Vaccine Preventable Diseases

Influenza

ACIP Recs | Disease | Vaccine | References | VIS live | VIS inactivated  | WHO modules | Archives


Advisory Committee on Immunization Practices (ACIP) Recommendations

All Age Groups
- All persons witout contraindications who are 6 months of age and older should receive annual vaccination with inactivated influenza vaccine (abbreviation: IIV; trade names: see the table below).
- Live attenuated influenza vaccine (abbreviation: LAIV; trade name: FluMist®) was previously recommended for non-pregnant persons between 2 and 49 years of age; however, in June 2016, the ACIP recommended that LAIV not be used until problems with low effectiveness during the past several seasons are addressed [1].
- Influenza vaccine should be given as soon as it becomes available (usually between August and October in the U.S.) in order to ensure the highest possible level of protection before rates of transmission increase. Peak transmission season is usually between December and March in the United States [2].

Infants and Children
- Children less than 9 years of age receiving IIV for the first time ever should receive two doses at least one month apart; otherwise, one dose per year is sufficient [1].

For More Information
ACIP recommendations: https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/flu.html
Immunization schedules: http://www.cdc.gov/vaccines/schedules/index.html
 

Disease 

Influenza is caused by RNA viruses of three types. Type A influenza is the cause of most human illness and has many subtypes based on the variations in the surface antigens (i.e., hemagglutinin (H) and neuraminidase (N)), such as H1N1 or H3N2. Type B influenza also infects humans but generally causes milder illness. Type C only very rarely causes human disease.

The surface antigens on influenza viruses are always evolving, faster than most other viruses that cause human disease. This continuous stream of minor mutations is called antigenic drift and is what makes influenza so adept at evading immunity induced by prior infection or vaccination. In most years, at least some of the circulating influenza strains have drifted compared to prior years, thus even those who were infected or vaccinated in years prior may develop influenza disease again.

Occasionally a major change in one or both surface antigens occurs, known as antigenic shift; the majority of the population is usually susceptible to the new virus. The new strains generated in this manner, such as the 2009 influenza A H1N1, have the potential to cause a worldwide pandemic.

The incubation period for influenza is generally 2 days [2]. The major clinical symptoms typically last a median of 4 days without treatment and include sore throat, fever, headache, myalgia, and nonproductive cough [2, 3]. The CDC estimated an average of 23,607 annual influenza-associated deaths in the United States between 1976 and 2007, although these estimates ranged widely from year to year [4].

Vaccine

Two types of vaccines have been available to protect against influenza in recent years: inactivated influenza vaccine (IIV) and live attenuated influenza vaccine (LAIV). However, LAIV is no longer recommended.

In the United States, quadrivalent IIV (IIV4) vaccines include Fluarix® Quadrivalent, FluLaval® Quadrivalent, and Fluzone® Quadrivalent; trivalent IIV (IIV3) include Afluria®, Fluvirin®, and Fluzone®. There are two recombinant influenza vaccines, Flublok® (RIV3) and Flublok® Quadrivalent (RIV4).  Trivalent vaccines contain one A/H3N2 strain, one A/H1N1 strain, and one B strain from one of the two B lineages (Yamagata and Victoria). The Quadrivalent vaccines contain a second B strain [1, 2].

The Food and Drug Administration (FDA) has recommended that the trivalent influenza vaccines used in the United States during the 2017-18 season contain an A/Michigan/45/2015 (H1N1)pdm09-like virus, an A/Hong Kong/4801/2014 (H3N2)-like virus, and a B/Brisbane/60/2008-like (B/Victoria lineage) virus; and that the quadrivalent vaccines also contain a B/Phuket/3073/2013-like (B/Yamagata lineage) virus [5].

