Prevention and Control of Seasonal Influenza with Vaccines ..

Recommendations for the Use of Influenza Vaccines, 2022–23

Groups Recommended for Vaccination

Routine annual influenza vaccination is recommended for all persons aged ≥6 months who do not have contraindications. Recommendations regarding timing of vaccination, considerations for specific populations, the use of specific vaccines, and contraindications and precautions are summarized in the sections that follow.

Timing of Vaccination

Because timing of the onset, peak, and decline of influenza activity varies, the ideal time to start vaccinating cannot be predicted each season. Decisions about timing necessitate balancing considerations regarding this unpredictability of the influenza season, possible waning of vaccine-induced immunity over the course of a season, and programmatic considerations. Influenza vaccines might be available as early as July or August; however, vaccination during these months is not recommended for most groups because of the possible waning of immunity over the course of the influenza season (19–32). For most persons who need only 1 dose of influenza vaccine for the season, vaccination should ideally be offered during September or October. However, vaccination should continue after October and throughout the influenza season as long as influenza viruses are circulating and unexpired vaccine is available.

Considerations for timing of vaccination include the following:

• For most adults (particularly adults aged ≥65 years) and for pregnant persons in the first or second trimester: Vaccination during July and August should be avoided unless there is concern that vaccination later in the season might not be possible.
• Children who require 2 doses: Certain children aged 6 months through 8 years require 2 doses of influenza vaccine for the season (see Children Aged 6 Months Through 8 Years: Number of Influenza Vaccine Doses) (Figure). These children should receive their first dose as soon as possible (including during July and August, if vaccine is available) to allow the second dose (which must be administered ≥4 weeks later) to be received, ideally, by the end of October.
• Children who require only 1 dose: Vaccination during July and August can be considered for children of any age who need only 1 dose of influenza vaccine for the season. While waning of immunity after vaccination over the course of the season has been observed among all age groups (19–32), there are fewer published studies reporting results specifically among children (19–22). Moreover, children in this group might visit health care providers during the late summer months for medical examinations before the start of school. Vaccination can be considered at this time because it represents a vaccination opportunity.
• Pregnant persons in the third trimester: Vaccination during July and August can be considered for pregnant persons who are in the third trimester because vaccination might reduce risk for influenza illness in their infants during the first months after birth, when they are too young to receive influenza vaccine (33–36). For pregnant persons in the first or second trimester during July and August, waiting to vaccinate until September or October is preferable, unless there is concern that later vaccination might not be possible.

Community vaccination programs should balance maximizing the likelihood of persistence of vaccine-induced protection through the season with avoiding missed opportunities to vaccinate or vaccinating after onset of influenza circulation occurs. Efforts should be structured to optimize vaccination coverage before influenza activity in the community begins. Vaccination should continue to be offered as long as influenza viruses are circulating and unexpired vaccine is available. To avoid missed opportunities for vaccination, providers should offer vaccination during routine health care visits and hospitalizations. No recommendation is made for revaccination (i.e., providing a booster dose) later in the season of persons who have been fully vaccinated for the season, regardless of when the current season vaccine was received.

During the 2022–23 influenza season, SARS-CoV-2 is expected to continue to circulate in the United States, and COVID-19 vaccinations are expected to continue. Current guidance for the administration of COVID-19 vaccines (“Coadministration of COVID-19 vaccines with other vaccines” at https://www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html#recommendations) indicates that these vaccines can be administered with influenza vaccines; providers should consult this page for updated information. Guidance for vaccine planning during the COVID-19 pandemic is available at https://www.cdc.gov/vaccines/pandemic-guidance/index.html.

Optimally, vaccination should occur before onset of influenza activity in the community. However, because timing of the onset, peak, and decline of influenza activity varies, the ideal time to start vaccinating cannot be predicted each season. Moreover, more than one outbreak might occur in a community in a single year. In the United States, localized outbreaks indicating the start of seasonal influenza activity can occur as early as October. However, in 29 (76%) of 38 influenza seasons from 1982–83 through 2019–20, peak influenza activity (which often is close to the midpoint of influenza activity for the season) has not occurred until January or later, and in 23 (61%) seasons, the peak was in February or later (37). Activity peaked in February in 17 (45%) of these seasons (37).

An increasing number of observational studies (19–32) have reported decreases in vaccine effectiveness with increasing time postvaccination within a single influenza season. Waning effects have not been observed consistently across age groups, influenza viruses (types, subtypes, and lineages), or seasons. Certain studies suggest waning occurs to a greater degree against influenza A(H3N2) viruses than against influenza A(H1N1) or influenza B viruses (26,27). This effect also might vary with recipient age; in certain studies, waning was more pronounced among older adults (19,23,26,30,32) and younger children (19). Relatively fewer reports include results specific to children (19–22); findings suggestive of waning have been reported in certain studies (19–21) but not others (22). Rates of decline in vaccine effectiveness also varied. A multiseason (2011–12 through 2014–15) analysis from the U.S. Influenza Vaccine Effectiveness (U.S. Flu VE) Network found that vaccine effectiveness decreased by approximately 7% per month for influenza A(H3N2) and influenza B and 6%–11% per month for influenza A(H1N1)pdm09 (25). Vaccine effectiveness remained greater than zero for at least 5–6 months after vaccination. In the Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN) during the 2015–16 through 2018–19 seasons, vaccine effectiveness against influenza-associated hospitalizations declined by approximately 8%–9% per month for all adults and approximately 10%–11% per month for those aged ≥65 years (32). An analysis of the 2010–11 through 2013–14 seasons noted estimated effectiveness ranging from 54% to 67% during days 0–180 postvaccination; estimated vaccine effectiveness was not significant during the period between days 181 and 365 (20). A third multiseason analysis (2010–11 through 2014–15) conducted in Europe noted a decline in vaccine effectiveness to 0% at 111 days postvaccination against influenza A(H3N2) viruses. Vaccine effectiveness against influenza B viruses decreased more slowly, and vaccine effectiveness against influenza A(H1N1)pdm09 viruses remained roughly stable at 50%–55% throughout the influenza season (27). A meta-analysis of 14 studies examining waning of influenza vaccine effectiveness using the test-negative design found a significant decline in effectiveness within 180 days after vaccination against influenza A (H3N2) and influenza B but not against influenza A(H1N1) (38). In addition to the factors observed to be associated with waning immunity across studies, observed decreases in protection might be at least in part attributable to bias, unmeasured confounding, or the late-season emergence of antigenic drift variants of influenza viruses that are less well-matched to the vaccine viruses.

