Conclusion
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.
Why This is an Issue
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 1.
Epidemiological Evidence
96% of the ORS cases reported in Canada during the 2000–2001 influenza season occurred after vaccination with Fluviral S/F® 2. The attributable risk of ORS for the 2001-2002 formulation of Fluviral S/F® was estimated to be 2.9 cases per 100 vaccinees 3. The 2012 report by the Institute of Medicine (IOM) 4, 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 3,5,6.
Most studies have not demonstrated a causal relationship between ORS and influenza vaccines used in the U.S. 7. 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 4. 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 8.
Proposed Biological Mechanism
The clinical presentation of ORS indicates that its pathogenesis is most likely immune-based1. 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 4. Possible mechanisms of complement activation by influenza viruses include direct binding of the matrix (M1) protein 9 and immune complex formation with preformed nonprotective antibodies leading to tissue pathology 10. Host factors involving cytokine production may also predispose some individuals to develop ORS after influenza vaccination 1.
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 3.
The 2012 IOM report described both experimental and clinical evidence 5,6,11-14 supporting a causal relationship between ORS and the aforementioned influenza vaccine 4.
References
1. Al-Dabbagh M, Lapphra K, Scheifele DW, Halperin SA, Langley JM, Cho P, Kollmann TR, Li Y, De Serres G, Fortuno ES, 3rd, Bettinger JA. Elevated inflammatory mediators in adults with oculorespiratory syndrome following influenza immunization: a public health agency of Canada/Canadian Institutes of Health Research Influenza Research Network Study. Clin Vaccine Immunol 2013; 20(8): 1108-14.
2. Squires SG, Pelletier L, Zabchuk P, Winchester B, Tam T. Influenza in Canada–1999-2000 season. Can Commun Dis Rep 2001; 27(1): 1-9.
3. Scheifele DW, Duval B, Russell ML, Warrington R, DeSerres G, Skowronski DM, Dionne M, Kellner J, Davies D, MacDonald J. Ocular and respiratory symptoms attributable to inactivated split influenza vaccine: evidence from a controlled trial involving adults. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2003; 36(7): 850-7.
4. Institute of Medicine. In: Stratton K, Ford A, Rusch E, Clayton EW, eds. Adverse Effects of Vaccines: Evidence and Causality. Washington (DC): National Academies Press (US); 2012.
5. De Serres G, Skowronski DM, Guay M, Rochette L, Jacobsen K, Fuller T, Duval B. Recurrence risk of oculorespiratory syndrome after influenza vaccination: randomized controlled trial of previously affected persons. Arch Intern Med 2004; 164(20): 2266-72.
6. Skowronski DM, De Serres G, Scheifele D, Russell ML, Warrington R, Davies HD, Dionne M, Duval B, Kellner J, MacDonald J. Randomized, double-blind, placebo-controlled trial to assess the rate of recurrence of oculorespiratory syndrome following influenza vaccination among persons previously affected. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2003; 37(8): 1059-66.
7. Hambidge SJ, Glanz JM, France EK, McClure D, Xu S, Yamasaki K, Jackson L, Mullooly JP, Zangwill KM, Marcy SM, Black SB, Lewis EM, Shinefield HR, Belongia E, Nordin J, Chen RT, Shay DK, Davis RL, DeStefano F. Safety of trivalent inactivated influenza vaccine in children 6 to 23 months old. Jama 2006; 296(16): 1990-7.
8. Grohskopf LA, Shay DK, Shimabukuro TT, Sokolow LZ, Keitel WA, Bresee JS, Cox NJ. Prevention and control of seasonal influenza with vaccines. Recommendations of the Advisory Committee on Immunization Practices–United States, 2013-2014. MMWR Recommendations and reports : Morbidity and mortality weekly report Recommendations and reports / Centers for Disease Control 2013; 62(Rr-07): 1-43.
9. Zhang J, Li G, Liu X, Wang Z, Liu W, Ye X. Influenza A virus M1 blocks the classical complement pathway through interacting with C1qA. J Gen Virol 2009; 90(Pt 11): 2751-8.
10. Monsalvo AC, Batalle JP, Lopez MF, Krause JC, Klemenc J, Hernandez JZ, Maskin B, Bugna J, Rubinstein C, Aguilar L, Dalurzo L, Libster R, Savy V, Baumeister E, Aguilar L, Cabral G, Font J, Solari L, Weller KP, Johnson J, Echavarria M, Edwards KM, Chappell JD, Crowe JE, Jr., Williams JV, Melendi GA, Polack FP. Severe pandemic 2009 H1N1 influenza disease due to pathogenic immune complexes. Nature medicine 2011; 17(2): 195-9.
11. De Serres G, Toth E, Menard S, Grenier JL, Roussel R, Tremblay M, Landry M, Robert Y, Rochette L, Skowronski DM. Oculo-respiratory syndrome after influenza vaccination: trends over four influenza seasons. Vaccine 2005; 23(28): 3726-32.
12. Fredette MJ, De Serres G, Malenfant M. Ophthalmological and biological features of the oculorespiratory syndrome after influenza vaccination. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 2003; 37(8): 1136-8.
13. Skowronski DM, Bjornson G, Husain E, Metzger DL, Scheifele DW. Oculorespiratory syndrome after influenza immunization in children. The Pediatric infectious disease journal 2005; 24(1): 63-9.
14. Skowronski DM, Strauss B, Kendall P, Duval B, De Serres G. Low risk of recurrence of oculorespiratory syndrome following influenza revaccination. CMAJ 2002; 167(8): 853-8.