Inactivated influenza vaccine (IIV)

Route of administration Primarily intramuscular (IM), one intradermal (ID); specified for each vaccine listed below
Vaccine virus Inactivated, split or subvirion
Trade names, doses available, age range of approval Standard dose
Fluzone® Quadrivalent (0.5 mL single-dose vial or prefilled syringe) (IM), for persons > 36 months of age;
Fluzone® Quadrivalent (5.0 mL multi-dose vial) (IM), for persons > 6 months of age;
Fluarix® Quadrivalent (0.5 mL single-dose prefilled syringe) (IM), for persons > 3 years of age;
FluLaval® Quadrivalent (5.0 mL multi-dose vial) (IM), for persons > 6 months of age;
Flucelvax® Quadrivalent (0.5 mL single-dose prefilled syringe) (IM), cell culture-based, for persons > 4 years of age;
Afluria® (0.5 mL single-dose prefilled syringe or 5.0 mL multi-dose vial) (IM), for persons > 5 years of age;
Afluria® Quadrivalent (0.5 mL prefilled syringe) (IM), for persons > 5 years of age;
Afluria® Quadrivalent (5.0 mL multi-dose vial) (IM), for persons > 5 years of age (by needle/syringe), for adults 18-64 years of age (by jet injector);
Fluvirin® (0.5 mL single-dose prefilled syringe or 5.0 mL multi-dose vial) (IM), for persons > 4 years of age;
Fluad® (0.5 mL single-dose prefilled syringe) (IM), adjuvanted, for adults > 65 years of age.
High dose
Fluzone® High-Dose (0.5 mL single-dose prefilled syringe) (IM) (higher antigen content), for adults > 65 years of age;
Recombinant
Flublok® (0.5 mL single-dose vial) (IM), for adults > 18 years of age;
Flublok® Quadrivalent (0.5 mL single-dose vial) (IM), for adults > 18 years of age;
Intradermal
Fluzone® Intradermal Quadrivalent (0.1 mL single-dose prefilled microinjection system) (ID) (lower antigen content), for adults 18-64 years of age.


Vaccine Effectiveness: The effectiveness of influenza vaccines varies each year in relation to the match between the vaccine strains and the circulating strain. Effectiveness can also vary by the age and health status of the vaccine recipient [2].

Vaccine Safety: Common adverse reactions to IIV include local reactions such as soreness, erythema and induration at the injection site, which are reported at variable rates, but are usually mild and typically last no more than 2 days. Systemic symptoms such as sensation of fever, chills, malaise, and myalgia are also common. These symptoms typically begin within 6–12 hours of vaccination and usually last for only a few hours. Such symptoms are usually mild but have been reported in 4-<30% of children receiving IIV [6-12]. Myalgia within a week of vaccination has been reported among 14-16% of adults receiving unadjuvanted IIV and 31-39% of adults receiving adjuvanted IIV [13], with even higher rates among recipients of the 2009 pandemic H1N1 vaccine [14].

Rarely, allergic reactions such as hives, angioedema, allergic asthma, or systemic anaphylaxis occur after vaccination, probably due to hypersensitivity to a vaccine component. See the Do Vaccines Cause Hypersensitivity Reactions? summary for more details.

Influenza vaccination in recent years has been associated with a very small increased risk of GBS in adults, leading to about 1-3 excess cases of GBS per million persons vaccinated. This is much less than the estimated risk after wild-type influenza infection, providing further evidence that the benefits of influenza vaccination greatly outweigh the risks [15]. See the Do Vaccines Cause Guillain-Barré Syndrome (GBS)? summary for more details.


Contraindications and Precautions: An important contraindication is having had a severe allergic reaction (e.g. anaphylaxis) to a vaccine component or previous vaccination. However, this does not include egg allergies, even though most influenza vaccines are grown in embryonated chicken eggs (an exception being the egg-free recombinant influenza vaccine, Flublok®) [1]. The following is a direct excerpt from the 2017-18 ACIP recommendations regarding the use of influenza vaccine in persons with egg allergy:

Persons with a history of egg allergy who have experienced only urticaria (hives) after exposure to egg should receive influenza vaccine. Any licensed and recommended influenza vaccine (i.e., any IIV or RIV) that is otherwise appropriate for the recipient’s age and health status may be used.
Persons who report having had reactions to egg involving symptoms other than urticaria (hives), such as angioedema, respiratory distress, lightheadedness, or recurrent emesis; or who required epinephrine or another emergency medical intervention, may similarly receive any licensed and recommended influenza vaccine (i.e., any IIV or RIV) that is otherwise appropriate for the recipient’s age and health status. 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 conditions.
A previous severe allergic reaction to influenza vaccine, regardless of the component suspected of being responsible for the reaction, is a contraindication to future receipt of the vaccine.
” [1]

Precautions include moderate to severe acute illness with or without fever, as well as a diagnosis of Guillain-Barré Syndrome (GBS) within 6 weeks after a previous dose of influenza vaccine [1]. The complete current recommendations of the ACIP regarding influenza vaccine delivery can be found at the following website: https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/flu.html.

