π Health and biotech
Beyond Covid: the promise of mRNA vaccines

mRNA vaccines: how do they work?

Agnès Vernet, Science journalist
On December 8th, 2021 |
3 min reading time
Marc Graille
Marc Graille
CNRS Research Director at BIOC* at Ecole Polytechnique (IP Paris)
Chantal Pichon
Chantal Pichon
Professor of Universities Exceptional Class 2 at Université d'Orléans
Key takeaways
  • The use of mRNA was already a hot topic in science long before the arrival of Covid-19. The pandemic has only confirmed this molecule’s potential, which is the result of 20 years of academic research.
  • One of the main reasons for the medical value of mRNA is its fragility. As it naturally degrades between in anywhere between a few tens of minutes to two days after injection, the risks of undesirable side effects are considerably reduced in the long term.
  • At the time of injection, mRNA stimulates a patient's immune system. This allows it to simulate a reaction to a pathogen, so that it can then recognise and remember it.
  • Today, the possible uses for this molecule are not limited to Covid-19. There have been numerous preclinical studies testing mRNA vaccines against influenza, chikungunya, Zika, Ebola or HIV.

Vac­cines against the coro­n­avirus respon­si­ble for Covid-19 have brought to light a bio­log­i­cal mol­e­cule that holds great promise for the med­ical treat­ments and the phar­ma­ceu­ti­cal indus­try. How­ev­er, the sto­ry of this dis­cov­ery does not begin in 2020. “Mes­sen­ger RNA (mRNA) vac­cines are the result of 20 years of aca­d­e­m­ic research,” says Marc Graille, an RNA spe­cial­ist at the Struc­tur­al Biol­o­gy of the Cell Lab­o­ra­to­ry (CNRS/Ecole Poly­tech­nique). These mol­e­cules exist nat­u­ral­ly in all liv­ing species. “They con­vert infor­ma­tion in DNA into pro­teins, which are the final prod­ucts that ensure cel­lu­lar func­tions,” explains the spe­cial­ist. These mol­e­cules are ‘mes­sen­gers’ because they make the link between the genet­ic infor­ma­tion locked in the nucle­us, and the rest of the cell. They are of great inter­est to the bio­med­ical world as they con­trol the man­u­fac­ture of pro­teins, bio­log­i­cal mol­e­cules respon­si­ble for effects; a fam­i­ly that includes both enzymes and receptors.

A fragile but promising molecule

Marc Graille explains, “mRNA vac­cines are made pos­si­ble thanks to two main dis­cov­er­ies. First­ly, the devel­op­ment of encap­su­la­tion sys­tems to inject syn­thet­ic mRNA into cells. And sec­ond­ly, the trans­for­ma­tion of mRNA com­po­nents to con­trol their degra­da­tion,” Because these mol­e­cules, which are omnipresent in the liv­ing world, are rapid­ly degrad­ed by the body. “Endoge­nous mRNAs [com­ing from with­in] in mam­mals have small chem­i­cal mod­i­fi­ca­tions that pre­vent them from being recog­nised as exoge­nous [com­ing from out­side] by the immune sys­tem and there­fore from being elim­i­nat­ed too quick­ly,” explains the specialist.

Katal­in Karikó and Drew Weiss­man, two researchers from the Uni­ver­si­ty of Penn­syl­va­nia, dis­cov­ered this phe­nom­e­non and pro­posed a strat­e­gy to mod­i­fy syn­thet­ic mRNAs. For their work, they are favourites for the next Nobel Prize in med­i­cine. “This dis­cov­ery was deci­sive. If the pan­dem­ic had occurred five years ear­li­er, we would not have been able to pro­duce such effec­tive mRNA vac­cines,” says Marc Graille. 

How­ev­er, despite these chem­i­cal trans­for­ma­tions, RNA remains a frag­ile mol­e­cule. This con­tributes to their bio­med­ical sig­nif­i­cance. “It’s a bit crazy to try to inject such frag­ile mol­e­cules,” admits Marc Graille. “These mol­e­cules do not accu­mu­late and break down nat­u­ral­ly between a few tens of min­utes and two days depend­ing on the mRNA,” he adds. This short lifes­pan in the body reduces the risk of long-term adverse effects.

