2022: Tixagevimab/Cilgavimab (Evusheld): Long-Acting COVID Prevention (2022)

Evusheld (tixagevimab co-packaged with cilgavimab, AstraZeneca) received FDA emergency use
authorisation in December 2021 for pre-exposure prophylaxis (PrEP) of COVID-19 in immunocompromised
individuals who were unlikely to mount an adequate response to vaccination. Commercial administration
was scaled in 2022, representing the first long-acting antibody cocktail authorised specifically
for COVID prevention rather than treatment, and the first application of half-life-extended
monoclonal antibodies—via YTE (YTE triple mutation in the Fc region) technology—to an infectious
disease prophylaxis indication.

The two antibodies were derived from B cells of convalescent COVID-19 donors and selected for
binding to non-overlapping epitopes on the SARS-CoV-2 spike receptor-binding domain, providing
additive neutralisation and a high barrier to resistance through complementary binding footprints.
The YTE Fc modification extended antibody serum half-life from approximately three weeks (for
unconjugated IgG1) to roughly six months, enabling protection with a single intramuscular injection
every six months rather than requiring frequent infusions.

The PROVENT Phase III trial demonstrated 77 % efficacy against symptomatic COVID-19 over six
months in immunocompromised participants who had inadequate vaccine responses. For severely
immunocompromised patients—including solid organ transplant recipients, those receiving B-cell-
depleting therapies, and individuals with primary immunodeficiencies—Evusheld filled an important
gap in protection that vaccines alone could not address.

The drug's utility was ultimately curtailed by the emergence of SARS-CoV-2 variants—particularly
BA.4/BA.5 and XBB subvariants—that harboured spike mutations reducing Evusheld neutralisation
by 1,000-fold or more, leading the FDA to revoke its authorisation in January 2023 for periods
when variants resistant to the antibody were predominating.