, chal­lenge tri­als may be the only option, but bal­anc­ing risk against the poten­tial ben­e­fits is tricky. COVID-19 could shift the nee­dle.

1Day Soon­er have just sub­mit­ted a for­mal UK peti­tion in sup­port of chal­lenge tri­al prepa­ra­tion which has found sup­port among promi­nent fig­ures in UK med­i­cine. Lord Ara Darzi, Nobel Lau­re­at, Sir Richard Roberts, and Dominic Wilkin­son (the head of med­ical ethics at Oxford) have all signed.

Rohrig at 1 Day Soon­er is opti­mistic, believ­ing it’s like­ly a chal­lenge tri­al will begin by the end of the year. Tens of thou­sands of young peo­ple have acknowl­edged the risks and still want to take part, he says. “We hope oth­ers do not speak on our behalf as to which risks are jus­ti­fi­able for us to take,” Rohrig adds.

How COVID has changed clinical trials

Coro­n­avirus lock­downs forced the world to stay at home. This also caused the pause and post­pone­ment of thou­sands of clin­i­cal tri­als, with patient enrol­ment in tri­als sig­nif­i­cant­ly down, by as much as 79 per cent in April com­pared to the pre­vi­ous year, accord­ing to Medi­da­ta.

But the lock­downs have also spurred inno­va­tion in the sec­tor. Tra­di­tion­al time­lines, for instance, are being bust­ed in a bid to get a coro­n­avirus vac­cine to mar­ket through greater col­lab­o­ra­tion between com­pa­nies and dif­fer­ent tri­al designs. In the Unit­ed States, the col­lab­o­ra­tive project Oper­a­tion Warp Speed aims to deliv­er a vac­cine by the end of the year by run­ning design, man­u­fac­tur­ing and deliv­ery oper­a­tions in par­al­lel rather than sequen­tial­ly.

Addi­tion­al­ly, clin­i­cal tri­als have moved out­side tra­di­tion­al tri­al sites with a boom in vir­tu­al tri­als, which use remote mon­i­tor­ing, tele­con­fer­enc­ing and dig­i­tal data col­lec­tion tools, such as wear­able devices. Arti­fi­cial intel­li­gence (AI) is also begin­ning to be used in the recruit­ment process to iden­ti­fy patients suit­able for tri­als.

The COVID-19 lega­cy will be a pos­i­tive one, says Gra­ham Bel­grave, senior vice pres­i­dent, head of Euro­pean oper­a­tions, at clin­i­cal research organ­i­sa­tion Advanced Clin­i­cal: “I believe the genie is out of the bot­tle and we will see an ever-increas­ing reliance on AI, on remote and vir­tu­al vis­its for clin­i­cal tri­als.” This, he says, is like­ly to become the new norm.