Safety of Influenza Vaccines

Inactivated Influenza Vaccines

Children: A large postlicensure population-based study assessed IIV3 safety in 251,600 children aged <18 years (including 8,476 vaccinations in children aged 6 through 23 months) enrolled in one of five health-care organizations within the Vaccine Safety Datalink (VSD) during 1993–1999. This study indicated no increase in clinically important medically attended events during the 2 weeks after IIV administration compared with control periods 2–4 weeks before and after vaccination (277). In a retrospective cohort study using VSD data from 45,356 children aged 6 -23 months during 1991–2003, IIV3 was not associated with statistically significant increases in any clinically important medically attended events other than gastritis/duodenitis during the 2 weeks after vaccination compared with control time periods before and after vaccination. Most vaccinated children with a diagnosis of gastritis/duodenitis had self-limited vomiting or diarrhea. Several diagnoses, including acute upper respiratory illness, otitis media and asthma, were significantly less common during the 2 weeks after influenza vaccination. Although there was a temporal relationship with vaccination, the vaccine did not necessarily cause nor prevent these conditions (278). A subsequent VSD study of 66,283 children aged 24- 59 months noted diagnoses of fever, gastrointestinal tract symptoms, and gastrointestinal disorders to be significantly associated with IIV3. Upon medical record review, none of the events appeared to be serious, and none were associated with complications (279).

In a study of 791 healthy children aged 1 through 15 years, postvaccination fever was noted among 12% of those aged 1 through 5 years, 5% among those aged 6 through 10 years, and 5% among those aged 11 through 15 years (103). Fever, malaise, myalgia, and other systemic symptoms that can occur after vaccination with IIV3 most often affect persons who have had no previous exposure to the influenza virus antigens in the vaccine (e.g., young children) (280). These reactions are generally self-limited and subside after 1–2 days.

Studies conducted during the 1970s of monovalent and bivalent whole-virus influenza vaccines demonstrated greater reactogenicity among young children as compared with older children and adults (133, 281-283). These findings were the basis for the recommendation that children aged 6 through 35 months receive half the dose of IIV (0.25 cc) compared with older children and adults. Whole virus IIVs are no longer available in the United States, having been replaced with split-virus and subunit IIVs. As a group, the newer IIVs are less reactogenic than the previous whole-virus products (284). A multisite randomized controlled trial comparing full-dose (0.5 mL) IIV3 with half-dose (0.25 mL) IIV3 in children aged 6 through 35 months reported no significant differences in local or systemic reactions (285).

Febrile seizures associated with IIV and pneumococcal conjugate vaccine (PCV13): Febrile seizures are not uncommon in young children. At least one febrile seizure is experienced by 2%–5% of children aged 6- 60 months; nearly all children who have a febrile seizure recover quickly and are healthy afterwards (286). Prior to the 2010–11 influenza season, an increased risk for febrile seizures following receipt of IIV3 had not been observed in the United States (278,287). During the 2010–11 influenza season, CDC and the Food and Drug Administration (FDA) conducted enhanced monitoring for febrile seizures following receipt of influenza vaccines after reports of an increased risk for fever and febrile seizures (up to nine febrile seizures per 1,000 vaccine doses) in young children in Australia associated with a 2010 Southern Hemisphere IIV3 produced by CSL Biotherapies (now Seqirus). . Because of the findings in Australia, ACIP does not recommend the U.S.-licensed CSL Seqirus IIV3, Afluria, for children aged <9 years (Table 1).

Surveillance among children receiving U.S.-licensed influenza vaccines during the 2010–11 influenza season subsequently detected safety concerns for febrile seizures in young children following receipt of IIV3 (289,290). Further assessment through a VSD study determined that risk for febrile seizures was increased  in children aged 6 months- 4 years from the day of vaccination until the day after (risk window: day 0–1). The risk was higher when children received concomitant PCV13 (i.e., when the two vaccines are administered at the same health care visit) and peaked at approximately age 16 months (290). The magnitude of the increased risk for febrile seizures in children aged 6- 23 months in the United States observed in this study (<1 per 1,000 children vaccinated) was substantially lower than the risk observed in Australia in 2010 (288). Findings from surveillance for febrile seizures in young children following influenza vaccine for the 2011–12 influenza season which had the same formulation as that of the 2010–11 season, were consistent with the 2010–11 season. An observational clinical study also showed that risk for fever in the 0-1 days after vaccination was higher when young children received 2011-12 IIV3 and PCV13 concomitantly versus receipt of IIV3 or PCV13 without other product (291). An increased risk for febrile seizures following receipt of IIV3 was not observed during the 2012-13 season (CDC, unpublished data, 2013) (292).   After evaluating the data on febrile seizures from the 2010–11 influenza season and taking into consideration benefits and risks of vaccination, ACIP recommended no policy change for use of IIV (293, 294). A subsequently published analysis of data from the 2010-11 season reported that there was no association between receipt of IIV3 (adjusted for concomitant PCV13 or DTaP) and febrile seizures (IRR adjusted for age and seasonality 1.36; 95% CI=0.78-2.39) (295). Same-day IIV3 and PCV13 vaccination was not associated with more febrile seizures compared with separate-day vaccination (1.08 fewer febrile seizures per 100,000 with same day administration; 95% CI= -5.68-6.09). However, a VSD study of data from the 2013-14 and 2014-15 seasons found an elevated risk for febrile seizures among 6 –through 23 month-olds 0-1 days after concomitant receipt of IIV3 and PCV 13 (RR: 5.30; 95% CI= 1.87-14.75). There was no significant increased risk following administration of IIV3 without PCV13 (296). Surveillance for febrile seizures following receipt of IIVs is ongoing through the Vaccine Adverse Event Reporting System (VAERS; https://vaers.hhs.gov/index), and VSD conducts near real-time sequential monitoring for seizures following receipt of IIV during the influenza season.

