Autoantibody production against phospholipid binding proteins has been documented as a consequence of exposure to infectious agents24, 25
but conflicting reports still exist about the appearance of these aPL after vaccine administration. In healthy subjects given the Hepatitis B recombinant vaccine who exhibited changes in aPL values, a significant increase was observed in β2GPI values but not in aCL values26
. After influenza vaccination, transient appearance of autoantibodies and progressively increased levels of aCL or anti-β2GPI were demonstrated in only approximately 8% of 92 apparently healthy adults after vaccination27
. This low rate of aCL positivity among healthy individuals was also seen in our study. Seven out of 101 healthy controls developed new onset low (n=2) or moderate (n=5) aCL after receiving the vaccine. Susceptible individuals may have an increased risk of developing a sustained autoimmune response and subsequent production of these autoantibodies after vaccination. Several case reports have recounted the occurrence of an autoimmune condition and production of aPL after influenza vaccination28, 29
Among SLE patients, production of aCL has been documented in one patient after pneumococcal vaccination30
and among nine patients after influenza vaccination31
. Looking further into the effect of influenza vaccination among SLE patients, a report by Tarjan et al. showed a remarkable elevation in the levels of β2GPI antibodies in aPL positive and negative patients, but did not show any clinical consequences in patients with previous aPL positivity32
. SLE patients with aCL tend to have these antibodies preceding initial clotting events by several years. Furthermore, the presence of early, pre-diagnosis aCL in this susceptible group correlates with a more varied and severe SLE clinical course and younger age at diagnosis21
. In this study, the titer of aCL antibody reactivity was significantly higher among SLE patients after vaccination at all time points.
Among SLE patients with APS, aPL have been demonstrated to be directed against epitopes expressed on β2GPI but not cardiolipin in contrast to aPL associated with infectious diseases33–35
. β2GPI binds to anionic phospholipids including cardiolipin adhering to activated platelets and inhibiting the contact activation of blood coagulation36, 37
. Anti-β2GPI have been shown to recognize different β2GPI epitopes including a major antigenic region recognized by monoclonal aPL isolated from APS patients38
. In addition, the group of de Laat et al. have shown that pathogenic aPL bind to a cryptic epitope (G40–R43) on the first domain of β2GPI39
. In our study, none of the individuals who developed aCL responses after vaccination had detectable β2GPI antibodies. No matched control and only one SLE patient with aCL reactivity prior to vaccination had detectable levels of anti-β2GPI. This could reflect the apparently benign nature of aCL observed in healthy individuals in the general population as well as the aCL induced by infectious agents, and potentially by influenza vaccine administration seen in our study. The significantly higher aCL reactivity seen among SLE patients in this study after vaccination, although almost uniformly non-reactive to β2GPI antibodies, can be further evaluated beyond 12 weeks to determine persistence of aPL in multiple years.
The varying levels of aCL reactivity seen among each of the subjects in this study on all time points before and after Influenza vaccination reinforces the transient nature of aPL reported among several studies which requires interaction between innate and acquired immunity in promoting thrombotic risk40, 41
. No specific clinical or laboratory variables have been identified to be associated with SLE flare following influenza vaccination42, 43
. Vaccines may trigger short term generation of autoantibodies however, this does not have long term affects on SLE disease course as seen in our study.