An Advisory Committee Statement (ACS)
National Advisory Committee on Immunization (NACI)*

SUPPLEMENTARY STATEMENT FOR THE 2002-2003 INFLUENZA SEASON: UPDATE ON OCULO-RESPIRATORY SYNDROME IN ASSOCIATION WITH INFLUENZA VACCINATION

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Preamble

The National Advisory Committee on Immunization (NACI) provides Health Canada with ongoing and timely medical, scientific,and public-health advice relating to immunization. Health Canada acknowledges that the advice and recommendations set out in this statement are based upon the best current available scientific knowledge, and is disseminating this document for information purposes. Persons administering or using the vaccine should also be aware of the contents of the relevant product monograph(s). Recommendations for use and other information set out herein may differ from that set out in the product monograph(s) of the Canadian licensed manufacturer(s) of the vaccine(s). Manufacturer(s) have only sought approval of the vaccine(s) and provided evidence as to its safety and efficacy when used in accordance with the product monographs.

Overview

Health Canada conducts national surveillance of vaccine-associated adverse events (VAAEs). During the 2000-2001 influenza season, Health Canada was first notified of the occurrence of an increased number of persons reporting ocular and/or respiratory symptoms in association with receiving the influenza vaccination^(1-3). Enhanced surveillance for VAAEs was commenced. Provinces and territories collected additional information on cases with the use of a supplementary case report form in addition to the routine VAAE report form.

The pattern of symptoms reported with increased frequency in association with receiving the 2000-2001 influenza vaccine was recognized as an “oculo-respiratory syndrome” (ORS). Public health experts and Health Canada devised an ORS surveillance case definition for the 2000-2001 influenza season (henceforth to be called the “2000 surveillance definition”) as follows: the presence of i) bilateral red eyes, and/or; ii) at least one of the following respiratory symptoms: cough, wheeze, chest tightness, difficulty breathing, or sore throat, and/or; iii) facial edema, occurring within 2 to 24 hours of influenza immunization and resolving within 48 hours.

ORS during the 2000-2001 influenza vaccination season

During the 2000-2001 influenza immunization season, 960 reports were classified as meeting the ORS case definition, out of a total of 2,450 reported influenza VAAEs⁽³⁾. The syndrome was generally noted to be mild and self-limited; about 25% reported oculo-respiratory symptoms lasting > 48 hours. Twenty-four percent of cases consulted a healthcare provider and 11 (1%) were hospitalized. There were no deaths reported in association with ORS which were causally attributed to the vaccine.

During the 2000-2001 season, 925 (96%) cases of ORS occurred following receipt of Fluviral^® S/F produced by BioChem Pharma (now Shire Biologics, a division of Shire BioChem Inc.), and 12 (1%) cases occurred following receipt of Fluzone^® or Vaxigrip^®, both produced by Aventis Pasteur Limited. In 23 (2%) cases the vaccine given was unknown. During the 2000-2001 influenza season, 3,799,890 doses of Fluviral^® S/F, 2,451,690 doses of Fluzone^®, and 5,951,750 doses of Vaxigrip^® were distributed in Canada. The actual number of doses administered is not known.

All three vaccines licensed in Canada during the 2000-2001 season used the same influenza strains and seed stocks. Fluviral^® S/F used deoxycholate to split the virus, whereas Fluzone^® and Vaxigrip^® used Triton X-100. Electron microscopic studies revealed a higher proportion of unsplit (whole) virus, and a higher proportion of aggregate virus particles in Fluviral^® S/F, compared to the other two vaccines, and compared to previous years. It was hypothesized that deoxycholate may not have caused adequate viral splitting, and the unsplit or aggregated (or both) virus in Fluviral^® S/F may have been etiologically associated with ORS^(2,4).