Varying data concerning the presence and rate of waning immunity after influenza vaccination, coupled with the unpredictable timing of the influenza season each year, prevent determination of an optimal time to vaccinate. Programmatic issues also are a consideration. Although delaying vaccination might result in greater immunity later in the season, deferral also might result in missed opportunities to vaccinate as well as difficulties in vaccinating a population within a more constrained period. The potential contributions of these factors among persons aged ≥65 years have been assessed using a simulated mathematical model examining various scenarios of vaccination timing, timing of onset of the influenza season, vaccine effectiveness, and rate of waning (39). In this model, during an influenza season beginning in October and peaking in January, delaying vaccination until October resulted in more hospitalizations if >14% of persons aged ≥65 years who would have been vaccinated in August or September failed to get vaccinated. However, these predictions varied considerably with assumed timing of season onset, rate of waning immunity, and vaccine effectiveness.

Vaccination efforts should continue throughout the season because the duration of the influenza season varies, and influenza activity might not occur in certain communities until February, March, or later. Providers should offer influenza vaccine routinely, and organized vaccination campaigns should continue throughout the influenza season, including after influenza activity has begun in the community. Although vaccination by the end of October is recommended, vaccine administered in December or later, even if influenza activity has already begun, might be beneficial in most influenza seasons. Providers should offer influenza vaccination to unvaccinated persons who have already become ill with influenza during the season because the vaccine might protect them against other circulating influenza viruses.

Guidance for Influenza Vaccination in Specific Populations and Situations

Populations at Higher Risk for Medical Complications Attributable to Severe Influenza

All persons aged ≥6 months who do not have contraindications should be vaccinated annually. However, vaccination to prevent influenza is particularly important for persons who are at increased risk for severe illness and complications from influenza and for influenza-related outpatient, emergency department, or hospital visits. When vaccine supply is limited, vaccination efforts should focus on vaccination of persons at higher risk for medical complications attributable to severe influenza who do not have contraindications. These persons include the following (no hierarchy is implied by order of listing):

• All children aged 6 through 59 months.
• All persons aged ≥50 years.
• Adults and children who have chronic pulmonary (including asthma), cardiovascular (excluding isolated hypertension), renal, hepatic, neurologic, hematologic, or metabolic disorders (including diabetes mellitus).
• Persons who are immunocompromised due to any cause (including but not limited to immunosuppression caused by medications or HIV infection).
• Persons who are or will be pregnant during the influenza season.
• Children and adolescents (aged 6 months through 18 years) who are receiving aspirin- or salicylate-containing medications and who might be at risk for experiencing Reye syndrome after influenza virus infection.
• Residents of nursing homes and other long-term care facilities.
• American Indian or Alaska Native persons.
• Persons who are extremely obese (body mass index ≥40 for adults).

An IIV4 or RIV4 (as appropriate for the recipient’s age) is suitable for persons in all risk groups. LAIV4 is not recommended for certain populations, including certain of these listed groups. Contraindications and precautions for the use of LAIV4 are noted (Tables 2 and 3).

Persons Who Live with or Care for Persons at Higher Risk for Influenza-Related Complications

All persons aged ≥6 months without contraindications should be vaccinated annually. However, emphasis also should be placed on vaccination of persons who live with or care for those who are at increased risk for medical complications attributable to severe influenza. When vaccine supply is limited, vaccination efforts should focus on administering vaccination to persons at higher risk for influenza-related complications as well as persons who live with or care for such persons, including the following:

• Health care personnel, including all paid and unpaid persons working in health care settings who have the potential for exposure to patients or to infectious materials. These personnel might include but are not limited to physicians, nurses, nursing assistants, nurse practitioners, physician assistants, therapists, technicians, emergency medical service personnel, dental personnel, pharmacists, laboratory personnel, autopsy personnel, students and trainees, contractual staff persons, and others not directly involved in patient care but who might be exposed to infectious agents (e.g., clerical, dietary, housekeeping, laundry, security, maintenance, administrative, and billing staff persons and volunteers). ACIP guidance for vaccination of health care personnel has been published previously (40).
• Household contacts (including children aged ≥6 months) and caregivers of children aged ≤59 months (<5 years) and adults aged ≥50 years, particularly contacts of children aged <6 months.
• Household contacts (including children aged ≥6 months) and caregivers of persons with medical conditions that put them at higher risk for severe complications from influenza.

