Influenza Vaccination: Formulations, Recommendations, and Resources for the Pharmacist

Michael R. Page, PharmD, RPh;

News

Media

Conferences

Publications

Clinical

Events

Resources

Publication

Article

November 4, 2016

Supplements

October 2016 Influenza Supplement

Volume0

Influenza Vaccination: Formulations, Recommendations, and Resources for the Pharmacist

Author(s):

Michael R. Page, PharmD, RPh

Although pharmacists administered vaccines historically, it was not until the late 1990s that pharmacy-based immunization programs were established in the modern community pharmacy setting.

Although pharmacists administered vaccines historically, it was not until the late 1990s that pharmacy-based immunization programs were established in the modern community pharmacy setting. Pharmacists have an important role as advocates for appropriate vaccination, can determine which patients are appropriate candidates for vaccination, and can administer vaccines.^1-3

With hundreds of millions of weekly visitors in the United States, pharmacies are a convenient location for vaccinations and expand access to treatment. Pharmacists in all 50 states and Puerto Rico can administer vaccinations at some level, and more than 200,000 pharmacists throughout the United States are trained to administer vaccines.^3,4

Pharmacists can perform targeted influenza vaccination programs by identifying high-risk patients based on their age and medication history. For instance, patients using medications such as digoxin, warfarin, or nitrates may have heart disease, and signs that a patient may have lung disease include chronic inhaler use and use of inhaled steroids. In addition to identifying patients who qualify for a variety of vaccines, pharmacists can perform outreach activities to increase vaccination rates, such as calling patients who received prescriptions for influenza antivirals in the previous year. One program using this tactic had a 75% success rate among contacted patients.^3,5

Burden of Influenza

Hospitalizations due to influenza in the United States exceed 200,000 each year, with influenza-related deaths ranging from approximately 3000 to 49,000 over 31 influenza seasons from 1976 to 2007. In a given year, 10% to 20% of the US population develops influenza-like illness, with severe illness occurring most often in the elderly, young children, and individuals with chronic illness. Although influenza-related hospitalizations are common in young children and the elderly, the vast majority (90%) of deaths associated with influenza occur in patients aged 65 years or older. Direct medical costs related to influenza in the United States are estimated at $1 billion to $3 billion yearly.^6-11

Characteristics of the Influenza Virus

There are 3 general types of influenza: A, B, and C, with type C influenza typically not associated with severe disease, epidemics, or pandemics. Type A influenza viruses are classified by surface antigens hemagglutinin (HA) and neuraminidase (NA), of which there are 16 and 9 known subtypes, respectively. Influenza is known to affect several types of animals in addition to humans, including pigs, birds, horses, cats, ferrets, dogs, and whales, although influenza B viruses have only been observed in humans.⁶

Antigenic Drift and Shift

Antigenic drift results from point mutations and recombination events that accrue during viral replication and result in changes to surface antigens of the virus. Due to these changes, changes to surface antigens may result in reduced immunity to circulating strains of influenza from year to year, necessitating annual vaccination. More extensive genetic changes in circulating strains of influenza are known as antigenic shifts. These changes generally occur only with influenza A viruses and may cause pandemics resulting from a lack of human immunity.^8,12

The most recent example of an antigenic shift resulting in an influenza pandemic occurred in April 2009, with rapid spread of a novel form of the influenza A(H1N1) virus. Scientists believe the causative virus was a mutated form of the influenza A(H1N1) virus that caused the influenza pandemic of 1918. This virus is believed to be of avian origin and was the first pandemic of the 20^th century, followed by the influenza pandemics of 1957 (H2N2) and 1968 (H3N2). All were caused by forms of influenza A.^6,8

Because influenza B viruses undergo antigenic drift at a slower rate than influenza A viruses, influenza B is less likely to cause widespread outbreaks. In the trivalent influenza vaccine, only 1 lineage of influenza B is included, which resulted in a lack of coverage for the predominant circulating B strain during half of influenza seasons between 2001 and 2011, and during 3 influenza seasons from 2004 through 2016. To help reduce this gap in vaccine coverage, some formulations of the influenza vaccine for the 2016-2017 season include an additional lineage of influenza B.^8,13

Because the influenza virus is constantly changing, the vaccine formulation is reviewed annually and updated based on data from more than 100 laboratories around the world. This surveillance process occurs year-round, with virus samples sent to 5 World Health Organization (WHO) centers in the United States, the United Kingdom, Australia, Japan, and China. Twice each year, scientists at the WHO review surveillance data, laboratory data, and clinical studies to recommend strains for vaccine development. The WHO selects strains for the Northern Hemisphere seasonal influenza vaccine in February and selects strains for the Southern Hemisphere in September.¹⁴

Influenza Surveillance

In addition to working with the WHO on worldwide surveillance, the CDC monitors the severity of seasonal influenza in the United States through the Influenza Hospitalization Surveillance Network (FluSurv-NET), which comprises reporting centers at 267 acute care hospitals and associated laboratories. These centers serve an estimated 27 million individuals, 9% of the United States population.¹⁵

For patients with influenza-like illness at any of these centers, laboratory results, which are ordered at the discretion of clinicians, are verified through any of several techniques, including indirect fluorescent antibody staining, rapid antigen testing, or real-time reverse transcription polymerase chain reaction (PCR). Epidemiologists also track outcomes in patients with confirmed influenza, including hospitalization rates and clinical outcomes during hospitalization, such as intensive care unit admission, use of mechanical ventilation, and mortality.¹⁵

During the most recent influenza season (2015-2016), consistent with previous years, influenza A was the predominant circulating type of influenza, with influenza A (H1N1)pdm09 being the most common strain (Figure 1¹⁷). According to the WHO, influenza A (H1N1)pdm09 continued to be the predominant circulating strain worldwide during the Southern Hemisphere winter, resulting in the inclusion of this strain in the 2016-2017 season influenza vaccine.¹⁶

Influenza in Recent Years

Peak influenza may occur at varying times, but it has historically occurred between October and April (Figure 2¹⁸), with peak activity most common in February (the peak month in 44% of seasons), followed by December (the peak month in 22% of seasons), March (the peak month in 19% of seasons), and January (the peak month during the remaining 15% of seasons). Weekly surveillance statistics collected during the 2009-2010 through 2015-2016 influenza seasons reflect this variability in peak influenza activity (Figure 3¹⁷).^8,17,18

In addition to tracking rates of influenza-like illness as a proportion of outpatient visits over time, the CDC records rates of mortality associated with influenza and pneumonia through the National Center for Health Statistics Mortality Surveillance System and monitoring centers in 122 cities across the United States. As shown in Figure 4,¹⁷ these systems report similar outcomes in recent years, with the highest rates of mortality observed during the 2012-2013 season, followed by the 2014-2015 season, the 2013-2014 season, and the 2015-2016 season. Notably, rates of mortality related to influenza and pneumonia during the 2011-2012 season did not reach epidemic levels.¹⁷

Systems that track mortality rates related to pneumonia and influenza may underestimate the burden of influenza-related deaths because of missed cases of mortality due to cardiopulmonary disorder exacerbations precipitated by influenza infection. To account for this underreporting, some researchers categorize excess respiratory and circulatory events that occur during the flu season. Accounting for these events, using data collected from 1979 to 2001, researchers estimated that influenza-associated hospitalizations number 55,000 to 431,000 per season, with an estimated 226,000 influenza-related hospitalizations occurring in an average year. Over a similar time period (1976 to 2007), annual influenza-related deaths in the United States ranged from approximately 3000 to 49,000 per season. However, these estimates predate the 2009 influenza pandemic.^8,10,19

During the 2009 influenza pandemic, in the United States, estimates of hospitalizations attributable to influenza ranged from 114,000 to 633,000, including 18,000 to 97,000 admissions to intensive care units. More than half of hospitalizations (54% to 70%) and the preponderance (71% to 85%) of the estimated 5000 to 28,000 deaths associated with influenza over the 2009-2010 influenza season occurred in adults aged 65 years or older.^8,20

