ViewPoints: CanSino sees some vector trouble in Phase I vaccine readout

Formalised clinical trial data have finally come down the pike for a COVID-19 vaccine candidate- albeit without necessarily engendering confidence that there will be a quick path forward to a broadly effective vaccine.

What happened

Phase I data from a COVID-19 vaccine candidate have finally made it through peer review, with researchers from CanSino Biologics publishing results from 108 patients treated with three separate doses of its Phase I candidate.

Neutralising antibodies against SARS-CoV-2 were successfully produced after 28 days in patients treated with all three doses. Antibody titres were highest with the highest dose; however, that dose was also associated with an adverse event profile that included grade 3 fever in 14% of patients, and severe muscle and joint pain that the authors said "might be associated with viremia caused by vector infection."

By day 28- when the authors said peak antibody levels were achieved- 75% of high dose patients saw a four-fold increase in neutralising antibody levels, compared to 50% at both the low and medium doses.

That dose responsiveness also carried over to T-cell activity, where both CD4 and CD8 T-cell responses were elicited in a dose-dependent-manner.

Importantly, the authors reported high levels of pre-existing immunity against their adenovirus-type 5 (Ad5) viral vector, which may have blunted immunogenicity. Across all three dosing cohorts, 51% of patients had high levels of Ad5-neutralising antibodies, defined as a titre greater than 1:200.

Seroconversion rates were also lower among older patients, although the authors noted the difficulty of drawing conclusions on account of the small number of older patients in the trial.

What matters most

CanSino is already underway on a Phase II trial of its candidate, having dropped the highest dose from its study design on account of the adverse event profile. The authors said they prioritised the readily-available safety data, rather longer-term immunogenicity results in order to accelerate development timelines. However, analysts were sceptical that the chosen Phase II doses will fare well in the trial, given the blunted immune responses in the face of pre-existing immunity to the company's Ad5 vector.

Patients with high levels of pre-existing Ad5 antibodies were less likely to achieve benchmarks of neutralising antibody production; even at the highest dose, 37% of patients with pre-existing anti-Ad5 failed to generate significant amounts of neutralising antibody. In the doses advanced to Phase II, up to 75% of patients with pre-existing antibodies failed to hit the benchmark, raising questions about the vaccine's utility in broad populations. Those concerns are compounded by the lower rates of seroconversion in older patients, who are in the greatest need of an effective vaccine.

While the authors acknowledge limitations around pre-existing antibodies, they emphasise that sustained T-cell responses could be the more important factor in real-world usage. While the study did not measure T-cell activity beyond day 28, they write that recovery from SARS and MERS was associated with transient antibody activity, but sustained T-cell responses.

Outside of the high baseline levels of pre-existing immunity, the company's Ad5 vector also carries a theoretical risk of HIV infection. The authors say that "while 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."

The bigger picture

The data from CanSino represent the first peer-reviewed synopsis of COVID-19 vaccine data; disclosures last week from Moderna, Inovio, and the University of Oxford prompted mixed reviews from analysts as they worked to dissect often incomplete disclosures, making the depth of detail available from CanSino a welcome change- even if there are limitations around its viral vector. (See ViewPoints: After Moderna vaccine reveal, attention shifts to Oxford and Sinovac)

 While animal data released last week from Oxford comes with its own caveats, it could have one advantage relative to CanSino upon release of its Phase I data. Oxford's vector uses a chimp-derived non-replicating adenoviral vector- which could negate much of the risk of pre-existing immunity in the programme. That same advantage should also be enjoyed by the DNA and mRNA vaccines at Moderna and Inovio, although the oligonucleotides products come with their own immunogenicity risks.

To read more ViewPoints articles, click here.