Health care personnel and persons who are contacts of persons in these groups (with the exception of contacts of severely immunocompromised persons who require a protected environment) may receive any influenza vaccine that is otherwise indicated. Persons who care for severely immunocompromised persons requiring a protected environment should not receive LAIV4. ACIP and the Healthcare Infection Control Practices Advisory Committee (HICPAC) have previously recommended that health care personnel who receive LAIV should avoid providing care for severely immunocompromised persons requiring a protected environment for 7 days after vaccination and that hospital visitors who have received LAIV should avoid contact with such persons for 7 days after vaccination (41). However, such persons need not be restricted from caring for or visiting less severely immunocompromised persons.

Influenza Vaccination of Persons with COVID-19

Vaccination of persons who have tested positive for COVID-19 or who are in quarantine after an exposure should include multiple considerations, such as whether bringing the person into a vaccination setting could expose others to COVID-19, whether the person is acutely ill and the severity of the illness, the presence of risk factors for severe influenza illness, the likelihood of being able to vaccinate at a later date, and the desire to avoid confusing postvaccination symptoms with those of COVID-19. Usually, persons who are in quarantine or isolation should not be brought to a vaccination setting if doing so could expose others to COVID-19. For those who have moderate or severe COVID-19, vaccination should usually be deferred until they have recovered, which is consistent with ACIP General Best Practice Guidelines for Immunization (42). For persons who have mild or asymptomatic COVID-19, further deferral might be considered to avoid confusing COVID-19 symptoms with postvaccination reactions. Because recommendations for vaccination of this population might continue to evolve, clinicians should check CDC guidance (https://www.cdc.gov/vaccines/pandemic-guidance/index.html) for up-to-date information.

Children Aged 6 Through 35 Months: Influenza Vaccine Dose Volumes

Five IIV4s are approved for children aged ≥6 months (Table 1). Four of these vaccines are egg based (Afluria Quadrivalent, Fluarix Quadrivalent, Flulaval Quadrivalent, and Fluzone Quadrivalent), and one is cell culture based (Flucelvax Quadrivalent). For these vaccines, the approved dose volumes for children aged 6 through 35 months are as follows (Table 4):

• Afluria Quadrivalent: 0.25 mL per dose. However, 0.25-mL prefilled syringes are not expected to be available for the 2022–23 season. For children aged 6 through 35 months, a 0.25-mL dose must be obtained from a multidose vial (43).
• Fluarix Quadrivalent: 0.5 mL per dose.
• Flucelvax Quadrivalent: 0.5 mL per dose.
• FluLaval Quadrivalent: 0.5 mL per dose.
• Fluzone Quadrivalent: either 0.25 mL or 0.5 mL per dose. Per the package insert, each dose may be given at either volume (44); however, the 0.25-mL prefilled syringes are no longer available.

For all of these IIV4s, persons aged ≥36 months (≥3 years) should receive 0.5 mL per dose.

Alternatively, healthy children aged ≥24 months (≥2 years) may receive LAIV4, 0.2 mL intranasally (0.1 mL in each nostril). LAIV4 is not recommended for certain populations and is not approved for children aged <2 years (see Contraindications and Precautions for the Use of LAIV4) (Table 2). RIV4 is not approved for children aged <18 years. High-dose inactivated influenza vaccine (HD-IIV4) and adjuvanted inactivated influenza vaccine (aIIV4) are not approved for persons aged <65 years.

Care should be taken to administer an age-appropriate vaccine at the appropriate volume for each dose. For IIV4s, the recommended volume may be administered from a prefilled syringe containing the appropriate volume (as supplied by the manufacturer), a single-dose vial, or a multidose vial. Single-dose vials should be used for only 1 dose, and multidose vials should be used only for the maximum number of doses specified in the package insert. Any vaccine remaining in a vial after the maximum number of doses has been removed should be discarded, regardless of the volume of the doses obtained or any remaining volume in the vial.

Children Aged 6 Months Through 8 Years: Number of Influenza Vaccine Doses

Children aged 6 months through 8 years require 2 doses of influenza vaccine administered a minimum of 4 weeks apart during their first season of vaccination for optimal protection (45–48). Determination of the number of doses needed is based on 1) the child’s age at the time of the first dose of 2022–23 influenza vaccine and 2) the number of doses of influenza vaccine received in previous influenza seasons.

• For children aged 6 months through 8 years, the number of doses of influenza vaccine needed for the 2022–23 influenza season is determined as follows (Figure):
  • Those who have previously received ≥2 total doses of trivalent or quadrivalent influenza vaccine ≥4 weeks apart before July 1, 2022, require only 1 dose for the 2022–23 season. The 2 previous doses of influenza vaccine do not need to have been received in the same season or consecutive seasons.
  • Those who have not previously received ≥2 doses of trivalent or quadrivalent influenza vaccine ≥4 weeks apart before July 1, 2022, or whose previous influenza vaccination history is unknown, require 2 doses for the 2022–23 season. The interval between the 2 doses should be ≥4 weeks. Children aged 6 months through 8 years who require 2 doses of influenza vaccine should receive their first dose as soon as possible (including during July and August, if vaccine is available) to allow the second dose (which must be administered ≥4 weeks later) to be received, ideally, by the end of October. Two doses are recommended even if the child turns age 9 years between receipt of dose 1 and dose 2.
• Adults and children aged ≥9 years need only 1 dose of influenza vaccine for the 2022–23 season.

