Lebanon Valley College

Study Design and Participants:
- Trials conducted in Henan Providence, China
- Double-blind, randomized, placebo-controlled Phase I and Phase II trials
- Participants: aged 18 to 59 years, no history of SARS-CoV (on-site inquiry) or SARS-CoV-2 (serological and nucleic acid test)
- Phase I Design: 96 participants, 3 vaccine dose groups (low 2.5 μg, medium 5 μg, and high 10 μg antigen protein content per dose) and a control group (received aluminum hydroxide adjuvant only), ratio of vaccine to placebo was 3:1, received intramuscular injections on days 0, 28, and 56.
- Phase II Design: 224 participants, 2 schedule groups that both received the 5 μg vaccine (days 0 and 14, and days 0 and 21), the vaccine to placebo ratio was 3:1.
- Sequential enrollment and sentinel data were used to keep the participants safe. The low dose in Phase I was used first and monitored for 7 days for adverse reactions. The medium dose group only received vaccines if there were no vaccine-related reactions in those 7 days, and the same procedure was followed for the high dose group and the phase II medium dose vaccinations. 

Methods

Xia, S., Duan, K., Zhang, Y., Zhao, D., Zhang, H., Xie, Z., Li, X., Peng, C., Zhang, Y., Zhang, W., Yang, Y., Chen, W., Gao, X., You, W., Wang, X., Wang, Z., Shi, Z., Wang, Y., Yang, X., … Yang, X. (2020). Effect of an Inactivated Vaccine Against SARS-CoV-2 on Safety and Immunogenicity Outcomes: Interim Analysis of 2 Randomized Clinical Trials. JAMA, 324(10), 951–960. https://doi.org/10.1001/jama.2020.15543

Effect of an Inactivated Vaccine Against SARS-CoV-2 on Safety and Immunogenicity Outcomes: Interim Analysis of 2 Randomized Clinical Trials

SARS-CoV-2 strain (WIV04 strain) was isolated from a patient at the Jinyintan Hospital in Wuhan. The cells were cultivated and the supernatant was treated with β-propiolactone to inactivate the virus. β-propiolactone is a chemical disinfectant and used as a sterilization technique, it is an alkylating agent that interacts with DNA. The cellular debris was ultra-filtered out and the vaccine was treated again with β-propiolactone. Finally, the vaccine was adsorbed onto 0.5 mg aluminum hydroxide and loaded into 0.5mL syringes with sterile phosphate-buffered saline. The placebo groups contained only the sterile buffer and the aluminum hydroxide adjuvant.

- https://pubchem.ncbi.nlm.nih.gov/compound/beta-Propiolactone#section=Metabolism-Metabolites 

Vaccine Creation

Safety Outcomes:
- Primary Safety Outcomes: participants recorded any injection site-specific adverse reactions and systemic adverse reactions for 7 days after injection.
- Secondary Safety Outcomes: participants recorded any unsolicited symptoms during the 28-day follow up period to the initial injection.
- Laboratory Safety Tests: performed before and 4 days after each injection to check for any toxic effects from the vaccination, included blood work, liver enzymes, bilirubin, and urine proteins. Considered Secondary Safety Outcomes.

Primary Humoral Immunogenicity Outcomes:
- Neutralizing antibody titers and specific IgG-binding antibody titers
- Phase I: blood samples collected before immunization, at days 4 and 14 after each injection, and 21 days after the first dose.
- Phase II: blood samples collected before immunization from all of the participants, and at day 14 in randomly selected half of the participants for the immunogenicity subset.
- PRNT was used to find the neutralization capacity against live SARS-CoV-2 and the values were used to determine the serum dilution that will still produce a 50% decrease in SARS-CoV-2 plaque formation.
- An enzyme-linked immunosorbent assay kit using the whole inactivated virus as the coating agent was used to measure the total specific IgG antibody responses.
- Seroconversion rate was defined and used to determine the threshold for the different antibody titers.

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