Influenza Vaccine

Number: 0035

Policy

Aetna considers standard or preservative-free injectable influenza vaccine a medically necessary preventive service for members when influenza immunization is recommended by the member's doctor. 

Aetna considers high-dose injectable influenza vaccine (Fluzone High-Dose) a medically necessary preventive service for members age 65 years of age or older when influenza immunization is recommended by the member's doctor.

Aetna considers intradermal influenza vaccine a medically necessary preventive service for members 18 to 64 years of age when influenza immunization is recommended by the member's doctor.

Aetna considers intradermal influenza vaccine experimental and investigational for all other indications because its effectiveness for indications other than the one listed above has not been established.

Aetna considers intranasally administered influenza vaccine medically necessary for members aged 2 through 49 years old.

Aetna considers Flucelvax (intramuscular use only) medically necessary for members 4 years of age and older.

See also CPB 0476 - Influenza Rapid Diagnostic Tests.

Background

Influenza viruses ("the flu") infect the respiratory tract.  Symptoms include fever, cough, sore throat, runny or stuffy nose, headache, muscle aches, and extreme fatigue.  Influenza viruses continually change over time, and each year the vaccine is updated to include the viruses that are most likely to circulate in the upcoming influenza season.

Influenza (the flu) is a contagious respiratory illness caused by influenza viruses. It can cause mild to severe illness, and at times can lead to death. Over a period of 30 years, between 1976 and 2006, the flu has led to 3,000 up to 49,000 deaths each year and on average 226,000 hospitalizations each year. Seasonal influenza may also lead to death from other causes, such as pneumonia, an infection of the lungs that is usually caused by bacteria or viruses. Globally, pneumonia causes more deaths than any other infectious disease. In 2009, 1.1 million people in the U.S. were hospitalized with pneumonia and more than 50,000 people died from the disease. Combined with pneumonia, influenza is the nation’s eighth leading cause of death. Due to the serious complication from these viruses, vaccines are available for both illnesses.

People who have the flu often feel some or all of these signs and symptoms: Fever Footnotes* or feeling feverish/chills; Cough; Sore throat; Runny or stuffy nose; Muscle or body aches; Headaches; Fatigue (very tired). Some people may have vomiting and diarrhea, though this is more common in children than adults.

Footnotes*Not everyone with flu will have a fever.

The Influenza virus vaccine imparts immunity against the influenza virus by stimulating production of antibodies that are specific to the disease. Patients who receive the vaccine will be immune only to those strains of the virus from which the vaccine was prepared. Influenza viruses are recognized by the surface antigens they carry, and two such antigens, hemagglutinin (H) and neuraminidase (N) have been identified and are used to classify the various viruses. Subtypes of these strains (H1, H2, H3, N1, N2) are associated with influenza A virus and have been recognized to cause disease in humans. Immunity to these surface antigens increases resistance to infection and decreases the severity of the disease if infection occurs. Eventually, antigenic variation can occur, and immunity to one strain may no longer impart immunity to distantly related subtypes of the virus. Influenza B viruses also exhibit antigenic variation, and new variants of both types of viruses continue to cause widespread epidemics of respiratory disease. Influenza virus vaccine is available as: Afluria, , Fluarix, Flublok, Flucelvax, FluLaval, FluMist, Fluvirin, and Fluzone.

Contraindications may include:

  • Severe allergic reaction (anaphylaxis) to any component of the vaccine, including egg protein, or to a previous dose of any influenza vaccine.
  • Concomitant aspirin therapy in children and adolescents (FluMist only).

The following warnings and precautions should be taken into account prior to administration of the influenza vaccine:

  • Guillain‐Barré Syndrome‐ If Guillain‐Barré syndrome has occurred within 6 weeks of receipt of prior influenza vaccine, the decision to give influenza vaccine should be based on careful consideration of the potential benefits and risks.
  • Altered Immunocompetence‐ Immunocompromised persons, including individuals receiving immunosuppressive therapy, the expected immune response may not be obtained.
  • Latex Allergy‐ The prefilled syringe tip caps for Fluarix, Fluvirin, Fluzone, and Fluzone high dose, contain natural rubber latex which may cause allergic reactions in latex-sensitive individuals.
  • Wheezing‐ In clinical trials, risks of hospitalization and wheezing were increased in children younger than 2 years of age who received FluMist. Children younger than 5 years of age with recurrent wheezing and persons of any age with asthma may be at increased risk of wheezing following the administration of FluMist.

Common side effects for the flu shot may include mild fever, body aches, and fatigue for a few days after the vaccine, and soreness at the injection site.

In the United States (U.S.), flu season usually peaks between late December and early March.  The best time to be vaccinated against influenza is from October through mid-November.  However, influenza vaccination can be taken at any time during the season.  Pneumococcal and influenza vaccinations may be given simultaneously when both are required.  Children may be given influenza vaccine at the same time as routine pediatric immunizations; however, vaccines should be given at different sites.

The Centers for Disease Control and Prevention's (CDC) Advisory Committee on Immunization Practices (ACIP) recommends annual influenza immunization for persons aged 6 months and older beginning with the 2010 to 2011 influenza season.  Prior to the expanded recommendations for the 2010 to 2011 influenza season, ACIP's recommendations for seasonal influenza vaccination had focused on vaccination of persons who have a higher risk for influenza complications.  These higher risk persons should continue to be a primary focus for vaccination as providers transition to routinely vaccinating all persons 6 months of age and older.  Higher risk individuals include:

  1. Children aged 6 months up to their 5th birthday; or
  2. Children aged 6 months up to their 19th birthday who are receiving long-term aspirin therapy and who therefore might be at risk for experiencing Reye syndrome after influenza virus infection; or
  3. Health-care personnel; or
  4. Household contacts and caregivers of children younger than 5 years of age and adults 50 years of age or older, with emphasis on vaccinating contacts of children younger than 6 months of age; or
  5. Household contacts and caregivers of persons with medical conditions that put them at high risk for severe complications from influenza; or
  6. Persons 50 years of age or older; or
  7. Persons who are American Indians/Alaska natives; or
  8. Persons who are immunosuppressed (including immunosuppression caused by medications or by human immunodeficiency virus); or
  9. Persons who are morbidly obese (body-mass index of 40 or greater); or
  10. Persons who have any condition that can compromise respiratory function or the handling of respiratory secretions or that can increase the risk for aspiration (e.g., cognitive dysfunction, spinal cord injuries, seizure disorders, or other neuromuscular disorders); or
  11. Persons who have chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, hematological or metabolic disorders (including diabetes mellitus); or
  12. Residents of nursing homes and other chronic care facilities; or
  13. Women who will be pregnant during the influenza season.

