Can viruses be used to fight bacterial infections ?

While the main causes of death in deve­lo­ped coun­tries, inclu­ding France, are can­cer and car­dio­vas­cu­lar disease¹, the World Health Orga­ni­sa­tion war­ned (well before Covid-19) that it consi­ders cer­tain infec­tious agents “one of the most serious threats to glo­bal health, food secu­ri­ty and deve­lop­ment”². This threat is anti­bio­tic-resis­tant bac­te­ria, which were res­pon­sible for 1.27 mil­lion deaths world­wide in 2019³ and could cause 10 mil­lion deaths annual­ly by 2050⁴.

Yet, it is dif­fi­cult to fight against this phe­no­me­non. Limi­ting and opti­mi­sing the use of anti­bio­tics can reduce the emer­gence of new anti­bio­tic resis­tant bac­te­ria. But the search for new anti­bio­tics has unfor­tu­na­te­ly not been very suc­cess­ful, while we also need treat­ments capable of coun­te­rac­ting the anti­bio­tic resis­tant bac­te­ria that alrea­dy exist… What if the solu­tion was even older than antibiotics ?

Decem­ber 1917. Félix d’Hé­relle, a scien­tist whose bio­gra­phy is worth a look, publi­shed a paper in the Pro­cee­dings of the Aca­de­my of Sciences⁵. He des­cri­bed invi­sible microbes, capable of des­troying the bac­te­ria res­pon­sible for dys­en­te­ry or typhoid fever by mul­ti­plying at their expense. He des­cri­bed these microbes as “bac­te­rio­phages”, i.e., lite­ral­ly, bac­te­ria eaters. As viro­lo­gy was still in its infan­cy at the time, Félix d’Hé­relle was not aware of it, but he had just des­cri­bed viruses capable of infec­ting and killing bac­te­ria ! Today, they are still cal­led bac­te­rio­phages, or phages for short.

The author­ship of this dis­co­ve­ry is dis­pu­ted as d’Hé­relle was not the first to make this kind of obser­va­tion. He was, howe­ver, the first to have the idea of using these viruses as treat­ments. His 1917 paper explains that phages can pro­tect rab­bits against dys­en­te­ry, without any side effects, and are spe­ci­fic to cer­tain strains of bac­te­ria : the foun­da­tions of phage the­ra­py were laid.

Indeed, since they are only a threat to bac­te­ria, these ene­mies of our ene­mies have the right pro­file to become our allies. Phage the­ra­py thus became an inter­na­tio­nal craze in the 1920s ! At the time, there was no other way to fight bac­te­rial infec­tions. Peni­cil­lin was dis­co­ve­red in 1928, but it was not puri­fied and used for medi­cal pur­poses until over a decade later.

Anti­bio­tics were inex­pen­sive, very effec­tive, easy to pro­duce, store and admi­nis­ter. As ear­ly as the 1940s, they repla­ced bac­te­rio­phages, whose effec­ti­ve­ness was less cer­tain, without repla­cing them enti­re­ly : the­ra­peu­tic phages were avai­lable in France until the end of the 1980s. But Alexan­der Flem­ming, the dis­co­ve­rer of peni­cil­lin, was right when he war­ned about the bac­te­ria’s capa­ci­ty for resis­tance. Could phages be more effec­tive than anti­bio­tics in this respect ?

Unlike these inert mole­cules, viruses evolve spon­ta­neous­ly to adapt to bac­te­rial adap­ta­tions. Their the­ra­peu­tic use should repro­duce the arms race clas­si­cal­ly obser­ved bet­ween a para­site and its host ins­tead of the dead end in which anti­bio­tics are stuck. And there are other rea­sons why phages are a pro­mi­sing alternative !

In terms of mecha­nisms of action, anti­bio­tics can be com­pa­red to bombs and bac­te­rio­phages to pre­ci­sion shoo­ting : the for­mer des­troy bac­te­ria en masse while the lat­ter are spe­ci­fic to a type of bac­te­ria. In the middle of the 20^th Cen­tu­ry, it was dif­fi­cult to cha­rac­te­rise bac­te­rial or viral strains and the wide range of action of anti­bio­tics was an advan­tage. Today, we know that our orga­nisms are true eco­sys­tems, contai­ning about as many bac­te­ria as human cells⁶. Bac­te­rio­phages would allow us to tar­get only those that are patho­ge­nic, pre­ser­ving the rest of our micro­bio­ta and concen­tra­ting spon­ta­neous­ly at the sites of infection.

