2009-10 Influenza Prevention & Control Recommendations

Adverse Events After Receipt of TIV

Children

Studies support the safety of annual TIV in children and adolescents. The largest published postlicensure population-based study assessed TIV safety in 251,600 children aged less than 18 years, (including 8,476 vaccinations in children aged 6—23 months) through the Vaccine Safety Datalink (VSD), who were enrolled in one of five health maintenance organizations (HMOs) during 1993—1999. This study indicated no increase in clinically important medically attended events during the 2 weeks after inactivated influenza vaccination compared with control periods 3—4 weeks before and after vaccination. A retrospective cohort study using VSD medical records data from 45,356 children aged 6—23 months provided additional evidence supporting overall safety of TIV in this age group. During the 2 weeks after vaccination, TIV was not associated with statistically significant increases in any clinically important medically attended events other than gastritis/duodenitis, and 13 diagnoses, including acute upper respiratory illness, otitis media and asthma, were significantly less common. On chart review, most children with a diagnosis of gastritis/duodenitis had self-limited vomiting or diarrhea. The positive or negative associations between TIV and any of these diagnoses do not necessarily indicate a causal relationship.

In a study of 791 healthy children aged 1—15 years, postvaccination fever was noted among 12% of those aged 1—5 years, 5% among those aged 6--10 years, and 5% among those aged 11—15 years. Fever, malaise, myalgia, and other systemic symptoms that can occur after vaccination with inactivated vaccine 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. Data about potential adverse events among children after influenza vaccination are available from the Vaccine Adverse Event Reporting System (VAERS). Because of the limitations of passive reporting systems, determining causality for specific types of adverse events usually is not possible using VAERS data alone.

Published reviews of VAERS reports submitted after administration of TIV to children aged 6—23 months indicated that the most frequently reported adverse events were fever, rash, injection-site reactions, and seizures; the majority of the limited number of reported seizures appeared to be febrile. Seizure and fever were the leading serious adverse events, defined using standard criteria, reported to VAERS in these studies; further investigation in VSD did not confirm an association with febrile seizures as identified in VAERS.

Adults

In placebo-controlled studies among adults, the most frequent side effect of vaccination was soreness at the vaccination site (affecting 10%—64% of patients) that lasted less than 2 days. These local reactions typically were mild and rarely interfered with the recipients' ability to conduct usual daily activities. Placebo-controlled trials demonstrate that among older persons and healthy young adults, administration of TIV is not associated with higher rates for systemic symptoms (e.g., fever, malaise, myalgia, and headache) when compared with placebo injections. One prospective cohort study found that the rate of adverse events was similar among hospitalized persons who either were aged 65 years and older or were aged 18--64 years and had one or more chronic medical conditions compared with outpatients. Adverse events in adults aged 18 years and older reported to VAERS during 1990—2005 were analyzed. The most common adverse events reported to VAERS in adults included injection-site reactions, pain, fever, myalgia, and headache. The VAERS review identified no new safety concerns. In clinical trials, severe adverse events were reported to occur after vaccination with TIV at a rate of less than 1%. A small proportion (14%) of the TIV VAERS reports in adults were classified as severe adverse events, without assessment of causality. The most common severe adverse event reported after TIV in VAERS in adults was Guillain–Barré Syndrome (GBS). The potential association between TIV and GBS has been an area of ongoing research (see Guillain-Barré Syndrome and TIV).

Pregnant Women and Neonates

FDA has classified TIV as a "Pregnancy Category C" medication, indicating that adequate animal reproduction studies have not been conducted. Available data indicate that influenza vaccine does not cause fetal harm when administered to a pregnant woman or affect reproductive capacity. One study of approximately 2,000 pregnant women who received TIV during pregnancy demonstrated no adverse fetal effects and no adverse effects during infancy or early childhood. A matched case-control study of 252 pregnant women who received TIV within the 6 months before delivery determined no adverse events after vaccination among pregnant women and no difference in pregnancy outcomes compared with 826 pregnant women who were not vaccinated. During 2000--2003, an estimated 2 million pregnant women were vaccinated, and only 20 adverse events among women who received TIV were reported to VAERS during this time, including nine injection-site reactions and eight systemic reactions (e.g., fever, headache, and myalgias). In addition, three miscarriages were reported, but these were not known to be causally related to vaccination. Similar results have been reported in certain smaller studies, and a recent international review of data on the safety of TIV concluded that no evidence exists to suggest harm to the fetus. The rate of adverse events associated with TIV was similar to the rate of adverse events among pregnant women who received pneumococcal polysaccharide vaccine in one small randomized controlled trial in Bangladesh, and no severe adverse events were reported in any study group.