Pregnant Persons

Pregnant and postpartum persons have been observed to be at higher risk for severe illness and complications from influenza, particularly during the second and third trimesters. Influenza vaccination during pregnancy is associated with reduced risk for respiratory illness and influenza among pregnant and postpartum persons as well as infants during the first several months of life (33–36,49). ACIP and the American College of Obstetricians and Gynecologists recommend that persons who are pregnant or who might be pregnant or postpartum during the influenza season receive influenza vaccine (50). Any licensed, recommended, and age-appropriate IIV4 or RIV4 may be used. LAIV4 should not be used during pregnancy but can be used postpartum. Influenza vaccine can be administered at any time during pregnancy (i.e., during any trimester), before and during the influenza season. Early vaccination (i.e., during July and August) can be considered for persons who are in the third trimester during these months if vaccine is available because this can provide protection for the infant during the first months of life when they are too young to be vaccinated.

Although experience with the use of IIVs during pregnancy is substantial, data specifically reflecting administration of influenza vaccines during the first trimester are limited (see Safety of Influenza Vaccines in the supplementary Background Document). Most studies have not noted an association between influenza vaccination and adverse pregnancy outcomes, including spontaneous abortion (miscarriage) (51–61). One observational Vaccine Safety Datalink (VSD) study conducted during the 2010–11 and 2011–12 seasons noted an association between receipt of IIV containing influenza A(H1N1)pdm09 and risk for miscarriage in the 28 days after receipt of IIV, when an H1N1pdm09-containing vaccine also had been received the previous season (62). However, in a larger VSD follow-up study, IIV was not associated with an increased risk for miscarriage during the 2012–13, 2013–14, and 2014–15 seasons, regardless of previous season vaccination (63).

Substantially less experience exists with more recently licensed IIVs (e.g., quadrivalent and cell culture–based vaccines) during pregnancy than with previously available products. For RIV (available as RIV3 from 2013–14 through 2017–18 and as RIV4 since 2017–18), data are limited to reports of pregnancies occurring incidentally during clinical trials, Vaccine Adverse Event Reporting System (VAERS) reports, and pregnancy registries. Pregnancy registries and surveillance studies exist for certain products, for which information can be found in package inserts.

Older Adults

ACIP recommends that adults aged ≥65 years preferentially receive any one of the following higher dose or adjuvanted influenza vaccines: quadrivalent high-dose inactivated influenza vaccine (HD-IIV4), quadrivalent recombinant influenza vaccine (RIV4), or quadrivalent adjuvanted inactivated influenza vaccine (aIIV4). If none of these three vaccines is available at an opportunity for vaccine administration, then any other age-appropriate influenza vaccine should be administered.

Older adults (aged ≥65 years) are at increased risk for severe influenza-associated illness, hospitalization, and death compared with younger persons (4,16,64). Influenza vaccines are often less effective in this population (65). HD-IIV, RIV, and aIIV have been evaluated in comparison with nonadjuvanted SD-IIVs in this age group. Two of these vaccines, HD-IIV and RIV, are higher dose vaccines, which contain an increased dose of HA antigen per virus compared with nonadjuvanted SD-IIVs (60 µg for HD-IIV4 and 45 µg for RIV4, compared with 15 µg for standard-dose inactivated vaccines). The adjuvanted vaccine contains 15 µg of HA per virus, similarly to nonadjuvanted SD-IIVs, but contains the adjuvant MF59.

HD-IIV, RIV, and aIIV have shown relative benefit compared with SD-IIVs in certain studies, with the most evidence available for HD-IIV3. Randomized efficacy studies comparing these vaccines with nonadjuvanted SD-IIVs against laboratory-confirmed influenza outcomes are few in number (66–68) and cover few influenza seasons. Observational studies, predominantly retrospective cohort studies using diagnostic code–defined (rather than laboratory-confirmed) outcomes, are more numerous and include more influenza seasons (69–79). Certain observational studies have reported relative benefit for HD-IIV, RIV, and aIIV in comparison with nonadjuvanted SD-IIVs, particularly in prevention of influenza-associated hospitalizations. The size of this relative benefit has varied from season to season and is not seen in all studies in all seasons, making it difficult to generalize the findings to all or most seasons. Studies directly comparing HD-IIV, RIV, and aIIV with one another are few and do not support a conclusion that any one of these vaccines is consistently superior to the others across seasons (70–72,79–81).

Of note, for the 2020–21 season, quadrivalent formulations of high-dose (HD-IIV4) and adjuvanted (aIIV4) influenza vaccines were introduced. Trivalent formulations of these vaccines are no longer available. Data summarizing comparisons of these newer quadrivalent formulations relative to nonadjuvanted SD-IIV4s against laboratory-confirmed influenza outcomes are not yet available.

Literature concerning the efficacy, effectiveness, and safety of HD-IIV, RIV, and aIIV versus nonadjuvanted SD-IIVs and of each of these three vaccines with one another was reviewed, focusing on published studies performed during nonpandemic influenza seasons. A description of the systematic review and GRADE is available at https://www.cdc.gov/vaccines/acip/recs/grade/influenza-older-adults.html. An abbreviated summary follows.

