Influenza vaccine

General adverse effects and adverse reactions

Local adverse reactions after flu immunization are few and infrequent. Slight to moderate tenderness, erythema, and induration at the injection site lasting 1–2 days occur in 15–30% of recipients. Fever, malaise, myalgia, and other symptoms of toxicity are rare (about 2%) and most often affect persons with no prior exposure to the flu antigens in the vaccine, for example young children. These reactions usually begin 6–12 hours after immunization and can last 1 or 2 days. They have been attributed to the vaccine, although the virus is inactivated. On the other hand, cases of respiratory diseases among vaccinees are coincidental. Although current flu vaccines are highly purified, they can cause hypersensitivity reactions such as hives or angioedema, perhaps due to residual egg protein [ , ]. Notwithstanding the fact that the egg protein content is small, asthma or anaphylactic reactions with vascular purpura and encephalopathy can occur in those who are sensitive to the material [ , ].

Incidence

A nationwide surveillance system covering illness after flu immunization in the USA in 1976–77 among over 48 million persons immunized in 1976 with A/New Jersey/76 influenza vaccine (swine flu vaccine) resulted in a total of 4733 reports of illness, including reports of 223 deaths [ ]. Since most of the deaths occurred within 48 hours of immunization, the figures for deaths per 100 000 vaccinees (by diagnosis) were compared with the expected death rate (by the same diagnosis) per 100 000 population for a 2-day period. In general, the crude expected death rate was much higher than the death rate among vaccinees. Other than Guillain–Barré syndrome and rare cases of anaphylaxis, no serious illnesses seemed to be causally associated with flu immunization. However, widespread under-reporting of illness and death in the passive phase of this surveillance system impaired the validity of the study. Allergic skin reactions were reported at a rate of 0.3 per 100 000 vaccinees and severe anaphylaxis at a rate of 0.024 per 100 000. There was a cluster of four cases of encephalitis within 1 week of vaccine administration in one state. There were three deaths from cardiovascular disease in chronically ill persons over 70 years of age immunized in one clinic. It was not possible to establish a causative link between immunization and death. Persons immunized in the clinic died at rate of 5 per 100 000 per day, in contrast to the expected rate of 17 per 100 000 per day for people aged 65 years and older in the respective state.

Case reports of complications temporarily connected with the administration of flu vaccine have been published. They include reports of acute disseminated encephalitis [ ], acute thrombocytopenic purpura [ ], acute transverse myelitis [ ], aseptic meningitis [ ], bullous pemphigoid [ ], encephalopathy [ ], erythromelalgia [ ], optic neuritis [ ] with reversible blindness [ ], optic atrophy [ ], pericarditis [ ], polymyalgia rheumatica [ ], microscopic polyangiitis involving the skin and joints [ ], acute symmetrical polyarthropathy with orbital myositis and posterior scleritis [ ], systemic vasculitis [ ], a trigeminal neuralgia-like symptoms [ ], and vascular purpura with histological features of cutaneous necrotizing vasculitis [ ].

The current status of adjuvanted influenza vaccines has been reviewed [ ]. The authors concluded that the vaccine produces a higher titer of antibodies than non-adjuvanted or virosomal vaccines. Local reactions occur more often, but are mild and transient. The results of a trial with two doses of an intranasally administered inactivated virosome-formulated influenza vaccine containing Escherichia coli heat-labile toxin as a mucosal adjuvant in 106 volunteers aged 33–63 years have been reported [ ]. About 50% of vaccinees had local adverse reactions (44% after the first dose and 54% after the second dose) or systemic adverse reactions (48% and 46%) after administration of the vaccine. Rhinorrhea, sneezing, and headache were the most common reactions; they were mild and transient and resolved within 24–48 hours. No febrile reactions were associated with immunization. Between 77 and 92% of vaccinees developed protective hemagglutination inhibition antibody titers against the two influenza A strains of the vaccine, whereas protective antibody titers against the B strain of the vaccine were achieved in only 49–58%.

Oculorespiratory syndrome

In 2000, oculorespiratory syndrome was identified as a new influenza vaccine-associated adverse effect in Canada. The case definition requires the presence of red eyes or respiratory symptoms or facial edema at 2–24 hours after immunization and lasting 48 hours [ , ]. About 20% of vaccinees with oculorespiratory syndrome described the symptoms as mild and 42% described them as severe. The cause of oculorespiratory syndrome is debated, but the main hypothesis Is that It Is due to large viral aggregates in the vaccine. The reduction In the number of oculorespiratory syndrome reports in 2001–02 with the use of reformulated vaccines with lower aggregate content supports this hypothesis. The authors recommended that manufacturers should consider oculorespiratory syndrome in order to improve the acceptance of influenza vaccines through limitation of the aggregate and unsplit virion content.

