Bioproduction of mRNA vaccines: a global industrial challenge?

RNAs are of interest in many med­ic­al fields. How­ever, to fully under­stand their value and bring them to patients we need to be able to pro­duce them. RNA biopro­duc­tion is at the cross­roads between tech­no­lo­gic­al issues and indus­tri­al policy.

The last few months have shown that we are cap­able of deliv­er­ing bil­lions of doses of mes­sen­ger RNA (mRNA) vac­cines. This might lead us to believe that the pro­duc­tion sys­tems for these bio­lo­gic­al molecules are ready. How­ever, in real­ity, this is not the case. New man­u­fac­tur­ing capa­cit­ies need to be anti­cip­ated: more and more clin­ic­al tri­als are eval­u­at­ing RNAs in med­ic­al applic­a­tions, for example in can­cer­o­logy, as a treat­ment for emer­ging dis­eases or genet­ic dis­eases. These are mRNAs, as in the case of vac­cines against Cov­id-19, or oth­er types of RNAs, anti­s­ense or effect­ors, which block or activ­ate bio­lo­gic­al pro­cesses. Thera­peut­ic interest in these molecules is grow­ing rap­idly and pro­duc­tion tools and tech­no­lo­gies need to keep pace.

To appre­ci­ate the issues at stake, it is import­ant to look at pro­duc­tion pro­cess. RNAs are syn­thes­ised in vitro using a DNA tem­plate and an enzyme: RNA poly­merase. The RNA is then pur­i­fied on chro­ma­to­graphy columns, which take advant­age of chem­ic­al prop­er­ties (pH or affin­ity) to sep­ar­ate the com­pon­ents of the solu­tion and isol­ate the product of interest. Finally, the RNA molecules are asso­ci­ated with vec­tors, i.e. envel­opes that pro­tect these fra­gile molecules and facil­it­ate their entry into the cell when the RNA drug is administered.

In order to pro­duce phar­ma­ceut­ic­al grade RNA, all these steps must be cer­ti­fied as Good Man­u­fac­tur­ing Prac­tice (GMP). This stand­ard is based on a large num­ber of con­trols to ensure patient safety, start­ing with the pro­duc­tion of tem­plate DNA. Glob­ally, there are very few man­u­fac­tur­ers able to per­form this step in accord­ance with GMP stand­ards and none are loc­ated in Europe. The main pro­du­cers of GMP DNA tem­plates are in the US and it takes many months to get access to the desired DNA. Glob­ally, there is there­fore a high demand for this product that is in short sup­ply, a situ­ation which has been exacer­bated by the cov­id-19 pan­dem­ic. In response, the Resi­li­ence part of the France Rel­ance recov­ery plan* has provided the Bes­ançon-based com­pany RD Biotech with €2 mil­lion in for the con­struc­tion of a new GMP stand­ard DNA pro­duc­tion site of over 1,000 m².

There are also sup­ply issues con­cern­ing access to the enzyme, RNA poly­merase, which reads the DNA tem­plate in order to syn­thes­ise RNA. How­ever, Enzyme pro­duc­tion is well con­trolled, and the phar­ma­ceut­ic­al industry there­fore tends to inter­n­al­ise it to secure its supply.

Finally, these pro­cesses require a large num­ber of con­sum­ables (fil­ter, plastic bag, etc.). The major pro­du­cers of these mater­i­als are also out­side Europe and there is cur­rently a mar­ket short­age when it comes to these products. In response to the health crisis, man­u­fac­tur­ers are now organ­ising them­selves in order to avoid sup­ply dis­rup­tions in the event of fur­ther bor­der clos­ures. For example, the Mer­ck com­pany is going to set up a new pro­duc­tion unit for sterile bags, neces­sary for the pro­duc­tion of vac­cines, in Molsheim in Alsace.