Randomized Studies Comparing HD-IIV, RIV, and aIIV with Nonadjuvanted SD-IIVs: Prevention of Influenza Illnesses. Randomized studies comparing HD-IIV, RIV, and aIIV with nonadjuvanted SD-IIVs against laboratory-confirmed influenza illness are few in number and were conducted over few influenza seasons. HD-IIV3 was more effective than SD-IIV3 in prevention of polymerase chain reaction (PCR)- or culture-confirmed influenza-like illness (ILI) in a two-season randomized study conducted among 32,000 persons aged ≥65 years (relative efficacy: 24%; 95% CI: 10%–36%; certainty level: 1, high) (66). Two single-season randomized trials of RIV versus nonadjuvanted SD-IIV, one a comparison of RIV3 versus nonadjuvanted SD-IIV3 that assessed culture-confirmed ILI (67) and the other a comparison of RIV4 versus nonadjuvanted SD-IIV4 that examined PCR-confirmed ILI (68), did not demonstrate relative benefit of RIV among those aged ≥65 years (pooled relative efficacy: 18%; 95% CI: −17% to 43%; certainty level: 2, moderate). The larger of these two studies noted a relative benefit of RIV4 over nonadjuvanted SD-IIV4 in prevention of PCR-confirmed influenza among the full study population of persons aged ≥50 years (relative efficacy: 30%; 95% CI: 10%–47%) as well as against culture-confirmed ILI among those aged ≥65 years (relative efficacy: 42%; 95% CI: 9%–65%) (68). No data are available from randomized trials of aIIV versus nonadjuvanted SD-IIVs against laboratory-confirmed influenza outcomes during nonpandemic influenza seasons.

Randomized Studies Comparing HD-IIV, RIV, and aIIV with Nonadjuvanted SD-IIVs: Prevention of Influenza-Associated Hospitalizations and Other Serious Events. No data are available from randomized trials evaluating prevention of laboratory-confirmed influenza-associated hospitalizations as a primary outcome. In a secondary analysis from a two-season randomized trial of HD-IIV3 versus nonadjuvanted SD-IIV3 assessing serious adverse events (SAEs) (including hospitalizations) associated with laboratory confirmation of influenza performed outside of the study (82) and a post hoc analysis of pneumonia- and influenza-related hospitalizations from a randomized study of HD-IIV3 versus nonadjuvanted SD-IIV4 (83), there was no difference in risk for these events between the two groups (certainty level: 2, moderate). However, additional data are available from two single-season, cluster-randomized studies conducted among U.S. nursing homes (in which nursing homes were randomized to vaccine groups rather than individual persons) that examined prevention of pneumonia and influenza diagnostic–coded hospitalizations. One such study noted a benefit of HD-IIV3 relative to nonadjuvanted SD-IIV3 (adjusted relative risk: 0.79; 95% CI: 0.66–0.95; certainty level: 2, moderate) (84). The second noted a benefit of aIIV3 relative to nonadjuvanted SD-IIV3 (adjusted hazard ratio: 0.79; 95% CI: 0.65–0.96; certainty level: 2, moderate) (85).

Observational Studies Comparing HD-IIV, RIV, and aIIV with Nonadjuvanted SD-IIVs: Prevention of Influenza-Associated Hospitalizations and Deaths. Observational studies comparing HD-IIV and aIIV with nonadjuvanted SD-IIVs are more numerous than randomized studies and cover more influenza seasons. Many of these studies assessed diagnostic code–defined (rather than laboratory-confirmed) outcomes. In these studies, an overall modest relative benefit in prevention of diagnostic code–defined influenza-associated hospitalizations has been observed for HD-IIV3 (70–77) and aIIV3 (70–72) versus nonadjuvanted SD-IIV3s. Relative benefit was not found in every study for all evaluated seasons for either HD-IIV3 or aIIV3. Published observational studies of RIV are fewer than for HD-IIV and aIIV. A retrospective analysis of relative effectiveness of RIV4 versus SD-IIV4 against influenza-coded hospitalizations among Medicare beneficiaries during the 2019–20 season noted a relative effectiveness of 17% (95% CI: 9%–24%; certainty level: 3, low) (72). Observational studies that address relative benefit in protection against influenza-associated deaths are limited. Two retrospective cohort studies including three influenza seasons noted a relative benefit of HD-IIV3 compared with nonadjuvanted SD-IIV3 (69,78) diagnostic code–defined deaths (pooled rate ratio: 0.69; 95% CI: 0.57–0.84; certainty level: 3, low).

Observational Studies Comparing Effectiveness of HD-IIV, RIV, and aIIV with One Another. Data reflecting comparisons of HD-IIV, aIIV, and RIV with one another are more limited than comparisons with nonadjuvanted SD-IIVs. Observational studies have compared HD-IIV3 versus aIIV3 (70–72,79–81), HD-IIV3 versus RIV4 (72), and aIIV3 versus RIV4 (72). A retrospective cohort analysis noted relative effectiveness of RIV4 compared with HD-IIV3 (relative effectiveness: 11%; 95% CI: 3%–18%; certainty level: 3, low) and with aIIV3 (relative effectiveness: 11%; 95% CI: 3%–17%; certainty level: 3, low); these data covered only a single influenza season. Data do not point to a consistent relative benefit of one of these three influenza vaccines over another across multiple seasons.

