Safety of Influenza Vaccines

Safety of Inactivated Influenza Vaccines (IIVs)

Children

Currently available IIVs are generally well-tolerated by children. A large postlicensure population-based study assessed IIV3 safety in 251,600 children aged <18 years (including 8,476 vaccinations in children aged 6–23 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 (329). 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 or prevent these conditions (330). 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 was associated with complications (331).

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) (332). These reactions are generally self-limited and subside after 1–2 days. 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 through10 years, and 5% among those aged 11 through 15 years (113). An observational study assessed post-vaccination fever frequency in 314 children aged 24-59 months receiving IIV during the 2013-14 influenza season. On the vaccination day to 2 days after vaccination (risk window 0-2 days), 7.1% and 6.0% of children had fever after IIV4 and IIV3, respectively (333).

Febrile Seizures: 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 afterward (334). Febrile seizures may occur in the context of febrile illnesses, including influenza. In an observational study of 143 children aged 6 months through 5 years who presented with febrile seizures to an emergency department, at least one virus was isolated from nasal or rectal specimens obtained from 102 children ( 71%); influenza was isolated from 19 (13%) (335). Seizures occurred within 14 days of administration of a vaccine in 16 (11%) children, none of whom had received an influenza vaccine within this period.

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 (330, 336). During the 2010–11 influenza season, CDC and FDA conducted enhanced monitoring for febrile seizures (primarily among children under 9 years of age) and febrile reactions 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) (337).

Following these events in Australia, from July 2010 through the 2016-17 season, ACIP did not recommend use of the U.S.-licensed CSL IIV3, Afluria, for children aged <9 years (304, 338). Subsequent laboratory investigation by CSL into the potential etiology of these reactions concluded that the 2010 Southern Hemisphere formulation induced a stronger inflammatory cytokine response than that associated with previous formulations of the vaccine, or with other IIVs. This was hypothesized to be related to the introduction of the viruses B/Brisbane/60/2006 and A/California/7/2009 to the vaccine, and believed to be mediated by higher concentrations of residual lipid and RNA remaining in the vaccine following splitting of the B, and to a lesser extent, the H1N1 components (339). At the time, lower concentrations of the detergent splitting agent taurodeoxycholate (TDOC) were used for the H1N1 and B viruses (0.9% and 0.5%, respectively) than for the H3N2 component (1.5%). Increasing the concentration of TDOC to 1.5% for all three viruses resulted in attenuation of the cytokine response in an in vitro model (340). In a study comparing fever rates among 402 children aged 5 through 9 years, 302 of whom received a trivalent Afluria produced using 1.5% TDOC for the B viruses and 100 of whom who received a licensed comparator (non-CSL) IIV4, prevalence of fever was similar in both groups (8.2% for Afluria IIV3 vs. 9.2% for the comparator IIV4) (341). In a randomized trial of 5- through 17-year-olds comparing Afluria IIV4 (manufactured using 1.5% TDOC for all four viruses) with a licensed comparator IIV4, higher prevalence of fever was observed with Afluria IIV4 (4.5% vs. 3.6% for 5- through 8-year-olds and 2.1% vs. 0.8% for 9- through17-year-olds); this difference was not statistically significant (342)

Subsequent to the events in Australia during 2010, surveillance among children receiving U.S.-licensed influenza vaccines in two different surveillance systems (VAERS and VSD) during the 2010–11 influenza season detected safety concerns for febrile seizures in young children following receipt of IIV3 (343, 344). Further assessment of this signal through the VSD 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 were administered at the same health care visit) and peaked at approximately age 16 months (344), but the effect of other concomitant vaccines was not evaluated. 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 (337). After evaluating the data on febrile seizures from the 2010–11 season and taking into consideration benefits and risks of vaccination, ACIP recommended no policy change for use of IIV (345, 346).

