Why was CSPC's new crown mRNA vaccine approved for marketing in the first place?

01

Recently, CSPC announced on the Hong Kong Stock Exchange that after the recommendation of the National Health Commission of China and the organization and approval of the National Medical Products Administration, the Group's novel coronavirus mRNA vaccine (SYS6006) was included in emergency use in China to prevent diseases caused by new coronavirus (SARS-CoV-2) infection.

This is also the first mRNA vaccine against the new coronavirus approved for marketing in mainland China.

Regarding the discussion of mRNA vaccines, it has always been Watson Biotech and Swei Biotech that have been running ahead, how can Stone Medicine be approved for marketing first?

02

The reason why Stone's mRNA vaccine was first approved is one word: autonomous and controllable.

mRNA vaccines are not difficult to make, the difficulty is to master the core process, but where one is stuck by others. That's like a chip, you can design, doesn't mean you can make it.

The core technology for the production of mRNA vaccines has three points: delivery system, capping technology and large-scale production process.

2.1 Delivery System

The delivery system binds to mRNA molecules and needs to protect them from degradation by RNA hydrolases in serum during systemic administration, so as to ensure that mRNA can reach the target cell smoothly, and then enter the cell by endocytosis as an endosome. After the endosomes enter the cytoplasm, they are sent directly to the lysosomes for decomposition. Therefore, the delivery system also needs to release the mRNA from the endosomes before they reach the lysosomes. After mRNA escapes the endosomes and enters the cytoplasm, it swims to the ribosome, where it translates into proteins.

At present, the delivery systems entering the clinic mainly include liposomes, lipid nanoparticles (LNP), lipid complexes, and lipid polymer complexes (LPPs), of which LNP is the most common.

LNP wraps mRNA

2.2 Capping technique

The gene sequence of mRNA is generally composed of 5'-cap (5' end cap), 5' UTR (5' noncoding region), ORF (coding region), 3' UTR (3' end noncoding region), and Poly(A) tail (polyadenylate tail).

5'-cap (5' end cap): In eukaryotes, it can bind to the translation initiation factor eIF4E to maintain the stability of mRNA, improve translation efficiency, and inhibit the degradation of mRNA by exonuclease and inhibit innate immune response. The most critical link in the in vitro transcription synthesis of mRNA molecules is how to cap them efficiently.

2.3 Large-scale production

In production, the ethanol phase containing lipids and the aqueous phase containing mRNA are mixed to form a lipid supersaturated state, which self-assembles into nanoparticles in milliseconds. In large-scale production, whether the LNP particle size is uniform and whether there are residues of impurities; Freezing/drying more easily and efficiently without losing component activity and thus maintaining stability for longer periods of time is key.

03

From the above analysis, we can see that to produce mRNA vaccines, the first thing to solve is the delivery system (lipid nanoparticles), this technology can not be conquered, then everything else is blind.

At present, the main domestic self-developed mRNA vaccine delivery systems are Swaim Biotech and CSPC Pharmaceutical Group. Swivee Bio adopts a different technical route from LNP, choosing LPP (lipopolyplex), LPP bilayer nanoparticles have better encapsulation and mRNA protection effect than traditional LNP, and can gradually release mRNA molecules with the degradation of polymers.

On December 8, 2022, the novel coronavirus mRNA vaccine (trade name: Sverk) independently developed by Siwelk ® was granted Emergency Use Authorization ("EUA") by Laos for the prevention of new coronavirus pneumonia through active immunization in people aged 18 and above.

If the large-scale production technology of SWP can also be solved, it is estimated that the subsequent approval in China will be soon.

According to CSPC's latest annual report[1], the company has established a comprehensive innovative R&D platform, covering small molecules, large molecules, nano preparations, ADCs, mRNA vaccines and small interfering nucleic acid (siRNA) drugs.

However, it can be seen that the company wants to emphasize the most is the nanomedicine technology platform (has successfully developed 4 nano dosage forms of heavy products), not only the relevant layout is in the international lead, but also developed a number of core delivery technologies including nanoliposomes, albumin nanopreparations, polymer micelles, and lipid nanoparticles for the delivery of nucleic acid drugs and nucleic acid vaccines.

With such a technical accumulation, it is only a matter of time before the delivery system of mRNA vaccines is broken.

04

Regarding the efficacy, Shiyao chose to compare with recombinant protein vaccines, which is also easy to understand, because the booster shots that are sequentially vaccinated after release are basically recombinant protein vaccines. SYS6006 has completed phase I, II and sequential booster clinical studies in China:

One dose of SYS6006 is given sequentially in addition to 2 or 3 doses of inactivated vaccine. During the epidemic period (10.12.2022-18.1.2023), 4000 cases of sequential booster immunization were carried out, and the protective efficacy of SYS6006 was 70.2% (95% CI: 53.6%-80.9%) 7-28 days after booster vaccination using recombinant protein vaccine as the control. The protective efficacy of SYS6006 was observed to be 85.3% (95% CI: 56.9% to 95.0%) 14 to 28 days after booster vaccination.

After a booster dose of SYS6006, the geometric mean titer (GMT) against Omicron BA.5 neutralizing antibody at 14 days is 236, which is 83 times higher than before booster vaccination[2].

And what is the level of recombinant protein vaccine, we take Rico Biotech and Clover Biopharmaceuticals as examples:

Compared with subjects receiving the third dose of inactivated vaccine as homologous booster immunization, Rico Bio ReCOV sequential booster induction against prototype strains and Omicron variants BA.2, BA.4/5, BA.2.75, neutralizing antibody titer increase factor ranged from 12.1 to 17.3 times.

In subjects who had previously received two doses of inactivated vaccine, Clover Biopharma SCB-2019 was vaccinated as a heterologous third dose. Against the Omicron strain, SCB-2019 induced about 6 times higher levels of neutralizing antibodies than the third dose of inactivated vaccine.

Although there is no direct head-to-head clinical trial, it can be roughly seen that the level of antibodies induced by SYS6006 is about an order of magnitude higher than that of recombinant protein vaccines, and this is still data for BA5 strains.

SYS6006 was approved for clinical trials in April 2022, less than a year later, and was urgently approved for marketing before completing phase III clinical trials, which shows the FDA's desire for domestic mRNA vaccines. However, this also means that a secondary infection should be imminent.

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reference

^https://stockn.xueqiu.com/01093/20230322244788.pdf

^https://stockn.xueqiu.com/01093/20230322983764.pdf