Safety of Influenza Vaccines

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 (382, 383). 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 younger 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 (382-384). In a VAERS analysis of 18,245 reports from 1990 through 2005, in the most common AEs among adults aged ≥18 years included injection site reactions, pain, fever, myalgia, and headache (385).  This VAERS review identified no new safety concerns. Fourteen percent of the IIV3 VAERS reports in adults were classified as serious adverse events (SAEs; defined as those involving death, life-threatening illness, hospitalization or prolongation of hospitalization, or permanent disability (386)), similar to proportions seen in VAERS for other adult vaccines. The most common SAE 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. During the 2013-14 and 2014-2015 influenza seasons, VSD found no increased risk after IIVs for 6 outcomes in populations that included adults (acute disseminated encephalomyelitis, anaphylaxis, Bell’s palsy, GBS, encephalitis, and transverse myelitis) (364).   Another VSD study found that overall there was no increased risk for venous thromboembolism (VTE) after IIV in adults in adults aged ≥50 years (387).

Injection site and systemic AEs were more frequent after vaccination with high-dose IIV3 (HD-IIV3; Fluzone High-Dose; Sanofi Pasteur), which contains 180 µg of HA antigen (60 per vaccine virus) than following standard dose IIV3 (15 µg per virus; Fluzone; Sanofi Pasteur), but were typically mild and transient. In one study, 915 (36%) of 2,572 persons who received HD-IIV3 reported injection site pain, compared with 306 (24%) of 1,262 who received SD-IIV3 (248). 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 AE (RR: 3.6, 95%CI 1.3–10.1).  A randomized study of HD-IIV3 versus SD-IIV3 including 9,172 participants found no difference in occurrence of SAEs or several specific AEs of interest (including GBS, Bell’s Palsy, encephalitis/myelitis, optic neuritis, Stevens-Johnson syndrome, and toxic epidermal necrolysis) (388). Safety monitoring of HD-IIV3 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 (389). 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 found that injection site and systemic side effects were more common after HD-IIV3 than after SD-IIV3 during the week after vaccination. There was no significant difference in prevalence of severe side effects or healthcare visits between groups (390).

A trivalent MF59-adjuvanted IIV3 (aIIV3), Fluad (Seqirus) 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 AEs 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  (259, 260).  In addition, rates of immune-mediated diseases after aIIV3 and SD-IIV3 were similar.

Fewer postmarketing safety data have thus far accumulated for IIV4s, 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 (122, 125, 127, 128, 391, 392). 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 AE reported following receipt of IIV4 among adults aged 18 through 64 years was injection-site pain. No specific safety concerns were identified (372).

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 AEs; no concerning pattern of AEs was identified (393).

Overall, fewer safety data are available pertaining to persons with specific underlying medical conditions relative to data from healthy populations. Most studies in these populations are small, limiting the extent to which uncommon or rare AEs may be captured. Few studies directly compare outcomes among persons with high risk conditions with those observed in healthier 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% (394). Another of 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 (378). No placebo comparison group was used in these studies. One prospective cohort study found that the rate of AEs 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 (395).

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) (396). 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 1 and 4 weeks.

Evidence indicates that IIVs are well tolerated in asthmatic children (397) and adults (197). 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) (398). 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 (399). 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 (400).

A non-randomized study compared AEs following receipt of IIV among 105 adults with type 2 diabetes with those occurring among 108 in nondiabetics. Local reactions such as tenderness, pain, redness, and swelling occurred less frequently in the diabetic group. Differences in systemic reactions such as myalgia, tiredness, headache, malaise, chills, and arthralgia were not statistically significant (401).

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 (402-407). 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 (406). Limited information is available about the effect of antiretroviral therapy on increases in HIV RNA levels after either influenza virus infection or influenza vaccination (408, 409).

IIV is generally well-tolerated by adult and pediatric solid organ transplant recipients (224). In small studies, IIV vaccination did not affect allograft function or cause acute rejection episodes in recipients of kidney (225, 227, 410, 411), heart (412), lung (410) or liver transplants (231, 232, 413). A literature review concluded that there is no convincing epidemiologic link between vaccination and allograft dysfunction (224). Guillain-Barré syndrome in a liver transplant recipient (414) and rhabdomyolysis leading to acute renal allograft dysfunction (415) after IIV vaccination have been reported.  Several case reports of corneal graft rejection have been reported following receipt of IIV (416-419), but no studies demonstrating an association have been conducted.