Cardiovascular

Influenza infection has been a significant problem in cardiac transplant patients; immunization of such patients could therefore be beneficial. However, its use has been limited by concern that stimulation of the immune system might in principle cause an increased risk of cardiac rejection. In the renal transplant experience, influenza infection itself can trigger an immunological response to cause graft rejection, as well as predisposing to other infections. Another concern is whether an immunosuppressed cardiac transplant recipient could seroconvert sufficiently. In a case-control study in 18 cardiac transplant recipients and 18 control patients 6 months or more beyond transplant surgery, there were no differences in the incidence of cardiac rejection or immune responses [ ].

There have been reports of pericarditis [ , ] in temporal relation to influenza vaccine.

Respiratory

Of 109 children with asthma aged 6 months to 18 years immunized with trivalent subvirion influenza vaccine, 59 vaccinees had no asthma symptoms on the day of immunization, but 50 had an exacerbation requiring prednisone [ ]. Antibody responses were not different in the two groups. Adverse effects, including local swelling at the injection site, fever, rash, and headache, were not different in the two groups.

Pulmonary edema is a rare complication of influenza immunization.

• Interstitial lung edema occurred 3 days after influenza immunization in a 67-year-old patient [ ]. An infectious cause was excluded and an allergic reaction was suspected. After antibiotic treatment and high-dosage glucocorticoids the patient

The safety of cold-adapted trivalent intranasal influenza virus vaccine (CAIV–FluMist) have been determined in 9689 children and adolescents aged 1–17 years using vaccine or placebo (randomization 2:1) [ ]. Children under 9 years of age received a second dose of CAIV or placebo 28–42 days after the first dose. Of the four prespecified diagnostic categories (acute respiratory tract events, systemic bacterial infection, acute gastrointestinal tract events, and rare events potentially associated with wild-type influenza), none was associated with the vaccine. For reactive airway disease there was a significantly increased relative risk in children aged 18–35 months, with a relative risk of 4.06 (90% CI = 1.29, 17.86). The authors concluded that CAIV was generally safe in children and adolescents.

Nervous system

Adverse effects of flu immunization on the nervous system range from polyneuropathy to meningoencephalitis and Guillain–Barré syndrome [ ].

Examination of new cases of multiple sclerosis among the 45 million swine flu vaccine recipients indicated no excess over the expected frequencies. Inactivated swine flu vaccine did not influence the onset or exacerbation of the disease [ ].

The Vaccine Safety Committee of the Institute of Medicine (IOM), Academies of Science, reviewed the data on influenza vaccine and neurological conditions [ ] and reached the following conclusions:

• Studies that examined the association between the swine influenza vaccine campaign in 1976 and Guillain–Barré syndrome, including analysis and reanalysis of nationwide data and state-based studies, consistently showed an increased risk of Guillain–Barré syndrome in the immunized population. The evidence therefore favors acceptance of a causal relation between the 1976 swine influenza vaccine and Guillain–Barré syndrome in adults.

• The Committee reviewed several population-based studies and a study of military personnel concerning the occurrence of Guillain–Barré syndrome after the use of influenza vaccines introduced after 1976. These studies differed in terms of their design, the case definitions for Guillain–Barré syndrome, the methods of ascertainment, the sizes of study populations, and the influenza seasons covered. The findings were mixed. The Committee concluded that the evidence that influenza vaccines other than the 1976 swine flu vaccine caused Guillain–Barré syndrome is inadequate to accept or reject a causal relation.

• The Committee examined reports on epidemiological studies of relapses among patients with multiple sclerosis after influenza immunization; it separately examined a smaller set of reports concerning the risk of onset of multiple sclerosis. All the studies concerned influenza vaccines in various years, including the swine flu vaccines of 1976. The Committee concluded that the evidence favors rejection of a causal relation between influenza vaccines and relapse of Guillain–Barré syndrome in adults. Only one of the small set of studies on influenza immunization and the onset of multiple sclerosis provided a thorough description of the study methods and outcomes. This study found no increased risk for the onset of multiple sclerosis associated with influenza immunization, but in the absence of confirmation from other sources the Committee concluded that the evidence is inadequate to accept or reject a causal relation between influenza vaccines and multiple sclerosis in adults.

• However, the biological mechanisms involved in the onset of multiple sclerosis are presumed to be related to those involved in relapse. With the data favoring the rejection of a causal relation between influenza vaccines and relapse of multiple sclerosis, the committee saw no reason to suspect that there might be a causal relation between influenza vaccines and the onset of multiple sclerosis.

• With a single epidemiological study available (on optic neuritis) and several case reports mentioning the occurrence of other demyelinating neurological disorders (acute disseminated encephalomyelitis, transverse myelitis) after influenza immunization, the Committee concluded that the evidence is inadequate to accept or reject a causal relation between influenza vaccines and other demyelinating neurological disorders.

• Based on the lack of published evidence on influenza vaccines and demyelinating neurological disorders in children, especially those aged 6–23 months, the Committee concluded that there is no evidence to support a causal relation between influenza vaccines and demyelinating neurological disorders in children aged 6–23 months.