he hunt for a vaccine for Covid-19, the disease caused by the novel coronavirus SARS-CoV-2, is one of the most pressing global tasks right now. According to the World Health Organization (WHO), as of May 22, more than 120 vaccine candidates have been proposed worldwide, 114 of which are in the pre-clinical evaluation stage, with 10 already having entered clinical trials. Among the 10 strongest candidates, five are from China, with the others developed by American and British scientists. Some have entered phase two clinical trials, but there is still much uncertainty over which is the most promising. Data from animal or human trials on levels of immune response published by several teams have shown different initial results.
On May 22, findings were published in medical journal The Lancet addressing the “safety, tolerability, and immunogenicity (the ability to produce an immune response) of a recombinant adenovirus type-5 vectored Covid-19 vaccine” developed by a research team led by Chen Wei, an academician with the Chinese Academy of Engineering and a researcher at the Institute of Military Medicine under the Academy of Military Sciences. The first-phase clinical trial was completed at the end of March, and the second phase was launched on April 12, making it the first Covid-19 vaccine in the world to have gone into second-phase clinical trials.
A researcher with Chen Wei’s team who spoke on condition of anonymity told NewsChina that human clinical trials of the vaccine are divided into three phases. The first is to understand the initial safety of the vaccine, phase 2 examines the safety of the vaccine in a larger sample and determines the optimal immune dose, and phase 3 applies the dose to large sample populations to assess its effectiveness.
The phase 1 clinical trial was rolled out between March 16 and March 27 in Wuhan, where the coronavirus outbreak started. The trial recruited 108 healthy adult participants aged between 18 and 60 years who were given either a low, medium or high dose of the vaccine. No serious adverse events were noted within 28 days post-vaccination. Neutralizing antibodies increased significantly at day 14 and peaked 28 days post-vaccination. Specific T-cell responses peaked at day 14 post-vaccination. T-cells are lymphocytes which participate in the immune response.
Xu Jianqing is the director of the Institute of New and Recurring Infectious Diseases of Shanghai Public Health Clinical Center and team leader for research and development of the institute’s Covid-19 vaccine. Xu said that the higher the neutralizing antibody titers are after the vaccination, the more effective the vaccine would be. A titer test measures the amount of antibodies present in the person or animal against the disease being vaccinated. A positive antibody response is defined as being at least a four-fold increase in post-vaccination titer from baseline.
On the 28th day, when the number of neutralizing antibodies peaked in the three dose groups of the Wuhan trial, only half of the subjects in the low and medium dose groups were able to achieve a four-fold increase in neutralizing antibodies, compared with 75 percent in the high dose group.
“The results of the vaccine trial aren’t very satisfactory,” said Tao Lina, a former immunologist at Shanghai’s Center for Disease Control and Prevention. “By the 28th day, we really need to see a 90 percent four-fold increase in neutralizing antibodies,” Tao said.
Despite some uncertainties, Chen’s team started phase 2 human trials in Wuhan on April 12. The second phase removed the age ceiling to enroll volunteers over 60, with the oldest being 84. It has expanded to involve 500 volunteers and introduced a placebo control group to further evaluate the immunogenicity and safety of the vaccine.
According to a source close to Chen’s team, preliminary results of the second phase trial were presented to the State Food and Drug Administration for review on May 16, and the results are expected to be published in June.
In the study, between 44 and 56 percent of volunteers had an immune response to adenoviruses - a group of viruses which cause many common infections - all of whom previously had high levels of antibodies when titer tested for adenoviruses. The numbers increased significantly after vaccination.
Zhu Fengcai, co-author of the paper published by Chen Wei’s team from the Center for Disease Control and Prevention of Jiangsu Province, told the reporter that the high level of adenovirus type-5 may have a negative impact on the persistence of vaccine-induced immune responses.
The root cause of the problem is related to the technical route of the vaccine: it was constructed using genetic engineering and carried by replicating defective human adenovirus type-5 as a vector, so as to express the Covid-19 S antigen. According to Xu, theoretically, about 80 percent of Chinese people are positive for type 5 adenoviruses, which means that when adenoviruses re-enter the body, adenoviruses attack the vector rather than the S protein it expresses, making the vaccine ineffective. This is often referred to as the carrier-blocking effect or a pre-existing immunity. This is why many of the vaccines using this technology have failed. One solution to the weakened immune response from adenoviruses is to adopt an immune-enhancing strategy, or strengthen the immune response in humans by injecting different types of vaccines. The first helps establish primary immunity and the second vaccine is used to re-energize the immune system. According to Chen’s team, previous studies have shown that this strategy can induce stronger and more enduring immune responses in populations with high pre-existing immunity. The Ebola vaccine is based on this method.