Some studies have evaluated high-dose or adjuvanted IIVs in immunocompromised populations. A randomized trial compared HD-IIV3 and SD-IIV3 in 190 persons with HIV infection; injection site pain was reported more frequently among the high-dose recipients, but overall the authors reported that no significant differences were observed in injection site or systemic reactions between the two groups (234).  In a randomized trial of HD- versus SD-IIV3 among 161 adult solid organ transplant recipients, frequencies of injection site reactions and fever were similar between the two groups.  Participants who received HD-IIV3 had a higher frequency of systemic symptoms, particularly gastrointestinal symptoms and arthralgia, but this difference was not statistically significant (420).  In a randomized trial of adjuvanted versus unadjuvanted IIV3 which enrolled 73 adult allogeneic hematopoietic stem cell transplant recipients (≥12 weeks post-transplant), no significant differences were reported in the prevalence of injection site or systemic reactions between the two groups.  Fever occurred more frequently among those who received the adjuvanted vaccine (236).

Guillain-Barré Syndrome (GBS) is an autoimmune disease of the peripheral nervous system.  Patients often present 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 (421-423). The annual incidence of GBS is 10–20 cases per 1 million adults (424). 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 (425).

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 (426). 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 (427, 428).

During three of four influenza seasons studied during 1977–1991, the overall relative risk estimates for GBS after influenza vaccination were not statistically significant (429-431).  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 (428). 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 (432). 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). Whether this was associated with protection against GBS due to influenza infection 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 (433). 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 (434). A third GPRD analysis found that GBS was associated with recent ILI, but not influenza vaccination (435). 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) (436).

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 (428). 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 (437-443). An analysis of chart-confirmed cases from the Medicare population during the 2009-10 season estimated that vaccination was associated with an attributable risk of 2.84 per 1 million doses (444). A subsequent four-season study in this population (2010-11 through 2013-14) obtained a similar estimate of excess risk for the 2010-11 season, but not for the three subsequent seasons (during which time the vaccine continued to contain an H1N1pdm09-like virus) (445). Of note, studies have also shown a higher risk for GBS following influenza infection than that following influenza vaccination (425, 446).

Persons with a history of GBS have a substantially greater likelihood of subsequently experiencing GBS than persons without such a history (424). 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 (447). 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 (448).

Oculorespiratory syndrome (ORS), an acute, self-limited reaction to IIV, was first described during the 2000–01 influenza season in Canada (449, 450). ORS was initially noted to be associated with one vaccine preparation (Fluviral S/F; Shire Biologics) not available in the United States during the 2000– 01 influenza season (450). After changes in the manufacturing process of the vaccine preparation associated with ORS during the 2000–01 season, the incidence of ORS in Canada diminished greatly (451). The cause of ORS has not been established; however, studies suggest that the reaction is not IgE-mediated (452). 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.

Thimerosal is an ethyl mercury-containing antimicrobial compound. It is primarily used in multidose vial preparations of IIVs as a preservative to inhibit microbial growth. For these preparations, the mercury content from thimerosal (as reported in package inserts) is ≤25 µg of mercury per 0.5 mL dose.

Although the evidence is reassuring regarding health risks associated with exposure to vaccines containing thimerosal (453-465), 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 (453, 457). LAIV4, RIV4, and single-dose vial or syringe preparations of IIVs that are expected to be available during the 2018-19 season do not contain thimerosal.

Adjuvants are compounds added to vaccines to improve immune response. Only one adjuvanted influenza vaccine, Fluad (adjuvanted inactivated influenza vaccine, trivialent [aIIV3], Seqirus) is currently licensed in the U.S. Fluad contains the squalene-based oil-in-water adjuvant, MF59. Currently, it is indicated for persons aged 65 years and older. In a randomized controlled study comparing aIIV3 with IIV3 among 7,000 persons aged ≥65 years, prevalence of some injection site and systemic reactions within the first 7 days after vaccination were higher in the aIIV3 group (259). Those who received aIIV3 were more likely to experience pain or tenderness, or myalgia. Most of these reactions were mild in severity, however. Prevalence of SAEs was similar between the two groups. Though not licensed for children in the U.S., aIIV3 has been used in the pediatric population in Europe and Canada. In studies conducted among children, MF59-adjuvanted vaccines were associated with greater likelihood of injection site redness and pain, fever, irritability, and loss of appetite than control vaccines (466).

