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