Signs and Symptoms of Influenza

Influenza has an incubation period of 1 to 4 days, with peak viral shedding occurring during the period from 1 day before to 3 days after symptom onset. Symptoms characteristic of influenza include abrupt onset of symptoms, such as chills, weakness, fatigue, nasal congestion, sore throat, chest discomfort, cough, and headache. Compared with symptoms of a cold, symptoms of influenza typically manifest abruptly, and can cause illness of mild to severe severity (Table 1²¹). Other characteristic symptoms include fever, chills, cough, sore throat, nasal congestion, muscle/body aches, headaches, and fatigue.²¹

In adults, more common symptoms include difficulty breathing, shortness of breath, pain or pressure in the chest/abdomen, sudden dizziness, confusion, severe or persistent vomiting, or symptoms that improve but return with fever and a worsened cough. Acute symptoms of influenza have a typical duration of 2 to 7 days, but symptoms of malaise and cough may persist for up to 2 weeks after onset. After the initial illness, patients may develop postinfectious complications, such as pneumonia, bronchitis, sinus infections, and ear infections.^6,21

The signs and symptoms of influenza in children may differ from those observed in adults. For instance, children with influenza are more likely to experience vomiting and diarrhea. Other signs of influenza in young children may include faster than usual or troubled breathing, bluish skin tone, drinking less than usual, being so irritable they are unwilling to be held, and having a fever accompanied by a rash. Urgent medical help may be indicated among children with influenza when they produce significantly fewer wet diapers, have no tears when crying, are unable to eat, or are having difficulty breathing.²¹

Elderly patients may experience symptoms different from those observed in younger adults and children. For instance, symptoms like sore throat, fever, and muscle pain are less common in the elderly than in younger adults, while more severe symptoms, such as anorexia, malaise, weakness, dizziness, profuse sweating, and mottling of the extremities, may be more common.²²

Special Populations

Influenza in Patients with Comorbid Health Conditions

Influenza may also worsen preexisting chronic health conditions, including asthma and congestive heart failure. Although serious health problems may occur in individuals in any age group, certain populations are at increased risk of serious complications, including patients with chronic health conditions, such as asthma, diabetes, or heart disease; pregnant patients; patients aged 65 years or older; and children. In patients with underlying chronic comorbid conditions, including acute ischemic heart disease, stroke, and pneumonia, influenza is the most common cause of mortality during the winter months.^21,23-26

Influenza in the Elderly

Influenza is a major health concern for the elderly. Over 30 years, from 1976 to 2007, 90% of deaths associated with influenza occurred in adults aged 65 years or older, with annual averages of 21,098 influenza-related deaths occurring in those 65 years or older, 2385 deaths occurring in adults aged 19 to 64 years, and 124 deaths occurring in young adults and children aged 19 years and younger.^8,20

It is important to recognize that manifestations of influenza in the elderly may differ from those observed in younger adults. As mentioned earlier, the symptoms of influenza may have a different pattern in the elderly than in younger adults. While the symptoms of influenza in young adults may include sore throat, fever, and muscle pain, elderly adults may experience fewer of the symptoms observed in younger adults but may experience more severe symptoms, such as anorexia, malaise, weakness, dizziness, profuse sweating, and mottling of the extremities.²²

Rates of influenza-associated hospitalization are especially high in elderly patients with underlying medical conditions. For instance, in patients aged 65 years or older, patients with underlying medical conditions were hospitalized for influenza or pneumonia at a rate of 55.6 per 10,000 individuals—a rate approximately 3 times greater than that observed in patients aged 65 years or older who had no underlying medical conditions (18.7 hospitalizations related to influenza and pneumonia per 10,000 individuals).^8,27

Age-related changes in immune function, which are known as immunosenescence, result in poorer response to influenza vaccination in adults older than 65 years than in younger individuals. In the elderly, both initial and long-term responses to vaccination are compromised. As a result, use of influenza vaccines specially designed for the elderly is an important consideration for pharmacists. These vaccines include the adjuvanted trivalent inactivated influenza vaccine (trade name: Fluad) and the high-dose trivalent inactivated influenza vaccine (trade name: Fluzone High Dose).^8,28,29

Studies of influenza vaccine effectiveness in older adults highlight the need for these specialized formulations. In a study of adults aged 50 years or older who sought care for acute respiratory illness, Chen and colleagues looked at data for 1047 patients from November through April during influenza seasons from 2006 to 2012, with the exception of 1 season (2009-2010). Complete data were collected for 88% of participants. Effectiveness of the trivalent standard-dose vaccine among patients aged 50 years or older was estimated at 59.4% (95% CI, 37.0%-75.6%) for prevention of laboratory-confirmed influenza requiring medical attention. Similar vaccine effectiveness estimates of 58.4% (95% CI, 7.9%-81.1%) were reported for patients aged 65 years or older. These results indicate moderate effectiveness of the influenza vaccine in older adults.³⁰

For patients aged 65 years and older receiving the high-dose influenza vaccine versus the standard-dose trivalent or quadrivalent vaccine, researchers modeled outcomes based on influenza-related health outcomes data and efficacy estimates drawn from meta-analyses of trivalent influenza vaccine efficacy. Through a mathematical model applied to the United States population, researchers estimated that the high-dose influenza vaccine would prevent 195,958 more cases of influenza, 22,567 more influenza-related hospitalizations, and 5423 more influenza-related deaths than the standard-dose trivalent or quadrivalent formulations.³¹

The improved protective efficacy of the high-dose vaccine has also been confirmed through a randomized, double-blind, active-controlled trial in nearly 32,000 elderly patients over 2 influenza seasons. In this study, the high-dose influenza vaccine was found to offer a 24.2% (95% CI, 9.7%-36.5%) improvement in protective efficacy versus the standard-dose vaccine in elderly patients. Rate of laboratory-confirmed influenza in patients receiving the high-dose vaccine was 1.4% versus 1.9% for patients receiving a standard-dose comparator vaccine.³²

Evidence supporting use of the adjuvanted trivalent inactivated influenza vaccine in adults aged 65 years or older includes an immunologic response study in 3545 patients receiving Fluad versus 3537 patients receiving a standard-dose comparator vaccine. For evaluable patients (including 91% of patients receiving Fluad and 92% of patients receiving the comparator standard-dose vaccine), researchers evaluated rates of seroconversion to antibody levels indicating immunity 22 days after vaccination. Although the study established noninferiority, when examining geometric mean titer antibody ratios for each of the 3 strains evaluated, the effect of the adjuvant is apparent (Figure 5³³).³³

Influenza in Children

Children develop influenza at a 30% to 50% higher frequency than adults, and, once infected, children are able to spread influenza for a longer period of time than adults. Influenza infection among children contributes to the societal and medical burden of influenza, both because children are the primary vector for community transmission of influenza and because illness among children results in lost productivity among parents. Despite the acknowledged importance of influenza vaccination among children, vaccination rates among children remain low—estimated at 59% for the 2015-2016 influenza season.^34-36

In pediatric patients, the vast majority (85%) of influenza-related deaths have occurred in unvaccinated children aged 6 months to 17 years. The risk of hospitalization is especially pronounced in children younger than 5 years versus children aged 5 to 17 years. Approximately half of all influenza-related hospitalizations in children occur in otherwise healthy children, while approximately 1 in 5 influenza-related hospitalizations among children occur with comorbid asthma or reactive airway disease.³⁷

In a 19-season retrospective study of influenza in children under the age of 15 years, seasonal influenza accounted for 6 to 15 additional outpatient visits per 100 children per year. Pediatric deaths attributable to influenza have been tracked on a national basis since 2004. In an ordinary influenza season, deaths due to influenza among children have numbered 37 to 171 per year, with the exception of the 2009 pandemic influenza, which resulted in the death of 358 children (Figure 6¹⁷).^8,17

Children aged 6 months through 8 years may require 2 doses of the influenza vaccine (separated by 28 days) if the child has not previously received 2 doses of any trivalent or quadrivalent influenza vaccine (including the live intranasal vaccine) at any time before July 1, 2016, regardless of whether the previous doses were administered during a single season, consecutive seasons, or 2 nonconsecutive seasons. This recommendation is based on studies showing poorer antibody response with a single dose of the vaccine among children receiving the vaccine for the first time, as well as studies showing lower vaccine effectiveness among children younger than 5 years who received 1 dose of the influenza vaccine in their first year of vaccination versus children who received 2 doses of the influenza vaccine in the first year of vaccination.^8,37,38,39

Pregnant Women

Pregnant women may be at increased risk of serious complications of influenza and influenza-related hospitalization. In an analysis of 6.2 million hospitalizations of pregnant women from 1998 through 2002, acute respiratory illness during influenza seasons was associated with an increase in the risk of preterm labor, cesarean delivery, and fetal distress. In addition to an association with adverse outcomes later in pregnancy, based on a 22-study meta-analysis, influenza infection during the first trimester of pregnancy is associated with an increased risk of congenital abnormalities, including neural tube defects, hydrocephaly, cleft lip, and abnormalities of the heart, digestive system, and limbs.^8,40,41

During the 2009 influenza pandemic, 280 pregnant women were admitted to intensive care units, and 56 women died, with nearly two-thirds (64%) of these deaths occurring during the third trimester of pregnancy. A study of more than 100,000 pregnant women in Norway during the 2009-2010 pandemic indicated a nearly doubled risk (adjusted hazard ratio, 1.91; 94% CI, 1.07-3.41) of fetal death in women infected with influenza.^8,42

Adults Aged 18 to 49 Years

Even among adults aged 18 to 49 years, influenza exacts a substantial burden, causing an estimated 5 million illnesses that result in 2.4 million outpatient visits and 32,000 hospitalizations. An estimated 680 individuals aged 18 to 49 years die of influenza each season. In adults aged 18 to 49 years, receiving the annual influenza vaccination is associated with lower rates of influenza-like illness, fewer absences from work, and fewer visits to health care professionals.^8,43

Influenza vaccination among patients aged 18 to 49 is also important due to the possibility of unusual patterns of influenza illness characteristic of pandemic influenza seasons. For instance, during the 2009 pandemic, among younger populations, the risk of hospitalization approached the risk of hospitalization in older populations. Rates of hospitalization for laboratory-confirmed influenza among adults aged 18 to 49 occurred at a rate of 3.0 per 10,000—comparable to the rate of 3.2 hospitalizations per 10,000 observed in individuals aged 65 years and older during the 2009-2010 pandemic influenza season.^8,44

The Importance of Vaccination of Health Care Professionals

As of the 2014-2015 influenza season, three-fourths (77%) of all health care professionals received the annual influenza vaccine. Unfortunately, these vaccination rates are well below the goal of 90% set by the Healthy People 2020 initiative. Institution-specific requirements contribute to these suboptimal rates of vaccination, with just over one-third (36%) of health care professionals reporting a vaccination requirement in their practice setting.^7,37,45

Although serious cases of influenza can occur in patients of any age, patients with comorbid medical conditions are at increased risk of serious complications. For example, among hospitalized patients, the median mortality rate for influenza acquired while hospitalized has been estimated at 16%. Because transmission of influenza from health care professionals to patients may occur 24 hours before symptom onset and for approximately 1 week after symptom onset, vaccination of health care professionals is an especially important measure for prevention of serious consequences in patients, many of whom may have chronic illnesses. For example, immunization of health care professionals caring for patients at 116 long-term care facilities was associated with a 42% lower rate of influenza-like illness among patients and a 29% lower risk of all-cause death.^7,46,47

Changes in Influenza Vaccination Guidelines Over Time

Guidelines for the use of influenza vaccine have changed over time. From the late 1990s until 1999, annual influenza vaccinations were recommended only for those aged 65 years or older. In 2000, the CDC expanded the population eligible for influenza vaccination to include adults aged 50 to 64 years. By 2005, annual influenza vaccination was expanded to not only include older adults, but also to include children aged 6 months to 23 months. Two years later, in 2007, annual vaccination was recommended for children aged 24 months to 5 years. The next year, in 2008, guidelines expanded eligible populations further to include children, young adults, and adolescents aged 5 through 18 years. Finally, in 2010, with a recommendation in favor of vaccination of adults aged 19 to 49 years, a universal vaccination policy of all qualifying individuals aged 6 months and older was reached, which has continued until the present time (Table 2^48-53).^48-53

Influenza Vaccination Guidelines for the 2016-2017 Season

Consistent with recommendations from the past 5 influenza seasons, for the 2016-2017 season, the Advisory Committee on Immunization Practices (ACIP) recommends use of the annual influenza vaccine for all persons aged 6 months or older who do not have contraindications to use of the vaccine (Table 3⁸). In prioritizing vaccine delivery, it may be important to consider the annual vaccine for individuals at especially high risk for serious consequences of influenza infection and others in close contact with high-risk individuals (Table 4⁸).⁸

Available influenza vaccine formulations for the 2016-2017 season include both trivalent and quadrivalent inactivated influenza vaccines, as well as a trivalent, recombinant influenza vaccine. Because the live attenuated intranasal vaccine had poor efficacy in prevention of influenza A(H1N1)pdm09 over the last 2 influenza seasons (2013-2014 and 2015-2016), ACIP recommends against using the live attenuated intranasal vaccine (trade name: FluMist) for any population during the 2016-2017 season.⁸

Strains included in the trivalent vaccine for the 2016-2017 season include A/California/7/2009 (H1N1), A/Hong Kong/4801/2014 (H3N2), and B/Brisbane/60/2008 (Victoria lineage). The quadrivalent vaccine includes an additional influenza B strain, B/Phuket/3073/2013 (Yamagata lineage). A total of 10 vaccines (not including the quadrivalent live attenuated intranasal vaccine) are available for the 2016-2017 season (Table 5⁸).⁸

Table 5. Available Influenza Vaccines for the 2016-2017 Season, Unites States^8,a

Trade name

Manufacturer

Presentation

Age indication

Mercury (from thimerosal), µg/0.5 mL

Latex

Route

Inactivated Influenza Vaccine, quadrivalent (IIV4), standard dose^b

Fluarix Quadrivalent

GlaxoSmithKline

0.5-mL single-dose prefilled syringe

≥3 yrs

IM^c

Flulaval Quadrivalent

ID Biomedical Corp of Quebec (distributed by GlaxoSmithKline)

0.5-mL single-dose prefilled syringe

≥3 yrs

5.0-mL multi-dose vial

≥3 yrs

<25

Fluzone Quadrivalent

Sanofi Pasteur

0.25-mL single-dose prefilled syringe

6 through 35 mos

0.5-mL single-dose prefilled syringe

≥36 mos

0.5-mL single-dose vial

≥36 mos

5.0-mL multi-dose vial

≥6 mos

Fluzone Intradermal Quadrivalent^d

Sanofi Pasteur

0.1-mL single-dose prefilled microinjection system

18 through 64 yrs

ID^e

Inactivated Influenza Vaccine, quadrivalent, cell culture-based (ccIIV4), standard dose^b

Flucelvax Quadrivalent

Seqirus

0.5-mL single-dose prefilled syringe

≥4 yrs

Inactivated Influenza Vaccine, trivalent (IIV3), standard dose^b

Afluria

Seqirus

0.5-mL single-dose prefilled syringe

≥9 yrs^f

5.0-mL multi-dose vial

≥9 yrs^f

(needle and syringe)

18 through 64 years

(jet injector)

24.5

Fluvirin

Seqirus

0.5-mL single-dose prefilled syringe

≥4 yrs

≤1

Yes^g

5.0-mL multi-dose vial

≥4 yrs

Adjuvanted Inactivated Influenza Vaccine, trivalent (aIIV3), standard dose^b

Fluad

Seqirus

0.5-mL single-dose prefilled syringe

≥65 yrs

Yes^g

Inactivated Influenza Vaccine, trivalent (IIV3), High Dose^h

Fluzone High-Dose

Sanofi Pasteur

0.5-mL single-dose prefilled syringe

≥65 yrs

Recombinant Influenza Vaccine, trivalent (RIV3)ⁱ

Flublok

Protein Sciences

0.5-mL single-dose vial

≥18 yrs

Live Attenuated Influenza Vaccine, quadrivalent (LAIV4)^j

FluMist Quadrivalent

MedImmune

0.2-mL single-dose prefilled intranasal sprayer

2 through 49 yrs

NAS

ACIP = Advisory Committee on Immunization Practices; ID = intradermal; IM = intramuscular; NAS = intranasal; NR = not relevant (does not contain thimerosal).