Since the 2013-14 season, in addition to previously available IIV3s, several IIV4 formulations have been licensed. IIV4s include products licensed for children as young as age 6 months. In prelicensure studies of IIV4s, overall frequencies of most solicited adverse events were similar to the corresponding comparator IIV3s (297-299). Most local and general adverse events are temporary and mild to moderate in severity. Among children, the most common safety complaint was a modest increase in injection-site pain (124, 126, 128, 300). The first postlicensure review of VAERS reports covering the 2013-14 and 2014-15 seasons noted that the most common adverse events reported following receipt of IIV4 among children aged 6 months through 17 years were injection-site reactions and fever. No specific safety concerns were identified; the safety profile was similar to that of IIV3 (301).

Adults: In placebo-controlled studies among older adults, the most frequent side effect of vaccination was soreness at the vaccination site (affecting 10%–64% of patients) that lasted <2 days (302,303). 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 IIV3 is not associated with higher rates for systemic symptoms (e.g., fever, malaise, myalgia, and headache) when compared with placebo injections (302–304). Adverse events in adults aged ≥18 years reported to VAERS during 1990–2005 were analyzed (305). The most common adverse events for adults described in 18,245 VAERS reports included injection-site reactions, pain, fever, myalgia, and headache. The VAERS review identified no new safety concerns. Fourteen percent of the IIV3 VAERS reports in adults were classified as serious adverse events (defined as those involving death, life-threatening illness, hospitalization or prolongation of hospitalization, or permanent disability) (306), similar to proportions seen in VAERS for other adult vaccines. The most common serious adverse event reported after IIV3 in VAERS in adults was Guillain-Barré syndrome (GBS) (see Guillain-Barré Syndrome and IIV). However, VAERA cannot assess whether a vaccine caused an event to occur. Injection-site reactions and systemic adverse events were more frequent after vaccination with high-dose IIV3 (Fluzone High-Dose, Sanofi Pasteur, Swiftwater, Pennsylvania), which contains 180 µg of HA antigen (60 for each vaccine use) than after vaccination with standard-dose IIV3 (45 µg) (Fluzone, Sanofi Pasteur, Swiftwater, Pennsylvania), but were typically mild and transient. In one study, 915 (36%) of 2,572 persons who received Fluzone High-Dose, compared with 306 (24%) of those who received Fluzone, reported injection site pain. Only 1.1% of Fluzone High-Dose recipients reported moderate to severe fever, but this was significantly higher than the 0.3% of Fluzone recipients who reported this systemic adverse event (RR: 3.6, 95% CI = 1.3–10.1) (181). A randomized study of high-dose versus standard-dose vaccine including 9,172 participants found no difference in occurrence of serious adverse events or several specific adverse events of interest (including GBS, Bell’s Palsy, encephalitis/myelitis, optic neuritis, Stevens-Johnson syndrome, and toxic epidermal necrolysis) (307). Safety monitoring of high-dose vaccine in VAERS during the first year after licensure indicated a higher-than-expected number of gastrointestinal events compared with standard-dose vaccine, but otherwise no new safety concerns were identified. Most of the reported gastrointestinal reports were nonserious (308). CDC and FDA will continue to monitor the safety of high-dose vaccine through VAERS.

Fewer postmarketing safety data have thus far accumulated for IIV4, which first became available during the 2013–14 season, compared with IIV3. Among adults the most common safety complaints were injection-site pain and systemic reactions, such as myalgia, headaches, and fatigue (123,125,127,129,130,309). The first postlicensure safety assessment of VAERS reports covering the 2013–14 and 2014–15 seasons noted a safety profile similar to that of IIV3. The most common adverse event reported following receipt of IIV4 among adults aged 18 through 64 years was injection-site pain. No specific safety concerns were identified (301).

