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What Moderna’s COVID-19 vaccine data does not say about protection

Parlays Phase I data for mRNA-1273 into $1.3 billion follow-on

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While Moderna’s interim Phase I data showing its COVID-19 vaccine successfully induced neutralizing antibodies against SARS-CoV-2 in humans are encouraging, they are difficult to interpret without disclosure of the titers.

Moreover, until it is clear how different titers translate to levels of protection, it is hard to get an early read on whether and how much any vaccine is effective.

The company also previewed mouse efficacy data backing mRNA-1273, a spike-encoding mRNA vaccine, but again, it did not provide detailed data from the mice regarding the titers of vaccine-induced antibodies.

Moderna Inc. (NASDAQ:MRNA) rose $13.31 (20%) to $80 on the news, a $4.9 billion gain in market cap. The company then raised $1.3 billion in a follow-on after-market close, hours after proposing the offering. It plans to use the cash infusion to fund manufacturing and global distribution of mRNA-1273. Morgan Stanley was the sole underwriter.

Human titers

All 45 volunteers, ages 18-55, generated antibodies against SARS-CoV-2 within 15 days of one immunization. The volunteers received either 25, 100 or 250 μg doses of mRNA-1273 and the immunogenicity was dose-dependent.

NIH’s National Institute of Allergy and Infectious Diseases (NIAID) is running the Phase I study.

While the company didn’t reveal titer numbers, volunteers who had received both prime and boost immunizations with the lowest dose had antibody titers at or above the median titer of convalescent sera samples, said CMO Tal Zaks on a conference call Monday.

Two vaccinations with the medium dose of 100 μg led to titers significantly higher than convalescent sera antibody levels.

Zaks said a similar result was seen for neutralizing antibodies. All eight evaluable volunteers -- four each from the lower dose cohorts -- generated neutralizing antibody titers at or above those generally detected in convalescent sera.

“In general, neutralization correlates with total binding antibodies once you’re above a certain threshold,” and that the neutralizing activity from the eight participants enables extrapolation of activity to the remaining vaccine recipients, said Zaks on the call.

The data are encouraging, but whether they will translate to protection cannot be surmised.

Two of the most pressing open questions about COVID-19 are how much neutralizing activity is needed to prevent infection, and what the thresholds are for achieving different levels of protection (see “Connecting COVID-19 Antibody Responses to Disease Protection”).

According to Zaks, “Just being at convalescent sera could be enough,” because confirmed cases of COVID-19 following recovery from an initial infection haven’t been reported.

However, antibody titers in convalescent plasma are variable.

People who have recovered from more severe infections typically have higher antibody titers than those who had milder disease.

“We desperately need to know what happens with asymptomatic, mild, moderate, severe disease; and then do people get reinfected or not in those classes?” Vanderbilt Vaccine Center Director James Crowe told BioCentury.

Breaking down the COVID-19 convalescent sera titers by disease severity may give a stronger indication of the titers that will prevent infections.

Alongside the interim Phase I readout, Moderna said its NIAID and academic partners generated mouse data showing mRNA-1273 prevented SARS-CoV-2 replication in the lungs, and that neutralizing antibodies were protective at titers consistent with the Phase I titers in the low and medium dose cohorts.

The preclinical data, combined with the Phase I immunogenicity, are the beginning of a suggestion that mRNA-1273 may prevent COVID-19.

The caveat of the mouse study was that it used a version of SARS-CoV-2 engineered to bind the mouse version of virus’ receptor angiotensin-converting enzyme 2 (ACE2).

Balancing immunogenicity with safety

mRNA-1273 was generally well tolerated and led to no grade 4 or worse adverse events.

The 100 μg dose led to one case of transient grade 3 erythema around the injection site; three volunteers who received the 250 μg dose developed self-resolving grade 3 systemic symptoms after the boost. On Monday’s conference call, Zaks described the systemic symptoms as flu-like and said he believes they are an “indirect measure of a strong immune responses.”

Based on the data, NIAID has amended the Phase I study to add a 50 μg dose cohort; and Moderna has amended its Phase II trial design to evaluate 50 and 100 μg doses. For the Phase III trial slated to begin in July, the company expects the dose to be between 25 and 100 μg.

The company has been taking steps to ramp up production of the vaccine. On May 2, it supplemented its own capabilities, partnering with Lonza Group Ltd. (SIX:LONN) to boost manufacturing capacity 10-fold (see “Lonza to Manufacture Moderna COVID-19 Vaccine”).

Editor’s note: This story was updated to reflect Moderna pricing its follow-on.

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