Safety. In comparative safety studies, certain injection site and systemic reactions were observed more frequently in older persons vaccinated with HD-IIV3 and aIIV3 compared with nonadjuvanted SD-IIV3 (86,87). In a randomized trial of RIV4 versus nonadjuvanted SD-IIV4 among persons aged ≥50 years, frequencies of solicited injection site events were similar or lower among RIV4 recipients; frequency of fever was similar between the two vaccines. Frequencies of SAEs were similar between the two groups, and none was judged to be related to a study vaccine (68). One postlicensure randomized clinical trial in the United States evaluated the comparative safety of aIIV3 compared with HD-IIV3 in 757 adults aged ≥65 years (88). For the primary outcome, the proportion of participants who reported moderate to severe injection site pain that limited or prevented activity after aIIV3 (12 participants [3.2%]) was noninferior compared with the proportion reporting this outcome after vaccination with HD-IIV3 (22 participants [5.8%]). No participant sought medical care for a solicited reaction symptom, and none had a SAE determined by study investigators to be related to vaccine within 43 days after vaccination.

Immunocompromised Persons

ACIP recommends that persons with compromised immunity (including but not limited to persons with congenital and acquired immunodeficiency states, persons who are immunocompromised due to medications, and persons with anatomic and functional asplenia) should receive an age-appropriate IIV4 or RIV4. ACIP recommends that LAIV4 not be used for these groups because of the uncertain but biologically plausible risk for disease attributable to the live vaccine virus. Use of LAIV4 in persons with these and other conditions is discussed in more detail (see Dosage, Administration, Contraindications, and Precautions) (Table 2).

Immunocompromised states comprise a heterogeneous range of conditions with varying risks for severe infections. In many instances, limited data are available regarding the effectiveness of influenza vaccines in the setting of specific immunocompromised states (89). Timing of vaccination might be a consideration (e.g., vaccinating during a period either before or after an immunocompromising intervention). The Infectious Diseases Society of America has published detailed guidance for the selection and timing of vaccines for persons with specific immunocompromising conditions (90). Immune response to influenza vaccines might be blunted in persons with certain conditions, such as congenital immune deficiencies, and in persons receiving cancer chemotherapy or immunosuppressive medications.

Persons with a History of Guillain-Barré Syndrome After Influenza Vaccination

A history of Guillain-Barré syndrome (GBS) within 6 weeks of a previous dose of any type of influenza vaccine is considered a precaution for influenza vaccination (Table 2). Persons who are not at higher risk for severe influenza complications (see Populations at Higher Risk for Medical Complications Attributable to Severe Influenza) and who are known to have experienced GBS within 6 weeks of a previous influenza vaccination typically should not be vaccinated. As an alternative to vaccination, providers might consider using influenza antiviral chemoprophylaxis for these persons (91). However, the benefits of influenza vaccination might outweigh the possible risks for certain persons who have a history of GBS within 6 weeks after receipt of influenza vaccine and who also are at higher risk for severe complications from influenza.

Persons with a History of Egg Allergy

Most available influenza vaccines, with the exceptions of RIV4 (Flublok Quadrivalent, licensed for those aged ≥18 years) and ccIIV4 (Flucelvax Quadrivalent, licensed for those aged ≥6 months), are prepared by propagation of virus in embryonated eggs and might contain trace amounts of egg proteins, such as ovalbumin. For persons who report a history of egg allergy, ACIP recommends the following:

• Persons with a history of egg allergy who have experienced only urticaria (hives) after exposure to egg should receive influenza vaccine. Any licensed, recommended influenza vaccine (i.e., any IIV4, RIV4, or LAIV4) that is otherwise appropriate for the recipient’s age and health status can be used.
• Persons who report having had reactions to egg involving symptoms other than urticaria (e.g., angioedema or swelling, respiratory distress, lightheadedness, or recurrent vomiting) or who required epinephrine or another emergency medical intervention can similarly receive any licensed, recommended influenza vaccine (i.e., any IIV4, RIV4, or LAIV4) that is otherwise appropriate for their age and health status. If a vaccine other than ccIIV4 or RIV4 is used, the selected vaccine should be administered in an inpatient or outpatient medical setting, including but not necessarily limited to hospitals, clinics, health departments, and physician offices. Vaccine administration should be supervised by a health care provider who is able to recognize and manage severe allergic reactions.

All vaccination providers should be familiar with their office emergency plan and be certified in cardiopulmonary resuscitation (42). No postvaccination observation period is recommended specifically for egg-allergic persons. However, ACIP recommends that vaccination providers consider observing patients (seated or supine) for 15 minutes after administration of any vaccine to decrease the risk for injury should syncope occur (42).

Persons with Previous Allergic Reactions to Influenza Vaccines

As is the case for all vaccines, influenza vaccines contain various components that might cause allergic and anaphylactic reactions. Most influenza vaccine package inserts list among contraindications to their use a history of previous severe allergic reaction (e.g., anaphylaxis) to any component of the vaccine or to a previous dose of any influenza vaccine. For ccIIV4 and RIV4, a history of a severe allergic reaction to any vaccine component is listed as a contraindication; no labeled contraindication is specified for a history of allergic reaction to any other influenza vaccine. However, severe allergic reactions, although rare, can occur after influenza vaccination, even among persons with no previous reactions or known allergies. Although vaccine components can be found in package inserts, identifying the causative component without further evaluation (i.e., through evaluation and testing for specific allergies) can be difficult. Severe allergic reactions after vaccination with an RIV have been reported to VAERS, some of which have occurred among persons reporting previous allergic reactions to egg or to influenza vaccines and which might represent a predisposition to development of allergic manifestations in affected persons (92–94). Because these rare but severe allergic reactions can occur, ACIP recommends the following for persons with a history of severe allergic reaction to a previous dose of an influenza vaccine (Table 3):