Applications beyond Covid-19

In the case of mRNA vac­cines, it is the mol­e­cules encod­ed in the mRNA sequence that pro­duce the immune response respon­si­ble for vac­ci­na­tion, i.e. the recog­ni­tion and mem­o­ri­sa­tion of a pathogen mark­er. It is a mol­e­cule of inter­est to vac­ci­nol­o­gy because “immuno­genic­i­ty is inher­ent in the mRNA itself”, says Chan­tal Pichon, the French spe­cial­ist in ther­a­peu­tic mRNA, a CNRS researcher and pro­fes­sor at the Uni­ver­si­ty of Orléans. “Even using mod­i­fied bases dis­cov­ered by Katal­in Karikó, syn­thet­ic mRNA does not quite resem­ble endoge­nous mRNA. It retains an immunos­tim­u­la­to­ry char­ac­ter, which makes it pos­si­ble to make vac­cines with­out the need for an adju­vant.” Thus, the mRNA mol­e­cule stim­u­lates an immune response at the time of injec­tion, thus improv­ing effec­tive­ness of the vaccine.

Chan­tal Pichon con­tin­ues, “We know the struc­ture of mRNAs. It takes the form of units whose sequence can be opti­mised accord­ing to the appli­ca­tion. This struc­ture makes it easy to build, rather like Lego bricks. For a giv­en field of appli­ca­tion, once the struc­ture of the mRNA has been opti­mised, the cod­ing sequence can eas­i­ly be changed accord­ing to the pro­tein that we want to pro­duce in the cell.” In the­o­ry, this mol­e­cule can there­fore be used for a wide range of applications.

More­over, the virus respon­si­ble for Covid-19, Sars-Cov­‑2, was not the first pathogen for which this strat­e­gy was envis­aged. “We see exam­ples of numer­ous pre­clin­i­cal stud­ies test­ing mRNA vac­cines against influen­za, chikun­gun­ya, Zika, Ebo­la or HIV,” explains Chan­tal Pichon. “If SARS-Cov­‑2 was the first to com­plete all the stages, it was because the con­text of the pan­dem­ic encour­aged fund­ing and risk-tak­ing by test­ing sev­er­al can­di­dates which were in the clin­i­cal research phas­es. And sev­er­al mRNA vac­cines could be devel­oped at the same time.”

A solution for dealing with new variants?

In the case of influen­za, the mRNA vac­cine is being con­sid­ered for two strate­gies: for sea­son­al vac­cines, i.e. vac­cines pre­pared each year to tar­get strains assumed to be in the major­i­ty in the fol­low­ing win­ter epi­dem­ic, or for a uni­ver­sal vac­cine. “This is the type of vac­cine we had to pro­duce in my lab­o­ra­to­ry as part of a Euro­pean project; one of the main avenues for cre­at­ing mRNA vac­cines against viral dis­eases with­out the prob­lems of vari­ants,” says the spe­cial­ist. “It is a chal­lenge because we need to find an mRNA that stim­u­lates an effec­tive response regard­less of the viral variant.”

Oth­er devel­op­ments are con­cerned with encap­su­la­tion sys­tems. In the future, they will assist in the slow release of RNA to pro­duce long-term effects. Sys­tems can also be cre­at­ed with the nec­es­sary hard­ware to ampli­fy RNA. “This is already pos­si­ble in research lab­o­ra­to­ries,” says Chan­tal Pichon. It may then be pos­si­ble to use RNA to com­pen­sate for miss­ing mol­e­cules to treat age-relat­ed dis­eases or genet­ic dis­eases. For the lat­ter, “clin­i­cal tri­als are under way to treat myocar­dial ischaemia (heart attack) or cys­tic fibro­sis”, she adds. The bio­med­ical future of this mol­e­cule seems to be assured.

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