Safety of Heterologous mRNA Vaccine Booster in Healthy Adults

Trial Design and Participants

We conducted a single-center, open clinical trial to evaluate the safety of heterologous boosting with the mRNA vaccine CS-2034 in China. Adults 18 years of age or older who were healthy and had completed three-dose of inactivated vaccines at least 6 months ago were eligible for participation in the trial. Key exclusion criteria included a medical history of Covid-19 or other coronavirus infection, serious vaccine-related hypersensitive reactions, systemic allergic reactions, diagnosis with an autoimmune disease, treatment with immunosuppressive therapy, any serious chronic conditions (diabetes, hyperlipidemia, thyroid diseases), or female participants with positive urine pregnancy test results.

The trial was reviewed and approved by the Clinical Trial Ethics Committee of West China Second Hospital of Sichuan University, and the trial process follows the National Medical Products Administration, the requirements of Good Clinical Practice (GCP), the Declaration of Helsinki, and relevant domestic laws and regulations. All the participants provided written informed consent before enrollment. Clinical monitoring, laboratory testing, data management, and statistical analysis were carried out in accordance with relevant regulations and guidelines.

CS-2034 Vaccine

The mRNA vaccine CS-2034 is co-developed by researchers at the CanSino (Shanghai) Biotechnologies Co., Ltd and CanSino (Shanghai) Biological Research Co., Ltd. The sequence-optimized mRNA vaccine encodes the full-length SARS-CoV-2 spike protein based on the original strain and contains four convergent mutations across different variants: K417N, E484K, N501Y, and D614G. Each dose of the mRNA vaccine CS-2034 contains 30 μg mRNA.

Trial Procedures

The mRNA vaccine CS-2034 was administered as a 0.3-mL intramuscular injection into the deltoid on day 0 of the study; follow-up visits were scheduled for 0, 7, and 14 days after vaccination and on day 180. Adverse events and serious adverse events were medically coded using MedDRA and classified by SOC and PT. In addition, statistical classification of solicited adverse events will be conducted according to the program requirements by the adverse events at the inoculation site (local) and the adverse events at the non-inoculation site (systemic). This study focused on a statistical analysis of treatment-emergent adverse reactions that occurred after vaccination. Collection of specimens, as well as monitoring for medically attended adverse events, development of new chronic medical conditions, and serious adverse events, was scheduled to continue throughout 6 months after the booster. These initial findings will be updated with final safety data when the results are available.

Trial Population

Between September 21, 2022, and October 27, 2022, a total of 877 participants aged between 18 and 59 years or 60 years older underwent screening at West China Second Hospital of Sichuan University in Sichuan Province, China. Of these participants, 58 participants met the exclusion rules and were excluded, while the other two were excluded for other reasons. A total of 817 eligible participants consented to participate in the trial and received the heterologous boost of mRNA vaccine CS-2034 at 30 µg (Figure 1). Among them, 58% were female, 20% were 60 years or older, and the mean age was 46 years. The participants had a mean body-mass index (the weight in kilograms divided by the square of the height in meters) of 25, and 42% had at least one underlying medical condition or medical history. The demographic characteristics of the participants are shown in Table 1. All enrolled participants completed vaccination and safety observation, and no participants withdrew from the study in advance.

Click to enlarge

The diagram represents all enrolled participants through September 21, 2022. Figure 1: Trial profile.

*The body-mass index is the weight in kilograms divided by the square of the height in meters. #Plus-minus values are mean ±SD. Table 1: Demographic Characteristics of the Participants at Baseline.

Preliminary Safety Data

Within 28 days after boosting, all adverse reactions occurred within 14 days and no adverse reactions occurred within 30 min and 15-28 days after the booster (Table 2). 4 participants had serious adverse events, none of which were considered by the investigators to have been vaccine-related, and were not included in the following analysis. No deaths or adverse events led to discontinuation from the study within 28 days (Table 3). The overall incidence of solicited adverse reactions within 28 days was 61.57% (503 cases).

The main adverse events were grade 1 (43.21%) and grade 2 (15.67%), and no grade 4 or above adverse events occurred (Table 3). Local adverse events, when present, were nearly all mild or moderate, including pain (56.18%), pruritus (16.40%), swelling (13.46%), induration (13.34%), and erythema (11.26%) at the injection site (Figure 2 and Table 3). The most common systemic adverse reactions were fever (12.48%) and fatigue (12.00%). Grade 3 systemic solicited adverse reactions were fever, fatigue, headache, and myalgia, with incidence rates of 1.84% (15 cases), 0.49% (4 cases), 0.49% (4 cases), and 0.24% (2 cases), respectively (Figure

2 and Table 3). Moreover, the overall incidence of non- solicited adverse reactions within 28 days was 3.92% (32 cases), among which grade 1 adverse reactions were 2.82% (23 cases), grade 2 were 0.98% (8 cases), and grade 3 were 0.12% (1 case), manifested as upper abdominal pain. No grade 4 or above adverse reactions occurred (Table 3).

Click to enlarge

A: The local adverse reactions in participants aged 18-59 years or ≥ 60 years. B: The systemic adverse reactions in participants aged 18-59 years or ≥ 60 years. The severity of solicited adverse events was graded as Grade 1, Grade 2, Grade 3, or Grade 4. Figure 2: Solicited systemic and local adverse reactions within 28 Days after the heterologous booster.

Reactogenicity events among the participants aged 18-59 years and 60 years or older were imbalance for the incidence of adverse events (66.11% vs. 43.40%), solicited adverse events (65.96% vs. 43.40%), and unsolicited adverse events (4.41% vs. 1.89%) (Table 3). The symptoms of adverse reactions were similar between the two age groups. Fever (14.13% vs. 5.66%), headache (10.64% vs. 1.89%), fatigue (13.98% vs. 3.77%), Myalgia (9.73% vs. 2.52%), and other symptoms were more common in participants between the ages of 18 and 59 years compared with age 60 or older (Table 3 & Figure 2). In general, the incidence of adverse reactions in participants aged 60 or older is lower than that in 18-59 years old. Safety monitoring will continue for 6 months after the administration of the heterologous mRNA vaccine CS-2034. Taken together, the mRNA vaccine CS-

2034 heterologous booster in healthy people aged 18 years or older is safe and well tolerated, and no serious adverse reactions related to the experimental vaccine have occurred.