In patients with hemophilia A, the development of antipolyethylene glycol (PEG) antibodies has been linked to the
use of certain PEGylated products, including SARS-CoV-2 mRNA vaccines, according to findings from a case study published in the journal Haemophilia.
Two mRNA-based COVID-19 vaccines are being used internationally to prevent the spread of SARS-CoV-2
infection—BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna). Both of these vaccines contain PEG-lipid conjugates. PEG and derivatives of PEG are known to be common ingredients in many widely used personal care products as well.
There have been several reports advising that the immune responses elicited by PEG-associated substances can lead to the formation of anti-PEG antibodies. The researchers posited that mRNA-1273 SARS CoV-2 vaccination generated anti-PEG antibodies in patients with hemophilia A, which facilitated the rapid clearance of PEGylated recombinant factor VIII (rFVIII), thus severely reducing the bioavailability and therapeutic efficacy of FVIII replacement therapy.
Although FVIII replacement therapy is the standard of care for individuals with hemophilia A, repeated infusions present challenges, particularly in pediatric patients. Several rFVIII products with extended circulating half-life properties have been created of late by covalent attachment of PEG to the FVIII molecule. Use of this PEGylation process extends the FVIII half-life, thus allowing higher trough levels of FVIII activity (FVIII:C) and decreased frequency of infusions.
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The patient described in this case study was a 21-year-old male with severe hemophilia A who had been receiving regular prophylaxis with standard rFVIII (turoctocog alfa; 30 IU/kg; Novo Nordisk), administered 3 times weekly. He had a prior history of developing FVIII inhibitors, which had been eradicated with the use of immune tolerance induction therapy when he was 3 years old.
The young man had received his first and second mRNA-1273 COVID-19 vaccines. Following each vaccination, prophylaxis with PEGylated rFVIII was considered for the patient in an effort to reduce the frequency of his infusions. He received his initial infusion of 30 IU/kg of turoctocog alfa pegol (N8-GP; Novo Nordisk) 49 days following his first mRNA-1273 vaccination and 21 days after his second immunization.
Routine laboratory work indicated that the patient’s FVIII:C levels in plasma prior to and 30 minutes following vaccination were 0.7 and 1.1 IU/dL, respectively. In fact, in vivo recovery of FVIII was less than anticipated, with little coagulant effect associated with the FVIII infusion. FVIII inhibitor was not detected.
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The next day, the patient presented with limited mobility and pain in the fourth finger of his left hand, which was indicative of an intra-articular hemorrhage. Treatment with standard FVIII (30 IU/kg of turoctocog alfa) was chosen. His FVIII:C prior to infusion was 0.3 IU/dL, which recovered to 71.7 IU/dL following therapy and was thus indicative of improved coagulation potential in whole blood.
The symptoms in his left hand resolved rapidly. The patient continues to receive regular prophylaxis with turoctocog alfa; FVIII inhibitors have not been detected.
“[O]ur data strongly confirm that clinicians should carefully assess the therapeutic effects of PEGylated-rFVIII infusions in persons with hemophilia A after receiving mRNA-1273 and BNT162b2 vaccination and vice versa,” the researchers concluded.
Nakajima Y, Ogiwara K, Shimonishi N, Furukawa S, Takeyama M, Nogami K. Intra-articular haemorrhage caused by reduced recovery of PEGylated recombinant factor VIII due to an anti-PEG antibody developed after mRNA-1273 SARS-CoV-2 vaccination in haemophilia A. Haemophilia. Published online April 11, 2023. doi:10.1111/hae.14786