Domestic Biopharma Firms Accelerate mRNA Vaccine Development with Promising Clinical Data

As of now, no mRNA vaccine has been approved for marketing in mainland China, but several companies, including Fosun Pharma, Walvax/Abogen, Stemirna Therapeutics, Amoytop/Lifanda Biotech, RiboBio, CanSino, and CSPC, have received approval to enter clinical trials in China. Among them, the fastest-progressing is the COVID-19 mRNA vaccine ARCoVaX (AWcorna), co-developed by Walvax Biotechnology Co., Ltd., the Academy of Military Medical Sciences, and Abogen Biosciences.

Table 1 mRNA COVID-19 Vaccines Approved for Clinical Trials in China

Source: Official websites of various companies

Clinical research on mRNA vaccines in China continues to update, and just recently, three mRNA vaccines released their latest trial data.

A

Walvax/Blue Magpie RQ3013 vs. BNT162b2 Head-to-Head Study

On May 27, 2022, the ClinicalTrials.gov website updated the clinical research information for Walvax and Bluebird Biotech's mRNA vaccine RQ3013.

Figure 1 Walvax/Blue Magpie RQ3013 Clinical Information (NCT05394012)

Clinical Study Design: According to the updated data from ClinicalTrials, this is a randomized, double-blind, controlled Phase Ia clinical study. The clinical trial plans to enroll 120 participants, with an estimated start date of June 2022. The clinical study includes two groups: the experimental group will receive intramuscular injections of RQ3013 at doses of 30 μg/0.15 mL and 60 μg/0.3 mL. The control group will be administered BNT162b2, developed by Pfizer/BioNTech, at a dose of 30 μg/0.3 mL. The primary clinical endpoint is the safety of RQ3013 in healthy adults (aged 18-59) who have not been vaccinated against COVID-19. Secondary endpoints include serious adverse events or specific adverse events within 12 months post-vaccination, geometric mean titer (GMT) of IgG antibodies against the Beta and Omicron variants (live/pseudovirus) and S protein, the extent of titer increase (GMFR), and seroconversion rate.

According to a clinical research article published on BioRxiv on May 10, 2022, they developed three mRNA candidate vaccines targeting the wild-type (WT) SARS-CoV-2, expressing the receptor-binding domain (RBD), S protein, and virus-like particles (VLP). RQ3011-RBD contains an mRNA encoding the receptor-binding domain of S with a C-terminal membrane anchor helix. RQ3012-Spike contains an mRNA encoding the full-length WT S. RQ3013-VLP contains three mRNAs encoding S, M, and E proteins, which can assemble into VLPs. RQ3013 was ultimately selected as the candidate drug.

Figure 2 Three mRNA candidate vaccines developed by Walvax/Blue Magpie

RQ3013 is an mRNA vaccine encoding nearly the full-length S protein, but with some modifications to the S immunogen, removing the cysteine-rich fragment at the C-terminus. Meanwhile, RQ3013 incorporates mutation sites based on variants, including all mutations of B.1.1.7 and K417N, E484K, A701V on B.1.351. Compared to the S2P structure adopted by Pfizer/BioNTech's BNT162b2 and Moderna's mRNA-1273, RQ3013 does not introduce proline substitutions, but modifies the furin cleavage site, preventing the S protein from being affected by protease-mediated proteolysis. Cryo-electron microscopy (cryo-EM) shows that RQ3013 induces the S protein in two states: the pre-fusion state and the post-fusion state, existing in a trimeric form.

Figure 3 RQ3013 mRNA vaccine design diagram (a), structural characterization of expressed antigen (b, c)

Preclinical studies evaluated the immunogenicity, efficacy, and safety of RQ3013 in various animal models. The results showed that RQ3013 elicited a strong immune response in mice, hamsters, and non-human primates, inducing high-titer antibodies with broad cross-neutralizing ability against the wild-type strain and variants B.1.1.7, B.1.351, B.1.617.2, and Omicron B.1.1.529. Mouse experiments demonstrated that two doses of RQ3013 protected the respiratory tract and lower respiratory tract from infection by SARS-CoV-2 and its variants. In rhesus monkey studies, both 30 µg and 100 µg doses significantly enhanced pseudovirus/live virus neutralizing titers and IgG titers. In viral challenge experiments, viral loads in the lungs, trachea, and bronchi of vaccinated rhesus monkeys were significantly lower than those in the placebo group. Pathological changes characterized by viral pneumonia and pulmonary fibrosis were moderate in the low-dose group and generally mild in the high-dose group, showing significant alleviation compared to the control group (Figure 4f). Preclinical animal study results indicated that RQ3013 has the potential for broad-spectrum prevention of multiple SARS-CoV-2 subtypes. The study also assessed the safety of RQ3013 in cynomolgus monkeys. At the end of the experiment, lung, brain, heart, liver, spleen, and kidney tissues were collected for histopathological analysis and safety evaluation of RQ3013. No vaccine-related immunopathological changes were observed in any tissue sections examined.

Figure 4 Immunogenicity and protective efficacy of RQ3013 in rhesus macaques (Placebo: blue circles; Low dose (30 μg): red squares; High dose (100 μg): green triangles)

B

Fosun Pharma "Comirnaty" Phase II Clinical Trial in China

Recently, Fosun Pharma released the phase II clinical study results of the COVID-19 vaccine "Comirnaty" in China.