Intradermal IIV, which was available as an IIV3 for the 2011-12 through 2014-15 seasons and as an IIV4 since 2015-16, has been observed to be associated with increased frequency of some injection-site reactions as compared with intramuscularly administeredIIV. In a randomized study of intradermal IIV3 versus intramuscular IIV3 among approximately 4,200 adults aged 18- 64 years, erythema, induration, swelling, and pruritus occurred with greater frequency following intradermal vaccine compared with intramuscular vaccine (310); frequency of injection-site pain were not significantly different. A review of studies comparing intradermal and intramuscular IIV3 similarly noted higher rates of erythema, induration, swelling, and pruritus among adults aged 18- 60 years within the first 7 days after receiving intradermal vaccine; local pain and ecchymosis and systemic reactions occurred with similar frequency (311). A review of VAERS reports covering the 2011–12 and 2012–13 seasons, the first two seasons that the intradermal IIV3 was available, revealed no new safety concerns (312). A randomized study comparing safety of the newer IIV4 with that of IIV3 revealed a similar adverse event profile (130).

Cell culture-based IIV3 (ccIIV3), licensed by FDA in 2013, appears to have a similar safety profile to other, previously licensed IIVs. A review of 629 VAERS reports related to ccIIV3 during the 2013–14 and 2014–15 seasons noted that injection-site and systemic symptoms were the most commonly reported adverse effects; no concerning pattern of adverse effects was identified (313). ACIP will continue to review safety data pertaining to cell culture based vaccines.

An MF59-adjuvanted IIV3 (aIIV3), Fluad (Seqirus, Holly Springs, North Carolina), approved in November 2015 for use in persons aged ≥65 years, will be available during the 2016–17 season. In clinical trials among persons in this age group, some local and systemic adverse events were observed to occur more frequently following aIIV3 compared with unadjuvanted IIV; most were mild in severity. The safety profile of MF59-adjuvanted IIV3 compares favorably to that of unadjuvanted IIV (314).

Pregnant women and neonates: Currently available IIVs are classified as either Pregnancy Category B or Category C† medications, depending on whether adequate animal reproduction studies have been conducted. Available data indicate that influenza vaccine does not cause fetal harm when administered to a pregnant woman. However, data on the safety of influenza vaccination in the early first trimester are limited (315). A matched case-control study of 252 pregnant women who received IIV3 within the 6 months before delivery determined that no serious adverse events occurred after vaccination and that no difference in pregnancy outcomes was identified among these pregnant women compared with 826 pregnant women who were not vaccinated (316). A case-control analysis of data from six health care organizations participating in the VSD found no significant increase in the risk for pregnancy loss in the 4 weeks following seasonal influenza vaccination during the 2005-06 and 2006-07 seasons (317). A review of health registry data in Norway noted an increased risk for fetal death associated with influenza A(H1N1) pdm09 infection, but no increased risk of fetal mortality associated with vaccination (68). During 1990–2009, VAERS reports of pregnant women after receipt of IIV3 did not find any new, unusual, or unexpected pattern of adverse pregnancy events or fetal outcomes (318).Background rates of spontaneous abortion vary from 10.4% in women aged <25 years to 22.4% in women aged >34 years (319); considering the number of pregnant women vaccinated, miscarriage following (but not attributable to) influenza vaccination would not be an unexpected event. Preliminary (as yet unpublished) results of a VSD study suggested an increased risk for spontaneous abortion in some pregnant women in the 1 to 28 days after receiving IIV3 during either the 2010–11 or the 2011–12 seasons; the increased risk was seen primarily in women who had also received a H1N1pdm09-containing vaccine in the previous season (320). A systematic review and meta-analysis of seven published observational studies (four involving unadjuvanted A[H1N1]pdm09 monovalent vaccine, two involving adjuvanted A[H1N1]pdm09 monovalent vaccine, and one involving A/New Jersey/8/76 monovalent vaccine) found decreased risk for stillbirth among women who were vaccinated (for all studies, RR: 0.73; 95% CI = 0.55–0.96; for studies of influenza A(H1N1)pdm09 vaccines RR: 0.69; 95% CI = 0.52–0.90); there was no significant difference in risk for spontaneous abortion between vaccinated and unvaccinated women (RR: 0.91; 95% CI = 0.68–1.22) (321). Several reviews of studies involving seasonal and 2009(H1N1) IIV in pregnancy concluded that no evidence exists to suggest harm to the fetus from maternal vaccination (322–324).