^aImmunization providers should check FDA-approved prescribing information for 2016-2017 influenza vaccines for the most complete and updated information, including (but not limited to) indications, contraindications, warnings, and precautions. Package inserts for US-licensed vaccines are available at http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm093833.htm. Availability of specific products and presentations might change and differ from what is described in this table.

^bStandard dose intramuscular IIVs contain 15 µg of each vaccine HA antigen (45 µg total for trivalents and 60 µg total for quadrivalents) per 0.5-mL dose.

^cFor adults and older children, the recommended site for intramuscular influenza vaccination is the deltoid muscle. The preferred site for infants and young children is the anterolateral aspect of the thigh. Specific guidance regarding site and needle length for intramuscular administration may be found in the ACIP General Recommendations on Immunization, available at http://www.cdc.gov/mmwr/preview/mmwrhtml/rr6002a1.htm.

^dQuadrivalent inactivated influenza vaccine, intradermal: a 0.1-mL dose contains 9 µg of each vaccine HA antigen (36μg total).

^eThe preferred injection site is over the deltoid muscle. Fluzone Intradermal Quadrivalent is administered using the delivery system included with the vaccine.

^fAge indication per package insert is ≥5 years; however, ACIP recommends that Afluria not be used in children aged 6 months through 8 years because of increased risk for febrile reactions noted in this age group with Seqirus’ 2010 Southern Hemisphere IIV3. If no other age-appropriate, licensed inactivated seasonal influenza vaccine is available for a child aged 5 through 8 years who has a medical condition that increases the child’s risk for influenza complications, Afluria can be used; however, providers should discuss with the parents or caregivers the benefits and risks of influenza vaccination with Afluria before administering this vaccine. Afluria may be used in persons aged ≥9 years. Afluria is licensed for administration by jet injector for persons aged 18 through 64 years only.

^gSyringe-tip cap might contain natural rubber latex.

^hHigh-dose IIV3 contains 60 μg of each vaccine antigen (180 μg total) per 0.5-mL dose.

ⁱRIV3 contains 45 μg of each vaccine HA antigen (135 μg total) per 0.5-mL dose.

^jACIP recommends that FluMist (LAIV4) not be used during the 2016-2017 season.

The recommendation against use of the quadrivalent live attenuated intranasal influenza vaccine stems from observational data from the US Influenza Vaccine Effectiveness Network indicating lower relative protective efficacy of the quadrivalent live attenuated intranasal influenza vaccine against influenza B, influenza A (H1N1)pdm09 viruses, or all A and B viruses combined in children aged 2 to 17 years. Based on observational data, compared with the IIV vaccine, use of the quadrivalent live attenuated intranasal influenza vaccine among children is associated with 2.5-fold greater odds of developing influenza of any type and showed a lower adjusted vaccine effectiveness rate against influenza A (H1N1)pdm09 (21%) versus IIV (65%).^8,37

The poor efficacy of the quadrivalent live attenuated intranasal influenza vaccine in protecting against influenza A (H1N1)pdm09 virus infection is particularly relevant, given that influenza A (H1N1)pdm09 is predicted to be the predominant circulating strain of influenza for the 2016-2017 season. Additional research will be required to determine whether the quadrivalent live attenuated intranasal influenza vaccine will be used in future years.^8,37

Recently approved influenza vaccine formulations include a trivalent adjuvanted inactivated influenza vaccine (Fluad), which is approved for use in adults aged 65 years and older, and a quadrivalent formulation of an inactivated influenza vaccine grown in cell culture (Flucelvax Quadrivalent). Although ACIP does not express a preference for quadrivalent over trivalent vaccines and does not express a preference for high-dose or adjuvanted vaccines in patients aged 65 years and older, ACIP notes that these vaccines may be used in qualifying individuals, based on vaccine-specific indications.⁸

In a change from guidelines released in previous years, for the 2016-2017 season, ACIP recommends that providers consider observing egg-allergic patients for 15 minutes after vaccination to reduce the risk of syncope-related injury, rather than observing patients for 30 minutes after vaccination. Additionally, ACIP recommends that patients with a history of severe allergic reaction to egg protein, defined as allergy-related symptoms more severe than hives, receive vaccination either in an inpatient or outpatient medical setting and under the supervision of a health care professional able to manage a severe allergic reaction.⁸

For the 2016-2017 season, 1 vaccine is egg-free: the recombinant trivalent influenza vaccine (trade name: Flublok). However, it is also notable that an inactivated vaccine produced through cell culture (trade name: Flucelvax) contains no more than one-half of 1 billionth of a microgram of total egg protein per dose.^8,54,55

Antiviral medications recommended for prophylaxis and treatment of influenza in the 2016-2017 season include the NA inhibitors oseltamivir (oral) and zanamivir (inhaled). Although the intravenously administered NA inhibitor peramivir was approved in December 2014, it is only indicated for use in adults aged 18 years and older. According to WHO surveillance data, circulating strains of influenza for the 2016-2017 season are likely to be susceptible to all 3 approved NA inhibitors. Amantadine and rimantadine should not be used, due to extremely high levels of resistance in circulating strains of influenza A and a lack of efficacy against influenza B.^8,37

Vaccine Efficacy

During years when vaccines are well matched for circulating influenza A viruses, vaccination confers 50% to 70% protective efficacy against influenza infection. Data on the efficacy of influenza vaccines administered over the past 11 seasons indicate protective efficacy ranging from 10% to 60%, with a median efficacy of 47% (Table 6⁵⁶).^6,56

During some seasons, vaccines may be less effective in some cases due to antigenic drift. For instance, a form of H3N2 that circulated during the 2004-2005 influenza season was found to have only 5% protective efficacy in vaccinated individuals due to a poor match between the H3N2 strain in the circulating H3N2 strain that had undergone antigenic drift over time. Even so, it is important to remind patients that receiving the influenza vaccine each year, preferably before the end of October each year per CDC recommendations, is the best way to reduce the risk of developing influenza.^6,8

Available Formulations and Key Characteristics

Afluria

Afluria by CSL Behring is a trivalent, inactivated influenza vaccine for intramuscular injection or administration using the PharmaJet Stratis Needle-Free Injection System. This formulation has been available since 2007 and is approved for prevention of influenza caused by influenza subtypes A and B for the 2016-2017 season. Afluria may be used in persons 5 years of age and older, when administered by intramuscular injection through a needle and syringe, or in persons aged 18 through 64 years when administered using the PharmaJet Stratis Needle-Free Injection System. Available formulations include a 0.5-mL prefilled syringe and as a 5-mL multi-dose vial, which supplies 10 doses of 0.5 mL each.⁵⁷

Key warnings and precautions include fever and febrile seizures. Increased rates of fever and febrile seizures were observed in children below the age of 5 years who received the 2010 Southern Hemisphere influenza vaccine compared with influenza vaccines administered in previous years. Children aged 5 through 8 have also experienced febrile events. In patients who have experienced Guillain-Barré syndrome within 6 weeks of receiving a previous influenza vaccination, the decision whether to administer the influenza vaccine should be based on careful consideration of potential benefits and risks. Appropriate medical resources must be available to manage potential anaphylactic reactions resulting from vaccine administration. For immunocompromised individuals, it should be noted that the immune response to the influenza vaccine may be diminished.⁵⁷

In children aged 5 through 17 years, pain, redness, and swelling were the most common injections-site adverse reactions, and the most common systemic adverse reactions were headache, myalgia, irritability, malaise, and fever. In adults aged 18 through 64 years receiving the influenza vaccine through a needle and syringe route, common injection-site reactions were tenderness, pain, swelling, redness, and itching, whereas common systemic adverse events included muscle aches, headache, and malaise. Adults aged 65 years and older receiving the vaccine through the needle and syringe mode of administration experienced common injection-site adverse reactions of tenderness and pain. However, systemic adverse events were uncommon, occurring in fewer than 10% of patients aged 65 years or older.⁵⁷

Adverse reactions in adults aged 18 through 64 years receiving the influenza vaccine using the PharmaJet Stratis Needle-Free Injection System included injection-site reactions of tenderness, swelling, pain, redness, itching, and bruising. Common systemic adverse events in patients receiving the vaccine through the PharmaJet Stratis Needle-Free Injection System included myalgia, malaise, and headache.⁵⁷

Use of Afluria is contraindicated in patients who have experienced a severe allergic reaction to any component of the vaccine, including egg protein, and in patients who have experienced a severe allergic reaction to a previous dose of any influenza vaccine. The rubber-tip cap and plunger of the single-dose syringe of Afluria and the rubber stoppers of the Afluria multi-dose vial are not made with natural rubber latex. Although the multi-dose vial of Afluria contains the preservative thimerosal, with each 0.5 mL containing 24.5 mcg of mercury, the single-dose prefilled syringe formulation of Afluria does not contain thimerosal or any other preservative.⁵⁷

Inactive components of each 0.5-mL dose of Afluria include sodium chloride (4.1 mg), monobasic sodium 420 phosphate (80 mcg), dibasic sodium phosphate (300 mcg), monobasic potassium phosphate 421 (20 mcg), potassium chloride (20 mcg), and calcium chloride (1.5 mcg). Components of each 0.5-mL dose of Afluria resulting from the manufacturing process include sodium taurodeoxycholate (≤10 ppm), ovalbumin (<1 mcg), sucrose (<10 mcg), neomycin sulfate (≤3 nanograms), polymyxin B (≤ 0.5 nanograms), and beta-propiolactone (≤ 2 nanograms).⁵⁷

Afluria Quadrivalent

Afluria Quadrivalent by CSL Behring is a quadrivalent inactivated influenza vaccine for intramuscular injection or administration using the PharmaJet Stratis Needle-Free Injection System. This formulation was approved in the United States for the first time this year (2016) and is approved for prevention of influenza caused by influenza subtypes A and B for the 2016-2017 season. Unlike the trivalent vaccine, Afluria quadrivalent contains an additional strain of influenza B. Afluria Quadrivalent may be used in persons aged 18 years and older, when administered by intramuscular injection through a needle and syringe, or in persons aged 18 through 64 years when administered using the PharmaJet Stratis Needle-Free Injection System. Available formulations include a 0.5-mL prefilled syringe and as a 5-mL multi-dose vial, which supplies 10 doses of 0.5 mL each.⁵⁸

In adults aged 18 through 64 years receiving the influenza vaccine through a needle and syringe route, the most common injection-site reaction was pain, whereas common systemic adverse events included myalgia and headache. Among adults 65 years and older receiving the vaccine through the needle and syringe mode of administration, the most common injection-site adverse reaction was pain and the most common systemic adverse event was myalgia.⁵⁸

Adverse reactions in adults aged 18 through 64 years receiving the trivalent influenza vaccine using the PharmaJet Stratis Needle-Free Injection System included injection-site reactions of tenderness, swelling, pain, redness, itching, and bruising. Common systemic adverse events in patients receiving the trivalent vaccine through the PharmaJet Stratis Needle-Free Injection System included myalgia, malaise, and headache.⁵⁸

Use of Afluria Quadrivalent is contraindicated in patients who have experienced a severe allergic reaction to any component of the vaccine, including egg protein, and in patients who have experienced a severe allergic reaction to a previous dose of any influenza vaccine. The rubber-tip cap and plunger of the single-dose syringe of Afluria Quadrivalent and the rubber stoppers of the Afluria Quadrivalent multi-dose vial are not made with natural rubber latex. Although the multi-dose vial of Afluria contains the preservative thimerosal, with each 0.5 mL containing 24.5 mcg of mercury, the single-dose prefilled syringe formulation of Afluria does not contain thimerosal, or any other preservative.⁵⁸

Inactive components of each 0.5-mL dose of Afluria include sodium chloride (4.1 mg), monobasic sodium 420 phosphate (80 mcg), dibasic sodium phosphate (300 mcg), monobasic potassium phosphate 421 (20 mcg), potassium chloride (20 mcg), and calcium chloride (0.5 mcg). Components of each 0.5-mL dose of Afluria resulting from the manufacturing process include sodium taurodeoxycholate (≤10 ppm), ovalbumin (<1 mcg), sucrose (<10 mcg), neomycin sulfate (≤62 nanograms), polymyxin B (≤ 11 nanograms), and beta-propiolactone (≤ 1.5 nanograms).⁵⁸

Fluad

Fluad by Seqirus, Inc is a trivalent, adjuvanted inactivated influenza vaccine for intramuscular injection. This formulation was approved and been available since 2015, and is approved for prevention of influenza subtypes A and B in persons aged 65 years and older for the 2016-2017 season. Fluad is available only as a 0.5-mL prefilled syringe.³³

In patients who have experienced Guillain-Barré syndrome within 6 weeks of receiving a previous influenza vaccination, the decision whether to administer the influenza vaccine should be based on careful consideration of potential benefits and risks. Appropriate medical resources must be available to manage potential anaphylactic reactions resulting from vaccine administration. It is important to note that the tip caps of the prefilled syringe of Fluad contains natural rubber latex, which may cause allergic reactions in latex-sensitive individuals.³³

Adults 65 years and older receiving Fluad experienced common injection-site adverse reactions of pain and tenderness. Common systemic adverse events included myalgia, headache, and fatigue.³³

Use of Fluad is contraindicated in patients who have experienced a severe allergic reaction to any component of the vaccine, including egg protein, and in patients who have experienced a severe allergic reaction to a previous dose of any influenza vaccine. Fluad does not contain any preservative.³³

Fluad contains an adjuvant, which is known as MF59C.1. This squalene-based oil-in-water emulsion has a milky-white appearance. The adjuvant MF59C.1 contains 9.75 mg squalene, 1.175 mg of polysorbate 80, 1.175 mg of sorbitan trioleate, 0.66 mg of sorbitan citrate dihydrate, and 0.04 mg of citric acid monohydrate. Each 0.5-mL dose of Fluad contains neomycin (<0.02 mcg), kanamycin (<0.03 mcg), barium (<0.5 mcg), residual egg proteins (<0.4 mcg), formaldehyde (≤10 mcg), or cetyltrimethylammonium bromide (≤12 mcg).³³

Fluarix Quadrivalent

Fluarix Quadrivalent by GlaxoSmithKline is a quadrivalent, inactivated influenza vaccine for intramuscular injection. This formulation was approved in the United States in 2012 and is approved for prevention of influenza caused by influenza subtypes A and B for the 2016-2017 season. Unlike the trivalent vaccine, Fluarix Quadrivalent contains an additional strain of influenza B. Fluarix Quadrivalent may be used in persons aged 3 years and older. This vaccine is available only as a 0.5-mL single-dose prefilled syringe.⁵⁹

In adults, the most common injection-site reaction was pain, whereas common systemic adverse events included muscle aches, headache, and fatigue. In children aged 3 to 17 years, injection-site adverse reactions were pain, redness, and swelling. Systemic adverse reactions in children differed by age group. For children aged 6 through 17 years, common systemic adverse events were fatigue, muscle aches, headache, arthralgia, and gastrointestinal symptoms. For children aged 3 to 5 years, common systemic adverse events were drowsiness, irritability, and loss of appetite.⁵⁹

Use of Fluarix Quadrivalent is contraindicated in patients who have experienced a severe allergic reaction to any component of the vaccine, including egg protein, and in patients who have experienced a severe allergic reaction to a previous dose of any influenza vaccine. The rubber-tip cap and plunger of the single-dose syringe of Fluarix Quadrivalent are not made with natural rubber latex. Fluarix Quadrivalent does not contain any preservative.⁵⁹

Inactive components of each 0.5-mL dose of Fluarix Quadrivalent include octoxynol-10 (<0.115 mg), alpha-tocopheryl hydrogen succinate (≤0.135 mg), and polysorbate 80 (≤0.550 mg). Components of each 0.5-mL dose of Fluarix Quadrivalent resulting from the manufacturing process include hydrocortisone (≤0.016 mcg), gentamicin sulfate (≤0.15 mcg), ovalbumin (≤0.050 mcg), formaldehyde (≤5 mcg), and sodium deoxycholate (≤65 mcg).⁵⁹

Flublok

Flublok by Protein Sciences Corporation is a trivalent, recombinant influenza vaccine for intramuscular injection. This formulation, which contains purified HA proteins, was approved in the United States for the first time in 2013 and is approved for prevention of influenza caused by influenza subtypes A and B for the 2016-2017 season. Flublok may be used in persons aged 18 years and older. Although data from a controlled clinical trial has shown a reduction in influenza disease after vaccination with Flublok in patients aged 18 through 49 years, the indication for use in individuals aged 50 years and older is based on immune response data. This vaccine is available only as a 0.5-mL single-dose vial (not a prefilled syringe).⁵⁴

In adults aged 18 to 49 years, the most common injection-site reaction was pain, whereas common systemic adverse events included headache, fatigue, and myalgia. In adults aged 50 to 64 years, injection-site adverse reaction was pain, whereas common systemic adverse reactions included headache, fatigue, and muscle pain.⁵⁴

Use of Flublok is contraindicated in patients who have experienced a severe allergic reaction to any component of the vaccine. The stopper of the single-dose vial of Flublok is not made with natural rubber latex. Flublok does not contain any preservatives, antibiotics, or egg proteins.⁵⁴

Inactive components of each 0.5-mL dose of Flublok include sodium chloride (4.4 mg), monobasic sodium phosphate (0.195 mcg), dibasic sodium phosphate (1.3 mg), and polysorbate 20 (27.5 mcg). Components of each 0.5-mL dose of Flublok resulting from the manufacturing process include residual amount of baculovirus and cell proteins from Spodoptera frugiperda (≤28.5 mcg), baculovirus and cellular DNA (≤10 ng), and Triton X-100 (≤100 mcg).⁵⁴

Flucelvax Quadrivalent

Flucelvax Quadrivalent by Seqirus, Inc is a quadrivalent, inactivated influenza vaccine for intramuscular injection that is manufactured through cell culture. This formulation was approved in the United States for the first time this year (2016) and is approved for prevention of influenza caused by influenza subtypes A and B for the 2016-2017 season. Unlike the trivalent vaccine, Flucelvax Quadrivalent contains an additional strain of influenza B. Flucelvax Quadrivalent may be used in persons aged 4 years and older. Approval in children and adolescents aged 4 to 17 years is based on immune response data. This vaccine is available only as a 0.5-mL single-dose prefilled syringe.⁵⁵

In adults aged 18 to 64 years, the most common injection-site reactions were pain, injection site erythema, and induration, whereas common systemic adverse events included headache, fatigue, and myalgia. In adults aged 65 years and older, the most common injection-site adverse reactions were pain and erythema. Adverse reactions in children differed by age group. For children aged 4 through <6 years, common injection-site and systemic adverse reactions were tenderness at the injection site, injection site erythema, sleepiness, irritability, injection site induration, and a change in eating habits. For children aged 6 to 8 years, common injection-site and systemic adverse reactions were pain at the injection site, injection site erythema, injection site induration, headache, fatigue, and myalgia. Finally, for children and adolescents aged 9 to 17 years, common injection-site and systemic adverse reactions were pain at the injection site, headache, injection site erythema, fatigue, myalgia, and injection site induration.⁵⁵

Use of Flucelvax Quadrivalent is contraindicated in patients who have experienced a severe allergic reaction to any component of the vaccine. The tip cap and plunger of the single-dose syringe of Flucelvax Quadrivalent are not made with natural rubber latex. Flucelvax Quadrivalent does not contain preservatives or antibiotics.⁵⁵

Inactive components of each 0.5-mL dose of Flucelvax Quadrivalent resulting from the manufacturing process include Madin-Darbey Canine Kidney (MDCK) cell protein (≤8.4 mcg), protein other than HA (≤160 mcg), MDCK cell DNA (≤10 ng), polysorbate 80 (≤1500 mcg), cetyltrimethylammonium bromide (≤18 mcg), and beta-propiolactone (<0.5 mcg).⁵⁵

FluLaval Quadrivalent

FluLaval Quadrivalent by GlaxoSmithKline is a quadrivalent, inactivated influenza vaccine for intramuscular injection. This formulation was approved in the United States for the first time in 2013 and is approved for prevention of influenza caused by influenza subtypes A and B for the 2016-2017 season. Unlike the trivalent vaccine, FluLaval Quadrivalent contains an additional strain of influenza B. FluLaval Quadrivalent may be used in persons aged 3 years and older. Available formulations include a 0.5-mL prefilled syringe and as a 5-mL multi-dose vial, which supplies 10 doses of 0.5 mL each.⁶⁰

In adults, the most common injection-site reaction was pain, whereas common systemic adverse events included muscle aches, headache, fatigue, and arthralgia. In children aged 3 to 17 years, the most common local adverse reaction was pain. Systemic adverse reactions in children differed by age group. For children aged 3 through 4 years, common systemic adverse events were irritability, drowsiness, and loss of appetite. For children and adolescents aged 5 to 17 years, common systemic adverse events included muscle aches, fatigue, headache, arthralgia, and gastrointestinal symptoms.⁶⁰

Use of FluLaval Quadrivalent is contraindicated in patients who have experienced a severe allergic reaction to any component of the vaccine, including egg protein, and in patients who have experienced a severe allergic reaction to a previous dose of any influenza vaccine. The rubber-tip cap and plunger of the single-dose syringe and the vial stopper of the multi-dose vial of FluLaval Quadrivalent are not made with natural rubber latex. Although the prefilled syringe formulation of FluLaval Quadrivalent does not contain any preservative, each dose of 0.5 mL drawn from the multi-dose vial contains 50 mcg of the preservative thimerosal (equivalent to <25 mcg of mercury). FluLaval Quadrivalent does not contain any antibiotics.⁶⁰

Inactive components of each 0.5-mL dose of FluLaval Quadrivalent include ovalbumin (≤0.3 mcg), formaldehyde (≤25 mcg), sodium deoxycholate (≤50 mcg), alpha-tocopheryl hydrogen succinate (≤320 mcg), and polysorbate 80 (≤887 mcg).⁶⁰

Fluvirin

Fluvirin by Seqirus, Inc is a trivalent, inactivated influenza vaccine for intramuscular injection. This formulation was approved in United States for the first time in 1988 and is approved for prevention of influenza caused by influenza subtypes A and B for the 2016-2017 season. Fluvirin may be used in persons aged 4 years and older but is not indicated for use in children younger than 4 years due to evidence of diminished immune response to the vaccine in this population. Available formulations include a 0.5-mL prefilled syringe and as a 5-mL multi-dose vial, which supplies 10 doses of 0.5 mL each.⁶¹

In patients who have experienced Guillain-Barré syndrome within 6 weeks of receiving a previous influenza vaccination, the decision whether to administer the influenza vaccine should be based on careful consideration of potential benefits and risks. For immunocompromised individuals, the immune response to the influenza vaccine may be diminished. It is important to note that the tip caps of the prefilled syringe of Fluvirin contain natural rubber latex, which may cause allergic reactions in latex-sensitive individual. However, the multi-dose vial stopper and the syringe stopper and plunger of the prefilled syringe do not contain latex.⁶¹

The most common adverse reactions with Fluvirin are mild hypersensitivity reactions, such as rash, local injection site reactions, and influenza like symptoms.⁶¹

Use of Fluvirin is contraindicated in patients who have experienced a severe allergic reaction to any component of the vaccine, including egg protein, and in patients who have experienced a severe allergic reaction to a previous dose of any influenza vaccine. The prefilled syringe form of Fluvirin is formulated without a preservative, but contains a trace amount of thimerosal required to manufacture the product (≤1 mcg mercury per dose). Multi-dose vials contain thimerosal as a preservative in an amount equivalent to 25 mcg of mercury per 0.5-mL dose.⁶¹

Inactive components of each 0.5-mL dose of Fluvirin include ovalbumin (≤1 mcg), polymyxin (≤3.75 mcg), neomycin (≤2.5 mcg), beta-propiolactone (≤0.5 mcg), and nonylphenol ethoxylate (≤0.015% w/v).⁶¹

Fluzone High-Dose

Fluzone High-Dose by Sanofi Pasteur is a trivalent, inactivated influenza vaccine for intramuscular injection. This formulation was approved in the United States for the first time in 2009 and is approved for prevention of influenza subtypes A and B in persons aged 65 years and older for the 2016-2017 season. Fluzone High-Dose is available only as a 0.5-mL prefilled syringe.⁶²

The most common adverse reactions with Fluzone High-Dose are pain at the injection site, myalgia, malaise, and headache.⁶²