Considerations in Pregnancy: Pregnant women may receive any licensed, recommended, age-appropriate influenza vaccine. Inactivated influenza vaccine (IIV) is routinely recommended during pregnancy. Live attenuated influenza vaccine (LAIV) is contraindicated during pregnancy[1].

Pregnant women and young children are at increased risk of complications and hospitalizations from influenza. Infection with influenza during pregnancy has been associated with an increased risk of adverse outcomes to the mother including respiratory hospitalization, pneumonia, adult respiratory distress syndrome, overwhelming sepsis and death [16]. A recent CDC study estimated that 12% of all pregnancy-related deaths during the 2009-2010 pandemic season were attributed to confirmed or possible infection with pandemic influenza [17].

IIV was shown to reduce non-specific febrile respiratory illness in pregnant women by over one third. Vaccine effectiveness was most pronounced during influenza season. Vaccination in pregnancy is beneficial not just for the mother, but for her unborn child as well. Maternal influenza vaccination was shown in one study to reduce proven influenza illness in infants under 6 months of age by up to 63% [18]. In several other studies, IIV was shown to reduce the risk of low birthweight and premature birth [19, 20]. Some studies have found that pregnant women who received influenza vaccine had a lower likelihood of stillbirth than those who did not [21-23], although the evidence for this is inconsistent and has methodological limitations [23-25].

A large body of evidence demonstrates the safety of IIV for both pregnant women and their unborn children [26-32]. Concomitant administration of Tdap and influenza vaccines during pregnancy is not associated with a higher risk of adverse outcomes compared to sequential vaccination [33].

Donahue et al. recently reported results from a case-control study examining the risk of spontaneous abortion (SAb) following receipt of inactivated influenza vaccines containing A/H1N1pdm2009 antigen in the 2010-11 and 2011-12 seasons [34]. The study found an association between influenza vaccine and SAb, particularly among women who had received pandemic H1N1 vaccine in the previous year as well [34]. The Donahue et al. findings need to be interpreted in the context of other epidemiological data [35]. One recent randomized trial recruiting women at 17-34 weeks gestation [36], thirteen other observational studies [37-49], two systematic reviews [30, 50], and one meta-analysis [21] have assessed a potential association between influenza vaccine and SAb or a related outcome, and none have found an association. However, none of these studies examined the effect of multiple dosing. Studies are in progress to assess whether this association is seen in subsequent influenza seasons. See the Do Vaccines Cause Spontaneous Abortion? summary for more details.

