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

SUPPLEMENTARY STATEMENT FOR THE 2001-2002 SEASON: INFLUENZA VACCINATION OF PERSONS WHO EXPERIENCED OCULO-RESPIRATORY SYNDROME FOLLOWING PREVIOUS 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

During the 2000-2001 influenza immunization season, Health Canada received a total of 2,450 influenza vaccine-associated adverse events of which 1,735 (71%) reported ocular or respiratory symptoms. Of these reports, 960 (39% of total) were classified as meeting the case definition for a newly recognized “oculo-respiratory syndrome (ORS)”⁽¹⁾. During the 2000-2001 season ORS was defined as the presence of bilateral red eyes or at least one of the following respiratory symptoms: cough, wheeze, chest tightness, difficulty breathing or sore throat or facial edema, occurring within 2 to 24 hours of influenza vaccination and resolving within 48 hours.

Of these cases, 74% were female and 71% were between 30 and 59 years of age. The syndrome was generally mild and self-limited, about 25% of people 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.

Nine hundred and twenty-five (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 were distributed in Canada, 2,451,690 doses of Fluzone^®, and 5,951,750 doses of Vaxigrip^®. The actual number of doses administered is not known.

Although the number of these reported adverse events is higher than in the past, conjunctivitis or respiratory symptoms following influenza immunization have been previously reported in Canada, in the United States and in Europe⁽¹⁾. Upon review, some of these cases fit the current definition of ORS, although vaccine-associated oculo-respiratory symptoms were not recognized as a syndrome in the past. Intensified surveillance for adverse events was initiated when ORS was recognized, and appropriate steps were taken to inform patients and the public. These factors must be considered when comparing the number of adverse events reported in past influenza seasons⁽¹⁾. It is possible that cases of what we now call ORS were not recognized, or reported, in the past.

The pathophysiologic mechanism that underlies ORS remains unknown. 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 (19.4% according to Shire studies), and a higher proportion of aggregate virus particles in Fluviral^® S/F as compared to the other two vaccines⁽¹⁾ and as compared to previous years. It has been 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⁽¹⁾. However there is no conclusive evidence at this time to prove or disprove this hypothesis.

Recent Studies

To ensure the safety of the new Fluviral^® S/F vaccine, Health Canada required special studies prior to licensure. Results of these studies were made available for review by the National Advisory Committee on Immunization (NACI), with permission of the manufacturer. For the 2001-2002 season, Shire Biologics has produced a new Fluviral^® S/F vaccine using sodium deoxycholate and Triton X-100 as splitting agents. Electron microscopic studies performed by Shire on their 2001-2002 vaccine revealed a lower percentage (1.1%) of unsplit virions, which is similar to the percentage reported for Fluviral^® S/F produced in 1999.

Health Canada did not require special safety studies of Fluzone^® or Vaxigrip^®, which assess the risk of vaccine-associated ORS, prior to licensure for the 2001-2002 influenza season. As noted previously, a minority of cases of ORS were reported in association with the use of these vaccines during the 2000-2001 season. The rate of recurrence of ORS with repeated use of these vaccines is unknown.

The studies of Fluviral^® S/F were performed in August, September and October 2001, in the following cities: Québec, Winnipeg, Calgary and Vancouver. The purpose of the first (labelled “01”) study was to determine the safety of the new Fluviral^® S/F vaccine administered to adults who had no previous experience of ORS. The study was randomized, blinded, placebo-controlled and cross-over in design. Two injections were administered 1 week apart. Subjects were observed for 30 minutes after vaccination, and a structured questionnaire was administered by telephone 24 hours later, and again during the follow-up period. Clinical examinations were arranged if required. The case definition of ORS was the same as that used for surveillance: the onset of bilateral red eyes, respiratory symptoms (cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness or sore throat), or facial swelling, occurring within 2 to 24 hours of influenza vaccination.

Six hundred and thirty-one adults 30 to 59 years of age were randomized and immunized in the 01 study. 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. Most of the reported cases of ORS were mild; no individuals contacted their own physicians, visited a health clinic/emergency room, or were hospitalized. Injection site soreness was the only non-ORS symptom that was associated with vaccine injection more often than placebo.