• For egg-based IIV4s and LAIV4:
  • A history of severe allergic reaction (e.g., anaphylaxis) to any influenza vaccine (i.e., any egg-based IIV, ccIIV, RIV, or LAIV of any valency) is a contraindication to future receipt of all egg-based IIV4s and LAIV4. Each individual egg-based IIV4 and LAIV4 is also contraindicated for persons who have had a severe allergic reaction (e.g., anaphylaxis) to any component of that vaccine (excluding egg) (see Persons with a History of Egg Allergy).
• For ccIIV4:
  • A history of a severe allergic reaction (e.g., anaphylaxis) to any egg-based IIV, RIV, or LAIV of any valency is a precaution for the use of ccIIV4. If ccIIV4 is administered in such instances, vaccination should occur in an inpatient or outpatient medical setting and should be supervised by a health care provider who is able to recognize and manage severe allergic reactions. Providers also can consider consultation with an allergist to help determine the vaccine component responsible for the allergic reaction.
  • A history of a severe allergic reaction (e.g., anaphylaxis) to any ccIIV of any valency or to any component of ccIIV4 is a contraindication to future receipt of ccIIV4.
• For RIV4:
  • A history of a severe allergic reaction (e.g., anaphylaxis) to any egg-based IIV, ccIIV, or LAIV of any valency is a precaution for the use of RIV4. If RIV4 is administered in such instances, vaccination should occur in an inpatient or outpatient medical setting and should be supervised by a health care provider who is able to recognize and manage severe allergic reactions. Providers can also consider consultation with an allergist to help determine the vaccine component responsible for the allergic reaction.
  • A history of a severe allergic reaction (e.g., anaphylaxis) to any RIV of any valency or to any component of RIV4 is a contraindication to future receipt of RIV4.

Vaccination Issues for Travelers

In temperate climate regions of the Northern and Southern Hemispheres, influenza activity is seasonal, occurring during approximately October–May in the Northern Hemisphere and April–September in the Southern Hemisphere. In the tropics, influenza might occur throughout the year. Travelers can be exposed to influenza when traveling to an area where influenza is circulating or when traveling as part of large tourist groups (e.g., on cruise ships) that include persons from areas of the world where influenza viruses are circulating (95–98).

Travelers who want to reduce their risk for influenza should consider influenza vaccination, preferably at least 2 weeks before departure. In particular, persons who live in the United States and are at higher risk for influenza complications and who were not vaccinated with influenza vaccine during the previous Northern Hemisphere fall or winter should consider receiving influenza vaccination before departure if they plan to travel to the tropics, to the Southern Hemisphere during the Southern Hemisphere influenza season (April–September), or with organized tourist groups or on cruise ships to any location. Persons at higher risk who received the previous season’s influenza vaccine before travel should consult with their health care provider to discuss the risk for influenza and other travel-related diseases before embarking on travel during the summer. All persons (regardless of risk status) who are vaccinated in preparation for travel before the upcoming influenza season’s vaccine is available should receive the current vaccine the following fall or winter.

Influenza vaccine formulated for the Southern Hemisphere might differ in viral composition from the Northern Hemisphere vaccine. For persons traveling to the Southern Hemisphere during the Southern Hemisphere influenza season, receipt of a current U.S.-licensed Southern Hemisphere influenza vaccine formulation before departure might be reasonable but might not be feasible because of limited access to or unavailability of Southern Hemisphere formulations in the United States. Most Southern Hemisphere influenza vaccine formulations are not licensed in the United States, and they are typically not commercially available. More information on influenza vaccines and travel is available at https://wwwnc.cdc.gov/travel/diseases/influenza-seasonal-zoonotic-and-pandemic.

Use of Influenza Antiviral Medications

Administration of IIV4 or RIV4 to persons receiving influenza antiviral medications for treatment or chemoprophylaxis of influenza is acceptable. Data concerning vaccination with LAIV4 in the setting of influenza antiviral use are not available. However, influenza antiviral medications might interfere with the action of LAIV4 because this vaccine contains live influenza viruses.

The package insert for LAIV4 notes that antiviral agents might reduce the effectiveness of the vaccine if given within the interval from 48 hours before to 14 days after vaccination (99). However, the newer influenza antivirals peramivir and baloxavir have longer half-lives than oseltamivir and zanamivir, approximately 20 hours for peramivir (100) and 79 hours for baloxavir (101), and could interfere with the replication of LAIV4 if administered >48 hours before vaccination. Potential interactions between influenza antivirals and LAIV4 have not been studied, and the ideal intervals between administration of these medications and LAIV4 are not known. Assuming a period of at least 5 half-lives for substantial decrease in drug levels (102), a reasonable assumption is that that peramivir might interfere with the mechanism of LAIV4 if administered from 5 days before through 2 weeks after vaccination and baloxavir might interfere if administered from 17 days before through 2 weeks after vaccination. The interval between influenza antiviral receipt and LAIV4 during which interference might occur could be further prolonged in the presence of medical conditions that delay medication clearance (e.g., renal insufficiency). Persons who receive these medications during these periods before or after receipt of LAIV4 should be revaccinated with another appropriate influenza vaccine (e.g., IIV4 or RIV4).