A systematic review and meta-analysis of studies of congenital anomalies after vaccination including data from 15 studies (14 cohort studies and one case-control study), eight of which reported data on first-trimester immunization showed that risk for congenital malformations was similar for vaccinated and unvaccinated mothers: in the cohort studies, events per vaccinated versus unvaccinated were 2.6% versus 3.1% (5.4% versus 3.3% for the subanalysis involving first-trimester vaccination); in the case-control study, the percentage vaccinated among cases versus controls was 37.3% versus 41.7% (325). There was no association between congenital defects and influenza vaccination in any trimester (OR: 0.96; 95% CI = 0.86–1.07) or specifically in the first trimester (OR: 1.03; 95% CI = 0.91–1.18). With respect to major malformations, there was no increased risk after immunization in any trimester (OR: 0.99; 95% CI = 0.88–1.11) or in the first trimester (OR: 0.98; 95% CI = 0.83–1.16). In a retrospective cohort study of 57,554 women, influenza vaccination was not associated with increased or decreased risk for preterm birth or small for gestational age birth (326).

Persons at higher risk for influenza-related complicationsOverall, safety data pertaining to persons with specific underlying conditions are more limited that pertaining to healthy populations. A study of 52 children aged 6 months through 4 years with chronic lung disease or congenital heart disease reported fever among 27% and irritability and insomnia among 25% (131); and a study among 33 children aged 6–18 months with bronchopulmonary dysplasia or congenital heart disease reported that one child had irritability and one had a fever and seizure after vaccination (284). No placebo comparison group was used in these studies. One prospective cohort study found that the rate of adverse events was similar among hospitalized persons who were aged either ≥65 years or 18–64 years and who had one or more chronic medical conditions compared with outpatients; injection-site soreness was the most common complaint (371).

Several randomized clinical trials comparing IIV to placebo among persons with COPD reported safety outcomes. A study of 125 COPD patients at a Thai hospital clinic reported that significantly more patients in the vaccine group had local reactions (27% versus 6% placebo; p = 0.002) (372). The most common local reactions among vaccinated patients were swelling, itching and pain when touched. The duration was usually <48 hours and did not require specific treatment. There were no significant differences between the two groups in systemic reactions, such as headache, myalgia, fever, skin rash, nor in lung function, dyspneic symptoms, and exercise capacity at one week and at 4 weeks.

IIV is safe and well tolerated in asthmatic children (373) and adults (205). A multicenter, randomized, double-blind, placebo-controlled crossover trial involving 2,032 asthmatic subjects aged 3–64 years found a similarly high frequency of asthma exacerbations during the 2 weeks following either vaccination or placebo injection (28.8% versus 27.7%). Only myalgia was reported more frequently following IIV3 (25% versus 21% placebo; p<0.001) (374). A randomized study of IIV3 versus placebo among 262 asthmatic adults noted that vaccination was associated with a decline in peak expiratory flow; however, this effect was no longer significant when adjusted for the presence of concomitant symptomatic cold symptoms (375). A randomized crossover design study of IIV3 versus saline placebo showed no significant difference in the occurrence of asthma exacerbations during the 14 days postvaccination (376).

Immunocompromised persons: Data demonstrating safety of IIV3 for HIV-infected persons are limited, but no evidence exists that vaccination has a clinically important impact on HIV infection or immunocompetence.Although some earlier studies demonstrated a transient increase in replication of HIV-1 in the plasma or peripheral blood mononuclear cells of HIV-infected persons after vaccine administration (224,377,378), better-designed studies have not documented a substantial increase in replication (379–382). 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 (383). Limited information is available about the effect of antiretroviral therapy on increases in HIV RNA levels after either influenza virus infection or influenza vaccination (384,385).

IIV generally has been shown to be well-tolerated in both adult and pediatric solid organ transplant recipients (231). In small studies, IIV vaccination did not affect allograft function or cause acute rejection episodes in recipients of kidney (232,233,386), heart (234), lung (386) or liver transplants (238,239,387) A literature review concluded that there is no convincing epidemiologic link between vaccination and allograft dysfunction (231). A single case of Guillain-Barré syndrome in a liver transplant recipient and another case of rhabdomyolysis leading to acute allograft dysfunction after IIV vaccination have been reported (388,389). Several case reports of corneal graft rejection have been reported following receipt of IIV (390–392), but no studies demonstrating an association have been conducted.

Immediate hypersensitivity reactions after influenza vaccines:

Vaccine components can occasionally cause allergic reactions, also called immediate hypersensitivity reactions. Immediate hypersensitivity reactions are mediated by preformed immunoglobulin E (IgE) antibodies against a vaccine component and usually occur within minutes to hours of exposure (416). Symptoms of immediate hypersensitivity range from urticaria (hives) to angioedema and 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, tongue 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 (416,417).