A num­ber of patients infec­ted with anti­bio­tic-resis­tant bac­te­ria have alrea­dy been saved by com­pas­sio­nate admi­nis­tra­tion of bac­te­rio­phages. These cures have some­times recei­ved signi­fi­cant media cove­rage, such as that of the spouse of Stef­fa­nie Stra­th­dee, an epi­de­mio­lo­gist who has since become co-direc­tor of the first phage the­ra­py research centre in the Uni­ted States⁷.

In France, the PHA­GEin­LYON pro­gram⁸ has trea­ted seve­ral dozen patients since 2017 and recent­ly recei­ved fun­ding from the ANR to expand access to phage the­ra­py. Its results are very pro­mi­sing, but we are still far from being able to deploy this approach on a large scale.

Cer­tain tech­ni­cal and admi­nis­tra­tive constraints remain res­tric­tive, star­ting with the pro­duc­tion of medi­cal phages, which need to meet high-qua­li­ty stan­dards. In France, there is cur­rent­ly only one com­pa­ny⁹ capable of pro­du­cing phages for human use. Bel­gium consi­ders phages as magis­tral pre­pa­ra­tions, not as drugs, which faci­li­tates their pro­duc­tion. In any case, the ques­tion of the paten­ta­bi­li­ty of these bio­lo­gi­cal enti­ties is not clear-cut, which may slow down indus­trial invest­ments. And there are still scien­ti­fic limits to the deve­lop­ment of phagotherapy.

For phage the­ra­py to be effec­tive, viruses must be iden­ti­fied that match the needs of each patient. It is not pos­sible to pre­dict which phage will be effec­tive against a given bac­te­rium. To find out, it is neces­sa­ry to test on a case-by-case basis and hope that the effects within the patient’s micro­bial eco­sys­tem will be iden­ti­cal to those obser­ved in vitro. In gene­ral, patients are trea­ted with cock­tails of seve­ral poten­tial­ly effec­tive phages.

In order to tar­get a maxi­mum num­ber of bac­te­ria, we need large reper­toires of phages from which to draw from. And even though there is a consi­de­rable natu­ral diver­si­ty of phages, esti­ma­ted at 10⁸ spe­cies¹⁰, we are far from having cata­lo­gued enough of them to be able to gene­ra­lise phage the­ra­py. Howe­ver, cer­tain struc­tures have been wor­king on this for decades : the coun­tries of the Soviet bloc did not have access to anti­bio­tics during the cold war, and their use of phages is par­ti­cu­lar­ly deve­lo­ped (which gene­rates medi­cal tourism).

Fur­ther­more, the effi­ca­cy of phage the­ra­py must be pro­per­ly eva­lua­ted beyond com­pas­sio­nate cases. A few stan­dard cli­ni­cal trials have been conduc­ted since 2010, against infec­tions for which phage cock­tails can be stan­dar­di­zed in a “rea­dy-to-wear” man­ner. Some of these trials are pro­mi­sing¹¹, but this eva­lua­tion metho­do­lo­gy is less adap­ted to “cus­to­mi­sed” uses of bacteriophages.

Final­ly, even if it only concerns cer­tain patients, one cha­rac­te­ris­tic of phages remains limi­ting : some areas of the body remain inac­ces­sible to them, such as the cen­tral ner­vous sys­tem or the inter­ior of our cells.

Des­pite its pro­mise, phage the­ra­py is not (yet) a the­ra­peu­tic revo­lu­tion. But this new approach should be thought of in com­bi­na­tion with the tools alrea­dy at our dis­po­sal ! Inter­es­ting syner­gies have been obser­ved with anti­bio­tics, for example.

The use of cer­tain pro­teins pro­du­ced by bac­te­rio­phages, nota­bly lysines, enzymes capable of degra­ding bac­te­rial walls and bio­films, is also being consi­de­red as a the­ra­peu­tic tool in its own right. Or to gene­ti­cal­ly modi­fy phages to tar­get refrac­to­ry bacteria.

It’s hard to pre­dict how bac­te­rio­phages will change our res­ponse to bac­te­rial infec­tions, but they seem to have the poten­tial to meet some of our cur­rent needs, and chances are we’ll be hea­ring more and more about them¹² !

Rela­ted event : sym­po­sium on anti­bio­tic resis­tance orga­ni­zed by Inserm and Ins­ti­tut Pas­teur, June 7 : https://​www​.pas​teur​.fr/​f​r​/​j​o​u​r​n​a​l​-​r​e​c​h​e​r​c​h​e​/​e​v​e​n​e​m​e​n​t​s​/​c​o​l​l​o​q​u​e​-​s​c​i​e​n​t​i​f​i​q​u​e​-​a​n​t​i​b​i​o​r​e​s​i​s​t​a​n​c​e-amr