During the 2009 pandemic, monovalent H1N1pdm09 vaccines containing squalene-based oil in water adjuvants (either MF59 or, more commonly, AS03) were used in several European countries and Canada. In June 2010, public health officials noted an increase in reports of narcolepsy cases among children and young adults. Subsequently, epidemiological studies noted an association between narcolepsy and receipt of AS03-adjuvanted monovalent H1N1pdm09 vaccine (467). No ASO3-containing vaccines are licensed in the U.S. No association of MF59 with narcolepsy has been documented to date (468, 469).

RIV was initially available in the U.S. during the 2013-14 season as RIV3 (Flublok, Protein Sciences). RIV4 (Flublok Quadrivalent, Protein Sciences; now manufactured by Sanofi Pasteur) was licensed in late 2016 and was first available for the 2017-18 season, and is expected to replace RIV3 for the 2018-19 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) (470). 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 (240, 471, 472), 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 AEs was generally similar between the two treatment groups (242).

As a relatively new category of vaccine, fewer postmarketing safety data have accumulated for RIVs. Although RIVs do not contain egg protein, 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 (473). All were considered to be consistent with possible anaphylaxis; 3 cases appeared to meet Brighton Collaboration criteria (474) 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 RIV3 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 RIV3 and IIV3 recipients, respectively, reported these events within 7 days following vaccination. Of these solicited events, rash was most frequently reported (RIV3 1.3%; IIV3 0.8%) over the 30 day follow-up period (471).

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 (475). Other smaller studies have reported similar findings (476, 477). 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) (478). 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 (479), and in three (13%) of 24 HIV-infected children compared with seven (28%) of 25 children who were not HIV-infected (480).

Transmission of shed LAIV vaccine viruses from vaccine recipients to unvaccinated persons has been documented, but has not been reported to be associated with serious illness. 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) (481).

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 (482). 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 (483).

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 (484). 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, 485-489). 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 SAEs was 0.2% in LAIV3 and placebo recipients; none of the SAEs was judged to be related to the vaccine by the study investigators (485).

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 (485). A 14-year follow-up study conducted among children who had enrolled in this trial at <3 years of age noted no increased risk for subsequent asthma diagnosis among the children who had received LAIV (490)

An open-label field trial was conducted between 1998 and 2002 among approximately 11,000 children aged 18 months through 18 years in which 18,780 doses of LAIV3 were administered. For children aged 18 months through 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(491). This trial later assessed LAIV3 safety among 2,196 children aged 18 months through 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 (492).

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 (493). Few (9%) of the LAIV3 VAERS reports concerned SAEs; respiratory events were the most common conditions reported. During 2005–2012, VAERS received 2,619 reports in children aged 2 through 18 years after receipt of LAIV3 (494). Consistent with the earlier VAERS study, few (7.5%) of these reports were serious and no new AE patterns were identified. A VSD self-controlled case series analysis of 396,173 children who received LAIV3 from September 2003 through March 2013 revealed a significant association of anaphylaxis and syncope with receipt of LAIV (495). Among the 5 syncope cases, 4 had also received injectable vaccines concurrently.  Both of these AEs were rare, with an estimated rate of 1.7 events per 1 million doses for anaphylaxis and 8.5 events per 1 million doses for syncope.

LAIV4 has been available in the U.S. since the 2013-14 season, and was not recommended for use in the U.S. during the 2016-17 and 2017-18 seasons.  Therefore fewer post-marketing surveillance data have accumulated than are available for LAIV3. During 2013–2014, after approximately 12.7 million doses of LAIV4 were distributed, VAERS received 770 reports (599 in children aged 2 through 17 years); the safety profile of LAIV4 was consistent with prelicensure clinical trials and data from postlicensure assessment of LAIV3 (496). An analysis of health maintenance organization data for the 2013-14 season including persons aged 2 through 49 years assessed risk for wheezing in children with a history of asthma or wheezing.  Risk of wheezing after LAIV4 was not higher than after IIV or unvaccinated children when the analysis was conducted in the total population. There was 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, 4 were evaluated in an emergency department, but none were hospitalized (497). An open label safety study of LAIV4 among 100 children aged 2- through 6 years conducted in Japan during the 2014-15 season noted an AE profile consistent with that of previous studies. The most frequently reported solicited symptoms were runny/stuffy nose (51%), cough (34%), fever (10%), and sore throat (7%). The only AE that occurred among greater than 5% of children was nasopharyingitis, in 13% (498). All AEs were characterized as mild in severity. In a randomized placebo-controlled trial of LAIV conducted among 1,301 children aged 7 through 18 years in Japan, the prevalence of AEs was similar among the LAIV4 and placebo groups (24.3% and 25.9%, respectively). Only 2.9% of these events were characterized as moderate in severity; none were rated as severe. The most commonly reported AE  was nasopharyingitis, occurring in 8.1% of LAIV4 recipients and 8.3% of placebo recipients. SAEs were uncommon, occurring in 0.3% of LAIV4 recipients and 0.7% of placebo recipients; all occurred > 100 days post-vaccination and were considered to be unrelated to study vaccine (498).