Allergic reactions might be caused by the vaccine antigen, residual animal protein, antimicrobial agents, preservatives, stabilizers, or other vaccine components (8,418). Manufacturers use a variety of compounds to inactivate influenza viruses and add many 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 (8). The Clinical Immunization Safety Assessment (CISA)Project (https://www.cdc.gov/vaccinesafety/ensuringsafety/monitoring/cisa) , a collaboration between CDC and medical research centers with expertise in vaccinology and vaccine safety, has developed an algorithm to guide evaluation and revaccination decisions for persons with suspected immediate hypersensitivity after vaccination (416).

Anaphylaxis after receipt of influenza vaccines is rare. A VSD study conducted during 2009–2011 observed that the incidence of anaphylaxis in the 0–2 days after any vaccine was 1.31 (95% CI=0.65-2.47) cases per million vaccine doses administered in all ages. The incidence of anaphylaxis in the 0–2 days after IIV3 (without other vaccines) was 1.35 (95% CI = 0.65–2.47) per million IIV3 doses administered in all ages (419) Anaphylaxis occurring after receipt of IIV and LAIV rarely has been reported to VAERS (305,409,420,421). A VSD study of children aged <18 years in four health maintenance organizations during 1991–1997 estimated the overall risk for postvaccination anaphylaxis after any type of childhood vaccine to be approximately 1.5 cases per 1 million doses administered. In this study, no cases were identified in IIV3 recipients (422).

Ocular and respiratory symptoms after receipt of IIV: Oculorespiratory syndrome (ORS), an acute, self-limited reaction to IIV, was first described during the 2000–01 influenza season in Canada (327,328). The initial case-definition for ORS was the onset of one or more of the following within 2–24 hours after receiving IIV3, and resolving within 48 hours of onset: red eyes, cough, wheeze, chest tightness, difficulty breathing, sore throat, or facial swelling (327,329). ORS was initially noted to be associated with one vaccine preparation (Fluviral S/F, Shire Biologics, Quebec, Canada) not available in the United States during the 2000–01 influenza season (327). After changes in the manufacturing process of the vaccine preparation associated with ORS during the 2000–01 season, the incidence of ORS in Canada was reduced greatly (330). The cause of ORS has not been established; however, studies suggest that the reaction is not IgE-mediated (331). When assessing whether a patient who experienced ocular and respiratory symptoms should be revaccinated, providers should determine if concerning signs and symptoms of IgE-mediated immediate hypersensitivity are present (see Immediate Hypersensitivity Reactions After Receipt of Influenza Vaccines). Health care providers who are unsure whether symptoms reported or observed after receipt of IIV represent an IgE-mediated hypersensitivity immune response should seek advice from an allergist/immunologist. Persons who have had red eyes, mild upper facial swelling, or mild respiratory symptoms (e.g., sore throat, cough, or hoarseness) after receipt of IIV without other concerning signs or symptoms of hypersensitivity can receive IIV in subsequent seasons without further evaluation. Two studies indicated that persons who had symptoms of ORS after receipt of IIV were at a higher risk for ORS after subsequent IIV administration; however, these events usually were milder than the first episode (332,333).

Guillain-Barré syndrome and IIV: Guillain-Barré Syndrome (GBS) is an autoimmune disease associated with rapid-onset muscle weakness. Evidence exists that multiple infectious illnesses, most notably Campylobacter jejuni gastrointestinal infections and upper respiratory tract infections, are associated with GBS (334–336).The annual incidence of GBS is 10–20 cases per 1 million adults (337). An analysis of 405 patients admitted to a single facility identified an association between serologically confirmed influenza virus infection and GBS, with time from onset of influenza illness to GBS of 3–30 days (338). The 1976 swine influenza vaccine was associated with an increased frequency of GBS, estimated at one additional case of GBS per 100,000 persons vaccinated. The risk for influenza vaccine–associated GBS was higher among persons aged ≥25 years than among persons aged <25 years (339). No subsequent study conducted using influenza vaccines other than the 1976 swine influenza vaccine has demonstrated an increase in GBS associated with influenza vaccines on the order of magnitude seen in the 1976–77 season (340,341).

