Endotyping of IgE-Mediated Polyethylene Glycol and/or Polysorbate 80 Allergy

by Selleckchem | Nov 16 2023

Background: Polyethylene glycol (PEG) and polysorbate 80 (PS80) allergy preclude from SARS-CoV-2 vaccination. The mechanism(s) governing cross-reactivity and PEG molecular weight dependence remain unclear.

Objectives: To evaluate PEGylated lipid nanoparticle (LNP) vaccine (BNT162b2) tolerance and explore the mechanism of reactivity in PEG and/or PS80 allergic patients.

Methods: PEG/PS80 dual- (n = 3), PEG mono- (n = 7), and PS80 mono-allergic patients (n = 2) were included. Tolerability of graded vaccine challenges was assessed. Basophil activation testing on whole blood (wb-BAT) or passively sensitized donor basophils (allo-BAT) was performed using PEG, PS80, BNT162b2, and PEGylated lipids (ALC-0159). Serum PEG-specific IgE was measured in patients (n = 10) and controls (n = 15).

Results: Graded BNT162b2 challenge in dual- and PEG mono-allergic patients (n = 3/group) was well tolerated and induced anti-spike IgG seroconversion. PS80 mono-allergic patients (n = 2/2) tolerated single-dose BNT162b2 vaccination. Wb-BAT reactivity to PEG-containing antigens was observed in dual- (n = 3/3) and PEG mono- (n = 2/3), but absent in PS80 mono-allergic patients (n = 0/2). BNT162b2 elicited the highest in vitro reactivity. BNT162b2 reactivity was IgE mediated, complement independent, and inhibited in allo-BAT by preincubation with short PEG motifs, or detergent-induced LNP degradation. PEG-specific IgE was only detectable in dual-allergic (n = 3/3) and PEG mono-allergic (n = 1/6) serum.

Conclusion: PEG and PS80 cross-reactivity is determined by IgE recognizing short PEG motifs, whereas PS80 mono-allergy is PEG-independent. PS80 skin test positivity in PEG allergics was associated with a severe and persistent phenotype, higher serum PEG-specific IgE levels, and enhanced BAT reactivity. Spherical PEG exposure via LNP enhances BAT sensitivity through increased avidity. All PEG and/or PS80 excipient allergic patients can safely receive SARS-CoV-2 vaccines.

Comments:

This is a research summary outlining a study conducted to evaluate the tolerance of the PEGylated lipid nanoparticle (LNP) COVID-19 vaccine BNT162b2 in patients with allergies to polyethylene glycol (PEG) and polysorbate 80 (PS80). The study aimed to explore the mechanisms behind cross-reactivity and the dependence on the molecular weight of PEG.

**Methods and Findings:**

1. **Patient Groups:** The study included three groups of patients:
   - PEG/PS80 dual-allergic patients (n = 3)
   - PEG mono-allergic patients (n = 7)
   - PS80 mono-allergic patients (n = 2)

2. **Tolerability:** Graded challenges with the BNT162b2 vaccine were administered to these patient groups to assess their tolerance. The findings indicated that the BNT162b2 vaccine was well-tolerated in dual-allergic and PEG mono-allergic patients. PS80 mono-allergic patients also tolerated a single dose of the BNT162b2 vaccine.

3. **Basophil Activation Testing (BAT):** Basophil activation testing was conducted using whole blood (wb-BAT) or basophils from sensitized donors (allo-BAT). Reactivity was assessed using various antigens, including PEG, PS80, BNT162b2, and PEGylated lipids (ALC-0159). The results showed reactivity to PEG-containing antigens in dual-allergic and some PEG mono-allergic patients, but not in PS80 mono-allergic patients. BNT162b2 induced the highest reactivity in vitro.

4. **Mechanism of Reactivity:** The reactivity to BNT162b2 was found to be IgE-mediated and complement-independent. It could be inhibited in allo-BAT by preincubation with short PEG motifs or by degrading the lipid nanoparticles (LNP) in the vaccine through the addition of detergents.

5. **Serum PEG-Specific IgE:** PEG-specific IgE was measured in patients (n = 10) and control subjects (n = 15). It was only detectable in dual-allergic and some PEG mono-allergic patients.

**Conclusion:**

The study's findings suggest the following conclusions:

- Cross-reactivity between PEG and PS80 is mediated by IgE recognizing short PEG motifs.
- PS80 mono-allergy is PEG-independent.
- PS80 skin test positivity in PEG-allergic patients is associated with a severe and persistent phenotype, higher serum PEG-specific IgE levels, and enhanced BAT reactivity.
- Exposure to spherical PEG via lipid nanoparticles (LNP) enhances BAT sensitivity through increased avidity.
- Allergic patients with allergies to PEG and/or PS80 excipients can safely receive SARS-CoV-2 vaccines.

In summary, the study provides insights into the mechanisms of cross-reactivity in patients with PEG and PS80 allergies and supports the safety of the BNT162b2 vaccine in these patients.