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%) (484). 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 SAEs; respiratory events were the most common conditions reported (493).

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 (499). In a study of 57 HIV-infected persons aged 18–58 years with CD4+ counts >200 cells/µL who received LAIV3, no SAEs attributable to vaccines were reported during a 1-month follow-up period (479). Similarly, another study demonstrated no significant difference in the frequency of AEs 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 (480). 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, AEs 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) (500).

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 through 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 (501). A study of LAIV and IIV3 among children aged 6 through 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 (502). 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 AEs (503). Available data are insufficient to determine the level of severity of asthma for which administration of LAIV would be inadvisable.

A Canadian retrospective cohort study was conducted among 198 persons aged 2 through 19 years with cystic fibrosis who received LAIV3 during the 2012-13 and 2013-14 seasons. Participants were followed for 55 days post-vaccination; rates of hospitalization, antibiotic prescriptions, and injection site and systemic symptoms during days 0 through 6 were compared with those occurring during days 7 through 55 (the control period). Rates of hospitalization and antibiotic prescriptions were similar between the two periods. Injection site and systemic symptoms were reported more commonly during days 0 through 6 as compared with that latter period; the pulmonary symptoms with the greatest magnitude of risk were chest congestion/increased sputum, and wheezing (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.

IIVs

Substantial data have accumulated which do not indicate fetal harm associated with IIVs administered during pregnancy.  However, data specifically concerning administration of these vaccines during the first trimester are limited (505).  A 2015 review of studies of maternal influenza vaccination and pregnancy outcomes noted that women vaccinated in the first trimester were underrepresented in these studies, contributing to imprecision in estimates for risk of outcomes such as fetal death, spontaneous abortion and congenital malformations (506).  Most available data are from observational studies rather than controlled trials.  Differences in methodology (for example, clinical definitions for outcomes of interest) complicates pooling of data and comparisons among estimates.

Background  rates  of  spontaneous  abortion (miscarriage) vary  from  10.4%  in women aged  <25  years  to  22.4% in women aged >34 years (507).  Considering the number of pregnant women vaccinated, spontaneous abortion following (but not attributable to) influenza vaccination would be expected to occur due to chance. Most studies (508-516) and systematic reviews (506, 517) that have evaluated risk of spontaneous abortion following receipt of IIVs have not found a statistically significant increased risk. However, data on the use of influenza vaccines are more limited during the early first trimester, when spontaneous abortions are more likely to occur; as discussed above, small sample sizes limit ability to obtain a precise estimate of risk.  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 (RR=0.73, 95%CI 0.55– 0.96 for all studies; RR=0.69, 95%CI 0.52–0.90 for studies of influenza A(H1N1)pdm09 vaccines) (517). There was no significant difference in risk for spontaneous abortion between vaccinated and unvaccinated women (RR=0.91, 95%CI 0.68–1.22).  Some reviews of studies involving seasonal and 2009(H1N1) IIV in pregnancy have concluded that no evidence exists to suggest harm to the fetus from maternal vaccination (518, 519). 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 (508).  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 (511). However, results of a subsequent 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 (520).  A follow-up study is in progress to evaluate this finding.

Multiple studies have found no increased risk for stillbirth among women who received IIV during pregnancy (180, 506, 509, 517, 521-526). A matched case-control study of 225 pregnant women who received IIV3 within the 6 months before delivery determined that no SAEs 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 (527). 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 (528) and 2010–2016 (529), concerning pregnant women after receipt of IIV3 did not find any new or unexpected pattern of adverse pregnancy events or fetal outcomes.