During three of four influenza seasons studied during 1977–1991, the overall relative risk estimates for GBS after influenza vaccination were not statistically significant (342–344). However, in a study of the 1992–93 and 1993–94 seasons, the overall relative risk for GBS was 1.7 (95% CI = 1.0–2.8; p = 0.04) during the 6 weeks after vaccination, representing approximately one additional case of GBS per 1 million persons vaccinated. GBS cases peaked 2 weeks after vaccination (341). Results of a study that examined health care data from Ontario, Canada, during 1992–2004 demonstrated a small but statistically significant temporal association between receiving influenza vaccination and subsequent hospital admission for GBS (relative incidence: 1.45; 95% CI = 1.05–1.99). However, no increase in cases of GBS at the population level was reported after introduction of a mass public influenza vaccination program in Ontario beginning in 2000 (345). Published data from the United Kingdom’s General Practice Research Database (GPRD) found influenza vaccination to be associated with a decreased risk for GBS (odds ratio: 0.16; 95% CI = 0.02–1.25), although whether this was associated with protection against influenza or confounding because of a “healthy vaccine” effect (i.e., healthier persons might be more likely to be vaccinated and also be at lower risk for GBS) is unclear (346). A separate GPRD analysis found no association between vaccination and GBS for a 9-year period; only three cases of GBS occurred within 6 weeks after administration of influenza vaccine (347). A third GPRD analysis found that GBS was associated with recent ILI, but not influenza vaccination (348). A meta-analysis of 39 observational studies of seasonal and 2009 pandemic influenza vaccines published between 1981 and 2014 found an overall relative risk for GBS of 1.41 (95% CI = 1.20–1.66); the risk was higher for pandemic vaccines (RR: 1.84; 95% CI = 1.36–2.50) than for seasonal vaccines (RR: 1.22; 95% CI = 1.01–1.48) (349).

The estimated risk for GBS (on the basis of the few studies that have demonstrated an association between seasonal IIV and GBS) is low: approximately one additional case per 1 million persons vaccinated (341). In addition, data from the systems monitoring influenza A(H1N1) 2009 monovalent vaccines suggest that the increased risk for GBS  is approximately one or two additional cases per 1 million persons vaccinated, which is similar to that observed in some years for seasonal IIV (350-356). Studies have also shown an increased risk for GBS following influenza infection, of higher magnitude than the risk observed following influenza vaccination (338,357).

Persons with a history of GBS have a substantially greater likelihood of subsequently experiencing GBS than persons without such a history (337). 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. Among 311 patients with GBS who responded to a survey, 11 (4%) reported some worsening of symptoms after influenza vaccination; however, some of these patients had received other vaccines at the same time, and recurring symptoms were generally mild (358). In a Kaiser Permanente Northern California database study among more than >3 million members conducted over an 11-year period, no cases of recurrent GBS were identified after influenza vaccination in 107 persons with a documented prior diagnosis of GBS, two of whom had initially developed GBS within 6 weeks of influenza vaccination (359).

As a precaution, persons who are not at high risk for severe influenza complications (see Persons at Risk for Medical Complications Attributable to Severe Influenza) and who are known to have experienced GBS within 6 weeks of influenza vaccination generally should not be vaccinated. As an alternative to vaccination, physicians might consider using influenza antiviral chemoprophylaxis for these persons. However, the benefits of influenza vaccination might outweigh the risks for certain persons who have a history of GBS and who also are at high risk for severe complications from influenza.

Thimerosal in multidose vials of IIV: Thimerosal, an ethyl mercury-containing antibacterial compound, is used in multidose vial preparations of IIV to reduce the likelihood of microbial growth that might occur if organisms are introduced via the needle and syringe. Although accumulating evidence shows no increased risks from exposure to vaccines containing thimerosal (360-370), the U.S. Public Health Service and other organizations have recommended that efforts be made to eliminate or reduce the thimerosal content in vaccines as part of a strategy to reduce mercury exposures from all sources (360,361). LAIV, RIV, and most single-dose vial or syringe preparations of IIV do not contain thimerosal. Persons recommended to receive IIV may receive any age- and risk factor–appropriate vaccine preparation, depending on availability.

Live Attenuated Influenza Vaccines

Shedding, transmission, and phenotypic stability of LAIV viruses: Children and adults vaccinated with LAIV can shed vaccine viruses after vaccination, although in lower amounts than occur typically with shedding of wild-type influenza viruses. Studies assessing shedding of vaccine virus have been based on viral cultures or RT-PCR detection of vaccine viruses in nasal aspirates from LAIV recipients. A study of 345 participants aged 5–49 years who received LAIV3 and for whom shedding was assessed by viral culture of nasal swabs (daily for days 1–7 postvaccination, every other day for days 9 through 25, and on day 28) indicated that 30% had detectable virus in nasal secretions obtained by nasal swabbing. The duration of virus shedding and the amount of virus shed was inversely correlated with age, and maximal shedding occurred within 2 days of vaccination. Symptoms reported after vaccination, including runny nose, headache, and sore throat, did not correlate with virus shedding (393). Other smaller studies have reported similar findings (394,395). In an open-label study of 200 children aged 6–59 months who received a single dose of LAIV3, shedding of at least one vaccine virus was detected on culture in 79% of children, and was more common among the younger recipients (89% of children aged 6–23 months compared with 69% of children aged 24–59 months) (396). The incidence of shedding was highest on the second day postvaccination. Mean duration of shedding was 2.8 days (3.0 and 2.7 days for the younger and older age groups, respectively); shedding detected after 11 days postvaccination was uncommon and nearly all instances occurred among children aged 6–23 months (an age group for which LAIV is not licensed). Titers of shed virus were low (396). Vaccine virus was detected from nasal secretions in one (2%) of 57 HIV-infected adults who received LAIV3 compared with none of 54 HIV-negative participants (397), and in three (13%) of 24 HIV-infected children compared with seven (28%) of 25 children who were not HIV-infected (398).