A follow-up VSD study assessed the risk for febrile seizure on days 0-1 with the concomitant administration of IIV3 and all other routine childhood vaccines in children aged 6-23 months during 5 influenza seasons (2006-2007 through 2010-11) (347). This study found that there was an increased risk for febrile seizure when IIV3 was administered simultaneously with either PCV or DTaP-containing vaccines, but no increased risk when IIV3 was administered alone. The increased risk with these vaccine combinations was observed to have been present in seasons prior to 2010-11. Another study done in the US to follow-up the 2010–11 season findings, using the separate FDA-sponsored PRISM (Post-licensure Rapid Immunization Safety Monitoring) system population, found no association between receipt of IIV3 (adjusted for concomitant PCV13 or DTaP) and febrile seizures among children 6-59 months of age during 2010-11 (IRR adjusted for age and seasonality: 1.36; 95% CI = 0.78–2.39) (348). 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, surveillance findings in subsequent seasons for febrile seizures in young children following influenza vaccine have been consistent with the original findings of an increased risk in 2010-11. During the 2011–12 season (for which had the influenza vaccine composition was the same as that of the 2010–11 season), an observational clinical study showed that risk for fever in the 0–1 days after vaccination was higher when children 6 to 23 months old received IIV3 and PCV13 concomitantly versus receipt of IIV3 or PCV13 without the other product (349). The viral composition of U.S. influenza vaccines was changed for the 2013-14 season, and this same composition was used for the 2014-15 season. VSD surveillance for 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 PCV13 (RR: 5.30; 95% CI = 1.87–14.75). There was no significant increased risk following administration of IIV3 without PCV13 (350). Similarly, analysis of 2013-14 data from the PRISM system revealed no increased risk for seizure following either IIV3 or LAIV when an individual-level, self-controlled risk interval comparison method was used, but did reveal increased risk for IIV3 and PCV13 administered concomitantly (but not alone) when using a method comparing current and historical rates (351). Surveillance for febrile seizures following receipt of IIVs is ongoing through the Vaccine Adverse Event Reporting System (VAERS; https://vaers.hhs.gov/indexexternal icon), and VSD conducts near real-time sequential monitoring for seizures following receipt of IIV during the influenza season.

Quadrivalent IIVs (IIV4s): 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 (352-355). 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 (125, 127, 129, 356). 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 (357).

Safety of Full-Dose IIV4 for children aged 6 through 35 months: The dose of IIV given to persons aged ≥3 years is 0.5 mL. During the last several seasons prior to November 2016, the only influenza vaccines licensed for children 6 through 35 months of age were Fluzone (IIV3) and Fluzone Quadrivalent (IIV4, Sanofi Pasteur, Swiftwater, Pennsylvania), given in a 0.25mL dose (half the dose given to persons aged ≥3 years). The rationale for this reduced dose was greater frequency of fever and other reactogenicity events noted in studies conducted during the 1970s among children in this age group, primarily with older, whole-virus vaccines (358-362). 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 generally less reactogenic than the previous whole-virus products (363). More recently, evaluations of some currently available split-virion IIVs have revealed comparable safety of the 0.5mL dose for children in this age group (364, 365). The safety of 0.5mL FluLaval Quadrivalent (IIV4, ID Biomedlcal Corporation of Quebec, Quebec, Canada) was compared with 0.25mL of Fluzone Quadrivalent in a randomized controlled trial conducted among 2,424 children aged 6 through 35 months; safety and reactogenicity (including prevalence of fever) were comparable between the two groups, with no significant differences in local or systemic adverse reactions.

In placebo-controlled studies of IIV3 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 (366, 367). These injection site 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 proportions of systemic symptoms (e.g., fever, malaise, myalgia, and headache) when compared with placebo injections (366-368). Adverse events in adults aged ≥18 years reported to VAERS during 1990–2005 were analyzed (369). 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) (370), 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, VAERS 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 per vaccine virus) than after vaccination with standard dose IIV3 (15 µg per virus; 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 1,262 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) (252). 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) (371). 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 events were nonserious (372). A survey of adults aged ≥65 years in the Minneapolis Veteran Affairs Health Care System who received influenza vaccines (547 high-dose and 541 standard dose) during October 2015 showed that local and systemic side effects were more common after high-dose influenza vaccine than after standard dose vaccine during the week after vaccination; there was no significant difference in prevalence of severe side effects or healthcare visits between groups (373). 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 (124, 126, 128, 130, 131, 374). 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 (375).

