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