Administration of Influenza Vaccines with Other Vaccines

IIV4s and RIV4 may be administered simultaneously or sequentially with other inactivated vaccines or live vaccines. Injectable vaccines that are given concomitantly should be administered at separate anatomic sites. LAIV4 can be administered simultaneously with other live or inactivated vaccines. However, if two live vaccines are not given simultaneously, at least 4 weeks should pass after administration of one live vaccine (such as LAIV4) before another live vaccine is administered (42).

Current guidance concerning administration of current U.S.-approved or -authorized COVID-19 vaccines indicates that these vaccines may be given with influenza vaccines (https://www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html). Providers should be aware of the potential for increased reactogenicity with coadministration and should consult updated CDC guidance as more information becomes available. If administered simultaneously, COVID-19 vaccines and influenza vaccines that might be more likely to cause an injection site reaction (e.g., aIIV4 or HD-IIV4) should be administered in different limbs, if possible. In an interim analysis of a study of concomitant administration of HD-IIV4 and a booster dose of an mRNA COVID-19 vaccine (administered in separate upper arm sites) compared with administration of either vaccine alone among 296 persons aged ≥65 years, overall reactogenicity up to 7 days postvaccination was similar between the coadministration group and the group that received the mRNA COVID-19 vaccine alone; reactogenicity rates in the group receiving HD-IIV4 alone were lower. No SAEs were observed. Immune response was similar between the mRNA COVID-19 and coadministration groups (103).

Relatively limited data are available on the concomitant administration of influenza vaccines with other vaccines. Studies of live attenuated zoster vaccine and IIV3 (104) or IIV4 (105) among persons aged ≥50 years noted similar antibody responses whether the two vaccines were administered concomitantly or 4 weeks apart. In certain studies, reduced responses have been noted to 13-valent pneumococcal conjugate vaccine (PCV13) (106,107), tetanus antigens (108), and pertussis antigens (108) when coadministered with IIV3 to adults; in most instances, the clinical significance of this is uncertain. Simultaneous administration of IIV4 and 23-valent pneumococcal polysaccharide vaccine (PPSV23) to persons aged ≥65 years was associated with lower seroprotection rates to one influenza B antigen at 4–6 weeks postvaccination compared with sequential administration 2 weeks apart. Seroprotection was not significantly different between the two groups for any of the four influenza antigens at 6 months postvaccination (109). Reassuring safety profiles have been noted for simultaneous administration of IIVs with live attenuated zoster vaccine (104,105); PCV13 (106,107); PPSV23 (109,110); tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine among adults (108); and Tdap in pregnancy (111). Although increased prevalence of injection site or systemic adverse reactions has been noted with concurrent administration in certain studies, these symptoms have usually been reported to be mild or moderate.

Among children aged 6 through 23 months, coadministration of IIV3 and PCV13 was associated with increased risk for fever on the day of vaccination and the day after (i.e., days 0–1 postvaccination) in an observational study conducted during the 2011–12 season (112). A randomized clinical trial during the 2017–18 influenza season suggested that delaying IIV4 administration by 2 weeks in children receiving diphtheria and tetanus toxoids and acellular pertussis (DTaP) and PCV13 did not reduce fever prevalence after vaccination (113). Increased risk for febrile seizures in this age group has been noted within days 0–1 after coadministration of IIV with PCV7, PCV13, or DTaP vaccines during the 2006–07 through 2010–11 seasons (114) and with PCV13 during the 2014–15 season (115). Although concerning to parents, most febrile seizures are brief and have a good prognosis (116). After considering the risks and benefits, no changes in the recommendations for administration of these vaccines were made. Surveillance of febrile seizures is ongoing through VAERS, and the VSD annual influenza safety surveillance includes monitoring for seizures after vaccinations. Studies of concomitant administration of LAIV with other vaccines are limited. Concurrent administration of LAIV3 with measles, mumps, and rubella (MMR) and varicella vaccine to children was not associated with diminished immunogenicity of antigens in any of the vaccines in one study (117); diminished response to rubella was observed in another study examining coadministration of LAIV3 and MMR (118). No safety concerns were noted in these studies.

In recent years, several vaccines containing nonaluminum adjuvants have been licensed for use in the United States for the prevention of various infectious diseases. These include AS01B (in Shingrix, recombinant zoster subunit vaccine) (119), MF59 (in Fluad Quadrivalent [aIIV4]) (120), and cytosine phosphoguanine oligodeoxynucleotide (in Heplisav-B, a recombinant hepatitis B surface antigen vaccine) (121). Data are limited regarding coadministration of these vaccines with other adjuvanted or nonadjuvanted vaccines, including COVID-19 vaccines. Coadministration of Shingrix with nonadjuvanted IIV4 has been studied, and no evidence of decreased immunogenicity or safety concerns was noted (122). The immunogenicity and safety of simultaneous or sequential administration of two nonaluminum adjuvant–containing vaccines have not been evaluated, and the ideal interval between such vaccines when given sequentially is not known. In the study of Shingrix and IIV4 (122), most reactogenicity symptoms resolved within 4 days. Because of the limited data on the safety of simultaneous administration of two or more vaccines containing nonaluminum adjuvants and the availability of nonadjuvanted influenza vaccine options, selection of a nonadjuvanted influenza vaccine may be considered in situations in which influenza vaccine and another vaccine containing a nonaluminum adjuvant are to be administered concomitantly. However, influenza vaccination should not be delayed if a specific vaccine is not available. As recommended for all vaccines, vaccines with nonaluminum adjuvants should be administered at separate anatomic sites from other vaccines that are given concomitantly (42).