Persons with Chronic Medical Conditions

In a randomized cross-over study of children and adults with asthma, no increase in asthma exacerbations was reported for either age group, and two additional studies also have indicated no increase in wheezing among vaccinated asthmatic children or adults. One study reported that 20%--28% of children with asthma aged 9 months--18 years had local pain and swelling at the site of influenza vaccination, and another study reported that 23% of children aged 6 months--4 years with chronic heart or lung disease had local reactions. A blinded, randomized, cross-over study of 1,952 adults and children with asthma demonstrated that only self-reported "body aches" were reported more frequently after TIV (25%) than placebo-injection (21%). However, a placebo-controlled trial of TIV indicated no difference in local reactions among 53 children aged 6 months--6 years with high-risk medical conditions or among 305 healthy children aged 3--12 years.

Among children with high-risk medical conditions, one study of 52 children aged 6 months—3 years reported fever among 27% and irritability and insomnia among 25%; and a study among 33 children aged 6--18 months reported that one child had irritability and one had a fever and seizure after vaccination. No placebo comparison group was used in these studies.

Immunocompromised Persons

Data demonstrating safety of TIV for HIV-infected persons are limited, but no evidence exists that vaccination has a clinically important impact on HIV infection or immunocompetence. One study demonstrated a transient (i.e., 2—4 week) increase in HIV RNA (ribonucleic acid) levels in one HIV-infected person after influenza virus infection. Studies have demonstrated a transient increase in replication of HIV-1 in the plasma or peripheral blood mononuclear cells of HIV-infected persons after vaccine administration. However, more recent and better-designed studies have not documented a substantial increase in the replication of HIV. CD4+ T-lymphocyte cell counts or progression of HIV disease have not been demonstrated to change substantially after influenza vaccination among HIV-infected persons compared with unvaccinated HIV-infected persons. Limited information is available about the effect of antiretroviral therapy on increases in HIV RNA levels after either natural influenza virus infection or influenza vaccination.

Data are similarly limited for persons with other immunocompromising conditions. In small studies, vaccination did not affect allograft function or cause rejection episodes in recipients of kidney transplants, heart transplants, or liver transplants.

Hypersensitivity

Vaccine components can rarely cause allergic reactions, also called immediate hypersensitivity reactions, among certain recipients. Immediate hypersensitivity reactions are mediated by preformed immunoglobulin E (IgE) antibodies against a vaccine component and usually occur within minutes to hours of exposure. Symptoms of immediate hypersensitivity range from mild urticaria (hives) and angioedema to anaphylaxis. Anaphylaxis is a severe life-threatening reaction that involves multiple organ systems and can progress rapidly. Symptoms and signs of anaphylaxis can include but are not limited to generalized urticaria, wheezing, swelling of the mouth and throat, difficulty breathing, vomiting, hypotension, decreased level of consciousness, and shock. Minor symptoms such as red eyes or hoarse voice also might be present.

Allergic reactions might be caused by the vaccine antigen, residual animal protein, antimicrobial agents, preservatives, stabilizers, or other vaccine components. Manufacturers use a variety of compounds to inactivate influenza viruses and add antibiotics to prevent bacterial growth. Package inserts for specific vaccines of interest should be consulted for additional information. ACIP has recommended that all vaccine providers should be familiar with the office emergency plan and be certified in cardiopulmonary resuscitation. The Clinical Immunization Safety Assessment (CISA) network, a collaboration between CDC and six medical research centers with expertise in vaccination safety, has developed an algorithm to guide evaluation and revaccination decisions for persons with suspected immediate hypersensitivity after vaccination.

Immediate hypersensitivity reaction after TIV and LAIV are rare. A VSD study of children aged less than 18 years in four HMOs during 1991—1997 estimated the overall risk of postvaccination anaphylaxis to be less than 1 case per 500,000 doses administered and in this study no cases were identified in TIV recipients. Reports of anaphylaxis occurring after receipt of TIV and LAIV in adults have rarely been reported to VAERS.

Some immediate hypersensitivity reactions after TIV or LAIV are caused by the presence of residual egg protein in the vaccines. Although influenza vaccines contain only a limited quantity of egg protein, this protein can induce immediate hypersensitivity reactions among persons who have severe egg allergy. Asking persons if they can eat eggs without adverse effects is a reasonable way to determine who might be at risk for allergic reactions from receiving influenza vaccines. Persons who have had symptoms such as hives or swelling of the lips or tongue, or who have experienced acute respiratory distress after eating eggs, should consult a physician for appropriate evaluation to help determine if future influenza vaccine should be administered. Persons who have documented (IgE)-mediated hypersensitivity to eggs, including those who have had occupational asthma related to egg exposure or other allergic responses to egg protein, also might be at increased risk for allergic reactions to influenza vaccine, and consultation with a physician before vaccination should be considered. A regimen has been developed for administering influenza vaccine to asthmatic children with severe disease and egg hypersensitivity.

Hypersensitivity reactions to other vaccine components also can rarely occur. Although exposure to vaccines containing thimerosal can lead to 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 typically has consisted of local delayed hypersensitivity reactions.