Dear Editor,
The ongoing debate revolves around whether autoimmune conditions are
triggered or exacerbated by natural SARS-CoV-2 infection or COVID-19
vaccination. Xu et al .’s recent investigation has reignited the
debate about whether autoimmunity is specifically linked to mRNA
vaccines or if non-mRNA vectored vaccines, inactivated virus vaccine, or
natural SARS-CoV-2 infection can also trigger autoimmune
responses1. Xu et al . have reported that 25%
(3 of 12) of the individuals who received mRNA vaccines (BNT162b2 or
mRNA-1273) developed neutralizing anti-type-I interferon antibodies
autoantibodies (IFN-I auto-nAbs), while no IFN-I nAbs were observed
among individuals (n=8) who received the viral-vectored vaccine
(Janssen). While it is an interesting observation, the measures of
outcomes are limited by its sample size (n=12 versus n=8) and without
any presented hazard ratios. However, there is a substantial body of
evidence suggesting that both SARS-CoV-2 natural infection and COVID19
vaccination (mRNA vaccines, vectored-vaccines, and inactivated virus
vaccines) are associated with the new onset or exacerbation of existing
autoimmune and autoinflammatory conditions1-9. I would
like to discuss if current evidence is enough to confirm COVID-19 and
vaccination as risk factors for autoimmunity or if more evidence is
needed.
During the early phase of the COVID-19 pandemic, Bastard et al. reported
that approximately 10% (101 out of 987) of individuals with
life-threatening COVID-19 pneumonia had IgG IFN-I autoantibodies. The
observations by Bastard et al . and Xu et al . are
complementary. Anti-IFN-I autoantibodies could impair the binding of
IFN-I to IFNAR1 and IFNAR2, resulting in the inhibition of
interferon-stimulated gene (ISGs) transcription3.
Imperatively administration of mRNA vaccines (Pfizer and Moderna) and
vectored vaccines (AstraZeneca) has been linked with post-vaccination
emergence of 31 cases of autoimmune conditions, including systemic lupus
erythematosus (SLE), thyroiditis, Graves’ disease, IgA vasculitis,
inflammatory arthritis, dermatomyositis, ulcerative colitis, autoimmune
hepatitis, autoimmune hemolytic anemia, autoimmune pancreatitis, ANCA
vasculitis, myasthenia gravis, and Sjögren’s syndrome (SS). Next, the
vectored vaccine Sputnik has also been linked to the emergence of 28
cases of autoimmune conditions in Mexico and
Argentina9.
Alqatri et al . reported that autoimmune cases were mostly linked
to mRNA vaccines (Pfizer and Moderna). These cases occurred within days
to weeks after the administration of the 1st, 2nd, or 3rd doses and were
diagnosed using standard laboratory tests2. However,
Blanco et al., who measured neuronal autoantibodies at 1-, 6-,
9-, and 12-months post-mRNA vaccination, confirm no triggers for
autoantibodies or exacerbation of disease among pwMS (n=390) or other
inflammatory neurological disorders (n=64). What’s the appropriate
washout period after SARS-CoV-2 infection and/or COVID-19 vaccination to
detect autoantibodies, while avoiding false measurements due to
transient autoimmune flares?
Natural SARS-CoV-2 infection is strongly associated with the emergence
of autoimmune diseases and the exacerbation of existing diseases, while
it has been firmly advocated that the administration of COVID-19
vaccines reduces the risk of autoimmunity4,7. In a
case-control analysis involving 888463 COVID-19 patients and 2926016
controls, Chang et al . identified COVID-19 as a risk factor for
several autoimmune conditions, including ankylosing spondylitis,
Behçet’s disease, celiac disease, dermatopolymyositis, inflammatory
bowel disease, mixed connective tissue disease, polymyalgia rheumatica,
psoriasis, rheumatoid arthritis (RA), SS, SLE, systemic sclerosis, type
1 diabetes mellitus, and vasculitis4. However,
receiving a two-dose vaccination of either the mRNA vaccine
(Pfizer-BNT162b2) or inactivated virus vaccines (Sinovac-CoronaVac) has
been associated with a decreased risk of anti-phospholipid antibody
syndrome, Graves’ disease, immune-mediated thrombocytopenia, pemphigoid,
and SLE7.
Decoupling antiviral immunity from the onset and exacerbation of
autoimmunity is challenging5. IFN-I is a disease
activity marker for SLE, SS, and RA and is essential for intrinsic
antiviral immunity5,10. It’s an age-associated marker,
with anti-IFN autoantibodies observed in patients with specific
autoimmune conditions, as well as those who’ve had SARS-CoV-2 infection
or received vaccines. Compared to SARS-CoV-2 infection, synthetic mRNA
vaccines involve the controlled presentation of spike S1 protein to the
host immune system, while both utilize the host-cell translation
machinery.
Intriguing evidence suggests stable autoantibody dynamics following mRNA
vaccination, in contrast to COVID-19 patients who show an increased
prevalence of new antibody reactivities4.
Understanding autoimmunity in the context of SARS-CoV-2 variants of
concern (VOCs) and the sequence of infection and vaccination introduces
additional complexity. However, it’s crucial to recognize that in the
aftermath of the COVID-19 pandemic, the prevalence of autoimmune
conditions has significantly increased. This extends beyond post-acute
sequelae of SARS-CoV-2 infection (PASC), and the root cause of
vaccine-induced autoimmunity should not be disregarded.
In summary, Xu et al . have presented a new line of evidence
supporting the hypothesis of vaccine-induced autoimmunity. Therefore,
monitoring the long-term effects of COVID-19 vaccines should be
conducted on an equal scale as monitoring autoimmunity induced by
SARS-CoV-2 infection.