References

1. Grohskopf LA, Sokolow LZ, Broder KR, Walter EB, Bresee JS, Fry AM, et al. Prevention and Control of Seasonal Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices - United States, 2017-18 Influenza Season. MMWR Recomm Rep. 2017;66(2):1-20.
2. Epidemiology and Prevention of Vaccine-Preventable Diseases. In: Hamborsky J KA, Wolfe S ed. 13 ed. Washington D.C.: Centers for Disease Control and Prevention; 2015.
3. Fry AM, Goswami D, Nahar K, Sharmin AT, Rahman M, Gubareva L, et al. Efficacy of oseltamivir treatment started within 5 days of symptom onset to reduce influenza illness duration and virus shedding in an urban setting in Bangladesh: a randomised placebo-controlled trial. Lancet Infect Dis. 2014;14(2):109-18.
4. Estimates of deaths associated with seasonal influenza --- United States, 1976-2007. MMWR Morb Mortal Wkly Rep. 2010;59(33):1057-62.
5. Blanton L, Alabi N, Mustaquim D, Taylor C, Kniss K, Kramer N, et al. Update: Influenza Activity in the United States During the 2016-17 Season and Composition of the 2017-18 Influenza Vaccine. MMWR Morb Mortal Wkly Rep. 2017;66(25):668-76.
6. Brady RC, Hu W, Houchin VG, Eder FS, Jackson KC, Hartel GF, et al. Randomized trial to compare the safety and immunogenicity of CSL Limited's 2009 trivalent inactivated influenza vaccine to an established vaccine in United States children. Vaccine. 2014;32(52):7141-7.
7. Greenberg DP, Robertson CA, Landolfi VA, Bhaumik A, Senders SD, Decker MD. Safety and immunogenicity of an inactivated quadrivalent influenza vaccine in children 6 months through 8 years of age. Pediatr Infect Dis J. 2014;33(6):630-6.
8. Baxter R, Jeanfreau R, Block SL, Blatter M, Pichichero M, Jain VK, et al. A Phase III evaluation of immunogenicity and safety of two trivalent inactivated seasonal influenza vaccines in US children. Pediatr Infect Dis J. 2010;29(10):924-30.
9. Nolan T, Richmond PC, McVernon J, Skeljo MV, Hartel GF, Bennet J, et al. Safety and immunogenicity of an inactivated thimerosal-free influenza vaccine in infants and children. Influenza Other Respir Viruses. 2009;3(6):315-25.
10. Domachowske JB, Pankow-Culot H, Bautista M, Feng Y, Claeys C, Peeters M, et al. A randomized trial of candidate inactivated quadrivalent influenza vaccine versus trivalent influenza vaccines in children aged 3-17 years. J Infect Dis. 2013;207(12):1878-87.
11. Langley JM, Carmona Martinez A, Chatterjee A, Halperin SA, McNeil S, Reisinger KS, et al. Immunogenicity and safety of an inactivated quadrivalent influenza vaccine candidate: a phase III randomized controlled trial in children. J Infect Dis. 2013;208(4):544-53.
12. Tregnaghi MW, Stamboulian D, Vanadia PC, Tregnaghi JP, Calvari M, Fragapane E, et al. Immunogenicity, safety, and tolerability of two trivalent subunit inactivated influenza vaccines: a phase III, observer-blind, randomized, controlled multicenter study. Viral Immunol. 2012;25(3):216-25.
13. Beran J, Peeters M, Dewe W, Raupachova J, Hobzova L, Devaster JM. Immunogenicity and safety of quadrivalent versus trivalent inactivated influenza vaccine: a randomized, controlled trial in adults. BMC Infect Dis. 2013;13:224.
14. Nicholson KG, Abrams KR, Batham S, Clark TW, Hoschler K, Lim WS, et al. Immunogenicity and safety of a two-dose schedule of whole-virion and AS03A-adjuvanted 2009 influenza A (H1N1) vaccines: a randomised, multicentre, age-stratified, head-to-head trial. Lancet Infect Dis. 2011;11(2):91-101.
15. Vellozzi C, Iqbal S, Broder K. Guillain-Barre syndrome, influenza, and influenza vaccination: the epidemiologic evidence. Clin Infect Dis. 2014;58(8):1149-55.
16. Tamma PD, Steinhoff MC, Omer SB. Influenza infection and vaccination in pregnant women. Expert Rev Respir Med. 2010;4(3):321-8.
17. Callaghan WM, Creanga AA, Jamieson DJ. Pregnancy-Related Mortality Resulting From Influenza in the United States During the 2009-2010 Pandemic. Obstet Gynecol. 2015;126(3):486-90.
18. Zaman K, Roy E, Arifeen SE, Rahman M, Raqib R, Wilson E, et al. Effectiveness of maternal influenza immunization in mothers and infants. N Engl J Med. 2008;359(15):1555-64.
19. Rasmussen SA, Jamieson DJ, Uyeki TM. Effects of influenza on pregnant women and infants. Am J Obstet Gynecol. 2012;207(3 Suppl):S3-8.
20. Phadke VK, Omer SB. Maternal vaccination for the prevention of influenza: current status and hopes for the future. Expert Rev Vaccines. 2016;15(10):1255-80.
21. Bratton KN, Wardle MT, Orenstein WA, Omer SB. Maternal influenza immunization and birth outcomes of stillbirth and spontaneous abortion: a systematic review and meta-analysis. Clin Infect Dis. 2015;60(5):e11-9.
22. Regan AK, Moore HC, de Klerk N, Omer SB, Shellam G, Mak DB, et al. Seasonal Trivalent Influenza Vaccination During Pregnancy and the Incidence of Stillbirth: Population-Based Retrospective Cohort Study. Clin Infect Dis. 2016;62(10):1221-7.
23. Fell DB, Platt RW, Lanes A, Wilson K, Kaufman JS, Basso O, et al. Fetal death and preterm birth associated with maternal influenza vaccination: systematic review. BJOG: An International Journal of Obstetrics & Gynaecology. 2015;122(1):17-26.
24. Fell DB, Bhutta ZA, Hutcheon JA, Karron RA, Knight M, Kramer MS, et al. Report of the WHO technical consultation on the effect of maternal influenza and influenza vaccination on the developing fetus: Montreal, Canada, September 30-October 1, 2015. Vaccine. 2017;35(18):2279-87.
25. Savitz DA, Fell DB, Ortiz JR, Bhat N. Does influenza vaccination improve pregnancy outcome? Methodological issues and research needs. Vaccine. 2015;33(47):6430-5.
26. Tamma PD, Ault KA, del Rio C, Steinhoff MC, Halsey NA, Omer SB. Safety of influenza vaccination during pregnancy. Am J Obstet Gynecol. 2009;201(6):547-52.
27. Bednarczyk RA, Adjaye-Gbewonyo D, Omer SB. Safety of influenza immunization during pregnancy for the fetus and the neonate. Am J Obstet Gynecol. 2012;207(3 Suppl):S38-46.
28. Keller-Stanislawski B, Englund JA, Kang G, Mangtani P, Neuzil K, Nohynek H, et al. Safety of immunization during pregnancy: a review of the evidence of selected inactivated and live attenuated vaccines. Vaccine. 2014;32(52):7057-64.
29. Vaccines against influenza WHO position paper - November 2012. Wkly Epidemiol Rec. 2012;87(47):461-76.
30. McMillan M, Porritt K, Kralik D, Costi L, Marshall H. Influenza vaccination during pregnancy: a systematic review of fetal death, spontaneous abortion, and congenital malformation safety outcomes. Vaccine. 2015;33(18):2108-17.
31. Polyzos KA, Konstantelias AA, Pitsa CE, Falagas ME. Maternal Influenza Vaccination and Risk for Congenital Malformations: A Systematic Review and Meta-analysis. Obstet Gynecol. 2015;126(5):1075-84.
32. Kharbanda EO, Vazquez-Benitez G, Lipkind H, Naleway A, Lee G, Nordin JD. Inactivated influenza vaccine during pregnancy and risks for adverse obstetric events. Obstet Gynecol. 2013;122(3):659-67.
33. Sukumaran L, McCarthy NL, Kharbanda EO, Weintraub ES, Vazquez-Benitez G, McNeil MM, et al. Safety of Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis and Influenza Vaccinations in Pregnancy. Obstet Gynecol. 2015;126(5):1069-74.
34. Donahue JG, Kieke BA, King JP, DeStefano F, Mascola MA, Irving SA, et al. Association of spontaneous abortion with receipt of inactivated influenza vaccine containing H1N1pdm09 in 2010–11 and 2011–12. Vaccine. 2017;35(40):5314-22.