A second (labelled “02”) randomized, blinded, placebo-controlled, cross-over study was conducted at the same sites in order to assess the safety of the new Fluviral^® S/F vaccine in adults who had experienced ORS associated with Fluviral^® S/F vaccination during the 2000-2001 season. As in the previous study (01), the protocol plan was to administer two injections 1 week apart. Subjects were monitored for 30 minutes after vaccination; a structured telephone questionnaire was administered on the evening of the immunization, 24 hours later, and again during the follow-up period. The definition of ORS was the same as in the 01 study. The planned enrollment was for 150 individuals who were > 19 years of age. 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, 61 subjects were participating and had received a single dose of either vaccine or placebo. ORS occurred in 10 of the 32 individuals who received Fluviral^® S/F, and in one of the 29 individuals who received placebo, yielding a vaccine-attributable ORS risk of 27.8% (95% confidence intervals 10.4% to 45.2%).

All of the 02 study subjects were > 19 years of age. Of the 10 individuals who experienced ORS in the 02 study, four described their previous syndrome experience (during the 2000-2001 season) as severe in intensity, three as moderate and three as mild. The study defined severe symptoms as those that prevented activities of daily living, moderate symptoms as those that interfered with activities of daily living, and mild symptoms as those that were easily tolerated. During the 02 trial, eight of the 10 individuals who experienced ORS described their symptoms as mild in intensity, one described their symptoms as intermediate between mild and moderate, and one as moderate. All 10 subjects reported that their symptoms were either of the same intensity, or milder, than symptoms associated with vaccination during the previous season. No subjects sought medical attention for their symptoms, visited a health clinic/emergency room, or were hospitalized. No individuals experienced anaphylaxis or other allergic symptoms. The extent to which subjects in the 02 study are, or are not, representative (in terms of demographics, comorbidities and severity of symptoms) of all those who experienced ORS during the 2000-2001 vaccination season is unclear at this time.

Further research studies to describe the pathophysiology of ORS (which at present remains unknown), as well as epidemiology, are required.

NACI Recommendations for the 2001-2002 Season

NACI has concluded that in those who have never previously been immunized with influenza vaccine, and those who have not previously experienced ORS following influenza immunization, immunization should proceed as planned with the usual informed consent procedure, using any licensed influenza vaccine⁽²⁾. In those who have experienced ORS following influenza immunization, a risk/benefit assessment, according to the algorithm shown in Figure 1 (with explanatory footnotes), should be conducted before proceeding with influenza immunization. Information regarding informed consent is provided in the algorithm notes. As in previous years, the process of obtaining informed consent for influenza vaccination involves a balanced discussion of the risks and complications of influenza, as well as the effectiveness and safety of the vaccine.

Studies have not been done using Vaxigrip^® or Fluzone^® vaccine in those who previously developed ORS after receiving Fluviral^® S/F vaccine. Nevertheless, NACI recommends that once the decision is made to offer influenza vaccine to those who previously developed ORS after Fluviral^® S/F (using the guidelines outlined in the algorithm), healthcare workers should initially offer Vaxigrip^® or Fluzone^® if either vaccine is available. If Vaxigrip^® or Fluzone^® are not available, Fluviral^® S/F should be offered.

A program for enhanced surveillance of influenza vaccine-associated adverse events during the 2001-2002 season is planned by Health Canada. Healthcare providers, and those receiving influenza vaccine, should continue to be vigilant in reporting any unexpected vaccine-associated adverse event to their local health authority.

Influenza remains a major cause of morbidity and mortality in Canada⁽²⁾. 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. Both NACI and Health Canada remain committed to the reduction of influenza related morbidity and mortality through the maintenance of a safe and effective national vaccination program.