Children younger than 6 months of age should not receive influenza vaccination.

It takes 1 to 2 weeks after receiving the vaccination for protective antibodies to form.  Influenza vaccines are 70 to 90 % effective in preventing influenza among healthy adults.  Among elderly persons or people with chronic conditions, the vaccine may be less effective in preventing disease than in preventing serious complications and death.

Children less than 9 years of age who have not been vaccinated previously should receive 2 doses of live attenuated (if age appropriate) or trivalent inactivated influenza vaccine (TIV).  Children who received only 1 dose of a seasonal influenza vaccine in the first influenza season that they received the vaccine should receive 2 doses, rather than 1, in the following influenza season.  In addition, for the 2010 to 2011 influenza season, children 6 months to 9 years of age who did not receive at least 1 dose of an influenza A (H1N1) 2009 monovalent vaccine should receive 2 doses of a 2010 to 2011 seasonal influenza vaccine, regardless of previous influenza vaccination history.  For all children, the second dose of a recommended 2-dose series should be administered 4 weeks or more after the initial dose (ACIP, 2010).

Only the subvirion or purified surface-antigen vaccines, i.e., those termed "split-virus" vaccines, should be administered to children younger than 13 years of age.  The whole-virus vaccines are associated with higher rates of adverse effects in young children.

Split-virus vaccine is recommended for children younger than 12 years of age; the recommended vaccine dose is 0.25 ml for children aged 6 to 35 months and 0.5 ml for children aged greater than 3 years.  Children less than 9 years of age who have not been vaccinated previously should receive 2 doses of vaccine at least 1 month apart.  A 0.5-ml dose of whole or split-virus vaccine is recommended for adolescents and adults.

Influenza vaccine should not be administered to persons with anaphylactic hypersensitivity to eggs or egg products.

On June 17, 2003, the FDA approved FluMist (manufactured by MedImmune, LLC), an intranasally administered trivalent live attenuated influenza vaccine (LAIV3), for the prevention of influenza disease caused by Influenza A subtype viruses and the type B virus contained in the vaccine. The nasal-spray influenza vaccine is a made from a cold-adapted live attenuated virus that is sprayed as an aerosol from a syringe into both nostrils.  The FDA originally approved the nasal-spray influenza vaccine only for healthy people ages 5 to 49 years of age, a group for whom influenza vaccination is considered elective.  On September 19, 2007, the FDA approved expanding the population for use of the nasal influenza vaccine FluMist to include children between the ages of 2 and 5 years based, in part, on its evaluation of randomized, controlled clinical trials demonstrating the efficacy of FluMist in the prevention of virus culture-confirmed influenza illness. In clinical trials, risks of hospitalization and wheezing were increased in children younger than 2 years of age who received FluMist (LAIV3).

On February 29, 2012, FDA approved FluMist Quadrivalent (LAIV4), a formulation containing two Influenza A subtype viruses and two type B viruses for use in persons 2 through 49 years of age. The effectiveness of FluMist Quadrivalent was based on an evaluation of immune responses in vaccinated persons, as well as the demonstrated effectiveness of the trivalent formulation. During the 2016–17 and 2017–18 influenza seasons, the Advisory Committee on Immunization Practices (ACIP) recommended that LAIV4 not be used because of concerns about low effectiveness against influenza A (H1N1) pdm09-like viruses circulating in the United States during the 2013–14 and 2015–16 seasons. Data from the U.S. Influenza Vaccine Effectiveness Network for the 2015-2016 season showed the estimate for LAIV VE among study participants in that age group against any flu virus was 3 percent (with a 95 percent Confidence Interval (CI) of -49 percent to 37 percent). This 3 percent estimate means no protective benefit could be measured. In comparison, IIV (flu shots) had a VE estimate of 63 percent (with a 95 percent CI of 52 percent to 72 percent) against any flu virus among children 2 years through 17 years. The data from 2015-2016 follows two previous seasons (2013-2014 and 2014-2015) showing poor and/or lower than expected vaccine effectiveness (VE) for LAIV. For the 2017–18 season, a new influenza A(H1N1)pdm09-like virus (A/Slovenia/2903/2015) was included in LAIV4, replacing A/Bolivia/559/2013. However, LAIV4 was not recommended for use in the United States during 2017–18, and no U.S. effectiveness estimates were available.

In February 2018, the US Centers for Disease Control and Prevention’s (CDC) Advisory Committee on Immunization Practices (ACIP) voted in favor of a renewed recommendation for the use of FluMist Quadrivalent for the prevention of influenza for the 2018-19 season. ACIP recommended against a preference for any influenza vaccine formulation. Next, the ACIP recommendations will be forwarded to the director of the CDC and the US Department of Health and Human Services for review and approval. Once approved, the final recommendations will be published in a future Morbidity and Mortality Weekly Report (MMWR). Providers should be aware that the effectiveness of the updated LAIV4 containing A/Slovenia/2903/2015 against currently circulating influenza A(H1N1)pdm09-like viruses is not yet known. 

Administration of vaccine via aerosol avoids local soreness from injection.  Nasal-spray influenza vaccine, however, is derived from a live attenuated virus and is associated with an increased incidence of upper respiratory symptoms (sore throat, rhinitis, cough) following administration (MedImmune, 2003).

The most common side effects seen with administration of the FluMist intranasal vaccine include: runny nose or nasal congestion, headache, sore throat, tiredness/weakness, muscle aches, cough, fever, and chills.

Certain patients should not receive the nasal spray flu vaccine including:

  • Children younger than two years of age and adults older than 50
  • Pregnant women and nursing mothers
  • People with a medical condition that places them at higher risk for complications from influenza, including those with chronic heart or lung disease, such as asthma or reactive airways disease; people with medical conditions such as diabetes or kidney failure; or people with illnesses that weaken the immune system, or who take medications that can weaken the immune system.
  • Any patient with asthma
  • Children 2‐4 years of age who had wheezing in the past 12 months. Children or adolescents 2 through 17 years of age currently taking aspirin or aspirin containing medication. Children or adolescents should not be given aspirin for 4 weeks after getting FluMist or FluMist Quadrivalent unless your healthcare provider tells you otherwise.
  • Patients who have had Guillain‐Barré syndrome (GBS), a rare disorder of the nervous system, with any prior influenza vaccinations.
  • People who have a severe allergy to egg proteins, chicken proteins, gentamicin, gelatin, arginine, or who are allergic to any of the nasal spray vaccine components.

Preservative-free influenza vaccine (e.g., FluZone, Aventis Pasteur, Inc. Swiftwater, PA; Afluria, CSL Biotherapies, King of Prussia, PA) does not contain the thimerosal, a mercury-containing preservative.  Standard thimerosal-preserved influenza vaccines contain trace amounts of mercury (AAP, 2003).  The American Academy of Pediatrics, the American Academy of Family Physicians, the Advisory Committee on Immunization Practices and the U.S. Public Health Service has issued a joint statement advising the removal of thimerosal-containing vaccines from vaccines routinely recommended for infants (AAP, 2000).  The joint statement explains that "[w]hile there was no evidence of any harm caused by low levels of thimerosal in vaccines and the risk was only theoretical, this goal was established as a precautionary measure.  There is public concern about the health effects of mercury exposure of any sort, and the elimination of mercury from vaccines was judged a feasible means of reducing an infant’s total exposure to mercury in a world where other environmental sources of exposure are more difficult or impossible to eliminate (e.g., certain foods)."  Other persons who are sensitive to thimerosal should avoid vaccines containing this preservative.  Furthermore, the U.S. Public Health Service recommended efforts be made to eliminate or reduce the thimerosal content in vaccines as part of an over-all strategy to reduce mercury exposures from all sources and ACIP and other federal agencies and professional medical organizations continue to support efforts to provide thimerosal preservative-free vaccine options (ACIP, 2008).

The American College of Obstetricians and Gynecologists and the American Academy of Family Physicians recommend routine vaccination of all pregnant women.  No preference is indicated for use of TIV that does not contain thimerosal as a preservative for any group recommended for vaccination, including pregnant women.  Live, attenuated influenza vaccine (LAIV) is not licensed for use in pregnant women (ACIP, 2008).

A high dose seasonal influenza vaccine specifically intended for people aged 65 and older was approved by the FDA on December 23, 2009.  Fluzone High-Dose (Sanofi Pasteur Inc.) was approved via the FDA's accelerated approval pathway.  It contains 4 times the total amount of virus hemagglutinin (180 mcg) found in other seasonal vaccines.  The higher-dose formulation is based on the theory that immune functions weaken with age and that the elderly are especially vulnerable to complications from seasonal influenza.  In clinical studies, Fluzone High-Dose demonstrated an enhanced immune response compared with Fluzone in individuals aged 65 and older.  Common side effects were more frequent with the high-dose than with regular-dose formulations, but the rate of serious adverse events was no higher.  Since the product received accelerated approval, the manufacturer must conduct further studies to verify the higher efficacy of the vaccine among older people (FDA, 2009). The Centers for Disease Control and Prevention (CDC) and its Advisory Committee on Immunization Practices (ACIP) have not expressed a preference for any flu vaccine indicated for people 65 and older (CDC, 2014).

On May 11, 2011, the FDA approved Sanofi Pasteur's supplemental Biologics License Application for licensure of Fluzone Intradermal (Influenza Virus Vaccine).  Fluzone intradermal vaccine is indicated for active immunization of adults 18 through 64 years of age against influenza disease caused by influenza virus subtypes A and type B contained in the vaccine.

The most common side effects observed with the administration of Fluzone Intradermal vaccine include injection‐site reactions, erythema, induration, swelling, pain, and pruritus. Erythema, induration, swelling, and pruritus occurred more frequently following Fluzone Intradermal than Fluzone.

In 2011, the ACIP provided the following recommendations regarding influenza vaccination of individuals with egg allergies:

Individuals who have experienced only hives may receive influenza vaccine with the following additional measures:

  • As studies published to date involved the use of  trivalent inactivated influenza vaccine (TIV), TIV rather than LAIV should be used;
  • Vaccine should be administered by a healthcare provider who is familiar with the subject of egg allergy;
  • Vaccine recipients should be observed for at least 30 minutes for signs for a reaction following administration of each vaccine dose.

Other measures, such as dividing and administering the vaccine by a 2-step approach and skin testing with vaccine are not necessary.

Egg allergy may be confirmed by a consistent medical history of adverse reactions to eggs and egg-containing foods, plus a skin and/or blood testing for IgE antibodies to egg proteins.

In 2012, the US Food and Drug Administration approved quadrivalent formulations of both the live-attenuated influenza vaccine and the inactivated influenza vaccine; these vaccines contain two strains of influenza A virus and two strains of influenza B virus (Hibberd, 2012). Fluarix Quadrivalent is a vaccine indicated for active immunization for the prevention of disease caused by influenza A subtype viruses and type B viruses contained in the vaccine. It is approved for use in persons 3 years of age and older. Safety has not been established in pregnant women or nursing mothers. (FDA, 2013).

For those persons 18‐49 years of age with an egg allergy of any severity, Flublok is available. It is an egg‐free vaccine option for those who could not previously receive a flu shot due to an egg allergy. It is the only licensed flu vaccine that does not use eggs in the manufacturing process. On January 16, 2013 the FDA approved Flublok in individuals aged 18 through 49 for active immunization against disease caused by influenza virus. Flublok is the first trivalent influenza vaccine made using an insect virus (baculovirus) expression system and recombinant DNA technology. Flublok's manufacturing technology allows for production of large quantities of the influenza virus protein, hemagglutinin (HA), the active ingredient in all inactivated influenza vaccines that is essential for entry of the virus into cells of the body. Flublok contains three, full-length, recombinant HA proteins to help protect against two influenza virus A strains, H1N1 and H3N2, and one influenza virus B strain (FDA, 2013).

Fluzone Quadrivalent received FDA approval on June 7, 2013.  Fluzone received approval for active immunization of persons 6 months of age and older for the prevention of influenza disease caused by influenza A subtype viruses and type B viruses contained in the vaccine (FDA, 2013c).

In a June 19-20, 2013 meeting, ACIP voted and unanimously approved language changes to the vaccine safety update to state that “for individuals who have no known history of exposure to egg but who are suspected of being egg-allergic on the basis of previously performed allergy testing, use of RIV3 or consultation with a physician with expertise in the management of allergic conditions should be obtained prior to vaccination.  If the patient only experiences hives after ingestion of egg, administer RIV3 (FluBlok) if the patient is aged 18to 49 years or administer a inactivated influenza vaccine (IIV) of choice and observe for at least 30 minutes following vaccination.  If more severe reactions have been noted with eggs administer RIV3 (FluBlok) or refer to a clinician with expertise in allergic reaction” (Lardy et al, 2013).

Nichol and colleagues (2007) examined the effectiveness of influenza vaccine in seniors over the long-term.  Data were pooled from 18 cohorts of community-dwelling elderly members of 1 U.S. health maintenance organization (HMO) for 1990 to 1991 through 1999 to 2000 and of 2 other HMOs for 1996 to 1997 through 1999 to 2000.  Logistic regression was used to estimate the effectiveness of the vaccine for the prevention of hospitalization for pneumonia or influenza and death after adjustment for important co-variates.  Additional analyses explored for evidence of bias and the potential effect of residual confounding.  There were 713,872 person-seasons of observation.  Most high-risk medical conditions that were measured were more prevalent among vaccinated than among unvaccinated persons.  Vaccination was associated with a 27 % reduction in the risk of hospitalization for pneumonia or influenza (adjusted odds ratio, 0.73; 95 % confidence interval [CI]: 0.68 to 0.77) and a 48 % reduction in the risk of death (adjusted odds ratio, 0.52; 95 % CI: 0.50 to 0.55).  Estimates were generally stable across age and risk subgroups.  In the sensitivity analyses, these researchers modeled the effect of a hypothetical unmeasured confounder that would have caused over-estimation of vaccine effectiveness in the main analysis; vaccination was still associated with statistically significant -- though lower -- reductions in the risks of both hospitalization and death.  The authors concluded that during 10 seasons, influenza vaccination was associated with significant reductions in the risk of hospitalization for pneumonia or influenza and in the risk of death among community-dwelling elderly persons.  They noted that vaccine delivery to this high-priority group should be improved.

In an editorial that accompanied the afore-mentioned study, Treanor (2007) stated that these findings support the current policy of vaccinating the elderly but also demonstrate that the inactivated influenza vaccine is by itself a relatively mediocre means for controlling flu in this population.  Until more immunogenic vaccines are developed, routine vaccination of children as well as health care workers could limit transmission and play an important role in controlling the development of influenza in the elderly.

Maternal influenza immunization is a strategy with substantial benefits for both mothers and infants.  Zaman et al (2008) evaluated the clinical effectiveness of inactivated influenza vaccine administered during pregnancy in Bangladesh.  In this randomized study, a total of 340 mothers were assigned to receive either inactivated influenza vaccine (influenza-vaccine group) or the 23-valent pneumococcal polysaccharide vaccine (control group).  Mothers were interviewed weekly to assess illnesses until 24 weeks after birth.  Subjects with febrile respiratory illness were assessed clinically, and ill infants were tested for influenza antigens.  These researchers estimated the incidence of illness, incidence rate ratios, and vaccine effectiveness.  Mothers and infants were observed from August 2004 through December 2005.  Among infants of mothers who received influenza vaccine, there were fewer cases of laboratory-confirmed influenza than among infants in the control group (6 cases and 16 cases, respectively), with a vaccine effectiveness of 63 % (95 % CI: 5 to 85).  Respiratory illness with fever occurred in 110 infants in the influenza-vaccine group and 153 infants in the control group, with a vaccine effectiveness of 29 % (95 % CI: 7 to 46).  Among the mothers, there was a reduction in the rate of respiratory illness with fever of 36 % (95 % CI: 4 to 57).  The authors concluded that inactivated influenza vaccine reduced proven influenza illness by 63 % in infants up to 6 months of age and averted about one-third of all febrile respiratory illnesses in mothers and young infants. 

According to the CDC, H1N1 (swine flu) is an influenza virus that was first detected in people in the U.S. in April 2009.  It spreads from person-to-person in much the same way that regular seasonal influenza viruses spread (i.e., through coughing or sneezing by people with influenza).  This virus was originally referred to as “swine flu” because laboratory testing showed that many of the genes in this new virus were very similar to influenza viruses that normally occur in pigs (swine) in North America.  However, studies have shown that this new virus is very different from what normally circulates in North American pigs.  It has two genes from flu viruses that normally circulate in pigs in Europe and Asia as well as genes from bird (avian) flu and human influenza strains.  It is referred to as a "quadruple reassortant" virus.  Symptoms are similar to seasonal influenza (e.g., fever and chills, cough, sore throat, muscle aches, headache, and extreme fatigue).  The CDC, however, reported that there is little 2009 H1N1 virus currently circulating in the U.S. and the Department of Health and Human Services has declared the end of the H1N1 influenza public health emergency as of June 23, 2010. With 2009 H1N1, aprroximately 90 % of estimated hospitalizations and 87 % of estimated deaths from April 2009 through January 16, 2010 occurred in people younger than age 65 years.  In contrast, with seasonal influenza, about 60 % of seasonal flu-related hospitalizations and 90 % of flu-related deaths occur in people aged 65 years and older.  These data confirm that the 2009 H1N1 impacted younger adults and children more than older adults compared to seasonal flu.  However, people in all age groups can develop severe illness from either seasonal flu or from 2009 H1N1.

Guidelines for preventing infections in hematopoietic cell transplant (HCT) recipients by the Center for International Blood and Marrow Transplant Research, National Marrow Donor Program, European Group for Blood and Marrow Transplantation, American Society for Blood and Marrow Transplantation, Canadian Blood and Marrow Transplant Group, Infectious Diseases Society of America, Society for Healthcare Epidemiology of America, Association of Medical Microbiology and Infectious Disease, and the CDC (Ljungman et al, 2009) indicated that intranasal influenza vaccine (live) should not be given to HCT recipients since an effective, inactivated alternative exist.

Available evidence shows that two doses of influenza vaccine does not improve antibody reponse in persons with hematologic malignancies.  In a randomized controlled study (n = 70), Ljungman and associates (2005) examined if 2 doses of influenza vaccine were more effective than one to elicit an immune response in patients with hematological malignancies.  These investigators found that responses were not improved by 2 doses compared with 1 (influenza A virus serotypes H1/N1 18 % versus 22 % and H3/N2 26 % versus 14 %; influenza B 25 % versus 22 %).  The results were similar in patients with ongoing and discontinued therapy.  Patients treated with monoclonal antibodies for lymphoma had very poor responses.  These researchers concluded that 2 doses of influenza vaccine do not improve the antibody response in patients with hematological malignancies.

Frenck and colleagues (2011) examined if reduced doses of trivalent inactivated influenza vaccine (TIV) administered by the intradermal (ID) route generated similar immune responses to standard TIV given intramuscularly (IM) with comparable safety profiles.  Recent changes in immunization recommendations have increased the number of people for whom influenza vaccination is recommended.  Thus, given this increased need and intermittent vaccine shortages, means to rapidly expand the vaccine supply are needed.  Previously healthy subjects 18 to 64 years of age were randomly assigned to 1 of 4 TIV vaccine groups: standard 15 μg HA/strain TIV IM, either 9 μg or 6 μg HA/strain of TIV ID given using a new microinjection system (BD Soluvia™ Microinjection System(1)), or 3 μg HA/strain of TIV ID given by Mantoux technique.  All vaccines contained A/New Caledonia (H1N1), A/Wyoming (H3N2) and B/Jiangsu strains of influenza.  Sera were obtained 21 days after vaccination and hemagglutination inhibition (HAI) assays were performed and geometric mean titers (GMT) were compared among the groups.  Subjects were queried immediately following vaccination regarding injection pain and quality of the experience.  Local and systemic reactions were collected for 7 days following vaccination and compared.  A total of 10 study sites enrolled 1,592 subjects stratified by age; 18 to 49 years (n = 814) and 50 to 64 years (n = 778).  Among all subjects, for each of the 3 vaccine strains, the GMTs at 21 days post-vaccination for both the 9 μg and the 6 μg doses of each strain given ID were non- inferior to GMTs generated after standard 15 μg doses/strain IM.  However, for the 3 μg ID dose, only the A/Wyoming antigen produced a GMT that was non-inferior to the standard IM dose.  Additionally, in the subgroup of subjects 50 to 64 years of age, the 6 μg dose given ID induced GMTs that were inferior to the standard IM TIV for the A/H1N1 and B strains.  No ID dose produced a GMT superior to that seen after standard IM TIV.  Local erythema and swelling were significantly more common in the ID groups but the reactions were mild-to-moderate and short-lived.  No significant safety issues related to intradermal administration were identified.  Participants given TIV ID provided favorable responses to questions about their experiences with ID administration.  The authors concluded that for the aggregated cohorts of adults 18 to 64 years of age, reduced doses (6 μg and 9 μg) of TIV delivered ID using a novel microinjection system stimulated comparable HAI antibody responses to standard TIV given IM.  The reduced 3 μg dose administered ID by needle and syringe, as well as the 6 μg ID for subjects aged 50 to 64 years of age generated poorer immune responses as compared to the 15 μg IM dose.

The CDC’s ACIP and the American College of Obstetricians and Gynecologists (2014) recommend that all adults receive an annual influenza vaccine.  Influenza vaccination is an essential element of pre-conception, pre-natal, and post-partum care because pregnant women are at an increased risk of serious illness due to seasonal and pandemic influenza.  Since 2010, influenza vaccination rates among pregnant women have increased but still need significant improvement.  It is particularly important that women who are or will be pregnant during influenza season receive an inactivated influenza vaccine as soon as it is available.  It is critically important that all obstetrician-gynecologists and all providers of obstetric care advocate for influenza vaccination, provide the influenza vaccine to their pregnant patients, and receive the influenza vaccine themselves every season.  It is imperative that obstetrician-gynecologists, other health care providers, health care organizations, and public health officials continue efforts to improve the rate of influenza vaccination among pregnant women.

Madhi et al (2014) conducted 2 double-blind, randomized, placebo-controlled trials of trivalent IIV (IIV3) in South Africa during 2011 in pregnant women infected with HIV and during 2011 and 2012 in pregnant women who were not infected.  The immunogenicity, safety, and efficacy of IIV3 in pregnant women and their infants were evaluated until 24 weeks after birth.  Immune responses were measured with a HAI assay, and influenza was diagnosed by means of reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assays of respiratory samples.  The study cohorts included 2,116 pregnant women who were not infected with HIV and 194 pregnant women who were infected with HIV.  At 1 month after vaccination, sero-conversion rates and the proportion of participants with HAI titers of 1:40 or more were higher among IIV3 recipients than among placebo recipients in both cohorts.  Newborns of IIV3 recipients also had higher HAI titers than newborns of placebo recipients.  The attack rate for RT-PCR-confirmed influenza among both HIV-uninfected placebo recipients and their infants was 3.6 %.  The attack rates among HIV-uninfected IIV3 recipients and their infants were 1.8 % and 1.9 %, respectively, and the respective vaccine-efficacy rates were 50.4 % (95 % CI: 14.5 to 71.2) and 48.8 % (95 % CI: 11.6 to 70.4).  Among HIV-infected women, the attack rate for placebo recipients was 17.0 % and the rate for IIV3 recipients was 7.0 %; the vaccine-efficacy rate for these IIV3 recipients was 57.7 % (95 % CI: 0.2 to 82.1).  The authors concluded that influenza vaccine was immunogenic in HIV-uninfected and HIV-infected pregnant women and provided partial protection against confirmed influenza in both groups of women and in infants who were not exposed to HIV.

In a systematic review, Prutsky and colleagues (2014) evaluated the evidence on LAIV in children younger than 2 years.  These investigators searched Medline, EMBASE, the Cochrane Library, Web of Science, Scopus, PsycInfo and CINAHL through February 2013 for existing systematic reviews, randomized controlled trials (RCTs) and observational studies (for safety).  They included studies enrolling healthy children less than 2 years of age who received LAIV, compared with placebo or IIV.  Data were extracted independently by 2 investigators.  The relative risk (RR) was pooled across studies using the random effects model.  These researchers found 7 eligible RCTs and 2 observational studies.  Randomized controlled trials included 6,281 children and were at low-to-moderate risk of bias.  Live attenuated influenza vaccine reduced the incidence of influenza compared with placebo (RR = 0.36, 95 % CI: 0.23 to 0.58, p < 0.05) with a number needed to vaccinate of 17.  Live attenuated influenza vaccine increased the incidence of minor side effects (fever and rhinorrhea); it had a similar effect in preventing influenza (RR = 0.76, 95 % CI: 0.45 to 1.30, p > 0.05) compared with IIV.  There was an increase of hospitalization rate (post-hoc analysis) and medical attended wheezing with LAIV.  The authors concluded that LAIV is highly effective in children less than 2 years of age compared with placebo and is as effective to IIV.  The safety profile of LAIV is reasonable although evidence is sparse.  They stated that LAIV may be considered as an option in this age group particularly during seasons with vaccine shortage.

In a Cochrane review, Dharmaraj and Smyth (2014) evaluated the effectiveness of influenza vaccination for people with cystic fibrosis (CF).  These investigators searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises of references identified from comprehensive electronic database searches and hand-searching of relevant journals and abstract books of conference proceedings.  They also contacted the companies which market the influenza vaccines used in the trials to obtain further information about RCTs.  Date of the most recent search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Cystic Fibrosis Trials Register: July 8, 2013.  All randomized and quasi-randomized trials (published or unpublished) comparing any influenza vaccine with a placebo or with another type of influenza vaccine were selected for analysis.  Two authors independently assessed study quality and extracted data.  Additional information was obtained by contacting the investigators when it was indicated.  A total of 4 studies enrolling a total of 179 participants with CF (143 (80 %) were children aged 1 to 16 years) were included in this review.  There was no study comparing a vaccine to a placebo or a whole virus vaccine to a subunit or split virus vaccine.  Two studies compared an intra-nasal applied live vaccine to an intra-muscular inactivated vaccine and the other 2 studies compared a split virus to a subunit vaccine and a virosome to a subunit vaccine (all intra-muscular).  The incidence of all reported adverse events was high depending on the type of influenza vaccine.  The total adverse event rate ranged from 48 out of 201 participants (24 %) for the intra-nasal live vaccine to 13 out of 30 participants (43 %) for the split virus vaccine.  With the limitation of a statistical low power there was no significant difference between the study vaccinations.  None of the events was severe.  All study influenza vaccinations generated a satisfactory serological antibody response.  No study reported other clinically important benefits.  The authors concluded that there is currently no evidence from randomized studies that influenza vaccine given to people with CF is of benefit to them.  They stated that there remains a need for a well-constructed clinical study, that assesses the effectiveness of influenza vaccination on important clinical outcome measures.

Pileggi et al (2015) stated that the primary influenza prevention strategy is focused on annual vaccination according to the categories identified in the various countries as being at greatest risk of complications.  Many studies were conducted in order to demonstrate that ID vaccine formulation represents a promising alternative to conventional IM formulation, especially in subjects with an impaired immune system.  However, there is no consensus whether the safety and effectiveness of ID is equivalent to IM in these subjects.  Therefore, these investigators performed a meta-analysis of RCTs to compare the immunogenicity and safety of ID and IM influenza vaccines in subjects with a depleted immune system.  These researchers conducted a search strategy of medical literature published until November 2014 in order to identify RCTs that evaluated the immunogenicity and safety of ID compared with IM influenza vaccines in immuno-compromised patients.  They identified a total of 269 citations through research in electronic databases and scanning reference lists.  Of these, 6 articles were included in the meta-analysis, for a total of 673 subjects.  The sero-protection rate induced by the ID vaccine is comparable to that elicited by the IM vaccine.  The overall RR was 1.00 (95 % CI: 0.91 to 1.10) for A/H1N1 strain, 1.00 (95 % CI: 0.90 to 1.12) for A/H3N2 and 0.99 (95 % CI: 0.84 to 1.16) for B strain.  No significant differences in the occurrence of systemic reactions were detected (17.7 % in the ID group versus 18.2 % in the IM group) with a pooled RR = 1.00 (95 % CI: 0.67 to 1.51), whereas ID administration caused significantly more injection site reactions with a mean frequency of 46 % in the ID group compared to 22 % in the IM group, with a pooled RR = 1.89 (95 % CI: 1.40 to 2.57).  The authors concluded that ID influenza vaccine had shown a similar immunogenicity and safety to the IM influenza vaccine in immuno-compromised patients, and it may be a valid option to increase compliance to influenza vaccination in these populations.

Remschmidt et al (2015) noted that patients with diabetes are at increased risk of severe influenza disease; influenza vaccination for these patients is therefore recommended by the World Health Organization (WHO) and several National Immunization Technical Advisory Groups.  However, no systematic review has evaluated the effects of influenza vaccines for patients with diabetes.  These researchers conducted a systematic review and meta-analysis by searching Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from inception until November 2014.  They included all types of studies reporting on the efficacy, effectiveness, and/or safety of influenza vaccination in patients with type 1 and type 2 diabetes mellitus of all ages.  They used the Newcastle-Ottawa scale to assess risk of bias in observational studies.  Residual confounding was addressed by comparing estimates of vaccine effectiveness (VE) during influenza seasons to those obtained during off-seasons.  Quality of the evidence for each outcome was assessed using the GRADE methodology.  Following review of 1,444 articles, 11 observational studies with a total of 170,924 participants were included.  In diabetic patients of working-age (18 to 64 years), influenza vaccination prevented all-cause hospitalization with a pooled VE of 58 % (95 % CI: 6 to 81 %) and hospitalization due to influenza or pneumonia (VE 43 %; 95 % CI: 28 to 54 %), whereas no effects on all-cause mortality and influenza-like illness (ILI) were observed.  In the elderly (65+), influenza vaccination prevented all-cause mortality (VE 38 %; 95 % CI: 32 to 43 %), all-cause hospitalization (VE 23 %; 95 % CI: 1 to 40 %), hospitalization due to influenza or pneumonia (VE 45 %; 95 % CI: 34 to 53 %), and ILI (VE 13 %; 95 % CI: 10 to 16 %).  However, significant off-season estimates for several outcomes indicated residual confounding, particularly in elderly patients.  Quality of the evidence was low to very low for all outcomes.  Laboratory-confirmed influenza infections were not reported.  The authors concluded that due to strong residual confounding in most of the identified studies, the available evidence is insufficient to determine the magnitude of benefit that diabetic people derive from seasonal influenza vaccination.  They stated that adequately powered RCTs or quasi-experimental studies using laboratory-confirmed influenza-specific outcomes are urgently needed.