35. Chambers CD, Xu R, Mitchell AA. Commentary on: "Association of spontaneous abortion with receipt of inactivated influenza vaccine containing H1N1pdm09 in 2010-11 and 2011-12". Vaccine. 2017;35(40):5323-4.
36. Steinhoff MC, Katz J, Englund JA, Khatry SK, Shrestha L, Kuypers J, et al. Year-round influenza immunisation during pregnancy in Nepal: a phase 4, randomised, placebo-controlled trial. Lancet Infect Dis. 2017;17(9):981-9.
37. Chambers CD, Johnson D, Xu R, Luo Y, Louik C, Mitchell AA, et al. Risks and safety of pandemic H1N1 influenza vaccine in pregnancy: birth defects, spontaneous abortion, preterm delivery, and small for gestational age infants. Vaccine. 2013;31(44):5026-32.
38. Chambers CD, Johnson DL, Xu R, Luo YJ, Louik C, Mitchell AA, et al. Safety of the 2010–11, 2011–12, 2012–13, and 2013–14 seasonal influenza vaccines in pregnancy: Birth defects, spontaneous abortion, preterm delivery, and small for gestational age infants, a study from the cohort arm of VAMPSS. Vaccine. 2016;34(37):4443-9.
39. Chavant F, Ingrand I, Jonville-Bera A, Plazanet C, Gras-Champel V, Lagarce L, et al. The PREGVAXGRIP Study: a Cohort Study to Assess Foetal and Neonatal Consequences of In Utero Exposure to Vaccination Against A(H1N1)v2009 Influenza. Drug Safety. 2013;36(6):455-65.
40. Huang WT, Tang FW, Yang SE, Chih YC, Chuang JH. Safety of inactivated monovalent pandemic (H1N1) 2009 vaccination during pregnancy: a population-based study in Taiwan. Vaccine. 2014;32(48):6463-8.
41. Ludvigsson JF, Strom P, Lundholm C, Cnattingius S, Ekbom A, Ortqvist A, et al. Maternal vaccination against H1N1 influenza and offspring mortality: population based cohort study and sibling design. Bmj. 2015;351:h5585.
42. Ma F, Zhang L, Jiang R, Zhang J, Wang H, Gao X, et al. Prospective cohort study of the safety of an influenza A(H1N1) vaccine in pregnant Chinese women. Clin Vaccine Immunol. 2014;21(9):1282-7.
43. Oppermann M, Fritzsche J, Weber-Schoendorfer C, Keller-Stanislawski B, Allignol A, Meister R, et al. A(H1N1)v2009: A controlled observational prospective cohort study on vaccine safety in pregnancy. Vaccine. 2012;30(30):4445-52.
44. Pasternak B, Svanström H, Mølgaard-Nielsen D, Krause TG, Emborg H-D, Melbye M, et al. Vaccination against pandemic A/H1N1 2009 influenza in pregnancy and risk of fetal death: cohort study in Denmark. BMJ : British Medical Journal. 2012;344.
45. Tavares F, Nazareth I, Monegal JS, Kolte I, Verstraeten T, Bauchau V. Pregnancy and safety outcomes in women vaccinated with an AS03-adjuvanted split virion H1N1 (2009) pandemic influenza vaccine during pregnancy: A prospective cohort study. Vaccine. 2011;29(37):6358-65.
46. Irving SA, Kieke BA, Donahue JG, Mascola MA, Baggs J, DeStefano F, et al. Trivalent Inactivated Influenza Vaccine and Spontaneous Abortion. Obstetrics & Gynecology. 2013;121(1):159-65.
47. Sammon CJ, Snowball J, McGrogan A, de Vries CS. Evaluating the hazard of foetal death following H1N1 influenza vaccination; a population based cohort study in the UK GPRD. PLoS One. 2012;7(12):e51734.
48. Heikkinen T, Young J, van Beek E, Franke H, Verstraeten T, Weil JG, et al. Safety of MF59-adjuvanted A/H1N1 influenza vaccine in pregnancy: a comparative cohort study. Am J Obstet Gynecol. 2012;207(3):177.e1-8.
49. de Vries L, van Hunsel F, Cuppers-Maarschalkerweerd B, van Puijenbroek E, van Grootheest K. Adjuvanted A/H1N1 (2009) influenza vaccination during pregnancy: description of a prospective cohort and spontaneously reported pregnancy-related adverse reactions in the Netherlands. Birth Defects Res A Clin Mol Teratol. 2014;100(10):731-8.
50. Bednarczyk RA, Adjaye-Gbewonyo D, Omer SB. Safety of influenza immunization during pregnancy for the fetus and the neonate. American Journal of Obstetrics & Gynecology. 2012;207(3):S38-S46.