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Two-dose schedule, infection levels may shift timelines for AZ-Oxford vaccine

Readouts from AZ-Oxford, BioNTech-Pfizer, CanSino raise expectations for virus-specific T cell responses

AstraZeneca and Oxford will likely move forward with a two-dose schedule for their adenoviral vaccine following an anticipated Phase I/II readout, a decision that could shift timelines, availability and tolerability of one of the COVID-19 vaccine front-runners.

Data from the University of Oxford’s Phase I/II trial of AZD1222 (formerly ChAdOx1 nCoV-19) showed the vaccine triggered both neutralizing antibodies and T cell responses against the virus’ spike protein when given as a one- or two-dose regimen, but a higher percentage of volunteers had antibody responses in the two-dose cohort.

The data were published in a Lancet paper on Monday.

The ability to trigger a humoral and cellular immune response is important at this stage because it isn’t yet clear which will correlate with protection against infection.

The AstraZeneca plc (LSE:AZN; NYSE:AZN) vaccine is one of three clinical candidates to report data on virus-specific T cell responses on Monday.

Partners BioNTech SE (NASDAQ:BNTX) and Pfizer Inc. (NYSE:PFE) also reported neutralizing antibody and T cell responses to a two-dose regimen of their mRNA vaccine BNT162b1 in a Phase I/II trial; and Chinese drugmaker CanSino Biologics Inc. (HKEX:6185) shared neutralizing antibody data for a single dose of its adenoviral data across different age groups, making it the first to report immunogenicity data in the over 55 population.

The five most advanced COVID-19 vaccines have generated neutralizing antibody levels comparable to those found in convalescent plasma donors and four have reported some level of T cell activity; however, variability across assays and even intra-assay variability between labs makes direct comparison difficult.

The collection of new data comes days after Moderna Inc. (NASDAQ:MRNA) released data on its mRNA vaccine. While the company said a CD4+ T cell response against the virus occurred, CD8+ T cell responses were low (see “Moderna, NIH Pick Phase III COVID-19 Vaccine Dose”).

Moderna shares were off $12.17 (13%) to $82.68 on Monday, likely reflecting the importance of triggering both types of immune responses at this stage of development. That said, the stock has been trading near its all-time high.

Share prices of other biotechs developing COVID-19 vaccines also responded to Monday’s data. Heat Biologics Inc. (NASDAQ:HTBX) gained 47% to $3.62; iBio Inc. (NYSE:IBIO) gained 64% to $6.41; and Tonix Pharmaceuticals Holding Corp. (NASDAQ:TNXP) rose 91% to $1.55. BioNTech gained 3% on its announcement and CanSino was up 2%.

AstraZeneca’s development plan

A single dose of the vaccine was the focus of the Oxford study, but data in a small percentage of volunteers enrolled in the trial point to a stronger immune response when two high doses are given 28 days apart.

The Phase I/II trial enrolled 1,077 healthy volunteers, including 10 who received two doses of the vaccine in an unblinded arm. The rest were randomized to receive a single 5x1010 dose of AZD1222 or a meningococcal conjugate vaccine active control.

Immunogenicity data were available from 35 volunteers in the single-dose treatment arm, and neutralizing antibodies were detected in 32 (91%) using a microneutralization assay (MNA).

The same assay detected neutralizing antibodies in 100% of patients (9/9) in the prime-boost arm.

The vaccine also induced a T cell response in 100% of participants, which peaked around day 14 and wasn’t highly affected by the boost dose.

Given the uncertainty around the types and levels of immune responses that correlate with protection from the virus, AstraZeneca EVP of BioPharmaceuticals R&D Menelas Pangalos said during a webinar on Monday that the company will likely go forward with the prime-boost regimen for its late-stage trials, even though that will further constrain availability if authorized.

“We are veering towards a two high doses strategy,” he said. “We want to maximize our chances of an efficacious readout. The last thing we want to do is to miss because we haven’t dosed enough.”

Pangalos added that the safest path is to conduct two-dose studies and then explore single doses and lower doses once a positive readout has been achieved.

AstraZeneca has a trio of late-stage trials under way in the U.K., Brazil and South Africa. It’s also planning to start a Phase III trial in the U.S. this summer, which would bring the total number of immunized volunteers to about 50,000 this year.

The company was aiming for late-stage efficacy data by September, but CEO Pascal Soriot said declining infection rates could delay trial outcomes. He’s now looking for a readout between September and November.

Requiring a second dose 28 days after the first could also push out timelines.

And while tolerability of a second dose has been higher for mRNA vaccines, tolerability seemed to go down for the second dose of AZD1222, though there was a very small number of individuals in the two-dose arm.

A two-dose regimen will also exacerbate the distribution bottleneck that will occur when any COVID-19 vaccine is approved.

AstraZeneca has committed to supply more than two billion doses of AZD1222 at no profit during the pandemic and is manufacturing at risk in parallel with clinical development. The company’s latest manufacturing deal, an agreement with Russia’s R-Pharm CJSC to produce and distribute the vaccine, was disclosed Friday.

If two high doses are needed for each patient, supply won’t stretch as far.

Pangalos said the purely cold chain supply of AZD1222 should be a distribution advantage over mRNA vaccines that require frozen chain. Multiple vaccines will need to be authorized to meet global demand, he added.

Pfizer, BioNTech data

Pfizer and BioNTech added to a growing body of clinical data for BNT162b1 on Monday. In a preprint medRxiv paper, the companies showed the candidate induced virus-specific T cell responses in addition to the strong antibody responses previously reported.

In a German Phase I/II trial evaluating four doses between one and 50 µg of the lipid nanoparticle encapsulated mRNA vaccine, 34 of 36 (94%) participants mounted a CD4+ T cell response specific for SARS-CoV-2 spike protein receptor binding domain seven days after the boost dose.

The vaccine induced CD8+ T cell responses in 80.6% (29) of the patients.

Geometric mean titers of SARS-CoV-2 neutralizing antibodies were 158 and 308 for the 10 and 30 μg doses seven days after boost. They reached 578 for the 50 μg dose.

Last week, the partners released data from a U.S. Phase I/II data from a separate trial showing the mRNA vaccine generated comparable neutralizing antibody levels at the 10 and 30 µg doses (see “BioNTech, Pfizer Vaccine Yields Highest Antibody Titers to Date”).

Triggering immunogenicity in older patients

The Phase II readout from CanSino’s adenovirus vaccine gives an early indication of how effective vaccines may be in older adults, but raises questions about the vector.

The Wuhan-based trial enrolled 508 participants between the ages of 18 and 83, and although the neutralizing antibody levels were lower than those generated by other vaccines in human trials, about 59% and 47% of participants in the high and low dose cohorts mounted a neutralizing antibody response to the live virus. Data were published in a Lancet paper.

Mean antibody titers were lower in patients over 55 and in participants with pre-existing immunity to the adenoviral vector, which was about half of all vaccinated volunteers.

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