Data are reassuring with regard to the risk of congenital malformations following maternal influenza vaccination, with a large number of studies noting no association (506, 508, 525, 530-534).  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, found 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%. 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) (533). A case-control analysis from VAMPSS of data from the 2011-12 through 2013-14 seasons noted an elevated OR for omphalocele (OR=5.16, 95%CI 1.44—18.7) during the 2011-12 season, no other significant associations were found (531).  A second study noted an increased risk for anophthalmia/microphthalmia during the 2011-12 season (OR=8.67, 95%CI 1.10—68.5); the authors noted the possibility that this association could be due to chance, in the context of multiple comparisons (534).  A VSD study found that first trimester maternal IIV exposure was not associated with an increased risk for selected major structural birth defects (530).

Assessments of association between 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 (526, 535-540).  A matched cohort study conducted in the VSD during 2004-05 through 2008-09 seasons found no increased risk or protective effect of IIV on preterm birth and small for gestational age (537). 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 (540).  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 no adjustment was made these potential effects, 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) (541).  This association was no longer statistically significant after adjusting for multiple comparisons.  A VSD matched case-control study of 413,034 infants born between January 2004 through June 2014 found no association between maternal receipt of influenza vaccine and infant hospitalization (aOR=1.00, 95%CI 0.96—1.04) or death (aOR=0.44, 95%CI 0.17—1.13) (542).

RIVs

Experience with the use of RIVs in pregnancy is limited compared to that with IIVs, as these vaccines have been available only since the 2013-14 influenza season. In two pre-licensure studies, 23 pregnancies occurred among participants who received RIV3. Complete follow-up was available for 18, for which outcomes included 11 uneventful, normal, term births; 2 in which the recipients experienced pregnancy-related AEs but delivered healthy infants; 4 elective terminations; and one spontaneous abortion (472). VAERS has received 3 RIV3 reports involving pregnant women. A pregnancy registry has been established for RIVs (237).

LAIVs

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 (528). Of 127 reports of administration of LAIV3/4 to pregnant women submitted to VAERS from July 2010 through May 2016, no AE 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 (529). Among 138 reports noted in a health insurance claims database, all outcomes occurred at similar rates to those observed in unvaccinated women (543).

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 (544). 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 (474, 544).

Vaccines contain multiple components that may potentially cause allergic reactions.  These include 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 should be consulted for additional information. The ACIP has recommended that all vaccine providers be familiar with their office emergency plan and be certified in cardiopulmonary resuscitation (545). The Clinical Immunization Safety Assessment (CISA) Project (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 (544).

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 doses administered in all ages (546). Anaphylaxis occurring after receipt of influenza vaccines rarely has been reported to VAERS (385, 493, 547, 548). 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 among IIV3 recipients (549).

Most currently available influenza vaccines (with the exceptions of RIV4 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 2017–18 season, reported maximum amounts were ≤1 µg/0.5 mL dose for IIVs and <0.024 µg/0.2 mL dose for LAIV4. Of the two vaccines for which viruses are not propagated in eggs, ccIIV4 and IIV4, currently only RIV4 (Flublok Quadrivalent; Sanofi Pasteur) is considered egg-free. For ccIIV4 (Flucelvax Quadrivalent; Seqirus), 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 one of the original viruses received from the WHO is 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 1.7×10^-8 μg/0.5 mL dose of total egg protein (Seqirus, data on file, 2018).

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 (of whom 513 reported a history of severe allergic reaction) there were no noted occurrences of anaphylaxis following administration of IIV3, though some milder reactions did occur (550). 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.  Moreover, none reported adverse reactions that were suggestive of allergic reaction or that required medical attention after 24 hours (551). 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 (552). 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 (553).  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).  A study that compared adverse reactions in eight egg-allergic and five nonegg-allergic children when given increasing doses of egg protein (554) showed only mild symptoms of rhinitis after exposure to 10–100 µg. This is substantially more than the concentration of ovalbumin reported in the LAIV package insert (<0.024 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.

Occasional cases of anaphylaxis in egg-allergic persons have been reported to the Vaccine Adverse Event Reporting System (VAERS) after administration of influenza vaccines(126, 127). The ACIP will continue to review available data regarding anaphylaxis cases following influenza vaccines.