Markedly Reduced FVIII Recovery Associated with Anti-FVIII Peg Antibodies after BNT162b2 Sars-Cov-2 Vaccination

Background

The covalent link of polyethylene glycol (PEG) chains to recombinant factor VIII (FVIII) molecule is one of the most established approaches to produce novel therapeutic FVIII products with extended half-life (EHL). To date, three PEGyated-FVIII molecules, rurioctocog alfa pegol, turoctocog alfa pegol, and damoctocog alfa pegol are available for treatment of hemophilia A patients. From the pivotal clinical studies data, they showed comparable safety profile and pharmacokinetic with a mean half-live 1.3-1.7 times longer than the standard non-PEGylated FVIII.

Although the PEG polymer is considered non immunogenic, antibodies against PEG, called pre-existing anti-PEG antibodies (APAs), have been reported in persons never treated with PEGylated drugs owing to PEG exposure during the activities of daily living. These antibodies can impact the clinical efficacy of PEGylated drug therapies by accelerating the blood clearance and changing pharmacokinetic. Recently, small amounts of PEG are also included in the lipid nanoparticles of the mRNA SARS-Cov-2 vaccines, BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna).

Aim

To describe a poor plasma FVIII recovery after the first infusion of a PEGylated FVIII product in two male patients with severe hemophilia A without inhibitor at about one month from the second dose of the BNT162b2 SARS-Cov-2 vaccination.

Method

About two months after the first dose of the SARS-Cov-2 vaccine and one month after the second, before switching from a standard half-life to a PEGylated FVIII product, patients underwent a PK study by infusion of 50 IU/kg of turoctocog alfa pegol (patient 1) or damoctocog alfa pegol (patient 2). FVIII activity was measured by Chromogenix Coamatic FVIII (Werfen) in plasma samples collected before and after the PEGylated FVIII infusion. Anti-PEGylated FVIII antibodies were searched by means of a home-made ELISA in plasma samples collected before administration of SARS-Cov-2 vaccine and at PK study. The assay was performed by using as capturing substrates each of the licensed PEGylated FVIII product (rurioctocog alfa pegol, turoctocog alfa pegol, and damoctocog alfa). Moreover, a non-PEGylated standard FVIII (Advate®) was employed as control substrate.

Results

FVIII coagulant activity measured after the infusion of 50 IU/kg of the PEGylated FVIII product showed a very low plasma recovery, 5% for patient 1 and 4% for patient 2. Anti-PEGylated FVIII antibodies reacting with each PEGylated FVIII products were found in plasma samples collected at PK baseline and after FVIII infusion but not in a sample obtained before the SARS-Cov-2 vaccination. No reactivity was found in vitro against the non-PEGylated standard FVIII product (figure).

Conclusions

Our finding of antibodies reacting with the PEGylated part of the FVIII molecule induced or boosted by BNT162b2 SARS-Cov-2 vaccination supports the view that the administration of the mRNA vaccine could impair plasma FVIII recovery after infusion of a PEGylated product.

Gualtierotti:Pfiser: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bayer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Ciavarella:Bayer: Consultancy, Other: Bayer Hemophilia Awards Fellowship. Novembrino:Werfen: Consultancy; Takeda: Consultancy. Mannucci:Bayer: Speakers Bureau; Bayer Award: Membership on an entity's Board of Directors or advisory committees; Kedrion: Speakers Bureau; Roche: Speakers Bureau. Peyvandi:Grifols: Other: educational meeting; Biomarin: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Other: educational meeting; Takeda: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees.