Trivalent Inactivated Influenza Vaccine (TIV): Side Effects and Adverse Reactions

Systemic Reactions

Fever, malaise, myalgia, and other systemic symptoms can occur after vaccination with inactivated vaccine and most often affect persons who have had no previous exposure to the influenza virus antigens in the vaccine (e.g., young children). These reactions begin 6--12 hours after vaccination and can persist for 1--2 days. Placebo-controlled trials demonstrate that among older persons and healthy young adults, administration of split-virus influenza vaccine is not associated with higher rates of systemic symptoms (e.g., fever, malaise, myalgia, and headache) when compared with placebo injections.

In a randomized cross-over study among both children and adults with asthma, no increase in asthma exacerbations was reported for either age group. An analysis of 215,600 children aged <18 years and 8,476 children aged 6--23 months enrolled in one of five HMOs reported no increase in biologically plausible medically attended events during the 2 weeks after inactivated influenza vaccination, compared with control periods 3--4 weeks before and after vaccination. In a study of 791 healthy children, postvaccination fever was noted among 11.5% of children aged 1--5 years, among 4.6% of children aged 6--10 years, and among 5.1% of children aged 11--15 years. Among children with high-risk medical conditions, one study of 52 children aged 6 months--4 years indicated that 27% had fever and 25% had irritability and insomnia; another study among 33 children aged 6--18 months indicated that one child had irritability and one had a fever and seizure after vaccination. No placebo comparison group was used in these studies.

A published review of the Vaccine Adverse Event Reporting System (VAERS) reports of TIV in children aged 6--23 months documented that the most frequently reported adverse events were fever, rash, injection-site reactions, and seizures. The majority of the small total number of reported seizures appeared to be febrile. Because of the limitations of passive reporting systems, determining causality for specific types of adverse events, with the exception of injection-site reactions, is usually not possible using VAERS data alone. A population-based study of TIV safety in children aged 6--23 months who were vaccinated during 1993--1999 indicated no vaccine-associated adverse events that had a plausible relationship to vaccination.

Health-care professionals should promptly report to VAERS all clinically significant adverse events after influenza vaccination, even if the health-care professional is not certain that the vaccine caused the event. The Institute of Medicine has specifically recommended reporting of potential neurologic complications (e.g., demyelinating disorders such as Guillain-Barré syndrome [GBS]), although no evidence exists of a causal relation between influenza vaccine and neurologic disorders in children.

Immediate, presumably allergic, reactions (e.g., hives, angioedema, allergic asthma, and systemic anaphylaxis) rarely occur after influenza vaccination. These reactions probably result from hypersensitivity to certain vaccine components; the majority of reactions probably are caused by residual egg protein. Although current influenza vaccines contain only a limited quantity of egg protein, this protein can induce immediate hypersensitivity reactions among persons who have severe egg allergy. Persons who have had hives or swelling of the lips or tongue or who have experienced acute respiratory distress or collapse after eating eggs should consult a physician for appropriate evaluation to help determine if vaccine should be administered. Persons who have documented immunoglobulin E (IgE)-mediated hypersensitivity to eggs, including those who have had occupational asthma or other allergic responses to egg protein, might also be at increased risk for allergic reactions to influenza vaccine, and consultation with a physician should be considered. Persons with a history of severe hypersensitivity (e.g., anaphylaxis) to eggs should not receive influenza vaccine.

Hypersensitivity reactions to any vaccine component can occur theoretically. Although exposure to vaccines containing thimerosal can lead to induction of hypersensitivity, the majority of patients do not have reactions to thimerosal when it is administered as a component of vaccines, even when patch or intradermal tests for thimerosal indicate hypersensitivity. When reported, hypersensitivity to thimerosal usually has consisted of local, delayed hypersensitivity reactions.

Thimerosal and Inactivated Influenza Vaccine

Thimerosal, a mercury-containing compound, has been used as a preservative in vaccines since the 1930s and is used in multidose vials of inactivated influenza vaccine to reduce the likelihood of bacterial contamination. Many of the single-dose syringes and vials of TIV are thimerosal-free or contain only trace amounts of thimerosal (Table 4). No scientific evidence indicates that thimerosal in vaccines, including influenza vaccines, leads to serious adverse events in vaccine recipients. However, in 1999, the U.S. Public Health Service and other organizations recommended that efforts be made to eliminate or reduce the thimerosal content in vaccines to decrease total mercury exposure, chiefly among infants. Since mid-2001, vaccines routinely recommended for infants in the United States have been manufactured either without or with only trace amounts of thimerosal, resulting in a substantial reduction in the total mercury exposure from vaccines for children. Vaccines containing trace amounts of thimerosal have <1 mcg mercury/dose.

The risks for severe illness from influenza virus infection are elevated among both young children and pregnant women, and persons in both groups benefit from vaccination. In contrast, no scientifically conclusive evidence exists of harm from exposure to thimerosal preservative-containing vaccine. In fact, evidence is accumulating that supports the absence of any harm resulting from exposure to such vaccines. Therefore, the benefits of influenza vaccination outweigh the theoretical risk, if any, from thimerosal exposure through vaccination. Nonetheless, certain persons remain concerned regarding exposure to thimerosal. As of February 2006, six states had enacted legislation banning the administration of vaccines containing mercury; the provisions defining mercury content vary. These laws might present a barrier to vaccination until sufficient numbers of doses of influenza vaccines without thimerosal as a preservative or in trace amounts are available.

The U.S. vaccine supply for infants and pregnant women is in a period of transition; the availability of thimerosal-reduced or thimerosal-free vaccine intended for these groups is being expanded by manufacturers as a feasible means of reducing an infant's total exposure to mercury, because other environmental sources of exposure are more difficult or impossible to eliminate. Reductions in thimerosal in other vaccines have been achieved already and have resulted in substantially lowered cumulative exposure to thimerosal from vaccination among infants and children. For all of those reasons, persons for whom inactivated influenza vaccine is recommended may receive vaccine with or without thimerosal, depending on availability.