Although the number of these reported adverse events was higher than in the past, conjunctivitis or respiratory symptoms following influenza immunization have been previously reported in Canada, the United States and Europe. In Italy in 1995-1996 an increased number of VAAEs consisting of fever, myalgia, respiratory and other symptoms were reported in association with an influenza vaccine licensed for the first time in Italy in 1995⁽⁵⁾. It is not known whether this vaccine contained a higher proportion of unsplit virus and/or aggregate viral particles. During the 1990's health officials in the Czech Republic also questioned whether unsplit virus and/or aggregate viral particles may have been associated with an observed increase in the number of influenza VAAEs, although data on the nature of these adverse events are unavailable at this time (Dr. J. Wood, National Institute for Biological Standards and Control, Potters Bar, England: personal communication, 2002).

ORS during the 2001-2002 influenza vaccination season

For the 2001-2002 influenza vaccine campaign, there were approximately 9.3 million doses of vaccine distributed in Canada. The majority of the vaccines were distributed in the four largest provinces: approximately 5.3, 1.6, 0.9 and 0.5 million doses were distributed in Ontario, Quebec, British Columbia and Alberta respectively. There were two manufacturers supplying vaccines in Canada: Aventis Pasteur Ltd. distributed approximately 7.3 million doses of Fluzone^® and Vaxigrip^®, and Shire Biologics distributed approximately 2 million doses of Fluviral^® S/F. Provinces varied in terms of the proportion of vaccines received from each manufacturer. Ontario received > 50% of the national supply of vaccine from Aventis Pasteur Ltd. and Quebec received > 50% of vaccine from Shire Biologics.

For the 2001-2002 season, Shire Biologics produced a new Fluviral^® S/F vaccine using sodium deoxycholate and Triton X-100 as splitting agents⁽⁴⁾. Electron microscopic studies performed by Shire on their 2001-2002 vaccine revealed a low percentage of unsplit virions, which was similar to the percentage reported for Fluviral^® S/F produced in 1999.

Enhanced surveillance for influenza VAAEs was continued during the 2001-2002 season. In total, Health Canada received 1,800 reports of influenza VAAEs in persons vaccinated between 1 September, 2001 and 21 March, 2002. In order to compare ORS occurring in the 2001-2002 season, with ORS occurring in the 2000-2001 season, Health Canada classified influenza VAAE reports using the 2000 surveillance ORS case definition. However, in the 15 November, 2001 edition of CCDR⁽⁴⁾, the National Committee on Immunization (NACI) changed the case definition in response to early reports from research studies suggesting that the onset time and duration stipulated in the 2000 surveillance definition may have excluded potential cases. The definition proposed in that publication (subsequently referred to as the “2001 definition”) was as follows: onset of bilateral red eyes and/or respiratory symptoms (cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness or sore throat) and/or facial swelling occurring within 24 hours of influenza immunization. For the 2001-2002 influenza season the number of ORS reports, and health outcomes for ORS cases, are presented in Table 1 using both ORS definitions.

Of the 1,800 reported VAAEs, 502 (28%) met the 2000 surveillance definition for ORS. The majority of cases with ORS reported mild symptoms and health outcomes were similar between ORS cases and non-ORS cases. Of the ORS cases, 86 (17%) consulted a healthcare practitioner, one (0.2%) was hospitalized and no deaths were reported. Of the non-ORS cases, 279 (22%) consulted a healthcare practitioner, 24 (1.9%) were hospitalized and two (0.2%) died within 12 days of immunization. The Advisory Committee on Causality Assessment (ACCA) has a mandate to review all serious VAAEs in order to determine causal relationships between events temporally associated with vaccination.

Risk factors associated with developing ORS were as follows: age, with the highest rates in those 40 to 59 years of age; and, no previous history of influenza immunization. There was no significant gender difference in ORS and non-ORS cases.

Provincial and territorial reporting of influenza VAAEs varied widely with Quebec providing the highest number of reports relative to the number of doses distributed for each of the available vaccines. The rates of ORS cases for influenza vaccines also varied widely between provinces and territories, likely reflecting the differences in reporting. The incidence of ORS per dose of vaccine distributed was calculated using comprehensive surveillance data from Quebec. In this province, there were 13.9 cases of ORS per 100,000 doses of vaccine distributed by Aventis Pasteur Ltd. (Fluzone^® and Vaxigrip^®), and 19.3 cases of ORS per 100,000 doses of vaccine distributed by Shire Biologics (Fluviral^® S/F). Data on the incidence of ORS per 100,000 doses of vaccine administered are not available.

