Prevention and Control of Influenza, Recommendations of the Advisory Committee on Immunization Practices (ACIP)

Nicole M. Smith, PhD; Joseph S. Bresee, MD; David K. Shay, MD; Timothy M. Uyeki, MD; Nancy J. Cox, PhD; Raymond A. Strikas, MD


Morbidity and Mortality Weekly Report. 2006;55(27):1-41. 

In This Article

Inactivated Influenza Vaccine Recommendations

Dosage recommendations vary according to age group ( Table 4 ). Among previously unvaccinated children aged 6 months-<9 years, 2 doses of inactivated vaccine administered ≥1 month apart are recommended for eliciting satisfactory antibody responses.[85,86,87,88] If possible, the second dose should be administered before the onset of influenza season. If a child aged 6 months-<9 years receiving influenza vaccine for the first time does not receive a second dose of vaccine within the same season, only 1 dose of vaccine should be administered the following season. Two doses are not required at that time. ACIP does not recommend that a child receiving influenza vaccine for the first time be administered the first dose of vaccine in the spring as a priming dose for the following season.[86,88]

Among adults, studies have indicated limited or no improvement in antibody response when a second dose is administered during the same season.[204,205,206] Even when the current influenza vaccine contains one or more antigens administered in previous years, annual vaccination with the vaccine is necessary because immunity declines during the year after vaccination.[207,208] Vaccine prepared for a previous influenza season should not be administered to provide protection for the current season (see Persons Who Should Not Be Vaccinated with Inactivated Influenza Vaccine).

The intramuscular route is recommended for inactivated influenza vaccine. Adults and older children should be vaccinated in the deltoid muscle. A needle length ≥1 inch should be considered for these age groups because needles <1 inch might be of insufficient length to penetrate muscle tissue in certain adults and older children.[209]

Infants and young children should be vaccinated in the anterolateral aspect of the thigh.[210] ACIP recommends a needle length of 7/8-1 inch for children aged <12 months for intramuscular vaccination into the anterolateral thigh. When injecting into the deltoid muscle among children with adequate deltoid muscle mass, a needle length of 7/8-1.25 inches is recommended.[210]

When educating patients regarding potential side effects, clinicians should emphasize that 1) inactivated influenza vaccine contains noninfectious killed viruses and cannot cause influenza, and 2) coincidental respiratory disease unrelated to influenza vaccination can occur after vaccination.

In placebo-controlled studies among adults, the most frequent side effect of vaccination is soreness at the vaccination site (affecting 10%-64% of patients) that lasts <2 days.[12,211,212,213] These local reactions typically are mild and rarely interfere with the person's ability to conduct usual daily activities. One blinded, randomized, cross-over study among 1,952 adults and children with asthma demonstrated that only body aches were reported more frequently after inactivated influenza vaccine (25.1%) than placebo-injection (20.8%).[214] One study reported 20%-28% of children with asthma aged 9 months-18 years experienced local pain and swelling,[81] and another study reported 23% of children aged 6 months-4 years with chronic heart or lung disease had local reactions.[76] A different study reported 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 in a placebo-controlled trial of inactivated influenza vaccine.[77] In a study of 12 children aged 5-32 months, no substantial local or systemic reactions were noted.[215] The interpretation of these findings should be made with caution given the small number of children studied.

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).[216,217] 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.[12,211,212,213]

In a randomized cross-over study among both children and adults with asthma, no increase in asthma exacerbations was reported for either age group.[214] 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.[218] In a study of 791 healthy children,[71] 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;[76] another study among 33 children aged 6-18 months indicated that one child had irritability and one had a fever and seizure after vaccination.[219] 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.[220] 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.[221]

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.[222] 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.[223,224,225] 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.[226,227] When reported, hypersensitivity to thimerosal usually has consisted of local, delayed hypersensitivity reactions.[226]

