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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.

We assessed sex-specific trends within passive vaccine safety surveillance in Ontario, Canada. AEFIs reported following vaccines administered between 2012 and 2015 were included. There were 2466 AEFI reports; 66.2% were female. Annualized reporting rates were 5.9 and 3.1 per 100,000 population, for females and males respectively. The female:male reporting rate ratio (RRR) was 1.9. Sex-specific differences by age group were greatest in adults 18-64years (RRR 6.3); whereas there were no differences in children

Oculorespiratory syndrome (ORS) is an infrequent adverse event following influenza vaccination. Its clinical presentation suggests that ORS is an immune-mediated phenomenon, but studies of symptomatic individuals have been few. This study measured cytokine levels in peripheral blood samples following influenza vaccination in those with and without current ORS symptoms. Canadian adults receiving the 2010-2011 seasonal influenza vaccine were recruited and asked to promptly report any adverse effects. ORS symptoms occurring 4 to 48 h after vaccination were identified using previously published criteria. Two blood samples were collected from each subject to measure blood plasma cytokine and hemagglutination inhibition antibody (HAI) titers; visit 1 occurred during the acute disease phase or 4 to 72 h after vaccination for controls, and visit 2 occurred another 21 days postimmunization. Nine ORS cases and 35 controls were enrolled. The median age of ORS cases was 49 years, and 89% were female. Most cases had multiple symptoms, but none required medical care. HAI titers before and after vaccination were similar for the cases and controls. Blood plasma cytokine concentrations did not differ between the ORS cases and controls for most cytokines measured (interleukin 4 [IL-4], IL-5, IL-10, IL-13, IL-1α, IL-8, tumor necrosis factor alpha [TNF-α], gamma interferon [IFN-γ], and IL-17A). However, ORS cases had higher levels of IL-10 and IL-3 than the controls at visits 1 and 2, even after all symptoms had subsided. Persistent higher levels of IL-10 and IL-3 in ORS cases suggest that host factors may have predisposed these individuals to develop ORS following influenza vaccination. Further investigations are warranted, as they might identify subjects who are at risk for ORS prior to vaccination.

Background The Joint Task Force on Practice Parameters (JTFPP) guidelines for the investigation and reimmunization of patients who experienced allergic-like events (ALEs) after immunization are predicated on the likelihood of anaphylaxis, assessed through the time to symptom onset (≤ or >4 hours) and number of systems involved. Objective The objectives of this study were to compare the management of a series of patients with ALE in actual practice relative to JTFPP guidelines and to discuss key concepts and considerations in their use. Methods This retrospective study was based on a chart review of patients who consulted for suspected vaccine-associated ALEs at a large allergy department in Canada. Results Only 3 of the 135 patients who presented ALEs after immunization were referred for suspected anaphylaxis. There was no significant difference in the frequency of skin testing or reimmunization of patients whatever the time to symptom onset or number of systems involved in the ALE. Eight patients whose initial ALE occurred within 1 hour after immunization had a recurrence on reimmunization. Another patient whose initial ALE occurred 10 hours after influenza immunization had throat tightening and difficulty swallowing without objective signs. Conclusions Most ALEs after immunization are not suggestive of anaphylaxis and should not be managed as such. The definition of anaphylaxis in the JTFPP guidelines is nonspecific and may need to be revisited. Restricting skin testing and graded dose reimmunization to patients whose ALE onset is ≤1 hour (compatible with IgE-mediated reaction) and to those meeting specific clinical criteria for anaphylaxis (whatever the timing) is likely a sufficiently sensitive and cautious approach.

OBJECTIVES. We assessed adverse events, including oculorespiratory syndrome, following influenza immunization during the first year of a publicly-funded program for infants, toddlers and their household members in Canada.METHODS. Parents bringing infants and toddlers for influenza immunization to clinics in Quebec or British Columbia consented to structured telephone interview 5 to 10 days later. One adult provided information for all household members. Symptom experience commencing before and after immunization was assessed. Non-immunized persons also served as a comparison group for immunized household members.RESULTS. Sample included 690 immunized infants and toddlers and 1801 household members, 1374 immunized. Only fussiness, fever, decreased appetite, drowsiness, and nasal congestion/coryza were reported for >5% of infants/ toddlers within 72 hours of immunization, but only arm discomfort was reported among >5% of immunized household contacts. In multivariate analysis, muscle ache was the only systemic symptom reported more often by immunized household members compared to non-immunized persons. Oculorespiratory symptoms were infrequent and there was no difference between immunized and non-immunized household members in their report. Less than 1% of adults required time off work because of adverse events following influenza immunization in the household. Less than 2% of subjects experiencing an adverse event following influenza immunization were considered unlikely to be vaccinated again.CONCLUSION. Influenza vaccine is well-tolerated by infants, toddlers and their household members. Post-marketing observational designs are an expedient way to assess adverse events following influenza immunization. These methods should be established and rehearsed annually in preparation for a pandemic.