In summary, using the same original case definitions for the two influenza seasons, there was a lower number of ORS cases reported to the national VAAE surveillance system during the 2001-2002 season as compared to the previous season. The majority of ORS cases reported had mild, self-limited illness and both of the vaccines used in Canada were associated with ORS. ORS was reported more frequently in persons without a previous history of influenza vaccination, as compared to those previously vaccinated; however, the effect of repeated doses of influenza vaccine needs to be further studied.

Research studies

Vaccine safety studies

Prior to the 2001-2002 influenza season a national randomized double-blind placebo controlled cross-over trial was initiated for persons >=19 years of age who previously experienced ORS during the 2000-2001 season (the “recurrence” study)^(4,6). The purpose of the study was to determine the risk of recurrence of ORS following vaccination with the reformulated Fluviral^® S/F vaccine produced for the 2001-2002 season. The planned enrollment was for 150 individuals. However the study was aborted when, according to protocol, the vaccine-attributable risk of ORS exceeded 10%. At the time that the study was terminated, 65 subjects were participating and had received a single dose of either vaccine or placebo. The vaccine-attributable ORS risk was 24.8% (95% confidence intervals 7.0% to 42.5%). Among the 11 persons who experienced ORS following vaccination, symptoms were generally milder than previously experienced, and none sought medical attention.

Another national study was undertaken prior to the 2001-2002 influenza season to determine the safety of the re-formulated Fluviral^® S/F vaccine administered to adults 30 to 59 years of age who had no previous experience of ORS (the “occurrence” study)^(4,7). ORS developed in 6.3% of those who received Fluviral^® S/F, and in 3.5% of those receiving placebo, yielding a vaccine-attributable ORS risk of 2.8% (95% confidence intervals 0.5% to 5.1%). No subjects experienced anaphylaxis or other allergic symptoms. Of the 39 ORS cases occurring after vaccine, 35 were mild. No individuals contacted physicians, or were hospitalized.

A retrospective cohort study was undertaken in Quebec in order to compare the risk of ORS following influenza vaccination using two vaccines (Fluviral^® S/F and Vaxigrip^®) produced for the 2001-2002 season⁽⁸⁾. The frequency of ORS symptoms was similar following either vaccine (p = 0.54). The risk of ORS was 10 times greater among those who had experienced vaccine-associated ORS in the 2000-2001 season, and who were revaccinated in this study, compared to those who had never previously experienced ORS. It should be noted that those experiencing severe ORS symptoms during the 2000-2001 season would not likely have been revaccinated for the 2001-2002 season.

In the fall of 2001, Skowronski et al. conducted telephone interviews among British Columbians >=18 years of age who were reported to have experienced an influenza vaccine-associated adverse event during the 2000-2001 season. (Dr. D. Skowronski, British Columbia Centre for Disease Control, Vancouver: personal communication, 2002). Among the interviewed subjects who reported oculo-respiratory facial symptoms (n = 485), only 10% reported onset > 24 hours following influenza vaccination, but 27% reported symptoms lasting > 48 hours.

Using a Likert scale to assess severity of symptoms, 24% of those meeting the 2000 ORS surveillance definition reported their symptom experience as having been mild (present but not bothersome), 34% as moderate (interfered with daily activities), 41% as severe (prevented daily activities), and 1% did not specify. Those who perceived their symptoms were severe were more likely to be older in age, be a smoker and have a history of lung disease. Nearly half of those who reported oculo-respiratory symptoms said they were unlikely or very unlikely to receive influenza vaccine again.

Immunologic studies

Skowronski et al. performed a skin test study to investigate whether ORS was due to failure of the splitting process during manufacturing of the 2000-2001 vaccine (resulting in micro-aggregates of unsplit virions), whether ORS was associated with a particular viral strain, and to identify persons at risk for subsequent ORS⁽⁹⁾. Intra-dermal injection of minute quantities of vaccine antigen was associated with the onset of ORS symptoms more commonly in persons previously affected by ORS compared to those without prior experience of ORS. The size or quality of the cutaneous reaction could not identify individuals at risk of ORS. Skin testing did not identify whether ORS was related to a failure of the splitting process during vaccine production or whether it was associated with a specific viral strain.

