US Pharm. 2018;43(11):6-10.

Despite the availability of vaccines, influenza continues to be a public-health concern. The flu is a highly contagious respiratory virus that affects thousands of people every year. It is spread from person to person primarily through respiratory droplets generated when an infected person coughs or sneeze; transmission can also occur upon direct or indirect contact with surfaces contaminated with the virus.¹ The flu can affect people of all ages, but the highest rates of complications and hospitalizations are most often seen in persons aged 65 years and older, young children, and those with certain underlying medical conditions (Table 1).¹ It is estimated that since 2010, influenza has resulted in up to 35.6 million illnesses, up to 710,000 hospitalizations, and up to 56,000 deaths annually.² The influenza season generally begins in October—with peaks seen in January and February—and can last until May.³

The 2017–2018 influenza season was considered to be one of the longest seasons in history, with activity above the national baseline for 19 weeks.⁴ In addition, it was considered to be a high-severity season; hospitalization rates were the highest ever recorded, the percentages of adult deaths attributed to pneumonia and influenza were at or above the epidemic threshold for 16 consecutive weeks, and as of September 18, 2018, a total of 181 pediatric deaths had been reported; this number exceeds the previous high for flu-associated deaths in children reported during a regular flu season.⁴ However, approximately 80% of these deaths occurred in children who had not received a flu vaccination.

Receiving the influenza vaccination is one of the most important strategies to help prevent the flu. Many patients are hesitant or do not fully understand the true potential of danger associated with influenza. Pharmacists, especially in the community setting, play a critical role in promoting the influenza vaccine. As an advocate, educator, and immunizer, the pharmacist is vital in helping maintain high immunization rates.

Influenza Virus

There are three types of influenza virus: A, B, and C. Influenza A infects both humans and animals, typically causes moderate-to-severe disease, and affects all ages. Influenza A has subtypes that are identified by the surface antigens hemagglutinin (HA), which is responsible for virus attachment to cells, and neuraminidase (NA), which is responsible for virus penetration into cells. These glycoproteins undergo continuous minor mutations (antigenic drift) and major mutations (antigenic shift), resulting in epidemics and pandemics, respectively.¹

Influenza B affects only humans and generally causes milder disease, primarily affecting children. It is categorized not into subtypes, but rather by genetically distinct lineages: Yamagata and Victoria. Influenza B is more immunologically stable than influenza A, resulting in fewer antigenic drifts. Influenza C rarely causes disease in humans.¹

The average incubation period for influenza is 2 days, with a range of 1 to 4 days.¹ Infected persons are considered contagious 1 day before symptoms appear and up to 5 days after onset. Children, a major source of transmission of influenza, may be contagious for up to 10 days or more. Once infected, patients may develop the classic clinical symptoms of influenza: abrupt fever (101°F-102°F), myalgia, chills, sore throat, and an unproductive cough.¹ Patients may also experience malaise, nasal congestion, and gastrointestinal symptoms, including nausea, vomiting, and diarrhea.⁵

In healthy individuals, influenza usually resolves inconsequentially; however, certain individuals are at increased risk for complications (Table 1). The most frequent complications associated with influenza are pulmonary: primary influenza pneumonia; secondary bacterial pneumonia (Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae); pneumonia due to unusual pathogens (Aspergillus, Chlamydia pneumoniae, B-hemolytic Streptococcus, Legionella pneumophila); and exacerbations of chronic pulmonary diseases.⁶ Neurologic complications may also occur, including encephalopathy, aseptic meningitis, febrile seizures, Reye syndrome, and Guillain-Barré syndrome; these are seen more commonly in young children.^6,7 In addition, exacerbations of underlying cardiovascular conditions may also occur.⁶

Influenza Vaccines

The influenza virus is constantly changing. Because of this, the vaccine composition is reviewed annually and updated as needed based on which influenza viruses are circulating, the extent to which those viruses are spreading, and how good the response was to the previous year’s vaccine. There are more than 100 laboratories in over 100 countries conducting year-round surveillance and providing data to the World Health Organization (WHO) Collaborating Centre for Reference and Research on Influenza. Twice a year, the WHO makes recommendations about specific viruses to include in the seasonal influenza vaccine. The FDA then makes the final decision as to which strains will be included in the upcoming season’s influenza vaccines for administration in the United States; this information is presented to an FDA advisory committee each February.⁸ The trivalent 2018–2019 influenza vaccine contains two influenza type A strains and one influenza type B strain. Quadrivalent vaccines contain all strains found in the trivalent, plus an additional B strain (Table 2).⁹

Influenza vaccines induce neutralizing antibodies against the viral surface proteins HA and NA, but the vaccine is quantified only for its HA content, and vaccine efficacy is determined by the presence of adequate HA inhibition.^10,11 There are two types of influenza vaccines available: inactivated influenza vaccine (IIV) and live attenuated influenza vaccine (LAIV). The IIVs have been in production since the 1940s and are the most commonly used formulations. They contain components of the influenza virus and consist of either split-virus or subunit influenza antigens, which do not replicate and cause active disease.^10,12,13 They are administered intramuscularly, resulting in both local and systemic immune responses.¹² The LAIV causes viral replication but does not cause infection. It is administered intranasally, mimicking the natural route of influenza infection. This results in a localized mucosal immune response.¹¹ Currently, there are three different influenza-vaccine technologies approved by the FDA: egg-based, cell-cultured, and recombinant.

Egg-based IIVs are prepared from inactivated and detergent-solubilized virion particles containing HA and NA proteins prepared in embryonated chicken eggs. The LAIV is prepared from attenuated, less virulent virus strains. Egg-based production of influenza vaccine takes about 6 months to complete.^12-14

Cell-cultured vaccines are produced by growing the influenza virus in animal cells (Madin-Darby Canine Kidney) which allows for a faster manufacturing process. In addition, cells utilized in this process may be frozen and stored for future use without the need for repeated full-range testing. Although this method does not require the use of fertilized hens’ eggs, small amounts of egg protein may be present.^15,16

Recombinant influenza vaccines are manufactured using recombinant technology and do not require the use of chicken eggs. This vaccine is produced in insect-cell culture and contains three times the amount of HA compared with the standard-dose preparation. Recombinant technology also does not require as much time as the standard-dose preparation, allowing the manufacturing process to be started quickly in cases of epidemics or pandemics.^14,17

High-Dose and Adjuvanted Inactivated Influenza Vaccines

There are currently two influenza vaccines that are indicated only in adults aged 65 years and older: high-dose IIV (HD-IIV) and adjuvanted IIV (aIIV). Both formulations are available only as trivalent vaccines. The HD-IIV contains four times the HA-antigen compared with the standard influenza vaccines, providing a better immune response and reducing clinical outcomes associated with influenza infection in this patient population.^18-20

Unlike HD-IIV, the aIIV is a standard-dose vaccine but is formulated with the adjuvant MF59. This MF59 adjuvanted vaccine is more immunogenic and provides better immunogenicity against drifted strains that are different from the strains included in the virus.²¹ aIIV has been shown to be more effective than unadjuvanted vaccines at preventing influenza-related complications in the elderly.²² To date, there are no studies directly comparing HD-IIV with aIIV; however, there is a prospective, randomized, blinded trial designed for the 2017–2018 and 2018–2019 influenza seasons to compare the safety and immunogenicity of these two vaccines.²³

Efficacy

The CDC evaluates the effectiveness of the influenza vaccine yearly. Vaccine effectiveness is based on two factors: characteristics of the recipient and the similarity (“match”) of the vaccine to the circulating strains in the community.²⁴ Since 2004, vaccine effectiveness has ranged from 10% to 60%.²⁵ The 2017–2018 vaccine effectiveness was determined to be about 40%, similar to the 2016–2017 season; the CDC estimated that the flu vaccine prevented an estimated 5.3 million illnesses, 2.6 million medical visits, and 85,000 hospitalizations associated with influenza during the 2016–2017 season. Numbers for the 2017–2018 season have not been released as of press time.^4,26

Recently, questions have arisen regarding the timing of influenza vaccination and vaccine effectiveness. Several studies have highlighted the waning immunity within a single influenza season.²⁷ Protective immunity generated by the vaccine typically takes up to 2 weeks to develop, with moderate effectiveness lasting about 6 months.^27,28 With the arrival of flu shots as early as July, the question is, how early is too early? The CDC recommends that patients be vaccinated before the flu season begins in early fall, but no later than the end of October, to provide adequate protection throughout the influenza season.

Safety

The IIV is generally well tolerated by most patients. The most common adverse events are injection-site reactions, with up to 65% of individuals experiencing pain, soreness, redness, tenderness, and swelling. Systemic effects, including fever, malaise, and myalgias, may occur in a small percentage of individuals, most often in those who have had no previous exposure to the influenza virus antigens in the vaccine. These reactions are usually mild and self-limiting, most resolving in 2 days or less. In clinical trials, HD-IIV injection-site and systemic reactions were more frequent. Similarly, the aIIV is associated with more pain and tenderness at the injection site within the first 7 days.^29,30 Although the influenza vaccine has been associated with Guillain-Barré syndrome, the actual risk is very low.^31,32

Adverse reactions reported after the administration of the LAIV include runny nose and nasal congestion in all age groups, with fever more prevalent in children aged 2 to 6 years and sore throat in adults. Children up to age 5 years may experience wheezing up to 42 days post vaccination.^31,32

Current Recommendations

The CDC’s Advisory Committee on Immunization Practices (ACIP) recommends that all persons aged 6 months and older without contraindications receive routine influenza vaccination. Children between the ages of 6 months and 8 years should receive two doses spaced 4 weeks apart during their first season of vaccination. If a child has received at least two total influenza vaccinations prior to July 1, 2018, the second vaccination for the 2018–2019 season is not needed. Contraindications to all formulations of influenza vaccines include history of a severe allergic reaction to any component of the vaccine or after receiving a previous dose of any influenza vaccine. Additional contraindications to the LAIV include concomitant aspirin- or salicylate-containing therapy in children or adolescents; immunosuppression; pregnancy; children aged 2 to 4 years who have received a diagnosis of asthma; close caregivers of severely immunocompromised patients; and receipt of influenza antiviral medication within the previous 48 hours. Precautions to consider for all influenza vaccines include moderate-to-severe acute illness with or without fever and history of Guillain-Barré syndrome within 6 weeks of receiving an influenza vaccine. Additional precautions for the LAIV include asthma in persons age 5 years and older and other underlying medical conditions that may predispose the individual to complications.³³

Egg allergy is no longer considered an absolute contraindication to receiving the influenza vaccine. In 2015, more than 7.4 million doses of IIV were administered and only 10 cases of anaphylaxis occurred; most of these reactions were not due to egg protein in the virus.³⁴ In addition, data from 28 studies showed that among 4,315 egg-allergic patients, no cases of anaphylaxis occurred after receiving an egg-based IIV.³⁵ Based on these data, the ACIP has removed this restriction on the administration of influenza vaccines.³⁶ People with a history of egg allergy of any severity may receive any licensed, recommended, and age-appropriate influenza vaccine. Any person reporting any reaction to eggs other than hives may receive any licensed and recommended flu vaccine, but it should be administered in an inpatient or outpatient medical setting and administration should be supervised by a healthcare provider who is able to recognize and manage severe allergic conditions.³⁶

Summary

Influenza continues to be a public health concern. Pharmacists play a key role in this public health issue, acting as advocates and educators to increase influenza immunization awareness as well as serving as immunization providers to help promote and maintain high immunization rates. All patients should be encouraged to be vaccinated against the flu, ideally by the end of October, but pharmacists should continue to provide immunizations throughout the entire flu season. Staying current with new developments and expert recommendations is vital to providing the best care and preventing the spread of this potentially deadly disease.

REFERENCES

1. CDC. Pink Book. Influenza.  Epidemiology of vaccine preventable diseases. July 27, 2018. www.cdc.gov/vaccines/pubs/pinkbook/flu.html. Accessed October 11, 2018.
2. CDC. Disease burden of influenza. May 22, 2018. www.cdc.gov/flu/about/disease/burden.htm. Accessed October 11, 2018.
3. CDC. The flu season.  July 12, 2018. www.cdc.gov/flu/about/season/flu-season.htm. Accessed October 11, 2018.
4. CDC. What you should know for the 2017-2018 influenza season. www.cdc.gov/flu/about/season/flu-season-2017-2018.htm. Accessed October 11, 2018.
5. Ghebrehewet S, MacPherson P, Ho A. Influenza. BMJ. 2016;355:i6258.
6. Rothberg MB, Haessler SD, Brown RB. Complications of viral influenza. Am J Med. 2008;121(4):258-264.
7. Rothberg MB, Haessler SD. Complications of seasonal and pandemic influenza. Crit Care Med. 2010;38(4 suppl):e91-e97.
8. CDC. Selecting viruses for the seasonal influenza vaccine. September 4, 2018. www.cdc.gov/flu/about/season/vaccine-selection.htm. Accessed October 13, 2018.
9. FDA. Influenza virus vaccine for the 2018-2019 season. www.fda.gov/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/post-marketactivities/lotreleases/ucm613863.htm. Accessed October 13, 2018.
10. Richards KA, Chaves FA, Alam S, Sant AJ. Trivalent inactivated influenza vaccines induce broad immunological reactivity to both internal virion components and influenza surface proteins. Vaccine. 2012;31(1):219-225.
11. Soema PC, Kompier R, Amorij JP, Kersten GFA. Current and next-generation influenza vaccines: formulation and production strategies. Eur J Pharm Biopharm. 2015;94:251-263.
12. Sridhar S, Brokstad KA, Cox RJ. Influenza vaccination strategies: comparing inactivated and live attenuated influenza vaccines. Vaccines. 2015;3(2):373-389.
13. Wong S-S, Webby RJ. Traditional and new influenza vaccines. Clin Microbiol Rev. 2013;26(3):476-492.
14. CDC. How influenza (flu) vaccines are made. September 24, 2018. www.cdc.gov/flu/protect/vaccine/how-fluvaccine-made.htm. Accessed October 14, 2018.
15. Hegde NR. Cell culture-based influenza vaccines: a necessary and indispensable investment for the future. Hum Vaccines Immunother. 2015;11(5):1223-1234.
16. CDC. Cell-based flu vaccines. October 4, 2018. www.cdc.gov/flu/protect/vaccine/cell-based.htm. Accessed October 16, 2018.
17. Cox MMJ, Hollister JR. FluBlok, a next generation influenza vaccine manufactured in insect cells. Biol J Int Assoc Biol Stand. 2009;37(3):182-189.
18. CDC. Fluzone high-dose seasonal influenza vaccine. www.cdc.gov/flu/protect/vaccine/qa_fluzone.htm. Published October 5, 2018. Accessed October 16, 2018.
19. Lee JKH, Lam GKL, Shin T, et al. Efficacy and effectiveness of high-dose versus standard-dose influenza vaccination for older adults: a systematic review and meta-analysis. Expert Rev Vaccines. 2018;17(5):435-443.
20. DiazGranados CA, Dunning AJ, Kimmel M, et al. Efficacy of high-dose versus standard-dose influenza vaccine in older adults. N Engl J Med. 2014;371(7):635-645.
21. Durando P, Icardi G, Ansaldi F. MF59-adjuvanted vaccine: a safe and useful tool to enhance and broaden protection against seasonal influenza viruses in subjects at risk. Expert Opin Biol Ther. 2010;10(4):639-651.
22. Domnich A, Arata L, Amicizia D, et al. Effectiveness of MF59-adjuvanted seasonal influenza vaccine in the elderly: a systematic review and meta-analysis. Vaccine. 2017;35(4):513-520.
23. ClinicalTrials.gov. FLUAD vs. Fluzone high-dose study. https://clinicaltrials.gov/ct2/show/NCT03183908. Accessed October 16, 2018.
24. CDC. Vaccine effectiveness—how well does the flu vaccine work? October 12, 2018. www.cdc.gov/flu/about/qa/vaccineeffect.htm. Accessed October 16, 2018.
25. CDC. Seasonal influenza vaccine effectiveness, 2004-2018. September 25, 2018. www.cdc.gov/flu/professionals/vaccination/effectiveness-studies.htm. Accessed October 16, 2018.
26. CDC. CDC reports on vaccine benefits from 2016-2017 season. May 22, 2018. www.cdc.gov/flu/spotlights/reports-vaccine-benefits-2016-2017.htm. Accessed October 16, 2018.
27. Rambhia KJ, Rambhia MT. Early bird gets the flu. What should be done about waning intraseasonal immunity against seasonal influenza? Clin Infect Dis. August 2018 [Epub ahead of print].
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29. CDC. Seasonal influenza vaccine safety: a summary for clinicians. October 3, 2017. www.cdc.gov/flu/professionals/vaccination/vaccine_safety.htm. Accessed October 17, 2018.
30. CDC. Safety of influenza vaccines. August 24, 2018. www.cdc.gov/flu/professionals/acip/2018-2019/background/safety-vaccines.htm. Accessed October 17, 2018.
31. Kwong JC, Vasa PP, Campitelli MA, et al. Risk of Guillain-Barré syndrome after seasonal influenza vaccination and influenza health-care encounters: a self-controlled study. Lancet Infect Dis. 2013;13(9):769-776.
32. Polakowski LL, Sandhu SK, Martin DB, et al. Chart-confirmed Guillain-Barre syndrome after 2009 H1N1 influenza vaccination among the Medicare population, 2009-2010. Am J Epidemiol. 2013;178(6):962-973.
33. Grohskopf LA. Prevention and control of seasonal influenza with vaccines: recommendations of the advisory committee on immunization practices—United States, 2018–19 influenza season. MMWR Recomm Rep. 2018;67:1-20.
34. McNeil MM, Weintraub ES, Duffy J, et al. Risk of anaphylaxis after vaccination in children and adults. J Allergy Clin Immunol. 2016;137(3):868-878.
35. Greenhawt M, Turner PJ, Kelso JM. Administration of influenza vaccines to egg allergic recipients: A practice parameter update 2017. Ann Allergy Asthma Immunol. 2018;120(1):49-52.
36.  CDC. Flu vaccine and people with egg allergies. www.cdc.gov/flu/protect/vaccine/egg-allergies.htm. Published December 28, 2017. Accessed October 17, 2018.