In a Cochrane review, Norhayati et al (2015) stated that acute otitis media (AOM) is one of the most common infectious diseases in children.  It has been reported that 64 % of infants have an episode of AOM by the age of 6 months and 86 % by 1 year.  Although most cases of AOM are due to bacterial infection, it is commonly triggered by a viral infection.  In most children it is self-limiting, but it does carry a risk of complications.  Since antibiotic treatment increases the risk of antibiotic resistance, influenza vaccines might be an effective way of reducing this risk by preventing the development of AOM.  These investigators evaluated the effectiveness of influenza vaccine in reducing the occurrence of AOM in infants and children.  They searched CENTRAL (2014, Issue 6), MEDLINE (1946 to Week 1, July 2014), EMBASE (2010 to July 2014), CINAHL (1981 to July 2014), LILACS (1982 to July 2014), Web of Science (1955 to July 2014) and reference lists of articles to July 2014.  Randomized controlled trials comparing influenza vaccine with placebo or no treatment in infants and children aged younger than 6 years old.  These researchers included children of either sex and of any ethnicity, with or without a history of recurrent AOM.  Two review authors independently screened studies, assessed trial quality and extracted data.  They performed statistical analyses using the random-effects and fixed-effect models and expressed the results as RR, risk difference (RD) and number needed to treat to benefit (NNTB) for dichotomous outcomes, with 95 % CI.  These investigators included 10 trials (6 trials in high-income countries and 4 multi-center trials in high-, middle- and low-income countries) involving 16,707 children aged 6 months to 6 years.  Eight trials recruited participants from a healthcare setting; 9 trials (and all 5 trials that contributed to the primary outcome) declared funding from vaccine manufacturers.  Four trials reported adequate allocation concealment and 9 trials reported adequate blinding of participants and personnel.  Attrition was low for all trials included in the analysis.  The primary outcome showed a small reduction in at least 1 episode of AOM over at least 6 months of follow-up (5 trials, 4,736 participants: RR 0.80, 95 % CI: 0.67 to 0.96; RD -0.04, 95 % CI: -0.07 to -0.02; NNTB 25, 95 % CI: 15 to 50).  The subgroup analyses (i.e., number of courses, settings, seasons or types of vaccine administered) showed no differences.  There was a reduction in the use of antibiotics in vaccinated children (2 trials, 1,223 participants: RR 0.70, 95 % CI: 0.59 to 0.83; RD -0.15, 95 % CI: -0.30 to -0.00).  There was no significant difference in the utilization of health care for the 1 trial that provided sufficient information to be included.  The use of influenza vaccine resulted in a significant increase in fever (6 trials, 10,199 participants: RR 1.15, 95 % CI: 1.06 to 1.24; RD 0.02, 95 % CI: -0.00 to 0.05) and rhinorrhea (6 trials, 10,563 children: RR 1.17, 95 % CI: 1.07 to 1.29; RD 0.09, 95 % CI: 0.01 to 0.16) but no difference in pharyngitis.  No major adverse events were reported.  Compared to the protocol, the review included a subgroup analysis of AOM episodes by season, and changed the types of influenza vaccine from a secondary outcome to a subgroup analysis.  The authors concluded that influenza vaccine results in a small reduction in AOM.  The observed reduction with the use of antibiotics needs to be considered in the light of current recommended practices aimed at avoiding antibiotic overuse.  Safety data from these trials are limited.  They stated that the benefits may not justify the use of influenza vaccine without taking into account the vaccine efficacy in reducing influenza and safety data.  The quality of the evidence was high-to-moderate; additional research is needed.

Booster Dose of Influenza

Liao and colleagues (2016) noted that booster influenza vaccination has been recommended for patients with chronic renal disease in order to enhance the immune response to the influenza vaccine; however, the effectiveness of a booster influenza vaccination is a matter of controversy.  These investigators performed a meta-analysis to determine the effectiveness in patients with hemodialysis (HD), peritoneal dialysis (PD) and renal transplant recipient (RT).  The sero-protection rate was used as a serologic parameter to describe the immune response to the vaccine.  Statistical analysis was performed to calculate the pooled rate difference (RD) and 95 % CI.  The pooled RD for the H1N1, H3N2 and B influenza vaccines was 0.02 (95 % CI: -0.02 to 0.06), 0.05 (95 % CI: -0.01 to 0.11), 0.04 (95 % CI: -0.02 to 0.10), respectively.  The authors concluded that a booster dose of the influenza vaccine did not effectively enhance immunogenicity.  Therefore, a booster dose of vaccine is not recommended for patients with hemodialysis, peritoneal dialysis and renal transplant recipients.

Prevention of Cardiovascular Diseases (e.g., e Acute Myocardial Infarction)

There is evidence to suggest that influenza vaccination improves the clinical course of coronary artery disease (CAD) and reduces the frequency of coronary ischemic events. In a randomized, double-blind, placebo-controlled trial, Ciszewski et al (2008) assessed the effect of influenza vaccination on the coronary events in patients with confirmed CAD.  This study included 658 optimally treated CAD patients (477 men, mean age of 59.9 +/- 10.3 years).  A total of 325 patients received the influenza vaccine, and 333 patients received a placebo.  Median follow-up was 298 days (inter-quartile range of  263 to 317).  Primary end-point was cardiovascular death.  Its estimated 12-month cumulative event rate was 0.63 % in the vaccine versus 0.76 % in controls (HR 1.06; 95 % CI: 0.15 to 7.56, p = 0.95).  There were 2 secondary composite end-points:
  1. the MACE (cardiovascular death, myocardial infarction, coronary re-vascularization) tended to occur less frequently in the vaccine group versus placebo with the event rate 3.00 % and 5.87 %, respectively (HR 0.54; 95 % CI: 0.24 to 1.21, p = 0.13),
  2. coronary ischemic event (MACE or hospitalization for myocardial ischemia) estimated 12-month event rate was significantly lower in the vaccine group 6.02 % versus 9.97 % in controls (HR 0.54; 95 % CI: 0.29 to 0.99, p = 0.047). 

The authors concluded that in optimally treated CAD patients, influenza vaccination improves the clinical course of CAD and reduces the frequency of coronary ischemic events.  They stated that large-scale studies are needed to evaluate the effect of influenza vaccination on cardiovascular mortality.

A Cochrane review concluded that despite the significant effects noted in available randomized controlled clinical trials, that there are not enough data to evaluate the effect of influenza vaccination on coronary heart disease (Keller et al, 2008).

Barnes and associates (2015) stated that acute myocardial infarction (AMI) is the leading cause of death and disability globally. There is increasing evidence from observational studies that influenza infection is associated with AMI.  In patients with known coronary disease, influenza vaccination is associated with a lower risk of cardiovascular events.  However, the effect of influenza vaccination on incident AMI across the entire population is less well established.  In a systematic review of case-control studies, these investigators
  1. estimated the association between influenza infection and AMI, and
  2. estimated the association between influenza vaccination and AMI. 

