LONDON – There were encouraging results from trials of three COVID-19 vaccines on July 20, with Astrazeneca plc, Biontech SE/Pfizer Inc. and Cansino Biologics Inc. all reporting T-cell responses in ongoing phase I/II studies of their respective products.

The trial of the Astrazeneca adenoviral vector vaccine, AZD-1222, run by Oxford University, showed it was well-tolerated and generated robust immune responses against the SARS-CoV-2 virus in all 1,077 healthy adult participants, ages 18 to 55.

The results published in The Lancet confirmed a single dose of AZD-1222 resulted in a fourfold increase in antibodies to the SARS-CoV-2 virus spike protein in 95% of participants one month after injection.

By 28 days after vaccination, neutralizing antibody responses against SARS-CoV-2 were detected in 32 of 35 participants using one assay, and in 35 of 35 participants when measured by another assay. Antibody responses remained high until day 56.

There was an increased level of antibodies in 10 subjects who received a second dose of the vaccine, indicating people do not develop immunity to the chimpanzee adenoviral vector.

T-cell responses targeting the SARS-CoV-2 spike protein also were markedly increased, peaking 14 days after vaccination, compared to placebo. The level had declined slightly by day 56 of the trial.

The T-cell response did not increase in 10 subjects who had a second dose of the vaccine, which the researchers at Oxford University say is consistent with other vaccines of this kind.

In the 508-subject phase II trial of Cansino’s vaccine, which also uses an adenoviral vector – in this case a common cold virus – 95% of participants in the high-dose group and 91% in the low-dose group showed antibody responses at 28 days post immunization.

Meanwhile, there were T-cell responses in 90% of the high-dose group and 88% of those getting the low dose, according to the details of the trial, also published in The Lancet.

There were no serious adverse reactions.

There is some evidence that the efficacy of the Cansino vaccine is compromised by being based on a common cold virus to which people have been pre-exposed. Those with a higher pre-existing immunity showed an inferior immune response to the vaccine.

Compared to the younger population, older volunteers generally had significantly lower immune responses.

Investigator Wei Chen, of the Beijing Institute of Biotechnology, said, “It is possible that an additional dose may be needed to induce a stronger immune response in the elderly population.”

The researchers said none of the subjects subsequently have been exposed to SARS-CoV-2, so there is no indication of possible efficacy. Phase III studies are now underway.

Commenting on the two papers in The Lancet, Daniel Altmann, professor of immunology at Imperial College London, said, “If the starting premise is that effective vaccines need to be able to safely induce decent levels of neutralizing antibodies, blocking virus entry, and to induce a good frequency of antiviral T cells, each of these studies show that these goals are achievable.”

Biontech published data from the German arm of the phase I/II study of its mRNA vaccine, BNT-162b1, as a preprint on Biorxiv, reporting for the first time that the product elicited strong CD4 and CD8 T-cell responses. The data indicate “a strong potential for cell-mediated antiviral activity,” with the cytokine profile showing a TH1 phenotype, which is associated with antiviral properties, the company said.

There was no dose dependence of the T-cell response across four doses, indicating that stimulation and robust expansion of T cells might be accomplished at a low-level mRNA dose.

That follows on from data from the U.S. arm of the phase I/II trial, reported on July 1, showing BNT-162b1 induced a strong antibody response.

“The preliminary data indicate that our mRNA-based vaccine was able to stimulate antibodies as well as a T-cell response, at remarkably low dose levels. We believe both may play an important role in achieving effective clearance of a pathogen such as SARS-CoV-2,” said Ozlem Tureci, chief medical officer and co-founder of Biontech.

Pfizer and Biontech are now determining the dose level for a phase IIb/III trial in up to 30,000 participants, that is expected to begin later this month.

Correlates of protection

That all three vaccines can induce antibody and T-cell responses is acknowledged as a step forward. But Adrian Hill, director of the Jenner Institute at Oxford University, and his colleague developing AZD-1222, emphasized how far there is to go.

In particular, while it is good to see strong immune responses, no one has much idea what a protective response looks like.

In a briefing held to discuss the AZD-1222 results, Hill made a call for vaccines developers to collaborate in trying to establish correlates of protection, suggesting that immune assays should be standardized and run at a single laboratory, so vaccines can be compared head-to-head.

That would remove lab-to-lab variation and make it possible to compare the qualities of different products. “It is hard to compare because there are no standardized assays,” Hill said.

Such comparisons “seldom happen in real vaccines” because by the time they reach phase III, a single company is working on them. “Here, I would argue, there should be comparisons,” Hill said.

The Gates Foundation and the Coalition for Epidemic Preparedness Innovation are funding work on assays. But, said Andrew Pollard, chief investigator in the AZD-1222 trial, “It’s still very early and it’s a lot of hard work to get quality assays set up.”

Pollard said it also is unclear as yet how many people in the placebo arms of phase III field trials will need to get infected by SARS-CoV-2 to provide the evidence that any particular vaccine is effective. “The number that is required is something that is being debated by international regulators,” he said.

No Comments