Viral RNA in the influenza vaccine may have contributed to the development of ANCA-associated vasculitis in a patient following immunisation

Abstract

A number of large studies have demonstrated influenza vaccinations to be safe and effective. However, there have been some sporadic case reports, describing a temporal association of influenza vaccination with onset or relapse of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. The nature of this association, beyond time of occurrence, remains unknown. The presentation of a previously healthy patient who developed ANCA-associated vasculitis (AAV) shortly after influenza vaccination provided us with the rare opportunity to study the possible mechanisms behind this observation. We tested the ability of different types and batches of influenza vaccines to stimulate proteinase-3 ANCA (PR3-ANCA) production in vitro. We found that only some influenza vaccines stimulated PR3-ANCA production in this patient. We demonstrated that this unusual response was associated with those vaccines that contained viral ribonucleic acid (RNA), the natural ligand for Toll-like receptor-7. Exome sequencing of the patient's DNA did not show any mutation in any of the molecules associated with Toll-like receptor signalling. We propose that hyper-reaction to viral RNA in the influenza vaccine may have contributed to the development of AAV following influenza vaccination in this patient.

Vaccination and Autoimmune Phenomena

“…In one patient with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis arising after influenza vaccination, a careful study of the patient's peripheral blood mononuclear cells in vitro demonstrated the production of pathogenic anti-proteinase 3 autoantibodies upon stimulation with influenza vaccines containing viral RNA (49). This finding supports the hypothesis that influenza vaccine, similarly to influenza infection, may trigger autoantibody production and consequent vasculitis by acting on innate immunity via Toll-like receptor 7 that binds viral RNA.…”

Toll-like receptor 7 deficiency protects apolipoprotein E-deficient mice from diet-induced atherosclerosis

“…This is an interesting and important topic for further exploration. Endogenous TLR7 ligands include mainly ssRNA such as those from viral infections 79–81 , or even single nucleotide such as guanosine (G)/2′-deoxyguanosine (dG) 82 . Such nucleotide(s) in atherosclerotic lesions may activate TLR7 and promote atherosclerosis.…”

MPO-ANCA associated vasculitis with mononeuritis multiplex following influenza vaccination

“…Since the patient showed overlapping sets of clinical features it was difficult to diagnose the exact subtype of AAV [ 10 , 11 ]. Currently, a handful of AAV cases have been reported in temporal association with influenza vaccination [ 12 – 17 ]. Recently, The Brighton Collaboration Vasculitis Working Group published a systematic literature review on adverse events following immunization (AEFI) suggesting an association between influenza vaccination and vasculitis, however no evidence is found to confirm this association yet [ 18 ].…”

“…According to the ASIA criteria defined by Alijotas-Reig, our patient met three major criteria, including exposure to an external stimulus, minimum latency time of days and muscle weakness [ 28 ]. Recently, another possible mechanism has been proposed regarding influenza vaccines containing viral RNA which may increase the production of Proteinase 3 (PR3-ANCA) and thus further contribute to the development of AAV following influenza vaccination [ 17 ].…”