Over the past 2 years, the mRNA vaccine has gone from obscurity to World War I fame due to the COVID-19 pandemic. In December 2020, Pfizer/BioNTech and Modena's mRNA covid-19 vaccines were authorized for emergency use; recently, Pfizer and BioNTech announced that they have launched clinical studies to evaluate the safety, tolerability and immunogenicity of candidate mRNA vaccines based on Omiclon.
As an "emerging weapon" in the vaccine industry, the progress of China's domestic mRNA new crown vaccine has been attracting much attention, and the company behind it has been warmly welcomed by the capital market in the past two years. Recently, Lancet's open access journal The Lancet Microbe published a study jointly completed online by Academician Li Lanjuan and others of the State Key Laboratory of Infectious Disease Diagnosis and Treatment at the First Affiliated Hospital of Zhejiang University School of Medicine, entitled "Safety and Immunogenicity of SARS-CoV-2 ARCoV mRNA Vaccine in Adults in China: A Randomized, Double-Blind, Placebo-Controlled Phase 1 Clinical Trial" (Safety and immunogenicity of the SARS-CoV-2 ARCoV mRNA vaccine in Chinese adults: a randomised, double-blind, placebo-controlled, phase 1 trial）。
Between October 30, 2020 and December 2, 2020, the research team conducted a Phase 1 clinical trial on 120 participants, and 118 people received two doses of the vaccine at 28 days apart. The mRNA vaccine was jointly developed by the Chinese Academy of Military Medical Sciences (AMMS), Abbott Biologics and Watson Biologics as a candidate mRNA vaccine ARCoV, which encodes the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein as an antigen.
The team believes that this single-centered, double-blind, randomized, placebo-controlled, and dose-escalating Phase 1 clinical trial showed that ARCoV showed safety, good tolerance, and immunogenicity at all doses of 5 micrograms, 10 micrograms, 15 micrograms, 20 micrograms, and 25 micrograms. No serious adverse events were reported within 56 days of vaccination, with most adverse events being mild or moderate. Fever is the most common systemic adverse effect, with an increase in frequency with increasing dose.
The research team mentioned that ARCoV has good stability and can be stored and transported under refrigerated conditions, which provides great convenience for the public to receive vaccinations. A multi-regional Phase 3 clinical trial is currently underway to test the effectiveness of ARCoV.
It is worth noting that under a variety of factors, the clinical progress of this vaccine is relatively slow compared with foreign countries. In addition to ARCoV in Phase 3 clinical trials, domestic Si microorganisms in Henan to carry out Phase 2 mRNA vaccine clinical trials; on March 16, 2021, Li fanda biologics' new crown mRNA vaccine was approved by THE NMPA to issue the "Drug Clinical Trial Approval", becoming the third domestic mRNA new crown vaccine after Aibo Bio and Si Microorganisms.
On November 29, 2021, Aibo Biotech announced the completion of a $300 million Series C+ round of financing. Three months before the new round of financing, the domestic mRNA vaccine "star" company had just set a new record for a single financing before the IPO of a Chinese biopharmaceutical company, announcing the completion of a $7.2 (more than 4.5 billion yuan) Series C financing.
Fever in grade 3 systemic adverse events
In June 2020, ARCoV was officially approved by the State Drug Administration for clinical trials, becoming the first mRNA vaccine approved for clinical trials in China. Prior to this, bnT162b2 developed by Pfizer/BioNTech and mRNA-1273 developed by Modena have gone faster.
The paper also commented on both vaccines, saying that both mRNA vaccines in Phase 3 clinical trials showed efficacy of more than 94%, and both vaccines chose SARS-CoV-2 full-length spike protein as an antigen.
The research team mentioned that the receptor binding domain (RBD) based on the SARS-CoV-2 spike protein has been identified to play a key role in helping coronaviruses enter human cells, and previous studies have also shown that RBD as an antigen can induce strong humoral and cellular immune responses when used in SARS-CoV and MERS-CoV studies. The team developed a candidate mRNA vaccine, ARCoV, which is also RBD encoding SARS-CoV-2 as an antigen.
