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Moderna vaccine first to produce sterilizing immunity in model system -- though only in mice

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The first detailed data from Moderna’s COVID-19 vaccine show mRNA-1273 induces neutralizing antibody titers in range of those from other leading candidates, at least in mice, and hint at sterilizing immunity.

Despite the major caveat of the model system, and the difficulty of understanding how the dosing relates to Moderna’s clinical trials, the data provide the first suggestion that a COVID-19 vaccine could be potent enough to shut down SARS-CoV-2 replication.

None of the five other companies that have presented mouse data from COVID-19 vaccines reported virus challenge studies.

And while three companies have published challenge studies in non-human primates, all of them failed to demonstrate sterilizing immunity. Each of the three vaccines did demonstrate some level of efficacy, however. The vaccines were CoronaVac from Sinovac Biotech Ltd. (NASDAQ:SVA), BBIBP-CorV from China National Pharmaceutical Group Corp. (Sinopharm), and AZD1222 AstraZeneca plc (LSE:AZN; NYSE:AZN) (see “Making Sense of the Deluge of Early COVID-19 Vaccine Data”).

The mouse data from Moderna Inc. (NASDAQ:MRNA) add another line of evidence to suggest that mRNA-1273 could be protective. In May, the company reported interim Phase I data showing the mRNA vaccine induced neutralizing antibodies, a prerequisite for immunity. But because titers were not disclosed, it was impossible to make an early prediction about how protective mRNA-1273 might be (see “What Moderna’s COVID-19 Vaccine Data Does Not Say About Protection”).

In a preprint posted Thursday on bioRxiv, the NIH Vaccine Research Center and Moderna-led team showed that mRNA-1273 was not only immunogenic in mice but that both double and single immunizations were protective.

Mice challenged with mouse-adapted SARS-CoV-2 at 5-13 weeks after single or double doses of 1 μg mRNA-1273 were “completely protected from viral replication in the lungs.” A single vaccination with a 10 μg dose also led to undetectable viral replication in the lungs.

In all but one of the mice immunized twice with 1 μg, viral replication was undetectable in nasal samples.

Mean neutralizing titers after prime-boost administration of the 1 μg dose ranged from 89 to 1,115 depending on the mouse strain, and appeared to increase about 10-fold over 1,115 with the 10 μg dose. Neutralizing antibody levels following single vaccinations with the 10 μg dose reached an average of 315.

Moderna’s neutralizing titers fit within the range of other vaccine candidates with mouse data. At the low end, a single AZD1222 vaccination led to titers of about 40-80; near the top, CoronaVac induced titers of about 3,000.

On safety, immunization with mRNA-1273 led to a balanced Th1/Th2 immune response that included a Th1-dominant CD4+ T cell responses, as well as CD8+ T cell responses against the spike. The result suggests low risk of vaccine-associated enhanced respiratory disease, which has been associated with Th2-biased responses in children immunized with RSV and flu whole inactivated virus vaccines.

Additionally, mice challenged with the virus after vaccination with 0.1 or 0.01 μg doses -- doses that reduced but didn’t completely prevent viral replication in the lungs, leaving the door open to vaccine-mediated disease enhancement -- had no evidence of lung pathology or excessive mucus production.

Moderna is testing 50 and 100 μg doses of mRNA-1273 in Phase II, and plans to assess the higher dose in a Phase III trial slated to begin in July.

Based on the Phase III dose, the company projected it can produce “approximately 500 million doses per year, and possibly up to 1 billion doses per year.” The previous projection of 1 billion or more doses per year was based on a 50 μg dose (see “Lonza to Manufacture Moderna COVID-19 Vaccine”; “Moderna COVID-19 Vaccine Phase III Will Be Conducted in NIH-managed Trial Network”).

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