The 1976 swine influenza vaccine was associated with an increased frequency of GBS.[228,229] Among persons who received the swine influenza vaccine in 1976, the rate of GBS was <10 cases/1 million persons vaccinated. The risk for influenza vaccine-associated GBS was higher among persons aged ≥25 years than persons aged <25 years.[228] Evidence for a causal relation of GBS with subsequent vaccines prepared from other influenza viruses is unclear. Obtaining strong epidemiologic evidence for a possible limited increase in risk is difficult for such a rare condition as GBS, which has an estimated annual incidence of 10-20 cases/1 million adults.[230]

Investigations to date have not documented a substantial increase in GBS associated with influenza vaccines (other than the swine influenza vaccine in 1976), and suggest that, if influenza vaccine does pose a risk, it is probably slightly more than one additional case/1 million persons vaccinated. During three of four influenza seasons studied during 1977-1991, the overall relative risk estimates for GBS after influenza vaccination were slightly elevated, but they were not statistically significant in any of these studies.[231,232,233] However, in a study of the 1992-93 and 1993-94 influenza seasons, the overall relative risk for GBS was 1.7 (CI = 1.0-2.8; p = 0.04) during the 6 weeks after vaccination, representing approximately 1 additional case of GBS/1 million persons vaccinated; the combined number of GBS cases peaked 2 weeks after vaccination.[234] VAERS has documented decreased reporting of postinfluenza vaccine GBS across age groups, despite overall increased reporting of other, non-GBS conditions occurring after influenza vaccination.[235] Cases of GBS after influenza infection have been reported, but no other epidemiologic studies have documented such an association.[236,237] Substantial evidence exists that several infectious illnesses, most notably Campylobacter jejuni and upper respiratory tract infections are associated with GBS.[230,238,239,240]

Even if GBS were a true side effect of vaccination in the years other than 1976, the estimated risk for GBS of approximately 1 additional case/1 million persons vaccinated is substantially less than the risk for severe influenza, which can be prevented by vaccination among all age groups, especially persons aged ≥65 years and those who have medical indications for influenza vaccination ( Table 1 ) (see Hospitalizations and Deaths from Influenza). The potential benefits of influenza vaccination in preventing serious illness, hospitalization, and death substantially outweigh the possible risks for experiencing vaccine-associated GBS. The average case fatality ratio for GBS is 6% and increases with age.[230,241] No evidence indicates that the case fatality ratio for GBS differs among vaccinated persons and those not vaccinated.

The incidence of GBS among the general population is low, but persons with a history of GBS have a substantially greater likelihood of subsequently experiencing GBS than persons without such a history.[231,242] Thus, the likelihood of coincidentally experiencing GBS after influenza vaccination is expected to be greater among persons with a history of GBS than among persons with no history of this syndrome. Whether influenza vaccination specifically might increase the risk for recurrence of GBS is unknown. However, avoiding vaccinating persons who are not at high risk for severe influenza complications and who are known to have experienced GBS within 6 weeks after a previous influenza vaccination is prudent. As an alternative, physicians might consider using influenza antiviral chemoprophylaxis for these persons. Although data are limited, for the majority of persons who have a history of GBS and who are at high risk for severe complications from influenza, the established benefits of influenza vaccination justify yearly vaccination.

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.[243] 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.[244] 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.[243,244,245] 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.[210] 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.[243,246,247,248] 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. 

Inactivated influenza vaccine should not be administered to persons known to have anaphylactic hypersensitivity to eggs or to other components of the influenza vaccine without first consulting a physician (see Side Effects and Adverse Reactions). Chemoprophylactic use of antiviral agents is an option for preventing influenza among such persons. However, persons who have a history of anaphylactic hypersensitivity to vaccine components but who also are at high risk for complications from influenza can benefit from vaccine after appropriate allergy evaluation and desensitization. Information regarding vaccine components is located in package inserts from each manufacturer. Persons with moderate-to-severe acute febrile illness usually should not be vaccinated until their symptoms have abated. However, minor illnesses with or without fever do not contraindicate use of influenza vaccine, particularly among children with mild upper-respiratory tract infection or allergic rhinitis.

As TIV contains only influenza virus subunits and no live virus, no contraindication exists to the coadministration of TIV and influenza antivirals (see sections on Chemoprophylaxis; and Control of Influenza Outbreaks in Institutions).


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