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 administered IIV. 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 receipt of intradermal vaccine compared with intramuscular vaccine (376); frequency of injection site pain was 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; injection site pain and ecchymosis and systemic reactions occurred with similar frequency (377). 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 (378). A randomized study comparing safety of the newer intradermal IIV4 with that of intradermal IIV3 revealed a similar adverse event profile (131).

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 (379). ACIP will continue to review safety data pertaining to cell culture based vaccines.

An MF59-adjuvanted IIV3 (aIIV3), Fluad (Seqirus, Holly Springs, North Carolina) was approved in November 2015 for use in persons aged ≥65 years. In clinical trials among persons in this age group, some injection site and systemic adverse events were observed to occur more frequently following aIIV3 compared with unadjuvanted SD-IIV3; most were mild in severity. The prevalence of SAEs was similar between the two groups (263).

Overall, safety data pertaining to persons with specific underlying conditions are more limited relative to data from healthy populations, and studies directly comparing persons with high risk conditions with healthy populations are few. 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% (380); 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 (363). 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 (381).

Several randomized clinical trials comparing IIV to placebo among persons with chronic obstructive pulmonary disease (COPD) and asthma have reported safety outcomes. A study of 125 COPD patients at a Thai hospital clinic reported that significantly more patients in the vaccine group had injection site reactions (27% versus 6% placebo; p = 0.002) (382). The most common injection site 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 well tolerated in asthmatic children (383) and adults (384). 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) (385). 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 (386). 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 (387).

Transient increases in replication of HIV-1 in the plasma or peripheral blood mononuclear cells of HIV-infected persons after vaccine administration have been observed in some, but not all studies (20, 388-392). However, IIV does not appear to have a clinically important impact on HIV infection or immunocompetence in HIV-infected persons. 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 (393). Limited information is available about the effect of antiretroviral therapy on increases in HIV RNA levels after either influenza virus infection or influenza vaccination (394, 395).

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 (233, 234, 396), heart (397), lung (396) or liver transplants (238, 239, 398). A literature review concluded that there is no convincing epidemiologic link between vaccination and allograft dysfunction (231). Guillain-Barré syndrome in a liver transplant recipient and another case of rhabdomyolysis leading to acute renal allograft dysfunction after IIV vaccination have been reported (399, 400). Several case reports of corneal graft rejection have been reported following receipt of IIV (401-404), but no studies demonstrating an association have been conducted.

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 (405-407). The annual incidence of GBS is 10–20 cases per 1 million adults (408). 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 (409).

The 1976 swine influenza vaccine was associated with an increased frequency of GBS, estimated at one additional case of GBS per 100,000 vaccinated persons. The risk for influenza vaccine–associated GBS was higher among persons aged ≥25 years than among persons aged <25 years (410). Data on the risk of GBS following IIV since the 1976 swine influenza vaccination program have been variable and inconsistent across influenza seasons, but have not demonstrated an increase in GBS associated with influenza vaccines on the order of magnitude seen in the 1976–77 season (411, 412).

During three of four influenza seasons studied during 1977–1991, the overall relative risk estimates for GBS after influenza vaccination were not statistically significant (413-415). 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 (412). 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 (416). Published data from the United Kingdom’s General Practice Research Database (GPRD) found influenza vaccination to be associated with a non-statistically significant decreased risk for GBS (OR: 0.16; 95% CI = 0.02–1.25), although whether this was associated with protection against influenza or confounding because of a “healthy vaccinee” effect (i.e., healthier persons might be more likely to be vaccinated and also be at lower risk for GBS) is unclear (417). 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 (418). A third GPRD analysis found that GBS was associated with recent ILI, but not influenza vaccination (419). 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) (420).

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 (412). 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 (421-427). Studies have also shown an increased risk for GBS following influenza infection; that is, of higher magnitude than the risk observed following influenza vaccination (409, 428).