Oculo-respiratory syndrome (ORS), a new influenza vaccine associated adverse event, was identified in 2000. The 2000 case definition (ORS-2000) required the presence of bilateral red eyes or respiratory symptoms or facial edema occurring between 2 and 24h following immunization and lastingor=48 h. We compared clinical manifestations of cases outside these timelines. Cases were classified as ORS-early (onset2 h after immunization), ORS-late (onset24 h), ORS-persistors (duration48 h).Overall, the distribution of symptoms was similar between ORS-2000 and other case categories. ORS-early and ORS-late had less ocular involvement, ORS-late and ORS-persistors had more cough and sore throat, ORS-early had more facial edema and ORS-late had less. In comparison to ORS-2000, ORS-early were younger whereas ORS-persistors and ORS-late were significantly older suggesting that clinical manifestations of ORS vary with age with a more rapid induction of symptoms in younger individuals and longer duration for older ones.

We assessed the occurrence of oculo-respiratory syndrome (ORS) following two influenza vaccines: Fluviral (Shire Biologics) or Vaxigrip (Aventis Pasteur). ORS was identified amongst 5.3 and 4.6% of recipients, respectively (P=0.54). With both vaccines, the risk of ORS was much greater in individuals who had ORS the previous year (2000) than in those without such history. In multivariate analysis, the odds ratio for ORS for patients with a prior history of ORS varied between 9.4 and 9.6 (P

In 2000, an influenza vaccine was associated with unusual ocular and respiratory symptoms (known as "oculorespiratory syndrome" [ORS]) that possibly were due to numerous microaggregates of unsplit viruses present in the product. We assessed the potential for an improved vaccine formulation (for use in 2001-2002) to cause ORS and other symptoms in adults, using a double-blind, randomized, crossover study design. Symptoms were ascertained 24 h after 622 doses of vaccine and 626 doses of saline placebo were injected. The risk of ORS was 6.3% after vaccine injection and 3.4% after placebo injection, which yielded a significant vaccine-attributable risk of 2.9% (95% confidence interval, 0.6-5.2). ORS symptoms were mild. Significant differences in risk after injection of vaccine versus placebo existed for ocular soreness and/or itching (2.4%), coughing (1.6%), and hoarseness (1.2%). Vaccine-attributable general symptoms were infrequent. We conclude that certain mild oculorespiratory symptoms were triggered by an influenza vaccine that was otherwise minimally reactogenic and, hence, that such symptoms might be associated with influenza vaccines in general.

10 AntexBiologics, Gaithersburg, Maryland During the 2000-2001 season in Canada, a newly identified oculorespiratory syndrome (ORS) was observed in patients after immunization with inactivated influenza vaccine. ORS was as- sociated with a high proportion of microaggregates of unsplit virions in the implicated vaccine and had clinical features sug- gesting delayed-onset hypersensitivity. We explore the associa- tion between in vitro cytokine balance (type 1 vs. type 2) and clinical ORS after influenza vaccination. We report the balance of interferon (IFN)-g, interleukin (IL)-10, IL-5, and IL-13 ex- pression by peripheral blood mononuclear cells (PBMC) among unvaccinated, vaccinated ORS-affected, and vaccinated ORS-un- affected persons after in vitro challenge with implicated and nonimplicated vaccines. Antigen-stimulated PBMC from vac- cinated persons produced significantly more IFN-g than did those from unvaccinated persons. There was a statistically sig- nificant type 2 polarization among unvaccinated compared with vaccinated persons. Although vaccinated ORS-affected individ- uals had less of a type 1 basis than did vaccinated unaffected individuals, this difference was not statistically significant. During the 2000-2001 season, a newly identified oculorespi- ratory syndrome (ORS) was detected across Canada as an ad