It has been hypothesized that the immune system of individuals experiencing ORS is biased towards a TH2 rather than TH1 cytokine response, and that aggregates of unsplit virions may influence this response. Skowronski et al. studied this hypothesis through cytokine measurements following in vitro challenge of peripheral blood mononuclear cells (PBMCs) taken from those with and without a history of ORS, using influenza antigen (Dr. D. Skowronski, British Columbia Centre for Disease Control, Vancouver: personal communication, 2002). This study could not clearly distinguish ORS affected from unaffected persons based on in vitro cytokine response.

What is the pathophysiology of ORS?

The pathophysiologic mechanism underlying ORS remains unknown. Initial theories suggested that deoxycholate may not have caused adequate viral splitting in the 2000-2001 season Fluviral^® S/F vaccine and that unsplit or aggregated virions, may have led to cytokine release through promotion of a TH2 immune response. For the 2001-2002 season, Shire Biologics produced a new Fluviral^® S/F vaccine using both sodium deoxycholate and Triton X-100 as splitting agents. As in previous years, Aventis Pasteur Ltd. continued to use Triton X-100 as their splitting agent. Nevertheless, during the 2001-2002 season ORS was reported in association with all three licensed Canadian vaccines.

The time course of ORS, skin test results and clinical presentation exclude Type 1 (IgE), Type 3 (immune complex-mediated) and Type 4 (classical delayed) hypersensitivity immune responses (Gell and Coombs classification system) as etiologic explanations. The release of interferon in response to viral aggregates is unlikely to be the exclusive cause of this syndrome because the symptoms (and projected signs) of ORS do not include the majority of adverse effects associated with high doses of interferon, and because there is no dose/response relationship.

One current hypothesis suggests that ORS is a localized specific T cell response to viral aggregates in influenza vaccine, resulting in release of neurotrophins and stimulation of neuropeptide secretion locally, as well as local synthesis of chemokines possibly mediated via antigen presenting cells located at key mucosal sites (Dr. R. Warrington, Department of Medicine, University of Manitoba, Winnipeg: personal communication, 2002). The immune mechanism leading to ORS manifestations may be partially genetically determined, and partially determined by previous exposure to influenza vaccine and wild virus antigen. It is possible that such reactions occur yearly in low numbers worldwide in those receiving influenza vaccine, but that increased numbers of cases are recognized by surveillance systems in particular years depending on the nature of the vaccine and interaction with “host” genetic and immune factors. The number of reports will also be determined by the sensitivity of the VAAE surveillance system.

Summary

During the 2000-2001 influenza season an increased number of VAAEs affecting the eyes and/or the respiratory system were reported in Canada. This phenomenon was observed primarily in association with the use of Fluviral^® S/F in 2000-2001. During the 2001-2002 season, fewer VAAEs fitting the newly created case definition of an oculo-respiratory syndrome (ORS) were reported compared to the previous season. However the syndrome was reported in association with the use of vaccine products from both Aventis Pasteur Ltd. and Shire Biologics.

In comparing reports of influenza VAAEs we must acknowledge that the intensification of surveillance, and provision of information to healthcare providers and the public during the 2000-2001 season, and continuing on into the next season, likely resulted in increased recognition and reporting of symptoms and signs which may or may not be etiologically related to influenza vaccine administration. The relationship, if any, of the Canadian experience of increased influenza VAAEs fitting an ORS pattern, with previous European published and unpublished experiences of increased VAAEs in selected years, is unclear at this time.

It is difficult to devise a satisfactory case definition for ORS. Many of the symptoms are nonspecific and can be caused by other conditions, including infection and allergy. We do not have a clinical or laboratory test to confirm or exclude ORS. There appears to be a spectrum of symptoms. In many if not most cases, we are unable to confirm clinical signs because the majority of individuals reporting symptoms do not see a healthcare provider.