Persons with a history of GBS have a substantially greater likelihood of subsequently experiencing GBS than persons without such a history (408). 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 (429). In a Kaiser Permanente Northern California database study among >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 (430).

Oculorespiratory syndrome (ORS), an acute, self-limited reaction to IIV, was first described during the 2000–01 influenza season in Canada (431, 432). 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 (431, 433). 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 (431). 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 (434).

The cause of ORS has not been established; however, studies suggest that the reaction is not IgE-mediated (435). 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 (436, 437).

Thimerosal, an ethyl mercury-containing antimicrobial compound, is primarily used in multidose vial preparations of IIV as a preservative to inhibit microbial growth. For these preparations, the mercury content from thimerosal is ≤25 µg of mercury per 0.5 mL dose. For one single-dose IIV preparation (Fluvirin, Seqirus, Holly Springs, North Carolina), thimerosal is used in the manufacturing process, and trace amounts remain in the finished vaccine (yielding a mercury content of ≤1 µg per 0.5 mL dose) (Table 1).

Although accumulating evidence is reassuring regarding health risks associated with exposure to vaccines containing thimerosal (438-450), 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 (438, 442). LAIV, RIV, and most single-dose vial or syringe preparations of IIV do not contain thimerosal.

RIV was initially available in the U.S. during the 2013-14 season as RIV3. RIV4 was licensed in late 2016, and is anticipated to be available for the 2017-18 season. In prelicensure studies of RIV3, 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) (354). Injection site pain and tenderness were reported significantly more frequently with RIV3 than placebo; however, most reports of pain following RIV3 were rated as mild. In studies comparing RIV3 to licensed comparator IIV3s among persons aged 50 years and older (246, 451, 452), safety profiles were generally similar to the comparator inactivated vaccines. In pre-licensure studies comparing safety of RIV4 with licensed comparator IIV4s among persons aged 18 through 49 years and ≥50 years, the frequency of injection site and systemic solicited adverse events was generally similar between the two treatment groups (247).

As a relatively new category of vaccine, fewer postmarketing safety data have accumulated for RIVs. Although RIV does not contain egg protein, it has been associated with anaphylactic and other, less severe reactions reported in VAERS. A review of VAERS reports from January 2013 through June 2014 noted 12 reports that included signs and symptoms consistent with acute hypersensitivity reactions following administration of RIV3 (453). All were considered to be consistent with possible anaphylaxis; 3 cases appeared to meet Brighton Collaboration criteria (454) for level 2 anaphylaxis. Although it is not possible to infer causality from these data, they illustrate that allergic reactions following influenza vaccination are not necessarily related to egg proteins. In a randomized study conducted among adults 50 years of age and older in which incidence of rash, urticaria, swelling, non-pitting edema, or other potential hypersensitivity reactions were actively solicited for 30 days following vaccination, 2.4% of Flublok recipients and 1.6% of IIV3 recipients reported such events within the 30 day follow-up period. A total of 1.9% and 0.9% of Flublok and IIV3 recipients, respectively, reported these events within 7 days following vaccination. Of these solicited events, rash was most frequently reported (Flublok 1.3%; IIV3 0.8%) over the 30 day follow-up period (451).

Safety of Live Attenuated Influenza Vaccine (LAIV)

Children and adults can shed vaccine viruses after receipt of LAIV; this shedding is less than that typical of shedding of wild-type influenza viruses during influenza infection. Measurements of 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 (455). Other smaller studies have reported similar findings (456, 457). In an open-label study of 200 children aged 6–59 months who received a single dose of LAIV3, shedding of low titers 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). 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) (458). 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 (459), and in three (13%) of 24 HIV-infected children compared with seven (28%) of 25 children who were not HIV-infected (460).

Transmission of shed LAIV vaccine viruses from vaccine recipients to unvaccinated persons has been documented. However, serious illnesses have not been reported among unvaccinated persons 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% CI = 0–1.7) (461).