It is worth mentioning that Pfizer/BioNTech also previously designed another mRNA vaccine, BNT162b1, which is also RBD encoding SARS-CoV-2 as an antigen, but eventually abandoned this path. Previously published comparative studies have shown that BNT162b2 has fewer side effects and a more extensive T cell response in immunogenicity than BNT162b1.
Li Lanjuan et al. also mentioned in the paper that preclinical studies have shown that in mice and non-human primates, two doses of immunity with ARCoV trigger a potent neutralizing antibody against SARS-CoV-2 and a helper T cell (Th1) response. In addition, ARCoV is a liquid formulation that can be stored under standard refrigerated conditions (2 °C-8 °C) for ease of transport and use.
The Phase 1 clinical trial was conducted at Shulan Hospital in Hangzhou, Zhejiang Province, and included healthy adults aged 18-59 years with NEGATIVE SARS-CoV-2, randomized grouped to receive intramuscular vaccination or placebo. Vaccine doses were 5 μg, 10 μg, 15 μg, 20 μg, 25 μg, and the placebo group was normal saline, each group of 20 participants, and the deltoid muscle was injected on days 0 and 28. All participants received the first dose of the vaccine and 118 people received the second dose.
Safety data show that no serious adverse events were reported within 56 days of vaccination, with most adverse events being mild or moderate. After the first or second dose of ARCoV, similar rates of systemic adverse events were reported.
Adverse reactions and 56 days after the first or second dose of inoculation.
The incidence of adverse events was 60% in the 5 μg group, 80% in the 10 μg group, 95% in the 15 μg group, 95% in the 20 μg group, 100% in the 25 μg group, and 5% in the placebo group. The most common adverse reactions reported were pain at the injection site, fever, headache, fatigue or discomfort, redness at the injection site, muscle pain, sclerosing and itching at the injection site, joint pain, diarrhea, and chills. The research team said the adverse events after the first or second dose were short-lived and resolved by simple standard medications, care management, or self-resolution. Most of the reported adverse reactions were mild or moderate in severity, with about 95% remission within the first 2 days after the first or second dose and the rest within 5 days. Only 1 participant experienced grade 3 pain at the injection site.
Noteworthy is fever of grade 3 systemic adverse events. No grade 3 fever was reported in the 5 μg group, while 3 of the 20 participants in the 10 μg group (15%) reported grade 3 fever. This incidence increased with dose, 30% in the 15 μg group, 35% in the 20 μg group, and 38% in the 25 μg group.
Active adverse reactions and 56 days after the first or second dose of vaccination.
In the discussion part of the paper, the research team pointed out that the incidence of grade 3 fever in ARCoV was similar to the results of the Pfizer/BioNTech BNT162b1 trial. They cite data that the incidence of grade 3 fever in BNT162b1 also varied significantly in the same 30-microgram group of adults aged 18-55 years, with no 1 (0%) of the 12 participants in the United States, 1 in 12 participants in Germany (8%), and 4 in 24 cases (17%) in China. This, they argue, suggests that different populations have different tolerances. In addition, the incidence of grade 3 fever in two mRNA vaccines based on the full-length spike protein, mRNA-1273 and BNT162b2, also differed in phase 1 and phase 3 trials.
The research team says the safety of ARCoV in large populations is under investigation. Previous studies have shown that systemic adverse events at high doses are more frequent and severe, which is consistent with the data they obtained. At the same time, several studies reported more frequent and severe systemic adverse events after the second vaccination. Not enough, this finding was not observed in ARCoV, where the incidence of adverse events was similar after the first and second vaccinations.
Immunogenicity is dose-dependent in the range of 5-15 micrograms
In terms of immunogenicity, preliminary data were presented in phase 1 clinical trials. 28 days after the first dose, only a few participants in the 15 μg and 20 μg groups detected RBD-specific immunoglobulin G (IgG). RBD-specific IgG antibodies were detected in most participants 15 days after the second dose, and the seroprevalence was 65% in the 5 μg group, 90% in the 10 μg group, 100% in the 15 μg group, 85% in the 20 μg group, and 81% in the 25 μg group.
