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SHOTS OF HOPE

The worldwide race for a Covid-19 vaccine has yielded initial results, yet the effectiveness of these vaccines is still unknown

By NewsChina Updated Aug.1

The 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. 

An employee at Sinopharm holds a sample of an inactivated Covid-19 vaccine, April 10, 2020

International Candidates
Among the top candidates in the global vaccine race, another adenovirus vaccine is the Oxford University/AstraZeneca Covid-19 vaccine ChAdOx1 nCoV-19. So far it has finished phase 1 trials and the project has begun phase 2 and 3 human trials. It aims to enroll up to 10,260 adults and children by the end of June. 

Internationally, in addition to Moderna Therapeutics’ mRNA vaccine in the US, there is the DNA vaccine INO-4800 from Inovio Pharmaceuticals in the US, which is also in the second phase of clinical trials. On April 23, an mRNA vaccine developed by the German company BioNTech and US pharmaceutical company Pfizer also started clinical trials. US biotech firm Novavax US started human clinical trials of a Covid-19 vaccine candidate called NVX-CoV2373 using the company’s nanoparticle technology in May, although the US government has not listed it as among the five most promising vaccine candidates, media reported. 

The five internationally recognized designations for a Covid-19 vaccine are a nucleic acid vaccine (including mRNA vaccine, DNA vaccine), a recombinant genetic engineering (protein recombination) vaccine, an inactivated vaccine, an attenuated influenza virus vector vaccine and an adenovirus vector vaccine. Nucleic acid vaccines, especially the mRNA vaccine technology, are most favored by researchers and investors. Three of the five vaccines in clinical trials abroad are mRNA vaccines, but none of the mRNA domestic vaccine candidates have entered this stage. 

Multiple Options
The Oxford University vaccine and Chen Wei’s vaccine from China are the two leading vaccines that use adenovirus vector technology.  

There are four other vaccines in China that have been through clinical trials, all inactivated vaccines developed by four different institutions or companies including the Wuhan Institute of Biological Products under the China National Pharmaceutical Group (Sinopharm) and Sinovac Research and Development Co. Ltd, a company based in Beijing and the Chinese Academy of Medical Sciences. The five vaccines are expected to complete their phase 2 clinical trials in July. Inactivated vaccines use particles of a virus or bacteria grown in a culture not able to produce disease, but the immune response produced is not as strong as a live vaccine.  

Unlike foreign vaccine developers, which tend to adopt new vaccine technologies, the rest of the domestic vaccines which are in clinical trials are based on traditional inactivated vaccine technologies. According to the results of Sinovac’s vaccine in animal trials, Xu Jianqing said the results of the activated antibody data in primates were good, but the vaccine used the entire inactivated Covid-19 virus to stimulate the human immune system. This makes the activated antibody type very broad, including a large number of non-neutralizing antibodies which would not act against disease. The subsequent safety of the vaccine needs to be tested in clinical trials. 

Addressing the varied effects of different types of vaccines, Professor of Pathology and Laboratory Medicine David O’Connor of the University of Wisconsin-Madison told NewsChina that “Both new and conventional approaches can and should be tested at the same time - there is no need to pick one over the other.”  

The titer level of neutralizing antibodies required for protection against Covid-19 is not known. If two vaccines exceed this threshold by a large margin, it does not necessarily matter which one has the greatest titer, O’Connor said. Other considerations such as ease of production, cost, lack of side effects and frequency of delivery might be more important if two vaccines are equally effective. This is why multiple candidates are moving forward simultaneously. “The best-case scenario would be many vaccines that are protective, with the option to choose the one that will most easily scale to millions or billions of doses. If multiple vaccine approaches work, they might also be used in conjunction to get more people vaccinated quicker, since no vaccine will be produced at the scale necessary to protect everyone globally immediately.” 

Although no vaccine in this global race has yet to go through phase 3 trials, domestically, the Covid-19 pandemic has been contained. This is now posing a difficulty in domestic vaccine development. One option is virus challenge testing, which means the use of viruses to attack vaccinated subjects to understand how the vaccine can produce an immune response protection. 

Xu said that the US and Europe allow virus challenge testing in vaccine trials, while China does not. After the outbreak of Covid-19, Europe and the US have discussed whether to allow human virus challenge tests. It is believed that if the vaccine is administered to young adults, if it fails to protect against the coronavirus, its pathogenicity, or ability to produce disease, is controllable. 

“We should consider allowing such challenge tests in a specific population so as to really accelerate the speed of the vaccine research process and better judge the effectiveness of the vaccine in the near future,” Xu said.

A lab technician injects a volunteer during phase 2 clinical trials for a Covid-19 vaccine in Wuhan, April 15, 2020. More than 200 people volunteered in the trial

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