Early study of Covid-19 vaccine developed in China sees mixed results – STAT

A Covid-19 vaccine candidate being developed by a Chinese drug maker appeared to induce an immune response in subjects, but also showed some concerning although not unexpected results.

Data on the vaccine, made by CanSino Biologics, were published Friday in the Lancet, the first time Phase 1 trial data from any Covid-19 vaccine have been published in a scientific journal. The results are likely to be closely examined, particularly in Canada, which recently announced it would test the vaccine and produce it there if results of the early studies were positive.

The study found that one dose of the vaccine, tested at three different levels, appeared to induce a good immune response in some subjects. But about half of the volunteers — people who already had immunity to the backbone of the vaccine — had a dampened immune response.

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The vaccine is what’s known as a viral vector vaccine; it uses a live but weakened human cold virus, adenovirus 5, onto which genetic material of the SARS-CoV-2 coronavirus has been fused. The Ad5 virus is effectively a delivery system that teaches the immune system to recognize the coronavirus.

But many people have had previous infections with adenovirus 5, raising concerns that the immune system would focus on the Ad5 parts of the vaccine rather than the SARS-Cov-2 part. Many research groups that work on viral-vectored vaccines stopped using Ad5 because of concerns about preexisting immunity, which can run to 70% or higher in some populations.

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“This is definitely one of the concerns about using vectored vaccines for which people might already have pre-existing immunity,” said Michael Mina, an infectious diseases epidemiologist at Harvard’s T.H. Chan School of Public Health.

“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,” he said.

In the study, Chinese scientists reported that while people who had high levels of preexisting immunity to Ad5 responded to the vaccine, the rise in antibodies to the SARS-Cov-2 virus was less robust than among those in the study who had low or no preexisting antibodies to Ad5. They also showed antibodies to the adenovirus itself soared among people who had prior immunity, suggesting their systems views the vaccination as a boost of their Ad5 immunity.

About half of the 108 people in the Phase 1 trial had high levels of pre-existing antibodies to Ad5. The problem was more common among subjects at the older end of the age range, among 45 to 60 year olds — a finding that raises questions about how well the vaccine would work in one of the demographic groups that most needs protection from this infection, older adults.

“This probably wouldn’t be a vaccine that you would want to give to the people over 65, because they may have higher levels [of pre-existing immunity],” said Kathryn Edwards, scientific director of the Vanderbilt Vaccine Research Program in Nashville, Tenn.

Gary Kobinger, director of the Infectious Disease Research Center at Laval University in Quebec, was not surprised by the findings.

“This was the assumption and they are just demonstrating that the assumption was correct,” he told STAT, adding that he doesn’t expect this vaccine to succeed.

Kobinger said CanSino — which also produced an Ebola vaccine using this viral vector — has argued it could override the problem of preexisting immunity by using higher doses of the vaccine or using an intra-nasal delivery mechanism, rather than injecting the vaccine into muscle. (In this study, the vaccine was injected.)

But in the highest of the three doses used in this study, the number of side effects was high — 75% of the people in the highest dose arm reported at least one side effect. Side effects included fever — some higher than 101.3, which is considered a Grade 3 or serious side effect — pain at the injection site, headache, fatigue, among others. Ten volunteers had Grade 3 side effects, representing 9% of the overall study group, with 17% of the people in the arm receiving the highest dose of vaccine reporting Grade 3 reactions.

The authors said the Phase 2 trial, which is already underway, is not using the highest of the three doses.

The authors also reported that among subjects who had high preexisting levels of immunity to Ad5, only five (25%) participants in the low-dose group, seven (37%) participants in the middle-dose group, and 10 (63%) participants in the high-dose group had at least a fourfold increase in their levels of neutralizing antibody for the coronavirus 28 days after receiving the vaccine.

Edwards acknowledged the findings relating to pre-existing immunity are “a cause for caution.”

But she noted it is not yet clear what degree of an immunity response is needed to achieve protection against the virus that causes Covid-19 — and maybe the antibody levels reached in people who had preexisting immunity to Ad5 will be high enough, even if they aren’t at the levels of people who had low level or no previous immunity to the vaccine vector.

“This is the story of Ad5,” Edwards said. “It’s the concern with Ad5 that’s been there from the beginning: That if you have antibody to the vector, then you don’t get as good a [vaccine] take.”

“Maybe this level of antibody is enough? I don’t know,” she added. “I think it’s reasonable to look at this and see what it does. It’s only a Phase 1 study.”

The problem with pre-existing immunity is not the potential issue with the Ad5 vaccine vector.

In 2007 a trial of an HIV vaccine using an Ad5 backbone was halted when it was seen that more people in the vaccine arms of the trial were becoming infected with HIV than those in the placebo arm. It remains unclear why that happened.

The authors of the Phase 1 Covid-19 trial noted the earlier troubling outcome, and said they will be monitoring for similar safety signals as they continue to study this vaccine.

“Although the association between HIV-1 acquisition risk and Ad5-vectored vaccine is controversial and its mechanism is unclear, the potential risks should be taken into account in studies with this viral vector delivery platform,” they wrote. “We plan to monitor the participants in our upcoming phase 2 and phase 3 studies to assess the indication for any such acquisition.”

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