An individual who experiences an influenza VAAE might meet the definition requirements of ORS, yet a good clinical assessment may reveal viral infection as the cause of the event. Such an individual should not be reported or labelled as having ORS. NACI urges healthcare workers to use good clinical judgment in assessing all VAAEs, including ORS.

The 2000 surveillance definition of ORS was devised in an effort to balance sensitivity with specificity. In the setting of a newly recognized vaccine-associated syndrome, it was felt to be important to capture as many potential cases as possible. The time criteria used in the definition were included in an attempt to help exclude other potential causes, such as allergy or infection. However, analysis of ORS reports from the 2000-2001 influenza season showed that ORS-like cases with onset < 2 hours after vaccination, and those with a duration > 48 hours, had a similar clinical profile to those cases meeting the 2000 surveillance case definition. Subsequently the revised 2001 definition of ORS relaxed the timelines presented in the earlier definition, thus making the definition more sensitive, and likely reducing specificity. The effect of the prevalence of “true” cases of ORS on the predictive value of the case definition must also be recognized. If ORS was caused by an immunologic reaction to the “trigger” of unsplit virus and/or viral aggregates present in 2000-2001 vaccine, and if the prevalence of this trigger diminishes in future seasons, we can expect that the predictive value of the case definition to detect “true” cases of ORS will decrease.

Recommendation for the 2002-2003 influenza season

In April 2002 in Quebec City⁽¹⁰⁾, and June 2002 in Winnipeg, national and international vaccine experts met along with Health Canada officials in order to identify future ORS research activities. In order to arrive at a more specific case definition, we will need a greater understanding of the underlying pathophysiology of this condition. A review of the specific symptoms experienced by subjects in the previously described recurrence study is also planned in the near future. Recurrent symptoms and/or signs associated with repeated vaccination may be more specific to the “ORS” phenomenon. Until  further information is available, NACI recommends continued use of the 2001 ORS case definition for surveillance and for the “triaging” of clinical assessments.

Assessment of the severity of ORS symptoms is based on the perception of the individual⁽⁴⁾. After questioning a person about his/her symptoms, the healthcare provider may classify the severity of ORS according to the following scale: mild (easily tolerated; present but not problematic), moderate (interferes with activities of daily living; bothersome, requires activity changes and possibly medication) or severe (prevents activities of daily living; unable to work or sleep).

Data from research studies indicate that revaccination of those who have experienced mild or moderate ORS symptoms may be done safely. Individuals who have previously experienced severe ORS consisting of non-lower respiratory symptoms (bilateral red eyes, cough, sore throat, hoarseness, facial swelling) may also be safely re-immunized with influenza vaccine. There is no longer any recommendation to use one vaccine product in preference to another, when revaccinating those who have previously experienced ORS.

Expert review of the risks and benefits of vaccination should be sought for those who have previously experienced severe lower respiratory symptoms (wheeze, chest tightness, difficulty breathing) within 24 hours of influenza vaccination. Expert review should also be sought for those experiencing severe difficulty swallowing, or symptoms which are not listed in the ORS case definition (e.g., severe throat constriction) but which raise concern regarding the safety of reimmunization. Healthcare providers who are unsure whether an individual previously experienced ORS versus an IgE-mediated hypersensitivity immune response should seek consultative advice. Consultation may be obtained from local Medical Officers of Health or other experts in infectious disease, allergy/immunology and/or public health who are familiar with the risks of influenza, the risks and benefits of influenza vaccination, and who have specific knowledge regarding ORS.

Informed consent is required for all vaccinations. For influenza vaccination, informed consent requires an understanding of the risks/benefits of influenza and influenza immunization, including information on ORS. Information on the ORS recurrence rate should be given to those who have previously experienced the syndrome. All individuals who are vaccinated should be advised to report adverse events to the health authorities, and to seek early medical attention when appropriate. For those who decline immunization, consider alternative risk reduction measures, such as antiviral prophylaxis, during outbreaks of influenza. Infection control measures, early diagnosis and appropriate use of antiviral therapy are measures that apply in the prevention and management of all cases of influenza.