A syndrome of red eyes and respiratory symptoms was noted following receipt of influenza vaccine in Canada during the 2000-2001 influenza season. We conducted intra-dermal skin testing to determine if oculo-respiratory syndrome (ORS) was related to failure of the splitting process during vaccine manufacturing, if it was associated with a particular viral strain and to identify individuals at risk for subsequent ORS reaction. Skin testing with minute quantities of vaccine antigen induced ORS symptoms at a higher rate amongst persons previously affected by this syndrome compared to previously unaffected persons. Skin test reaction size or quality could not identify persons at risk of ORS. Skin testing could not identify a specific strain or the stage in the manufacturing process during which the trigger may have been introduced.

Clinical experience suggests Oculorespiratory Syndrome (ORS) following influenza vaccination is rare in HIV but this is not well evaluated. We assessed ORS incidence in a randomized influenza vaccine trial of HIV participants. The overall incidence was 0.8% suggesting that influenza vaccine ORS incidence is reduced in HIV.

Objective To evaluate the immunogenicity and reactogenicity of a monovalent 2009 pandemic influenza vaccine in Japanese adolescents. Study design A total of 111 junior high school and high school students aged 13 to 18 years participated. Subjects received two doses of a monovalent inactivated unadjuvanted 2009 influenza A vaccine. Immunogenicity of the vaccine was evaluated according to the international criteria. We also asked subjects to report adverse reactions. Results After the first dose of vaccine, the seroprotection rate was 91% (95% CI, 85%-96%), the seroconversion rate was 78% (70%-86%), and the geometric mean titer ratio was 11.9 in all subjects. Antibody titers achieved did not differ significantly after the first and the second doses. With multivariate analysis, an independent negative effect of a prevaccination titer of ≥1:40 on ≥4 fold antibody increase was indicated. No serious adverse reaction was reported. Conclusion The monovalent pandemic vaccine generally was safe, and a single dose of the vaccine given to adolescents induced sufficient immunity. Pre-existing antibody showed substantial effect on antibody response. The effect of pre-existing titer should be considered when evaluating the immunogenicity of influenza vaccines, especially in studies conducted during pandemic waves.

Background: Oculo-respiratory syndrome (ORS) following influenza vaccination was identified in Canada in 2000. This report describes trends of ORS reported during four consecutive seasons 2000, 2001, 2002 and 2003 in the province of Quebec, Canada. Methods: Data come from the vaccine-associated adverse event (VAAE) passive reporting system of the Province of Quebec. Results: The rate of ORS reported per 100 000 doses distributed declined from 46.6 in 2000 to 34.2, 20.6 and 9 in 2001, 2002 and 2003, respectively. There was no significant difference in rates for ORS between the two vaccines in use in Canada (Fluviral and Vaxigrip) both in 2001 and 2002. During the 4 years, incidence was highest in people aged 40–59 years and declined in older age groups. The clinical profile of ORS has remained remarkably stable over years. Overall, ocular, respiratory symptoms or facial edema were reported by 58%, 84% and 31% of patients, respectively, and 15% had symptoms including all three symptom categories. ORS lasted more than a week in 8–13% of the cases. Conclusion: ORS is an adverse event that occurred with both influenza vaccines used in Canada. Its frequency has declined substantially but is still present after 4 years. It constitutes a clinical entity distinct from anaphylactic allergy. Unlike anaphylaxis, ORS does not constitute an absolute contraindication to further doses.

We report the ophthalmological and laboratory findings of 6 patients who, after influenza vaccination, were affected by oculorespiratory syndrome (ORS), complaining of red eyes, photophobia, blurred vision, palpebral edema, ocular pain and itching, and conjunctival secretions. The conjunctivae were mildly hyperemic with few follicles, but the ophthalmological examination findings were otherwise normal. Patients had lymphopenia and decreased levels of the total hemolytic complement and the third and fourth component of the complement. We conclude that ORS causes conjunctivitis and seems to involve the complement.

