Hot on the heels of biotech company Moderna’s recent announcement of successful phase 1 trials for its mRNA COVID-19 vaccine, two more promising candidates are delivering encouraging early data as several vaccines race into phase 2 human testing.
A new article in The Lancet is presenting the first peer-reviewed and published data from any phase 1 human trial testing a COVID-19 vaccine. The vaccine is called Ad5-nCoV, and is being developed by Chinese drug-maker CanSino Biologics.
Phase 1 vaccine trials are designed to primarily investigate safety in healthy human subjects. Efficacy is tracked by examining how well the vaccine stimulates the body’s immune response, as measured by watching levels of T-cells and neutralizing antibodies.
“The trial demonstrates that a single dose of the new adenovirus type 5 vectored COVID-19 (Ad5-nCoV) vaccine produces virus-specific antibodies and T cells in 14 days, making it a potential candidate for further investigation,” says Wei Chen from the Beijing Institute of Biotechnology.
The data presented is encouraging, but there are several concerning warning signs that hurdles may lie ahead. Three dose levels were tested in the trial and the majority of all subjects in the trial encountered some level of mild to moderate adverse side effects. These included fever, headache and fatigue.
Perhaps the biggest issue that Ad5-nCoV may face in broader phase 2 trials is the inconsistency seen in its ability to generate an effective antibody and T-cell immune response. The vaccine utilizes a weakened common cold virus, called adenovirus type 5 (Ad5), to deliver genetic material that ultimately trains the immune system to fend off the SARS-CoV-2 virus. The problem seen in this early data is that subjects with high levels of pre-existing immunity to Ad5 seemed to show significantly reduced antibody and T-cell responses to the vaccine.
“Our study found that pre-existing Ad5 immunity could slow down the rapid immune responses to SARS-CoV-2 and also lower the peaking level of the responses,” says Feng-Cai Zhu, from Jiangsu Provincial Center for Disease Control and Prevention in China. “Moreover, high pre-existing Ad5 immunity may also have a negative impact on the persistence of the vaccine-elicited immune responses.”
This inconsistency in immune system response may suggest the Ad5-nCoV vaccine could be less effective in older subjects, as they potentially have higher levels of pre-existing immunity to this common adenovirus. Speaking to STATNews, Michael Mina from Harvard’s T.H. Chan School of Public Health, says this is a common problem with vaccines using this kind of adenovirus delivery system.
“If you already have seen a virus or have some pre-existing immunity to it … you run the risk of having your immune response get skewed and picking up primarily the thing you’re already immune to or that you’ve already seen and not focusing so much on the new aspect, which in this case would be the coronavirus proteins that were placed onto the adenovirus vector,” says Mina.
Another vaccine progressing to more advanced clinical trials is called ChAdOx1 nCoV-19, which is being developed by scientists at Oxford University. This vaccine is moving through a compressed, and somewhat unconventional, trial timeline having already dosed over 1,000 subjects as part of its first safety phase testing. Phase 2 of the Oxford trial will recruit 10,000 more subjects, spanning older and younger demographics, to assess safety and immune responses across a broad subset of the population.
No data from human testing of the Oxford vaccine has been published yet, however, a pre-print study was recently revealed outlining successful results from initial animal studies. The Oxford vaccine also uses a common cold virus as its primary delivery system, albeit a different adenovirus to the Ad5-nCoV vaccine being developed in China.
“The clinical studies are progressing very well and we are now initiating studies to evaluate how well the vaccine induces immune responses in older adults, and to test whether it can provide protection in the wider population,” says head of the Oxford Vaccine Group, Andrew Pollard. “We are very grateful to the huge support of the trial volunteers in helping test whether this new vaccine could protect humans against the pandemic coronavirus.”
The next stage of testing for the Oxford vaccine relies on COVID-19 continuing to spread through the local community at rates high enough to ascertain efficacy. The scientists are not planning to deliberately infect volunteers with the virus to test the vaccine, so instead, they require relatively high rates of the virus to be spreading through the community to evaluate success.
Adrian Hill, also from the Oxford Vaccine Group, suggests the strange irony the researchers currently face is that decreasing levels of community transmission could significantly slow progress in testing the vaccine.
“It’s a race against the virus disappearing, and against time,” Hill recently said. “We said earlier in the year that there was an 80% chance of developing an effective vaccine by September. But at the moment, there’s a 50% chance that we get no result at all. We’re in the bizarre position of wanting COVID to stay, at least for a little while.”
These two COVID-19 vaccines, along with Moderna’s, may be the most advanced in development at this point, but there are at least seven other vaccines in active early stages of human testing, and over 100 vaccines in preclinical stages of development.
The new Ad5-nCoV phase 1 data was published in the journal The Lancet.
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