The Fluviral S/F® and Vaxigrip® vaccines used in Canada between 2000 and 2003 (but never used in the United States) did commonly cause oculorespiratory syndrome (ORS) within 24 hours of vaccination, at an estimated rate of up to 2.9 cases per 100 vaccinations. Changes have been made in the formulation of these vaccines that have resulted in a dramatic decrease in the risk of ORS.
There have been reports of ORS-like symptoms after receipt of inactivated influenza vaccines (IIV) in routine use in the United States. However, these reports are rare, and symptoms are generally mild and transient.
ORS is an adverse event associated with influenza vaccine that was first described in Canada during the 2000-2001 influenza season. It is characterized by conjunctivitis, facial swelling, and upper respiratory symptoms that develop within 24 hours of vaccination. ORS is generally mild, resolving within 48 to 72 hours .
96% of the ORS cases reported in Canada during the 2000–2001 influenza season occurred after vaccination with Fluviral S/F® . The attributable risk of ORS for the 2001-2002 formulation of Fluviral S/F® was estimated to be 2.9 cases per 100 vaccinees . The 2012 report by the Institute of Medicine (IOM) , now called the National Academy of Medicine (NAM), described three studies with sufficient validity and precision that demonstrated an association between ORS and the aforementioned influenza vaccine [2, 4, 5].
Most studies have not demonstrated a causal relationship between ORS and influenza vaccines used in the U.S. . However, according to the 2012 IOM report, this could be due to underreporting of the typically mild symptoms of ORS as well as the annual variance in influenza vaccine formulation . The ACIP recommendations for influenza vaccines in 2013-2014 noted several investigations that identified persons with symptoms meeting an ORS case definition in safety monitoring systems and trials that had been conducted before 2000 in Canada, the United States, and Europe .
The clinical presentation of ORS indicates that its pathogenesis is most likely immune-based . One mechanism suggested for the development of ORS after influenza vaccination is activation of the complement system, in which a cascade of proteolysis and successive release of cytokines functions to amplify the immune response but can damage host cells if not properly regulated . Possible mechanisms of complement activation by influenza viruses include direct binding of the matrix (M1) protein  and immune complex formation with preformed nonprotective antibodies leading to tissue pathology . Host factors involving cytokine production may also predispose some individuals to develop ORS after influenza vaccination .
The presence of numerous microaggregates of unsplit viruses in the 2000-2001 Canadian formulation has been proposed as an important factor behind that season’s high rates of ORS, and an improved formulation in following years brought decreased rates .
The 2012 IOM report described both experimental and clinical evidence [4, 5, 11-14] supporting a causal relationship between ORS and the aforementioned influenza vaccine .
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