Enhanced surveillance of influenza VAAEs during the 2002-2003 season will continue. Healthcare providers, and those receiving influenza vaccine, should continue to be vigilant in reporting any unexpected VAAE to their local health authority.

Influenza is a major cause of morbidity and mortality in Canada. Vaccination of persons at high risk of complications from influenza, as well as those capable of transmitting the virus to those in high-risk categories, continues to be the most effective measure for reducing the impact of influenza^(3,11). NACI and Health Canada are committed to the reduction of influenza related morbidity and mortality through the maintenance of a safe and effective vaccination program.

Acknowledgements

NACI gratefully acknowledges the assistance of the following individuals in the preparation of this manuscript: Yogesh Choudhri, Wikke Walop, Susan Squires, Theresa Tam, Arlene King, Danuta Skowronski, Richard Warrington and John Wood.

References

1. National Advisory Committee on Immunization. Supplementary statement on influenza vaccination: continued use of Fluviral^® influenza vaccine in the 2000-2001 season. CCDR 2001;27(ACS-1, 2):1-3.

2. National Advisory Committee on Immunization. Statement on influenza vaccination for the 2001-2002 season. CCDR 2001;27(ACS-4):1-24.

3. Boulianne N, De Serres G, Duval B et al. Clinical manifestations and incidence of oculo-respiratory syndrome following influenza vaccination - Quebec 2000. CCDR 2001;27:85-90.

4. National Advisory Committee on Immunization. Supplementary statement for the 2001-2002 season: influenza vaccination of persons who experienced oculo-respiratory syndrome following previous influenza vaccination. CCDR 2001;27(ACS-7):1-7.

5. Spila-Alegiani S, Salmaso S, Rota MC et al. Reactogenicity in the elderly of nine commercial influenza vaccines: results from the Italian SVEVA study. Vaccine 1999;17:1898-904.

6. Skowronski DM, De Serres G, Warrington R et al. Oculo-respiratory syndrome following influenza vaccine: recurrence risk with re-formulated vaccine for 2001-2002. Abstract S42. Fifth Annual Conference on Vaccine Research, Baltimore, MD: 6 May 2002, p. 61.

7. Scheifele DW, Duval B, Russell M et al. Oculo-respiratory syndrome (ORS) among healthy adults given a reformulated influenza vaccine previously linked with ORS. Abstract S43. Fifth Annual Conference on Vaccine Research, Baltimore, MD: 6 May 2002, p. 61.

8. De Serres G, Boulianne N, Duval B et al. Oculo-respiratory syndrome after influenza vaccination: similar risk with two 2001-2002 influenza vaccines. Abstract S44. Fifth Annual Conference on Vaccine Research, Baltimore, MD: 6 May 2002, p. 61.

9. Skowronski DM, De Serres G, Hebert J et al. Skin testing to evaluate oculo-respiratory syndrome (ORS) associated with influenza vaccination during the 2000-2001 season. Vaccine, in press.

* Members: Dr. V. Marchessault (Chairperson), Dr. A. King (Executive Secretary), J. Rendall (Administrative Secretary), Dr. I. Bowmer, Dr. G. De Serres, Dr. S. Dobson, Dr. J. Embree, Dr. I. Gemmill, Dr. J. Langley, Dr. A. McGeer, Dr. P. Orr, Dr. B. Tan, A. Zierler.

Liaison Representatives: S. Callery (CHICA), Dr. J. Carsley (CPHA), Dr. V. Lentini (DND), Dr. M. Douville-Fradet (ACE), Dr. T. Freeman (CFPC), Dr. R. Massé (CCMOH), K. Pielak (CNCI), Dr. J. Salzman (CATMAT), Dr. L. Samson, (CPS), Dr. D. Scheifele (CAIRE), Dr. M. Wharton (CDC), Dr. A. McCarthy (CIDS).

Ex-Officio Representatives: Dr. M. Dawar (FNIHB), Dr. L. Palkonyay (BGTD), Dr. T. Tam (CIDPC).

† This statement was prepared by Dr. P. Orr and approved by NACI.

[Canada Communicable Disease Report]