Figure 1: Decision-making algorithm for influenza immunization of persons with oculo-respiratory syndrome (ORS) following previous influenza immunization

*Algorithm notes:

(1) Oculo-Respiratory Syndrome (ORS): Onset of bilateral red eyes or respiratory symptoms (cough, wheeze chest tightness, difficulty breathing, difficulty swallowing, hoarseness or sore throat) or facial swelling within 24 hours of influenza immunization.

(2) Mild, moderate or severe ORS: On questioning by the healthcare provider, the person’s self-assessment of the intensity of ORS and the healthcare provider’s assessment of the severity of ORS.

Mild: easily tolerated (present, but not problematic).

Moderate: interferes with activities of daily living (bothersome, requires activity changes and possibly medication).

Severe: prevents activities of daily living (unable to work or sleep).

(3) Persons at high risk of influenza-related complications include:

• Adults and children with chronic cardiac or pulmonary disorders severe enough to require regular medical follow-up or hospital care;

• People of any age who are residents of nursing homes and other chronic care facilities;

• People >= 65 years of age;

• Adults and children with other chronic conditions;

• Children and adolescents with conditions treated for long periods with acetylsalicylic acid;

• People at high risk of influenza complications embarking on travel to foreign destinations where influenza is likely to be circulating.

(4) Persons capable of transmitting influenza to those at high risk for influenza-related complications/Others include:

• Healthcare workers and other personnel who have significant contact with people in the high-risk groups previously described;

• Household contacts (including children) of people at high risk who either cannot be vaccinated, or may respond inadequately to vaccination;

• People who provide essential community services;

• Healthy persons, including healthy pregnant women.

(5) Offer influenza immunization: Informed consent should include the risks/benefits of influenza and influenza immunization, information on ORS, absence of data on rate of ORS recurrence in those who received Vaxigrip^® (or Fluzone^®) this year, information on ORS recurrence in those who received Fluviral^® S/F this year and NACI recommendation regarding use of Vaxigrip^® or Fluzone^®, if available, in those who have experienced ORS in previous years. For those who decline immunization, consider alternative risk reduction measures^† during outbreaks of influenza.

(6) Consider expert review of risk/benefit: Assessment should include risks/benefits of influenza and influenza immunization, information on ORS, absence of data on rate of ORS recurrence in those who received Vaxigrip^® or Fluzone^® this year, information on ORS recurrence in those who received Fluviral^® S/F this year and NACI recommendation regarding the use of Vaxigrip^® or Fluzone^® if available, in those who have experienced ORS in previous years. For those not offered immunization, consider risk reduction measures^† during outbreaks of influenza.

(7) Counsel deferral of influenza vaccine during the 2001-2002 season and offer alternatives: Consider risk reduction measures^† during outbreaks of influenza.

† Alternative risk reduction measures may include antiviral prophylaxis, infection control measures and/or early diagnosis and treatment. For advice and information on influenza immunization and alternative risk reduction measures, please refer to your local Medical Health Officer as well as Canada Communicable Disease Report, Volume 27, ACS-4, 1 August 2001, Statement on Influenza Vaccination for the 2001-2002 Season. The document is available on the Health Canada website:  <http://www.phac-aspc.gc.ca/publicat/ccdr-rmtc/01vol27/27sup/acs4.html>.

Acknowledgements

NACI gratefully acknowledges the assistance of the following individuals in the preparation of this manuscript: Dr Arlene King, Dr Eleni Galanis and Dr Laszlo Palkonyay.

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 of Influenza vaccination for the 2001-2002 season. CCDR 2001;27(ACS-4):1-24.

* Members: Dr. V. Marchessault (Chairperson), Dr. J. Spika (Executive Secretary), J. Brousseau (Administrative Secretary), Dr. I. Bowmer, Dr. G. De Serres, Dr. S. Dobson, Dr. J. Embree, Dr. I. Gemmill, Dr. J. Langley, Dr. M. Naus, Dr. P. Orr, Dr. B. Ward, 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. A. King (CIDPC), Dr. L. Palkonyay (BGTD), Dr. P. Riben (FNIHB).

This statement was prepared by Dr. Pamela Orr and approved by NACI.

[Canada Communicable Disease Report]