Clinical Study Design: This Phase II clinical trial adopted a randomized, double-blind, placebo-controlled design, led by the Jiangsu Provincial Center for Disease Control and Prevention. The study population consisted of healthy or medically stable individuals aged 18-85 from two clinical sites in China. Participants were divided into two age groups: 18-55 years and 56-85 years. They were randomly assigned in a 3:1 ratio to receive two intramuscular injections of either 30μg of the mRNA COVID-19 vaccine BNT162b2 (720 participants) or placebo (239 participants), administered 21 days apart. The primary immunogenicity endpoints were the seroconversion rate (SCR) and geometric mean titer (GMT) of neutralizing antibodies one month after the second dose. Safety assessments included reactogenicity within 14 days post-vaccination, adverse events, and clinical laboratory parameters.

Clinical Research Results: A total of 959 subjects aged 18-85 were recruited between December 5, 2020, and January 9, 2021. In the live virus microneutralization assay, the 50% neutralization GMT for the BNT162b2 group was 294.4 (95% CI; 281.1-308.4), compared to 5 for the placebo group. The SCR was 99.7% (95% CI; 99%-100%) for the BNT162b2 group and 0 (95% CI; 0%-1.5%) for the placebo group. One month after receiving the second dose, participants showed a higher antibody response compared to one week after vaccination. Clinical trial results demonstrated that healthy Chinese adults or those with stable underlying diseases developed a strong immune response after receiving two doses of "Comirnaty" administered 21 days apart. The vaccine also effectively neutralized the Alpha, Beta, and Delta variants, showing good tolerability and safety.

Figure 5 GMT and SCR before vaccination and at 1 week and 1 month after the second dose

C

Abogen/Walvax mRNA Vaccine ARCoVaX (AWcorna)

On May 31, an article (preprint) was published on the medRxiv platform, revealing the immunogenicity and safety data of the Abogen/Walvax mRNA vaccine ARCoVaX (AWcorna) as a heterologous booster in Chinese adults.

Clinical Study Design: This is a clinical study exploring the safety and immunogenicity of using AWcorna as a third heterologous booster dose in Chinese adults who have received two doses of inactivated vaccine (ChiCTR2100053701). A total of 300 adults (aged ≥18 years) were recruited. All eligible participants had received two doses of the inactivated vaccines CoronaVac or BBIBP-CorV. At approximately 6 months, all participants were randomly assigned to receive either AWcorna (n=200; heterologous) or CoronaVac (n=100; homologous) as a booster dose, with median ages of 43 years and 40 years in the two groups, respectively. All participants completed enrollment, vaccination, and three blood tests before or at day 0, 14±2 days, and 28±2 days post-booster.

Figure 6 Flowchart of the Clinical Study

Clinical Research Results: Against the original strain, Delta, and Omicron variants, the AWcorna group showed superior neutralizing antibody GMT compared to the inactivated vaccine. No severe adverse events were found in either group, with overall safety being controllable. The AWcorna booster increased the impact on WT SARS-CoV-2 by 66.59 times, with GMT reaching 293.9 and 242.4 at 14 and 28 days post-booster, respectively, while the GMT for the CoronaVac group was only 89.1 and 64.3. Similarly, after the third dose of AWcorna and CoronaVac boosters, neutralizing antibody titers against the Delta variant significantly increased. At 14 and 28 days post-booster, the GMT of the AWcorna group was 5.1 and 6.5 times higher than that of the CoronaVac group.

Figure 7 Neutralizing Antibody GMT for the Original Strain and Delta Variant

Twenty-eight days after the booster, the GMTs against the Omicron variant were significantly lower compared to those against the WT SARS-CoV-2 virus. Twenty-eight days after the AWcorna booster, the GMT against Omicron remained at 28.1, while in the CoronaVac booster group, the GMT was only 6.4. Most importantly, 83.75% of participants in the AWcorna booster group reached the neutralizing antibody titer threshold of 1:8 against Omicron, compared to only 35% in the CoronaVac booster group (Figure 8b).

Figure 8 GMT of Neutralizing Antibodies Against Omicron Strain

In summary, although COVID-19 vaccines produced in China, such as those by Sinopharm and Sinovac, have been approved for marketing, a study in Brazil showed that six months after completing two doses of the Sinovac inactivated vaccine, the hospitalization and mortality protection rate for people over 80 years old was only about 41.4%. However, after using the BNT162b2 vaccine as a booster, the protection rate increased to approximately 89%. For the 60-79 age group, the protection rate also rose from 72.6% to over 90%. This demonstrates the significant market potential of mRNA vaccines used as heterologous booster shots. On the other hand, RNA technology has become one of the hottest biotechnologies globally and has the potential to become a mainstream technology platform of the next generation. This is also a crucial area where China needs to catch up.

China implements the strictest management system for vaccines. To date, no mRNA vaccine has been approved for marketing in China. However, with the relentless efforts of domestic researchers, Chinese-produced mRNA vaccines will emerge when the technology and talent reserves are sufficient.

References:

1、A COVID-19 mRNA vaccine encoding SARS-CoV-2 virus-like particles induces a strong antiviral-like immune response in mice.

2、Preclinical evaluation of RQ3013, a broad-spectrum mRNA vaccine against SARS-CoV-2 variants.

3、Immunogenicity and Safety of BNT162b2 mRNA Vaccine in Chinese Adults: A Randomized Clinical Trial.

4、Safety and superior immunogenicity of heterologous boosting with an RBD-based SARS-CoV-2 mRNA vaccine in Chinese adults.