Rarely, shed vaccine viruses can be transmitted from vaccine recipients to unvaccinated persons. However, serious illnesses have not been reported among unvaccinated persons who have been infected inadvertently with vaccine viruses. One study of 197 children aged 9-36 months in a child care center assessed the potential for transmission of LAIV3 vaccine viruses from 98 vaccinated children to 99 unvaccinated children; 80% of vaccine recipients shed one or more virus strains (mean duration: 7.6 days). One influenza B vaccine virus strain isolate was recovered from a placebo recipient and was confirmed to be vaccine-type virus. The influenza B virus isolate retained the cold-adapted, temperature-sensitive, attenuated phenotype. The placebo recipient from whom the influenza B vaccine virus strain was isolated had symptoms of a mild upper respiratory illness. The estimated probability of transmission of vaccine virus within a contact group with a single LAIV recipient in this population was  0.58% (95% C=0-1.7) (399).

In clinical trials, viruses isolated from vaccine recipients have retained attenuated phenotypes. In one study, nasal and throat swab specimens were collected from 17 study participants for 2 weeks after vaccine receipt. Virus isolates were analyzed by multiple genetic techniques. All isolates retained the LAIV3 genotype after replication in the human host, and all retained the cold-adapted and temperature-sensitive phenotypes (400). Children:

In a randomized trial published in 2007, LAIV3 and IIV3 were compared among children aged 6–59 months (262). Children with medically diagnosed or treated wheezing in the 42 days before enrollment or with a history of severe asthma were excluded from participation. Among children aged 24–59 months who received LAIV3, the proportion of children who experienced medically significant wheezing was not greater than among those who received IIV3. Wheezing was observed more frequently following the first dose among previously unvaccinated younger LAIV3 recipients, primarily those aged <12 months; LAIV3 is not licensed for this age group. In a previous randomized placebo-controlled safety trial among children without a history of asthma, an increased risk for asthma events (RR: 4.1; 95% CI = 1.3–17.9) was documented among the 728 children aged 18–35 months who received LAIV3. Of the 16 children with asthma-related events in this study, seven had a history of asthma on the basis of subsequent medical record review. None required hospitalization, and increased risk for asthma events was not observed in other age groups (401).

In a subset of healthy children aged 60 -71 months from one clinical trial, certain signs and symptoms were reported more often after the first dose among LAIV3 recipients (n = 214) than among placebo recipients (n = 95), including runny nose (48% and 44%, respectively); headache (18% and 12%, respectively); vomiting (5% and 3%, respectively); and myalgia (6% and 4%, respectively) (402). However, these differences were not statistically significant. In other trials, signs and symptoms reported after LAIV3 administration have included runny nose or nasal congestion (18%–82%), headache (3%–46%), fever (0–32%), vomiting (3%–17%), abdominal pain (2%), and myalgia (0–21%) (242,243,252,401,403-406). These symptoms were associated more often with the first dose and were self-limited. In a placebo-controlled trial in 9,689 children aged 1–17 years assessed pre-specified medically attended outcomes during the 42 days after vaccination, LAIV3 was associated with increased risk for asthma, upper respiratory infection, musculoskeletal pain, otitis media with effusion, and adenitis/adenopathy. In this study, the proportion of serious adverse events was 0.2% in LAIV3 and placebo recipients; none of the serious adverse events was judged to be related to the vaccine by the study investigators (401).

An open-label field trial was conducted among approximately 11,000 children aged 18 months -18 years in which 18,780 doses of LAIV3 were administered between 1998–2002 For children aged 18 months -4 years, no increase was reported in asthma visits 0–15 days after vaccination compared with the prevaccination period. A significant increase in asthma events was reported 15–42 days after vaccination, but only in vaccine year 1 (407). This trial later assessed LAIV3 safety among 2,196 children aged 18 months -18 years with a history of intermittent wheezing who were otherwise healthy. Among these children, no increased risk was reported for medically attended acute respiratory illnesses, including acute asthma exacerbation, during the 0–14 or 0–42 days after receipt of LAIV3 compared with the pre- and postvaccination reference periods (408).