During the 2000-2001 influenza immunization campaign in Canada, an oculorespiratory syndrome (ORS) was recognized as adverse event associated with one of the vaccines administered. The initial surveillance case definition for ORS in 2000-2001 specified onset within 24 h after vaccination and resolution within 48 h after onset; the restriction on the duration of ORS was removed from the case definition for the vaccine distributed during the 2001-2002 influenza season. The implicated vaccine contained large aggregates of unsplit virions; alterations to the manufacturing process for the vaccine distributed during 2001-2002 addressed this. A randomized, double-blind, placebo-controlled trial assessed the safety of the reformulated version in previously affected adults. The trial was halted early, after 61 participants had received an injection (34 had received vaccine, and 27 had received placebo). The vaccine-attributable recurrence rate for onset of ORS within 24 h after injection was 33% (95% confidence interval [CI], 10%-53%); for cases that resolved within 48 h, this rate was 27% (95% CI, 5%-47%). Previously affected persons should be informed of the risk of ORS recurrence but also that episodes of such recurrence are mild and well tolerated.

During the 2000-2001 influenza immunization campaign in Canada, a new adverse event, oculo-respiratory syndrome (ORS), was noted in association with administration of vaccine supplied by one manufacturer. The original case definition for ORS specified bilateral conjunctivitis, facial edema, or respiratory symptoms beginning 2-24 h after influenza vaccination and resolving within 48 h after onset. To characterize the spectrum, severity, and impact of ORS, we contacted persons who had reported any influenza vaccine-associated adverse event in British Columbia, Canada, during the 2000-2001 vaccination campaign. With use of a standardized telephone interview, we collected information from 609 (79%) of 769 eligible persons. Thirteen percent of ORS-affected persons reported onsetor=2 h after vaccination, 27% experienced symptoms for48 h, and 42% considered the symptoms to be severe. The surveillance case definition for ORS for 2001-2002 was revised to include onsetor=24 h after vaccination, with no restriction on duration. ORS should be incorporated into annual influenza vaccine safety monitoring.

We read with interest Miller and colleagues findings on the association between narcolepsy and the AS03 adjuvanted pandemic A/H1N1 2009 vaccine in England and, in particular, their call for investigations of other A/H1N1 2009 vaccines to ascertain the risk of narcolepsy.1 Risk estimates above 10 are unusual, and in pharmacoepidemiology lead to the suspicion of unknown confounding factors. The English data, confirming previous reports,2 3 considerably lessens the likelihood of confounding. However, the mechanisms by which this vaccine’s components may have contributed to an increased risk for narcolepsy are unclear and may be difficult to dissect, as the still uncertain pathogenesis of Guillain-Barre syndrome after flu vaccination illustrates. Previous observations suggest that similar vaccines may have subtle differences that manifest themselves in different ways or in different seasonal formulations. Oculorespiratory syndrome has been associated with one split seasonal vaccine product but not with others.4 Perhaps appropriate in the context of narcolepsy cases occurring …

Background Oculorespiratory syndrome (ORS) after influenza vaccination has many features of an allergic reaction. Methods The objective of the study was to estimate the recurrence rate of ORS after receipt of either of 2 influenza vaccines available in Canada for the 2002-2003 influenza season in individuals who experienced ORS in 2000 or 2001. We designed a randomized, crossover, double-blind, placebo-controlled trial in which patients received the vaccine and the placebo 7 days apart. Patients were contacted by telephone at 24 hours and seen at 7 days to collect information about the recurrence of ORS symptoms. The 146 patients belonged to 3 groups: group A (46 patients) had ORS in 2000 but were not revaccinated in 2001, group B (50 patients) had ORS in 2000 and were revaccinated in 2001, and group C (50 patients) had ORS in 2001 but not in 2000. Half of the participants received Fluviral S/F (Shire Biologics) and half received Vaxigrip (Aventis Pasteur). The main outcome measure was the risk difference in ORS symptoms in the 24 hours after receiving the vaccine and after receiving placebo. Results Recurrence attributable to the vaccine occurred in 34% (95% confidence interval, 21%-47%) of patients after receiving Fluviral S/F and in 15% (95% confidence interval, 2%-28%) after receiving Vaxigrip. The rate was twice as high in group A vs groups B and C. The risk of ORS was highest and most significant in group A patients vaccinated with Fluviral S/F. Most cases were mild, with 94% of patients with recurrence indicating that they would still be revaccinated the next year. Conclusions Despite high recurrence rates, revaccination of persons previously affected by ORS seems to be safe. Oculorespiratory syndrome is not anaphylactic, and most recurrences are benign. Most patients remain willing to be revaccinated.