LONDON – Results from the phase I/II trial of Coronavac, a COVID-19 vaccine based on a traditional inactivated whole SARS-CoV-2 virus that circulated in China in the early days of the pandemic, show it is safe and induces an antibody response in healthy volunteers ages 18 to 59.
In the trial, published in The Lancet Infectious Diseases, antibody responses were induced within 28 days of the first immunization, after administering two doses of the vaccine, 14 days apart.
The study identified the optimum dose to generate the highest antibody responses, while taking account of side effects and production capacity, as 3 µg. That is being studied further in phase III trials of the Sinovac Biotech Ltd. vaccine.
Mean neutralizing antibody titers induced by Coronavac ranged from 23.8 to 65.4. That is lower than levels seen in people who have recovered from COVID-19, where the average level is 163.7.
However, the researchers still believe Coronavac could provide sufficient protection against COVID-19 based on their experience with other vaccines and data from preclinical studies with macaques.
The phase II did not assess T-cell responses and that will be studied in ongoing phase III studies.
The trial was not designed to assess efficacy, so results from phase III studies, underway in Brazil, Indonesia and Turkey, all countries where levels of COVID-19 infection are high, will be crucial for determining if the immune response generated by Coronavac is sufficient to protect from SARS-CoV-2 infection.
The researchers note the persistence of the antibody response also needs to be verified in future studies, to determine how long-lived any protection might be. Further trials also will be needed to test the vaccine in other age groups and in people who have pre-existing medical conditions.
“Our findings show that Coronavac is capable of inducing a quick antibody response within four weeks of immunization by giving two doses of the vaccine at a 14-day interval. We believe that this makes the vaccine suitable for emergency use during the pandemic,” said Fengcai Zhu, of the Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China, the joint lead author of the study, adding, “In the longer term, when the risk of COVID-19 is lower, our findings suggest that giving two doses with a one-month interval, rather than a two-week interval, might be more appropriate for inducing stronger and potentially longer-lasting immune responses.”
Coronavac is a chemically inactivated whole virus vaccine based on a strain of SARS-CoV-2 that was originally isolated from a patient in China.
Between the phase I and phase II trials, the process for manufacturing the vaccine was changed to increase production capacity. There was no difference in reported side effects; however, the immune responses were much stronger in the second phase of the study after the new process was introduced, and the proportion of participants producing antibodies to SARS-CoV-2 was higher.
It subsequently became clear that the new manufacturing process resulted in a greater number of intact spike proteins, through which the virus enters the host cells, remaining on the surface of the inactivated virus.
“Two lessons arise from this study,” said Naor Bar-Zeev, associate professor at Johns Hopkins University, in an accompanying commentary on the results. “First, we can use existing tried and tested platforms to produce vaccines. We know their limitations, but we also know that in previous incarnations they are usually acceptably safe. And second, unexpected things can happen in science as in life. A change in manufacturing process to scale up production can change the performance of a vaccine.”
Safety and antibody results
The phase I/II trial was carried out in the Suining County of Jiangsu province, China. Only people with no history of infection with COVID-19, who had not traveled to areas with high incidence of the disease and did not have signs of fever at the time of recruitment, were included in the study.
In the first phase, 144 healthy volunteers were enrolled between April 16 and April 25. Participants were split into two groups to receive one of two vaccination schedules, either two injections given 14 days apart (day zero and 14 schedule), or two injections given 28 days apart (day zero and 28 schedule).
Within each of the two groups, participants were randomly assigned to receive either a low dose of the vaccine (3 µg, 24 participants), a high dose (6 µg, 24 participants) or placebo (24 participants). In total, in this first phase, 96 participants received two doses of Coronavac and 47 received the placebo (one participant withdrew from the placebo group). Antibody levels were checked 14 days and 28 days after the final immunization.
For the first seven days after each dose, participants used paper diary cards to record any side effects, such as pain or redness at the injection site, fever or cough. Serious adverse events were collected throughout the study and until six months after the last dose.
In the phase I trial, the overall incidence of adverse reactions was similar in the low- and high-dose groups at both vaccination schedules, indicating no dose-related safety concerns. Most of the reported side effects were mild and participants recovered within 48 hours, with the most common symptom being pain at the injection site.
There was one case of severe allergic reaction within 48 hours of receiving the first dose in the 6-µg group of the day zero and 14 vaccination schedule, which was considered to be possibly related to vaccination. However, the participant was treated and recovered within three days, and did not experience a similar reaction after the second dose of vaccine.
Phase II of the trial started when all participants in phase I had finished a seven-day observation period after their first dose. Some 600 healthy volunteers were enrolled in the study between May 3 and May 5.
Overall, the researchers found the day zero and 28 schedule induced the strongest antibody responses.
However, even at the highest levels, antibodies induced by Coronavac were lower than those that have been observed in patients who have recovered from COVID-19, with the mean neutralizing antibody titres for Coronavac reaching 65.4 and for COVID-19 patients, 163.7.
Gang Zeng, medical manager at Sinovac, one of the authors of the study, noted there are many vaccines in development, each with their own advantages and disadvantages. “Coronavac could be an attractive option because it can be stored in a standard refrigerator between 2 and 8 degrees centigrade, which is typical for many existing vaccines, including flu,” he said.
In addition, Coronavac will remain stable for up to three years in storage. That could offer advantages for distribution to regions where access to refrigeration is challenging.