To comment on this article, contact rdavidson@uspharmacist.com.

PATIENT INFORMATION

How do I get the flu?

The flu is spread by being in close contact with an infected person who sneezes or coughs. A person can begin to spread the flu 1 day before knowing he or she is sick. You can also get the virus from touching a contaminated surface and then touching your nose, mouth, or eyes. The virus can live on some surfaces for up to 48 hours.

What are complications of the flu?

Complications can develop in some people, especially in very young children, people over the age of 65 years, and people with other medical conditions. Pneumonia is the most common complication. Some people who develop complications have an increased risk of death. Contact your healthcare provider if you begin to have trouble breathing, chest pain, severe dizziness, confusion, trouble going to the bathroom, or continuous vomiting.

Who should get the flu shot, and when should it be given?

All persons aged 6 months and older should receive the flu shot. Certain groups of people should not receive the shot. Talk to your pharmacist or healthcare provider. You should get the shot before the flu season starts. It takes about 2 weeks for the vaccine to work. If you are aged 65 years or older, you should get the high-dose vaccine or the adjuvanted vaccine for older adults.

What else can I do to prevent the flu?

Other things you can do to protect yourself include washing your hands often; covering your mouth and nose when you cough and sneeze; avoiding touching your eyes, nose, and mouth; and staying away from others who may be sick.

Are there side effects to the flu vaccine?

Most people do not have any problems after receiving the vaccine. Some common side effects that you may experience include redness, swelling, and soreness at the injection site; headache; tiredness; and mild fever. These reactions usually go away in a day or two. You do not get the flu from the vaccine.

More serious side effects are rare. If you have ever had a severe allergic reaction to latex, eggs, or a previous dose of a vaccine, let your healthcare provider know.

Where can I receive more information about flu vaccines?

You can speak with your pharmacist, doctor, or other healthcare provider, or you can contact your local or state health department. You can also contact the CDC at 1-800-232-4636 (1-800-CDC-INFO) or visit www.cdc.gov/vaccines.