Indus­tri­al research is pre­par­ing new pro­cesses in par­al­lel with these short-term adjust­ments. The plan is to move from in vitro pro­duc­tion (enzymat­ic syn­thes­is) to in vivo pro­duc­tion, by using yeast to pro­duce the RNA. This strategy has many advant­ages. Firstly, it avoids the need to pro­duce RNA poly­merase, which is nat­ur­ally pro­duced by yeast. Secondly, it lim­its the indus­tri­al risks asso­ci­ated with the use of very large volumes of highly explos­ive eth­an­ol dur­ing the pro­duc­tion pro­cess. Thirdly, as the cells are equipped with mul­tiple sys­tems to improve the accur­acy of the tran­scrip­tion (by lower­ing the error rate inher­ent in each RNA poly­merase), the RNA pro­duced will be of high­er qual­ity. It will also be pos­sible to pro­duce longer RNAs and to devel­op increas­ingly com­plex applic­a­tions such as mul­ti­valent vac­cines, not­ably with vac­cines dir­ec­ted against dif­fer­ent flu vari­ants. Finally, in vivo pro­duc­tion will allow modi­fic­a­tions to be made to the molecule after it has been syn­thes­ised, still in the yeast cell. These modi­fic­a­tions can, for example, ‘human­ise’ the bio­molecule and thus increase its lifespan and effect­ive­ness in human cells.

In vivo pro­duc­tion sys­tems such as this one are being developed in France as part of a col­lab­or­at­ive pro­gramme sup­por­ted for which Grand Défi “Bio­medi­cines: improv­ing yields and con­trolling pro­duc­tion costs” has provided €1.4M of sup­port. This research pro­gramme led by Chant­al Pichon (Univ. d’Orléan) at the CNRS Molecu­lar Bio­phys­ics Centre, in part­ner­ship with INSERM, INRAe, and the Poly­théragène and San­ofi-Pas­teur com­pan­ies, is expec­ted to reach indus­tri­al matur­ity in three to five years. The French phar­ma­ceut­ic­al giant has also shown its will­ing­ness to devel­op its RNA pro­duc­tion by acquir­ing the Amer­ic­an bio­tech­no­logy com­pany Trans­late Bio. It plans to set up an RNA pro­duc­tion unit at its Marcy-l’Étoile site in the Lyon region.

Oth­er aven­ues of research com­bine a med­ic­al and eco­nom­ic advant­age. They focus on address­ing thera­peut­ic molecules, i.e. the pre­ci­sion with which RNAs reach the patient’s tar­get cells. By redu­cing the dis­per­sion of the molecules in the body, the risk of side effects from the treat­ments is reduced. It also reduces the effect­ive dose, and there­fore the total cost of treatment.

The price of bio­ther­apies and there­fore of RNA is a major issue. In the case of anti-cov­id vac­cines, the doses of RNA required are small. Lar­ger quant­it­ies of bio­molecules will be needed for can­cer applic­a­tions. As is often the case with bio­med­ic­al innov­a­tions, it will be a ques­tion of find­ing a bal­ance between the fin­an­cing of phar­ma­ceut­ic­al research, pro­duc­tion costs and the access­ib­il­ity of products for all. The glob­al phar­ma­ceut­ic­al mar­ket as a whole is cur­rently worth more than $1,300bn. If the new bio­tech­no­lo­gies covered all needs, this mar­ket would be worth $4,800bn, which is not sus­tain­able for our health sys­tems. The phar­ma­ceut­ic­al industry is aware that it will not be able to sell innov­at­ive thera­peut­ic products tomor­row if this trend con­tin­ues. The fin­an­cial issue is there­fore crit­ic­al to the suc­cess of future of biotherapies.

To meet this chal­lenge of access­ib­il­ity to innov­at­ive ther­apies, the research com­munity and industry are work­ing to devel­op tech­no­lo­gies with more eco­nom­ic­al pro­duc­tion while guar­an­tee­ing patient safety. France wants to be a major play­er in this sec­tor and the State sup­ports this sec­tor with­in the frame­work of its Strategy for Accel­er­at­ing Bio­ther­apies and Biopro­duc­tion of Innov­at­ive Ther­apies fin­anced via the Future Invest­ment Pro­gramme and announced by the Pres­id­ent of the Repub­lic dur­ing his speech on the Health Innov­a­tion 2030 plan.