Asthma, particularly severe eosinophilic asthma, is characterized by airway hyperresponsiveness (AHR) and increased risk of bronchospasm. The BNT162b2 mRNA COVID-19 vaccine, while generally safe and effective, has been associated with rare instances of bronchospasm in asthmatic patients, raising concerns about its potential impact on airway function. Existing research shows conflicting results regarding the vaccine's effect on antibody response in severe asthmatics treated with biologics. While most individuals with allergic diseases can safely receive the vaccine, early reactions such as bronchospasm within minutes of the first dose highlight a potential link between mRNA vaccination and asthma exacerbation, particularly in exacerbation-prone asthma (EPA). This study sought to directly examine the acute effects of BNT162b2 on human airway smooth muscle (ASM) in an ex vivo model to determine if the vaccine might have a detrimental effect on airways of patients with severe asthma, characterized by baseline AHR and eosinophil infiltration.

The literature review focuses on the heterogeneous nature of asthma and the high risk of AHR in severe asthmatics, particularly those with EPA. The BNT162b2 vaccine composition, including lipid nanoparticles (LNP) containing mRNA encoding for the SARS-CoV-2 spike protein, and the excipients, particularly polyethylene glycol (PEG) as part of ALC-0159, are described. The review highlights the increased rate of allergic reactions to COVID-19 mRNA vaccines in patients with high-risk allergies and the conflicting results regarding the antibody response in severe asthmatics receiving biologics. Reports of significant bronchospasm after the first vaccine dose underscore the need for investigation into the vaccine's effect on human airways.

The study utilized an ex vivo, prospective, randomized, controlled, and blinded design. Human isolated bronchi were obtained from lung cancer patients without respiratory disorders, corticosteroid treatment, or elevated IgE levels. Passive sensitization mimicked AHR by exposing airways overnight to sensitizing serum from an asthmatic patient. Eosinophil activation was induced by challenging airways with PAF. BNT162b2's effects on resting tone and response to histamine (at EC20) were assessed. The impact on parasympathetic activation was measured via electrical field stimulation (EFS). Experiments were also conducted using mRNA-denatured BNT162b2 to determine if the effect was due to the mRNA or excipients. Contractions were measured using an organ bath system with isometric force transducers. Data analysis included two-way ANOVA with multiple comparisons.

BNT162b2 (100-1000 ng/mL) significantly increased resting tone (+11.82 ± 2.27%) in passively sensitized and PAF-challenged (sens+PAF) airways compared to controls (p<0.001). In airways partially pre-contracted with histamine (at EC20), BNT162b2 (1-1000 ng/mL) significantly increased the contractile response (+42.97 ± 9.64%, p<0.001) and shifted the concentration-response curve leftward (0.76 ± 0.09 logarithm, p<0.001). BNT162b2 also significantly enhanced the response to EFS (+28.46 ± 4.40%, p<0.001) in sens+PAF airways. Importantly, mRNA denaturation did not alter BNT162b2's effects, suggesting that excipients, particularly PEG within ALC-0159, are responsible for the increased contractility.

The study's findings show that BNT162b2 increases contractile sensitivity to histamine and parasympathetic activation specifically in hyperresponsive airways, modeling severe eosinophilic asthma. This effect is not related to the vaccine's active component (tozinameran) but likely to an excipient, possibly PEG. The consistent effect on both histamine and EFS responses suggests direct and indirect actions on ASM, vagal fibers, and intramural ganglia. While BNT162b2 did not impair ASM contractility in control airways, its detrimental effect in the asthma model requires further investigation. The potential clinical implications are discussed, considering the biodistribution of LNP and estimated concentrations of ALC-0159 in the respiratory system, highlighting the possibility that even low concentrations could induce bronchospasm in susceptible individuals, like asthmatic patients, particularly after the first dose.

This study demonstrates that BNT162b2 can elicit bronchospasm in hyperreactive airways, an effect likely due to an excipient, such as ALC-0159 containing PEG, rather than the active component. Asthmatic patients, especially children and adolescents, may be at increased risk. Pre-treatment with inhaled corticosteroids/formoterol before vaccination may offer protection, but further research is needed to confirm this. The study highlights the importance of considering excipient-related effects when assessing the safety of mRNA vaccines in at-risk populations.

The ex vivo nature of the study limits the direct translation of findings to real-life situations. Using tissue from lung cancer patients might introduce bias compared to tissue from individuals without lung cancer. Lack of data on the detailed safety profile of BNT162b2 from the phase 3 RCTs hinders a comprehensive assessment of bronchospasm risk. Finally, individual lipid excipients were not investigated separately.