In a study of genotypic and phenotypic stability of LAIV vaccine viruses, 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 (462). In a more recent study, serial passage of the LAIV H1N1pdm09 monovalent vaccine virus in Madin-Darby canine kidney (MDCK) cells at increasing temperatures resulted in a variant that reproduced at higher temperatures and produced severe disease in mice (463).

Among healthy children aged 60–71 months enrolled in one clinical trial, some 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). However, these differences were not statistically significant (464). 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%) (268, 269, 275, 465-469). 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 which assessed prespecified 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 (465).

In a randomized trial published in 2007, LAIV3 and IIV3 were compared among children aged 6–59 months (288). 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 (465).

An open-label field trial was conducted between 1990 and 2002 among approximately 11,000 children aged 18 months–18 years in which 18,780 doses of LAIV3 were administered. 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 (470). 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 MAARI, including acute asthma exacerbation, during the 0–14 or 0–42 days after receipt of LAIV3 compared with the pre- and postvaccination reference periods (471).

A review of 460 reports (including persons aged 2 through 70 years) to VAERS following 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 (472). Few (9%) of the LAIV3 VAERS reports concerned serious adverse events; respiratory events were the most common conditions reported. During 2005–2012, VAERS received 2,619 reports in children aged 2–18 years after receipt of LAIV3 (473). Consistent with the earlier VAERS study, few (7.5%) of these reports were serious and no new adverse event patterns were identified. During 2013–2014, after approximately 12.7 million doses of LAIV4 were distributed, VAERS received 770 reports (599 in children aged 2–17 years); the safety profile of LAIV4 was consistent with prelicensure clinical trials and data from postlicensure assessment of LAIV3 (357). An analysis of health maintenance organization data for the 2013-14 season including persons aged 2 through 49 years noted a slightly higher risk of wheezing events among children aged 2 through 4 years who received LAIV4 relative to unvaccinated controls (hazard ratio 1.50, 95%CI 1.03—2.20). Of the 66 LAIV4 recipients who experienced these events, 5 were evaluated in an emergency department, but none were hospitalized (474).

Among healthy adults aged 18–49 years in one clinical trial, 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% versus 10%), runny nose (44% versus 27%), sore throat (27% versus 16%), chills (89% versus 6%), and tiredness/weakness (25% versus 21%) (464). A review of 460 reports (involving persons aged 2 through 70 years) 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. Few (9%) of the VAERS reports described serious adverse events; respiratory events were the most common conditions reported (472).

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 (475). 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 (459). 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 (460). 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) (476).

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. 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 (477). 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 (289). A VSD study, conducted among children aged ≥2 years with a history of asthma between 2007 and 2014, found no increased risk of exacerbation during 2 weeks following LAIV or IIV, and a decreased risk following LAIV, compared with IIV (478). Another VSD study assessed the safety of LAIV in persons with asthma during 3 influenza seasons (2008-2009 through 2010-2011). This study found that LAIV was not associated with an increased risk of medically attended respiratory adverse events (479). Available data are insufficient to determine the level of severity of asthma for which administration of LAIV would be inadvisable.

IIVs: Substantial data have accumulated which do not indicate fetal harm associated with inactivated influenza vaccines administered during pregnancy. However, data specifically concerning administration of these vaccines during the first trimester are limited (480). This can contribute to imprecision in estimates for risk of outcomes such as fetal death, spontaneous abortion and congenital malformations (481).

A matched case-control study of 225 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 (482). A review of health registry data in Norway noted an increased risk for fetal death associated with clinically diagnosed (not laboratory-confirmed) influenza A(H1N1) pdm09 infection, but no increased risk for fetal mortality associated with vaccination (69). Reviews of VAERS reports during 1990–2009 (483) and 2010-2016 (484), concerning pregnant women after receipt of IIV3 did not find any new or unexpected pattern of adverse pregnancy events or fetal outcomes

Background rates of spontaneous abortion vary from 10.4% in women aged <25 years to 22.4% in women aged >34 years (485). Considering the number of pregnant women vaccinated, miscarriage following (but not attributable to) influenza vaccination would therefore not be an unexpected event. However, data on the use of influenza vaccines are more limited during the early first trimester, when spontaneous abortions are more likely to occur. Among 7 observational studies summarized in a 2015 systematic review, none reported an increased risk of spontaneous abortion associated with influenza vaccination (481). A cohort study from the Vaccines and Medications in Pregnancy Surveillance System (VAMPSS) of vaccine exposure during the 2010-11 through 2013-14 seasons found no significant association of spontaneous abortion with influenza vaccine exposure in the first trimester or within the first 20 weeks of gestation (486). A case-control analysis of data from six health care organizations participating in 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 (487). However, results of a later VSD study using similar methods 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 (488).

