LONDON – Biontech SE announced positive preliminary data from the ongoing phase I/II trial of one of the four COVID-19 vaccines it is developing with Pfizer Inc., with participants in each of three dose groups mounting immune responses that were greater than seen in patients who recovered from COVID-19 infections.

The two companies said they are on track to begin a phase IIb/III study involving up to 30,000 healthy volunteers before the end of July, and if successful, expect to manufacture 100 million doses by the end of 2020 and potentially more than 1.2 billion doses by the end of 2021.

The four vaccine candidates being evaluated each have a different combination of messenger RNA (mRNA) format and target antigen, with the preliminary data released on July 1 relating to BNT-162b1, which encodes a SARS-CoV-2 receptor binding domain (RBD) antigen.

Taken overall, the results from the 45-subject U.S. arm of the trial demonstrate BNT-162b1 was well-tolerated and generated dose-dependent immunogenicity, as measured by both SARS-CoV-2 neutralizing antibodies and RBD immunoglobulin G (IgG) concentration.

Ugur Sahin, CEO, Biontech

The data are positive, but the study at the moment “has several limitations,” said Ugur Sahin, CEO and co-founder of Mainz, Germany-based Biontech.

A key unknown is the correlates of protection that will render a vaccinated person immune to SARS-CoV-2. “We have high neutralizing antibody titers, but we don’t know if there will be protection,” Sahin told attendees of a teleconference held to discuss the data.

Immunogenicity was assessed by referencing a panel of sera from 38 recovered COVID-19 patients. Sahin said that included patients with more and less severe infections, and compared to published studies seems to represent the spectrum of disease. “We believe the collection of sera is a good representation of the disease course of COVID-19 patients, including those that do not require hospitalization,” he said.

In addition, there is no information as yet on T-cell responses. Sahin said those are being assessed in the German arm of the trial and will be published within the next few weeks.

In 12 subjects who received two 10-mg doses of BNT-162b1 administered three weeks apart, neutralizing antibody titers increased 1.8-fold compared to recovered patients.

Meanwhile, in 12 subjects who received two 30-mg doses, titers were 2.8-fold higher than in the convalescent sera.

Levels of RBD-binding IgG antibodies were eight times higher in the 10-mg group and 46.3 times higher in the 30-mg group, than in convalescent sera.

There was a strong booster effect, with the highest levels of neutralizing titers seen seven days after the second injection, at both doses.

Sahin said that reflects what he sees as a significant advantage of lipid nanoparticle-delivered mRNA vaccines, compared to adenoviral vector vaccines delivering the genetic code for the same antigens.

While adenovirus vaccines generate higher antibody titers from the first dose, there is an immune response against the vector, limiting the additional response to a second dose.

The lipid nanoparticle vectors are not immunogenic, as demonstrated by the response to the second dose, Sahin said. “I’m pleased to see the boost in the immune response after the second injection.”

Sahin said that “ideally” people should have high antibody titers over a longer time than the 28 days in this interim assessment. “We will follow up for the next six months,” he said. Other immune biomarkers will be assessed over the next two years.

Twelve volunteers received a single 100-mg injection of BNT-162b1. They showed more marked systemic reactions, experiencing fever, and also more marked local reactions at the injection site.

Given those reactions, and the fact there were no significant increases in immunogenicity compared to 2 x 30 mg dosing, the 12 participants in the 100-mg group were not given a second dose.

In the other two cohorts, 8.3% of the participants in the 10-mg group and 75% of those in the 30-mg group developed transient fevers, but those all resolved by day 28.

It is “encouraging” to see that BNT-162b1 is able to produce neutralizing antibody responses at or above the levels of convalescent sera, “and that it does so at relatively low doses,” said Sahin.

Sahin previously has said it is possible that two, or even three, of the four vaccine candidates could be taken forward, if the results are positive. The two companies said they are awaiting further data from the 500-subject phase I/IIa before picking the lead candidate and selecting the dose.

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