The IgG antibody titer in the 15 μg group peaked on the 15th day after the second dose was administered, with a geometric average titer of 2414.8 ELISA units, and the remaining 4 vaccine groups were lower than the 15 μg group.
Neutralization activity trials on the original wild-type pseudoviruses showed that after the first dose, only a few participants produced low titer neutralizing antibodies, while after the second dose, most participants developed high-titer anti-SARS-CoV-2 neutralizing antibodies.
Consistent with the pseudoviral trial, ARCoV induced high concentrations of neutralizing antibodies against active SARS-CoV-2, the research team said. 15 days after the second dose was inoculated, the sero-positive conversion rates for the neutralizing antibody against live SARS-CoV-2 were: 80% of the 5 μg group, 90% of the 10 μg group, 95% of the 15 μg group, 95% of the 20 μg group, and 94% of the 25 μg group. After the second dose, the geometric average titer of the NEUTRALIZING ANTIBODY OF SARS-CoV-2 in all vaccine groups increased rapidly. 15 days after the second dose, a peak titer of antibodies against the neutralizing antibody of live SARS-CoV-2 was detected in the 15 μg group, with a geometric average titer about 2 times that of the group of patients who recovered from COVID-19.
ARCoV antibodies and neutralization reactions in Phase 1 clinical trials.
Finally, the team also performed ELISpot assays on SARS-CoV-2 RBD using peripheral blood mononuclear cells isolated from Participants in Phase 1 clinical trials to evaluate the SARS-CoV-2-specific T cell responses obtained by participants after ARCoV inoculation.
The data showed that after the first dose, only a small percentage of participants in each vaccine group were positive for IFN-γ expression cells. After the second dose, all participants in the 5-20 μg group were positive for IFN-γ expression cells and 1 participant in the 25 μg group was negative. Similarly, all participants, except 1 person in the 25 μg group, were positive for IL-2 expression cells on day 7 after the second dose of inoculation. The average values of IFN-γ and IL-2-expressing cells remained unchanged for 15 days after the second inoculation.
The research team concluded that participants in all vaccine groups had strong humoral and cellular immunity after the second dose. In the 5 μg, 10 μg, and 15 μg groups, secretion of RBD-specific IgG, SARS-CoV-2 live virus neutralizing antibodies, IFN-γ, and IL-2 cytokines were all dose-dependent. For SARS-CoV-2 live virus neutralizing antibodies, the geometric mean titer of the 15 μg group was significantly higher than that of the 5 μg group and the 10 μg group.
They noted that the immunogenicity of ARCoV was dose-dependent in the 5-15 microgram range, but there was no significant improvement in immunogenicity in the 20-25 microgram range, which was similar to BNT162b1 and BNT162b2. They explain that the underlying mechanism of this phenomenon remains to be determined and may be partly related to an imbalance in the host's innate and adaptive immune responses.
ArCoV-induced specific T cell responses in Phase 1 clinical trials.
In particular, they discussed the protective role of the cellular immune response in SARS-CoV-2 infection. Current clinical results from mRNA-based vaccines and adenovirus vaccines have shown that the vaccine induces a strong Th1 cell response in most participants.
It is worth noting that the ideal effect of vaccination is to induce long-term immunity. The research team pointed out in the paper that previous studies have pointed out that previous studies on SARS convalescents have shown that SARS-specific memory T cells can be detected in patients after 11 years of infection. For SARS-CoV-2, there is also growing evidence that T cells also play an important role, detecting SARS-CoV-2-specific memory T cells in convalescent patients.
They noted the presence of SARS-CoV-2-specific T cells in participants vaccinated against COVID-19, "which is a promising sign that the vaccine may produce immunity, but whether these T cells provide long-term protection remains to be tested." ”
The research team also pointed out several limitations of the study. First, data interpretation is based on small sample sizes, and more data from Phase 2 and Phase 3 trials will provide further data to assess the safety and efficacy of ARCoV. Second, the trial is limited to Chinese adult participants aged 18-59, and trials of the elderly are ongoing. Third, the long-term safety and tolerability of ARCoV and the persistence of the initiated immune response have yet to be evaluated.