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) (489). 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 (490-492).

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% (493). 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). A case-control analysis from VAMPSS of data from the 2011-12 through 2013-14 seasons noted an elevated OR for omphalocele (5.16, 95%CI 1.44—18.7) during the 2011-12 season; no other significant associations were found (494).

Assessments of any association with influenza vaccination and preterm birth and small for gestational age infants have yielded inconsistent results, with most studies reporting no association or a protective effect against these outcomes (495-500). Protective effects observed in some studies may be due to biases arising from temporal variability in access to vaccine, timing of exposure to vaccination in pregnancy, and confounding due to differences in the study populations at baseline (501). A VSD study of 46,549 pregnancies during the 2009-2010 season found a strong protective effect against preterm birth of monovalent H1N1pdm09 vaccination when these potential effects were ignored, but no effect with adjustment for them (502). 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 (497).

Few studies have assessed infant health outcomes outside the neonatal period, among infants born to mothers receiving IIV during pregnancy. A retrospective cohort study of electronic medical record data including nearly 197,000 women noted no association between receipt of IIV in any trimester and diagnosis of an autism spectrum disorder (ASD) in the child. When data were analyzed by trimester, an increased risk was noted following vaccination during the first trimester (adjusted hazard ratio 1.20, 95%CI 1.04—1.39) (503). This association was no longer statistically significant after adjusting for multiple comparisons.

RIVs: Experience with the use of RIVs in pregnancy is limited, as these vaccines have been available only since the 2013-14 influenza season. In two pre-licensure studies of RIV3, 23 pregnancies occurred among participants who received RIV3. Complete follow-up was available for 18 pregnancies. Outcomes included 11 pregnancies which ended in uneventful, normal, term births; two in which the recipients experienced pregnancy-related AEs but delivered healthy infants; four elective terminations, and one spontaneous abortion (452). VAERS has received 3 RIV3 reports involving pregnant women. A pregnancy registry has been established for RIV3 and RIV4 (241, 354).

LAIV: As a live virus vaccine, LAIV has not been recommended for use during pregnancy. However, occasional reports of its use for pregnant women are reported to VAERS. 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 (483). Of 127 reports of administration of LAIV3/4 to pregnant women submitted to VAERS from July2010 through May 2016, no adverse event was reported in 112 instances; the remaining 15 included two reports each of spontaneous abortion, elective termination, and nasal congestion and one report each of transverse myelitis, abdominal pain, preterm delivery, chest pain with dyspnea secondary to trauma, pure cell aplasia, headache, common cold, pulmonary hypertension in a newborn infant, and one unspecified pregnancy complication. Only the instance of pulmonary hypertension in the infant was reported as a serious event (484). Among 138 reports noted in a health insurance claims database, all outcomes occurred at similar rates to those observed in unvaccinated women (504).

Under the previous FDA labeling regulations, influenza vaccines were classified as either Pregnancy Category B or Category C on the basis of risk of reproductive and developmental adverse effects and on the basis of such risk weighed against potential benefit. In 2014, new regulations updated the format and content requirements of labeling for human prescription drugs and biological products, including vaccines. Under the new regulations, the previous pregnancy risk categories are replaced with a narrative summary of risk based on human and animal data for the specific product. In accordance with a defined implementation plan, many influenza vaccines are now labeled using the new format.

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 (505). 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 (454, 505).