Use of Fluzone High-Dose is contraindicated in patients who have experienced a severe allergic reaction to any component of the vaccine, including egg protein, and in patients who have experienced a severe allergic reaction to a previous dose of any influenza vaccine. Fluzone High-Dose is not made with natural rubber latex, is formulated without a preservative, and does not contain any antibiotics.⁶²

Inactive components of each 0.5-mL dose of Fluzone High-Dose include formaldehyde (≤100 mcg) and octylphenol ethoxylate (≤250 mcg).⁶²

Fluzone Intradermal Quadrivalent

Fluzone Intradermal Quadrivalent by Sanofi Pasteur is a quadrivalent, inactivated influenza vaccine for intradermal injection. This formulation was approved in the United States for the first time in 2014 and is approved for prevention of influenza subtypes A and B in persons aged 18 through 64 years for the 2016-2017 season. Unlike the trivalent vaccine, Fluzone Intradermal Quadrivalent contains an additional strain of influenza B. Fluzone Intradermal Quadrivalent is available only as a 0.1-mL prefilled syringe for intradermal injection.⁶³

In adults aged 18 through 64 years, the most common injection-site adverse reactions with Fluzone Intradermal Quadrivalent were pain, pruritus, erythema, swelling, and induration. Common systemic adverse reactions included myalgia, headache, malaise, and shivering.⁶³

Use of Fluzone Intradermal Quadrivalent is contraindicated in patients who have experienced a severe allergic reaction to any component of the vaccine, including egg protein, and in patients who have experienced a severe allergic reaction to a previous dose of any influenza vaccine. Fluzone Intradermal Quadrivalent is not made with natural rubber latex, is formulated without a preservative, and does not contain any antibiotics.⁶³

Inactive components of each 0.5-mL dose of Fluzone Intradermal Quadrivalent include formaldehyde (≤20 mcg) and octylphenol ethoxylate (≤55 mcg).⁶³

Fluzone Quadrivalent

Fluzone Quadrivalent by Sanofi Pasteur is a quadrivalent, inactivated influenza vaccine for intramuscular injection. This formulation was approved in the United States for the first time in 2013, and is approved for prevention of influenza caused by influenza subtypes A and B for the 2016-2017 season. Unlike the trivalent vaccine, Fluzone Quadrivalent contains an additional strain of influenza B. Fluzone Quadrivalent may be used in children and adults aged 6 years and older. Available formulations include a 0.25-mL prefilled syringe, a 0.5-mL prefilled syringe, a 0.5-mL single-dose vial, and a 5-mL multi-dose vial.⁶⁴

In adults aged 18 years or older, the most common injection-site reaction was pain, whereas common systemic adverse events included myalgia, headache, and malaise. Among adults aged 65 years and older receiving the vaccine, the most common injection-site reaction was pain, with common systemic adverse events of myalgia, headache, and malaise.⁶⁴

In children aged 6 months to 35 months, common injection-site reactions included pain or tenderness, erythema, and swelling. Other common adverse reactions included irritability, abnormal crying, malaise, drowsiness, appetite loss, myalgia, vomiting, and fever. For children aged 3 through 8 years, common injection-site reactions included pain, erythema, and swelling, and common systemic adverse reactions included myalgia, malaise, and headache.⁶⁴

Use of Fluzone Quadrivalent is contraindicated in patients who have experienced a severe allergic reaction to any component of the vaccine, including egg protein, and in patients who have experienced a severe allergic reaction to a previous dose of any influenza vaccine. Fluzone Quadrivalent is not made with natural rubber latex, is formulated without a preservative, and does not contain any antibiotics. Although the prefilled syringe formulations and the single-dose vial form of Fluzone Quadrivalent do not contain any preservative, the multi-dose vial contains the preservative thimerosal (equivalent to 25 mcg of mercury for each 0.5-mL dose and 12.5 mcg mercury for each 0.25-mcg dose).⁶⁴

Inactive components of each 0.5-mL dose of Fluzone Quadrivalent include formaldehyde (≤50 mcg per 0.25 mL; ≤100 mcg per 0.5 mL) and octylphenol ethoxylate (≤125 mcg per 0.25 mL; ≤250 mcg per 0.5 mL).⁶⁴

Conclusions

Pharmacists have an important role as vaccinators administering, advocating for, and evaluating patients for use of a variety of vaccines, including the influenza vaccine. For the 2016-2017 season, several formulations of the influenza vaccine are available, each of which has unique characteristics and age restrictions for use. Pharmacists must be aware of all available vaccine formulations, and they must be ready to answer questions and administer each of these formulations to promote improved vaccination rates and better health through this year’s influenza season.

Michael R. Page, PharmD, RPh, has worked as a community pharmacist at CVS Pharmacy and is currently clinical editor in clinical and scientific affairs at Pharmacy Times.

