Reduced FVIII recovery associated with anti-FVIII PEG antibodies after BNT162b2 SARS-CoV-2 vaccination

Abstract

Prophylactic therapy has become the standard of care for patients with hemophilia A (HA); however, prophylaxis regimens that require 2 to 3 weekly infusions of drug are challenging. In the past decade, new factor VIII (FVIII) molecules with extended plasma half-life have been produced with the goal of reducing the number of infusions while maintaining higher trough levels of FVIII in plasma. [1][2][3][4] One of the most established approaches to prolong the circulation time while preserving the biological activity is the covalent link of polyethylene glycol (PEG) chains to therapeutic proteins. To date, several PEGylated drugs are available for the treatment of a variety of chronic diseases including the recently marketed SARS-CoV-2 vaccines, BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna), containing PEGylated lipids. [5][6][7] Moreover, PEG is widely used in the formulation of common personal care products. 8 Concerning the treatment of HA, 3 novel PEGylated recombinant FVIII (rFVIII) products, rurioctocog alfa pegol, turoctocog alfa pegol, and damoctocog alfa pegol, have been authorized by the Food and Drug Administration and European Medicines Agency; these rFVIII molecules have a mean half-life 1.3 to 1.7 times longer than the standard rFVIII and show comparable safety and pharmacokinetic (PK) profiles. 9Although PEG is a nonimmunogenic polymer, pre-existing anti-PEG antibodies (APAs) have been reported in persons never treated with PEGylated biopharmaceutics with increasing incidence up to 72% over the years. 10,11 Usually, pre-existing APAs have no clinical relevance but in few cases showed the potential to bind a PEGylated drug, enhancing its blood clearance and reducing therapeutic efficacy. 12,13 In this report, we describe the poor plasma FVIII recovery observed in 2 patients with HA following their first infusion with the PEGylated rFVIII products associated with the presence of anti-PEGylated rFVIII antibodies after the BNT162b2 SARS-CoV-2 vaccination.Patient 1 is a 42-year-old man on prophylaxis with 37 IU/kg every 3 days of a standard rFVIII product (NovoEight, Novo Nordisk A/S). In April and May 2021, the patient received his first and second dose of the BNT162b2 vaccine. In June 2021, 52 days after the first and 25 days after the second dose, before his switch to a novel PEGylated rFVIII, he underwent the PK study by the injection of 50 IU/kg of turoctocog alfa pegol (Figure 1).Patient 2 is a 24-year-old male on prophylaxis with 32 IU/kg 2 times a week of a standard rFVIII product (Kovaltry, Bayer AG). In October and November 2021, he received his first and second dose of the BNT162b2 vaccine. In December 2021, 57 days after the first dose and 26 days after the second dose, he underwent the PK study with the injection of 50 IU/kg of damoctocog alfa pegol (Figure 1). Plasma samples from both patients were collected before and after the PEGylated rFVIII infusion as well as before the first SARS-CoV-2 vaccination. For patient 1, a further plasma sample was obtained almost 1 year after the second ...

Cases of less‐than‐expected FVIII activity in previously treated patients during post‐marketing surveillance of N8‐GP

“…Both in this report and N8‐GP clinical trials, some patients with haemophilia A had anti‐PEG antibodies prior to N8‐GP exposure. Studies have shown that exposure to PEG molecules through medication and consumer products is widespread in the general population (e.g., packaged foods, paracetamol, COVID‐19 vaccines) 16–18 . COVID‐19 lipid nanoparticle mRNA vaccines contain small amounts of PEG, which have been shown to induce anti‐PEG antibodies in some individuals 19 .…”

“…Studies have shown that exposure to PEG molecules through medication and consumer products is widespread in the general population (e.g., packaged foods, paracetamol, COVID-19 vaccines). [16][17][18] COVID-19 lipid nanoparticle mRNA vaccines contain small amounts of PEG, which have been shown to induce anti-PEG antibodies in some individuals. 19 It is currently unknown how transient the anti-PEG antibody response is, and whether the concentration of the induced anti-PEG antibodies can affect the exposure of PEGylated medicines.…”

“…19 It is currently unknown how transient the anti-PEG antibody response is, and whether the concentration of the induced anti-PEG antibodies can affect the exposure of PEGylated medicines. At least one reported case from Valsecchi et al (2023) suggests a relationship between COVID-19 mRNA vaccination, anti-PEG antibodies, and reduced N8-GP exposure. 18 An estimated 0.2%-25% of people with no exposures to PEGylated medication have anti-PEG antibodies.…”

“…At least one reported case from Valsecchi et al (2023) suggests a relationship between COVID-19 mRNA vaccination, anti-PEG antibodies, and reduced N8-GP exposure. 18 An estimated 0.2%-25% of people with no exposures to PEGylated medication have anti-PEG antibodies. 20,21 Additionally, the incidence of patients with anti-PEG antibodies may be higher in haemophilia populations due to the use of PEGylated interferon therapy to treat hepatitis C infections before the introduction of viral inactivation of plasma concentrates.…”

“…At least one reported case from Valsecchi et al. (2023) suggests a relationship between COVID‐19 mRNA vaccination, anti‐PEG antibodies, and reduced N8‐GP exposure 18 . An estimated 0.2%–25% of people with no exposures to PEGylated medication have anti‐PEG antibodies 20,21 .…”