Allergic reactions might be caused by the vaccine antigen, residual animal proteins, antimicrobial agents, preservatives, stabilizers, or other vaccine components. Manufacturers use a variety of compounds to inactivate influenza viruses and may 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 (506). The Clinical Immunization Safety Assessment (CISA) Project, 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 (505).

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 = 0.90–1.84) cases per million vaccine doses 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 (507). Anaphylaxis occurring after receipt of IIV and LAIV rarely has been reported to VAERS (369, 472, 508, 509). 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 (510). Some studies have noted higher rates of anaphylaxis following AS03-adjuvanted monovalent H1N1pdm09 vaccines as compared with other vaccines (511, 512); no influenza vaccines containing this adjuvant are marketed in the United States.

Most currently available influenza vaccines (with the exceptions of RIVs and ccIIV4) are prepared by propagation of influenza viruses in embryonated eggs, and therefore may contain egg proteins such as ovalbumin. Among influenza vaccines for which ovalbumin content was disclosed during the 2011–12 through 2016–17 seasons, reported maximum amounts were ≤1 µg/0.5 mL dose for IIVs and <0.24 µg/0.2 mL dose for LAIV4. Of the three vaccines produced using nonegg based technologies, currently only RIV3 and RIV4 (Flublok and Flublok Quadrivalent; Protein Sciences, Meriden, Connecticut) are considered egg-free. For ccIIV4 (Flucelvax Quadrivalent; Seqirus, Holly Springs, North Carolina), ovalbumin is not directly measured. Influenza viruses for ccIIV4 are propagated in mammalian cells rather than in eggs; however, egg proteins are potentially introduced at the start of manufacture, because some of the original viruses received from the WHO are egg-derived. From that point forward, no eggs are used, and dilutions at various steps during the manufacturing process result in a theoretical maximum of 5×10-8 μg/0.5 mL dose of total egg protein (Seqirus, data on file, 2016).

Reviews of studies of experience with use of IIV, and more recently LAIV, indicate that severe allergic reactions to the currently available egg-based influenza vaccines in persons with egg allergy are unlikely. In a 2012 review of published data, including 4,172 egg-allergic patients (513 reporting a history of severe allergic reaction) there were no noted occurrences of anaphylaxis following administration of IIV3, though some milder reactions did occur (513). Subsequently, several evaluations of LAIV use in persons with egg allergy have been published. In a prospective cohort study of children aged 2 through 16 years (68 with egg allergy and 55 without), all of whom received LAIV, none of the egg-allergic subjects developed signs or symptoms of an allergic reaction during the one hour of postvaccination observation, and none reported adverse reactions that were suggestive of allergic reaction or that required medical attention after 24 hours (514). In a larger study of 282 egg-allergic children aged 2 through 17 years (115 of whom had experienced anaphylactic reactions to egg previously), no systemic allergic reactions were observed after LAIV administration (515). Eight children experienced milder, self-limited symptoms that might have been caused by an IgE-mediated reaction. In another study of 779 egg-allergic children aged 2 through 18 years (270 of whom had previous anaphylactic reactions to egg), no systemic allergic reactions occurred. Nine children (1.2%) experienced milder symptoms, possibly allergic in nature within 30 minutes of vaccination (four rhinitis, four localized/contact urticaria, and one oropharyngeal itching) (516). A study that compared adverse reactions in eight egg-allergic and five nonegg-allergic children when given increasing doses of egg protein (517) showed only mild symptoms of rhinitis after exposure to 10–100 µg. This is substantially more than the concentration of ovalbumin reported on the LAIV package insert (<0.24 µg per 0.2 mL dose). All eight egg-allergic children tolerated LAIV doses without any allergic symptoms. These data indicate that LAIV4 may be administered safely to persons with a history of egg allergy. However, ACIP recommends that LAIV4 not be used in any population during the 2017–18 season because of concerns regarding effectiveness against influenza A(H1N1)pdm09.

Occasional cases of anaphylaxis in egg-allergic persons have been reported to the Vaccine Adverse Event Reporting System (VAERS) after administration of influenza vaccines (508, 509). ACIP will continue to review available data regarding anaphylaxis cases following influenza vaccines.