Invivyd's VYD2311 beats mRNA vaccine on safety in Phase 3 LIBERTY study
Invivyd has reported positive topline data from LIBERTY, its Phase 3 active-controlled trial comparing VYD2311, its investigational COVID-19 monoclonal antibody, to an approved mRNA vaccine. The New Haven-based company said VYD2311 met every primary and secondary endpoint, with statistically superior safety and tolerability versus COMIRNATY across both a six-day and a 56-day observation window.
The results are being positioned by Invivyd as the foundation for a Biologics License Application (BLA) submission to the US Food and Drug Administration under the Accelerated Approval Programme, contingent on supportive data from the companion DECLARATION pivotal study, which are now expected in October.
What the data show
LIBERTY enrolled 210 healthy adults aged 18 to 49, randomised equally across three arms: VYD2311 alone (250 mg intramuscular), COMIRNATY alone, and the two given in combination. Over the first six days, 56.5% of the VYD2311 monotherapy arm experienced any treatment-emergent adverse event, injection site reaction, or hypersensitivity event, compared with 91.4% in the mRNA vaccine arm (p less than 0.0001). Systemic adverse events over the same period occurred in 44.1% of VYD2311 patients versus 68.1% in the COMIRNATY arm (p = 0.008). No adverse events related to VYD2311 exceeded Grade 2, and no hypersensitivity or anaphylaxis was recorded in any arm.
The combination arm showed a numerically lower adverse-event rate than COMIRNATY alone at six days, though the 56-day result for the combination did not reach statistical significance. Invivyd separately reported that VYD2311 co-administration boosted vaccine-induced neutralising titres approximately 2.5-fold over 56 days, and that removing VYD2311 from combination samples returned titres to the level seen with mRNA vaccine alone, confirming no immunological interference.
"Today's LIBERTY data alone, even before DECLARATION data, provide more robust contemporary human clinical information than the data associated with recently approved updated COVID-19 vaccines," said Michael Mina, Chief Medical Officer and Chief Epidemiologist of Invivyd.
Regulatory path and competitive context
Invivyd intends to file a BLA using LIBERTY and DECLARATION data, and is drawing an explicit parallel to the evidentiary standard applied to annually updated COVID vaccines, which are authorised on immunogenicity rather than fresh efficacy trials. That argument carries some regulatory logic given FDA precedent, but will face scrutiny: neutralising titres as a surrogate for clinical protection in a broad population remain contested, and the Accelerated Approval route requires post-approval confirmatory evidence of efficacy. Invivyd plans to continue accumulating PCR-confirmed symptomatic COVID-19 events in a blinded post-approval cohort targeting a 70% to 90% relative risk reduction versus placebo.
The monoclonal antibody space for COVID-19 prophylaxis has contracted sharply since the peak of the pandemic. Several authorised products, including AstraZeneca's Evusheld, were withdrawn as variants eroded their neutralising activity. Invivyd itself holds an EUA for pemivibart, and VYD2311 is engineered from the same antibody backbone using serial molecular evolution to track contemporary SARS-CoV-2 lineages. If the Accelerated Approval strategy succeeds, VYD2311 would occupy a differentiated position as a jabbed prophylactic option for immunocompromised and high-risk adults who cannot mount adequate vaccine responses, a population that remains underserved by mRNA-only strategies.
DECLARATION topline safety and immunogenicity data are expected in October, with the full clinical-events readout to follow post-approval if the BLA proceeds as planned. Investors will be watching whether the neutralising-titer bar set by LIBERTY translates into convincing DECLARATION immunogenicity results and, ultimately, whether FDA accepts the proposed surrogate endpoint framework for Accelerated Approval.