In a randomized trial published in 2007, LAIV3 and IIV3 were compared among children aged 6–59 months (262). Children with medically diagnosed or treated wheezing in the 42 days before enrollment or with a history of severe asthma were excluded from participation. Among children aged 24–59 months who received LAIV3, the proportion of children who experienced medically significant wheezing was not greater than among those who received IIV3. Wheezing was observed more frequently following the first dose among previously unvaccinated younger LAIV3 recipients, primarily those aged <12 months; LAIV3 is not licensed for this age group. In a previous randomized placebo-controlled safety trial among children without a history of asthma, an increased risk for asthma events (RR: 4.1; 95% CI = 1.3–17.9) was documented among the 728 children aged 18–35 months who received LAIV3. Of the 16 children with asthma-related events in this study, seven had a history of asthma on the basis of subsequent medical record review. None required hospitalization, and increased risk for asthma events was not observed in other age groups (401).

Adults : In one clinical trial among a subset of healthy adults aged 18 -49 years, signs and symptoms reported significantly more often (p<0.05; Fisher exact test) among LAIV3 recipients (n = 2,548) than placebo recipients (n = 1,290) within 7 days after each dose included cough (14% versus10%,), runny nose (44% versus 27%, respectively), sore throat (27% versus 16%, respectively), chills (89% versus 6%), and tiredness/weakness (25% versus21%) (402). A review of 460 reports to VAERS after distribution of approximately 2.5 million doses of LAIV3 during the 2003–04 and 2004–05 influenza seasons did not indicate any new safety concerns (409). Few (9%) of the VAERS reports described serious adverse events; respiratory events were the most common conditions reported.

Persons at higher risk for influenza-related complications: Limited data assessing the safety of LAIV use for certain groups at higher risk for influenza-related complications are available. LAIV3 was well-tolerated among adults aged ≥65 years with chronic medical conditions (412). In a study of 57 HIV-infected persons aged 18–58 years with CD4+ counts >200 cells/µL who received LAIV3, no serious adverse events attributable to vaccines were reported during a 1-month follow-up period (397). Similarly, another study demonstrated no significant difference in the frequency of adverse events or viral shedding among 24 HIV-infected children aged 1–8 years on effective antiretroviral therapy who were administered LAIV3 compared with 25 HIV-uninfected children receiving LAIV3 (398). In a study comparing immunogenicity and shedding of LAIV4 among 46 HIV-infected (CD4+ counts >200 cells/µL) and 56 uninfected persons aged 2 through 25 years, adverse events were similar between the two groups. Shedding of vaccine virus was somewhat more prevalent among the HIV-infected participants, 67% of whom shed any vaccine virus up to 14–21 days postvaccination, compared with 50% of uninfected participants (p = 0.14) (413).

Among 27 reports to VAERS involving inadvertent administration of LAIV3 to pregnant women during 1990–2009, no unusual patterns of maternal or fetal outcomes were observed (318); among 138 reports noted in a health insurance claims database, all outcomes occurred at similar rates to those observed in unvaccinated women (414). These findings suggest that persons at risk for influenza complications who have inadvertent exposure to LAIV are not expected to have significant adverse events or prolonged viral shedding and that persons who have contact with persons at higher risk for influenza-related complications may receive LAIV.

Data on the relative safety of LAIV and IIV are limited for children and adults with chronic medical conditions conferring a higher risk for influenza complications. Safety data were collected from 1,940 children aged 2–5 years with asthma or prior wheezing from two randomized, multinational trials of LAIV3 and IIV3 (415). The results showed that wheezing, lower respiratory illness, and hospitalization were not significantly increased among children receiving LAIV3 relative to IIV3; however, increased prevalence of rhinorrhea (8.1% LAIV versus 3.1% IIV3; p = 0.002) and irritability (2.0% versus 0.3%, p = 0.04) were observed among LAIV3 recipients. A study of LAIV and IIV3 among children aged 6–17 years with asthma noted no significant difference in wheezing events after receipt of LAIV3 (264). Available data are insufficient to determine the level of severity of asthma for which administration of LAIV would be inadvisable.

Recombinant Influenza Vaccine

RIV, currently available as a trivalent vaccine (RIV3) has been available in the United States since the 2013–14 season. In prelicensure studies, the most frequently reported injection-site reaction (reported in ≥10% of recipients) was pain (37% among those aged 18 through 49 years; 32% among those aged 50 through 64 years, and 19% among those aged ≥65 years); the most common solicited systemic reactions were headache (15%, 17%, and 10%, respectively), fatigue (15%, 13%, and 13%, respectively), and myalgia (11% among persons aged 18 through 49 years and 11% among those aged 50 through 64 years) (273). Local pain and tenderness were reported significantly more frequently with RIV3 than placebo; however, most reports of pain following RIV3 were rated as mild. As a relatively new vaccine, fewer postmarketing safety data have accumulated for RIV3.