References

Hogue MD, Grabenstein JD, Foster SL, Rothholz MC. Pharmacist involvement with immunizations: a decade of professional advancement. J Am Pharm Assoc. 2006;46(2):168-179; quiz 179-182.
Grabenstein JD. Pharmacists and immunization: increasing involvement over a century. Pharm Hist. 1999;41(4):137-152.
Rothholz M. American Pharmacists Association. Role of community pharmacies/pharmacists in vaccine delivery in the United States. http://media.pharmacist.com/imz/ACIPpresentationRothholzJune2013.pdf. Accessed September 2016.
American Pharmacists Association. Pharmacist administered vaccines. Types of vaccines authorized to administer. www.pharmacist.com/sites/default/files/files/Pharmacist_IZ_Authority_1_31_15.pdf. Accessed September 2016.
American Pharmacists Association. APhA Immunization Champion Award. www.pharmacist.com/sites/default/files/ImmunChampAwards_2012.pdf. Accessed September 2016.
Blanton L, Brammer L, Finelli L, et al. CDC. Chapter 6: Influenza. www.cdc.gov/vaccines/pubs/surv-manual/chpt06-influenza.pdf. Accessed September 2016.
Committee on Infectious Diseases. Influenza immunization for all health care personnel: keep it mandatory. Pediatrics. 2015;136(4):809-818. doi: 10.1542/peds.2015-2922.
Grohskopf LA, Sokolow LZ, Broder KR, et al. Prevention and control of seasonal influenza with vaccines. MMWR Recomm Rep. 2016;65(5):1-54. doi: 10.15585/mmwr.rr6505a1.
Azziz Baumgartner E, Dao CN, Nasreen S, et al. Seasonality, timing, and climate drivers of influenza activity worldwide. J Infect Dis. 2012;206(6):838-846. doi: 10.1093/infdis/jis467.
CDC. Estimates of deaths associated with seasonal influenza --- United States, 1976-2007. MMWR Morb Mortal Wkly Rep. 2010;59(33):1057-1062.
Szucs T. The socio-economic burden of influenza. J Antimicrob Chemother. 1999;44(suppl B):11-15.
Cox NJ, Subbarao K. Influenza. Lancet. 1999;354(9186):1277-1282.
Ambrose CS, Levin MJ. The rationale for quadrivalent influenza vaccines. Hum Vaccin Immunother. 2012;8(1):81-88. doi: 10.4161/hv.8.1.17623.
CDC. Selecting viruses for the seasonal influenza vaccine. www.cdc.gov/flu/about/season/vaccine-selection.htm. Accessed September 2016.
Chaves SS, Lynfield R, Lindegren ML, Bresee J, Finelli L. The US influenza hospitalization surveillance network. Emerg Infect Dis. 2015;21(9):1543-1550. doi: 10.3201/eid2109.141912.
WHO. Recommended composition of influenza virus vaccines for use in the 2016-2017 northern hemisphere influenza season. www.who.int/influenza/vaccines/virus/recommendations/2016_17_north/en/. Accessed September 2016.
CDC. Weekly US influenza surveillance report. www.cdc.gov/flu/weekly/. Accessed September 2016.
CDC. The flu season (peak month). www.cdc.gov/flu/about/season/flu-season.htm. Accessed September 2016.
Thompson WW, Shay DK, Weintraub E, et al. Influenza-associated hospitalizations in the United States. JAMA. 2004;292(11):1333-1340.
Reed C, Chaves SS, Daily Kirley P, et al. Estimating influenza disease burden from population-based surveillance data in the United States. PLoS One. 2015;10(3):e0118369. doi: 10.1371/journal.pone.0118369.
CDC. Flu Symptoms & Severity. www.cdc.gov/flu/consumer/symptoms.htm. Accessed September 2016.
Cohen YZ, Dolin R. Influenza. In: Harrison’s Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill; 2015:224. http://accessmedicine.mhmedical.com/content.aspx?sectionid=79738663&bookid=1130&jumpsectionID=79738694&Resultclick= 2&q=influenza+pathogenesis. Accessed September 2016.
Lang PO, Mendes A, Socquet J, Assir N, Govind S, Aspinall R. Effectiveness of influenza vaccine in aging and older adults: comprehensive analysis of the evidence. Clin Interv Aging. 2012;7:55-64. doi: 10.2147/CIA.S25215.
Nichol KL, Nordin J, Mullooly J, Lask R, Fillbrandt K, Iwane M. Influenza vaccination and reduction in hospitalizations for cardiac disease and stroke among the elderly. N Engl J Med. 2003;348(14):1322-1332.
Reichert TA, Simonsen L, Sharma A, Pardo SA, Fedson DS, Miller MA. Influenza and the winter increase in mortality in the United States, 1959-1999. Am J Epidemiol. 2004;160(5):492-502.
Fleming DM, Cross KW, Pannell RS. Influenza and its relationship to circulatory disorders. Epidemiol Infect. 2005;133(2):255-262.
Mullooly JP, Bridges CB, Thompson WW, et al; Vaccine Safety Datalink Adult Working Group. Influenza- and RSV-associated hospitalizations among adults. Vaccine. 2007;25(5):846-855.
McElhaney JE, Zhou X, Talbot HK, et al. The unmet need in the elderly: how immunosenescence, CMV infection, co-morbidities and frailty are a challenge for the development of more effective influenza vaccines. Vaccine. 2012;30(12):2060-2067. doi: 10.1016/j.vaccine.2012.01.015.
Weinberger B, Herndler-Brandstetter D, Schwanninger A, Weiskopf D, Grubeck-Loebenstein B. Biology of immune responses to vaccines in elderly persons. Clin Infect Dis. 2008;46(7):1078-1084. doi: 10.1086/529197.
Chen Q, Griffin MR, Nian H, et al. Influenza vaccine prevents medically attended influenza-associated acute respiratory illness in adults aged ≥50 years. J Infect Dis. 2015;211(7):1045-1050. doi: 10.1093/infdis/jiu578.
Chit A, Roiz J, Briquet B, Greenberg DP. Expected cost effectiveness of high-dose trivalent influenza vaccine in US seniors. Vaccine. 2015;33(5):734-741. doi: 10.1016/j.vaccine.2014.10.079.
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. doi: 10.1056/NEJMoa1315727.
Fluad (influenza vaccine) [package insert]. Holly Springs, NC: Seqirus, Inc; 2016.
Cheung S, Wang HL, Mascola L, El Amin AN, Pannaraj PS. Parental perceptions and predictors of consent for school-located influenza vaccination in urban elementary school children in the United States. Influenza Other Respir Viruses. 2015;9(5):255-262. doi: 10.1111/irv.12332.
Harper SA, Bradley JS, Englund JA, et al; Expert Panel of the Infectious Diseases Society of America. Seasonal influenza in adults and children--diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(8):1003-1032. doi: 10.1086/598513.
CDC. National early season flu vaccination coverage, United States, November 2015. www.cdc.gov/flu/pdf/fluvaxview/nifs-estimates-nov2015-update.pdf. Accessed September 2016.
Committee on Infectious Diseases. Recommendations for prevention and control of influenza in children, 2016-2017 [Epub ahead of print]. Pediatrics. 2016. pii: e20162527.
Neuzil KM, Englund JA. Influenza vaccine for young children: two doses are better than one. J Pediatr. 2006;149(6):737-738.
Allison MA, Daley MF, Crane LA, et al. Influenza vaccine effectiveness in healthy 6- to 21-month-old children during the 2003-2004 season. J Pediatr. 2006;149(6):755-762.
Luteijn JM, Brown MJ, Dolk H. Influenza and congenital anomalies: a systematic review and meta-analysis. Hum Reprod. 2014;29(4):809-823. doi: 10.1093/humrep/det455.
Edwards MJ. Review: hyperthermia and fever during pregnancy. Birth Defects Res A Clin Mol Teratol. 2006;76(7):507-516.
Håberg SE, Trogstad L, Gunnes N, et al. Risk of fetal death after pandemic influenza virus infection or vaccination. N Engl J Med. 2013;368(4):333-340. doi: 10.1056/NEJMoa1207210.
Molinari NA, Ortega-Sanchez IR, Messonnier ML, et al. The annual impact of seasonal influenza in the US: measuring disease burden and costs. Vaccine. 2007;25(27):5086-5096.
Centers for Disease Control and Prevention (CDC). Update: influenza activity - United States, 2009-10 season. MMWR Morb Mortal Wkly Rep. 2010;59(29):901-908.
CDC. Health care personnel and flu vaccination, internet panel survey, United States, November 2015. www.cdc.gov/flu/fluvaxview/hcp-ips-nov2015.htm. Accessed September 2016.
Salgado CD, Farr BM, Hall KK, Hayden FG. Influenza in the acute hospital setting. Lancet Infect Dis. 2002;2(3):145-155.
Ahmed F, Lindley MC, Allred N, Weinbaum CM, Grohskopf L. Effect of influenza vaccination of healthcare personnel on morbidity and mortality among patients: systematic review and grading of evidence. Clin Infect Dis. 2014;58(1):50-57. doi: 10.1093/cid/cit580.
Centers for Disease Control and Prevention (CDC). Updated recommendations from the Advisory Committee on Immunization Practices in response to delays in supply of influenza vaccine for the 2000-01 season. MMWR Morb Mortal Wkly Rep. 2000;49(39):888-892.
Harper SA, Fukuda K, Uyeki TM, Cox NJ, Bridges CB; Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP). Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2004;53(RR-6):1-40.
Kroger AT, Atkinson WL, Marcuse EK, Pickering LK; Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC). General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006;55(RR-15):1-48.
Fiore AE, Shay DK, Broder K, et al; Centers for Disease Control and Prevention (CDC); Advisory Committee on Immunization Practices (ACIP). Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2008. MMWR Recomm Rep. 2008;57(RR-7):1-60.
Fiore AE, Uyeki TM, Broder K, et al; Centers for Disease Control and Prevention (CDC). Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Recomm Rep. 2010;59(RR-8):1-62.
Chang DH, Bednarczyk RA, Becker ER, et al. Trends in US hospitalizations and inpatient deaths from pneumonia and influenza, 1996-2011. Vaccine. 2016;34(4):486-494. doi: 10.1016/j.vaccine.2015.12.003.
Flublok (influenza vaccine) [package insert]. Meriden, CT: Protein Sciences Corporation; 2016.
Flucelvax Quadrivalent (influenza vaccine) [package insert]. Holly Springs, NC: Seqirus, Inc; 2016.
CDC. Seasonal influenza vaccine effectiveness 2005-2016. www.cdc.gov/flu/professionals/vaccination/effectiveness-studies.htm. Accessed September 2016.
Afluria (influenza vaccine) [package insert]. King of Prussia, PA: Seqirus, Inc; 2016.
Afluria Quadrivalent (influenza vaccine) [package insert]. King of Prussia, PA: Seqirus, Inc; 2016.
Fluarix Quadrivalent (influenza vaccine) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2016.
FluLaval Quadrivalent (influenza vaccine) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2016.
Fluvirin (influenza vaccine) [package insert]. Holly Springs, PA: Seqirus, Inc; 2016.
Fluzone High-Dose (influenza vaccine) [package insert]. Swiftwater, PA: Sanofi Pasteur Inc; 2016.
Fluzone Intradermal Quadrivalent (influenza vaccine) [package insert]. Swiftwater, PA: Sanofi Pasteur Inc; 2016.
Fluzone Quadrivalent (influenza vaccine) [package insert]. Swiftwater, PA: Sanofi Pasteur; 2016.

Articles in this issue

Influenza Guide for Pharmacists

Influenza Vaccination: Formulations, Recommendations, and Resources for the Pharmacist