Cases included those conducted with first-time AMI or any AMI cases.  Studies were appraised for quality and meta-analyses using random effects models for the influenza exposures of infection, and vaccination were conducted.  A total of 16 studies (8 on influenza vaccination, 10 on influenza infection and AMI) met the eligibility criteria, and were included in the review and meta-analysis.  Recent influenza infection, influenza-like illness or respiratory tract infection was significantly more likely in AMI cases, with a pooled odds ratio (OR) of 2.01 (95 % CI: 1.47 to 2.76).  Influenza vaccination was significantly associated with AMI, with a pooled OR of 0.71 (95 % CI: 0.56 to 0.91), equating to an estimated vaccine effectiveness of 29 % (95 % CI: 9 % to 44 %) against AMI.  The authors concluded that the findings of this meta-analysis of case-control studies found a significant association between recent respiratory infection and AMI.  The estimated vaccine effectiveness against AMI was comparable with the effectiveness of currently accepted therapies for secondary prevention of AMI from clinical trial data.  They stated that al large-scale RCT is needed to provide robust evidence of the protective effect of influenza vaccination on AMI, including as primary prevention.

In a Cochrane review, Clar and colleagues (2015) evaluated the potential benefits of influenza vaccination for primary and secondary prevention of cardiovascular diseases.  These investigators searched the following electronic databases on October 18, 2013: The Cochrane Library (including Cochrane Central Register of Controlled Trials (CENTRAL), Database of Abstracts of Reviews of Effects (DARE), Economic Evaluation Database (EED) and Health Technology Assessment database (HTA)), Medline, Embase, Science Citation Index Expanded, Conference Proceedings Citation Index - Science and ongoing trials registers (www.controlled-trials.com/ and www.clinicaltrials.gov).  They examined reference lists of relevant primary studies and systematic reviews, and performed a limited PubMed search on February 20, 2015, just before publication.  Randomized controlled trials of influenza vaccination compared with placebo or no treatment in participants with or without cardiovascular diseases, assessing cardiovascular death or non-fatal cardiovascular events.  These researchers used standard methodological procedures as expected by the Cochrane Collaboration; they performed meta-analyses only for cardiovascular death, as other outcomes were reported too infrequently.  They expressed effect sizes as RRs and used random-effects models.  The authors included 8 trials of influenza vaccination compared with placebo or no vaccination, with 12,029 participants receiving at least 1 vaccination or control treatment.  They included 6 new studies (n = 11,251), in addition to the 2 included in the previous version of the review; 4 of these trials (n = 10,347) focused on prevention of influenza in the general or elderly population and reported cardiovascular outcomes among their safety analyses; 4 trials (n = 1,682) focused on prevention of cardiovascular events in patients with established coronary heart disease.  These populations were analyzed separately; follow-up continued between 42 days and 1 year; 5  RCTs showed deficits in at least 3 of the risk of bias criteria assessed.  When reported (7 studies), vaccination provided adequate immunogenicity or protection against influenza.  Cardiovascular mortality was reported by 4 secondary prevention trials and was significantly reduced by influenza vaccination overall (RR of 0.45, 95 % CI: 0.26 to 0.76; p value of 0.003) with no significant heterogeneity between studies, and by 3 trials reporting cardiovascular mortality as part of their safety analyses when the numbers of events were too small to permit conclusions.  In studies of patients with coronary heart disease, composite outcomes of cardiovascular events tended to be decreased with influenza vaccination compared with placebo.  Generally no significant difference was found between comparison groups regarding individual outcomes such as MI.  The authors concluded that in patients with cardiovascular disease, influenza vaccination may reduce cardiovascular mortality and combined cardiovascular events.  However, studies had some risk of bias, and results were not always consistent, so additional higher-quality evidence is needed to confirm these findings.  They stated that not enough evidence was available to establish whether influenza vaccination has a role to play in the primary prevention of cardiovascular diseases.

Flucelvax

Flucelvax is an inactivated vaccine indicated for active immunization for the prevention of influenza disease caused by influenza virus subtypes A and type B contained in the vaccine.  Flucelvax is approved for use in persons 4 years of age and older; for intramuscular use only.



Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

CPT codes covered if selection criteria are met:

90630 Influenza virus vaccine, quadrivalent (IIV4), split virus, preservative free, for intradermal use
90653 Influenza vaccine, inactivated (IIV), subunit, adjuvanted, for intramuscular use
90654 Influenza virus vaccine, trivalent (IIV3), split virus, preservative-free, for intradermal use
90655 Influenza virus vaccine, trivalent (IIV3), split virus, preservative free, 0.25 mL dosage, for intramuscular use
90656 Influenza virus vaccine, trivalent (IIV3), split virus, preservative free, 0.5 mL dosage, for intramuscular use
90657 Influenza virus vaccine, trivalent (IIV3), split virus, 0.25 mL dosage, for intramuscular use
90658 Influenza virus vaccine, trivalent (IIV3), split virus, 0.5 mL dosage, for intramuscular use
90661 Influenza virus vaccine (ccIIV3), derived from cell cultures, subunit, preservative and antibiotic free, 0.5 mL dosage, for intramuscular use
90662 Influenza virus vaccine (IIV), split virus, preservative free, enhanced immunogenicity via increased antigen content, for intramuscular use
90672 Influenza virus vaccine, quadrivalent, live (LAIV4), for intranasal use
90673 Influenza virus vaccine, trivalent (RIV3), derived from recombinant DNA, hemagglutinin (HA) protein only, preservative and antibiotic free, for intramuscular use
90674 Influenza virus vaccine, quadrivalent (ccIIV4), derived from cell cultures, subunit, preservative and antibiotic free, 0.5 mL dosage, for intramuscular use
90682 Influenza virus vaccine, quadrivalent (RIV4), derived from recombinant DNA, hemagglutinin (HA) protein only, preservative and antibiotic free, for intramuscular use
90685 Influenza virus vaccine, quadrivalent (IIV4), split virus, preservative free, 0.25 mL dosage, for intramuscular use
90686 Influenza virus vaccine, quadrivalent (IIV4), split virus, preservative free, 0.5 mL dosage, for intramuscular use
90687 Influenza virus vaccine, quadrivalent (IIV4), split virus, 0.25 mL dosage, for intramuscular use
90688 Influenza virus vaccine, quadrivalent (IIV4), split virus, 0.5 mL dosage, for intramuscular use
90756 Influenza virus vaccine, quadrivalent (ccIIV4), derived from cell cultures, subunit, antibiotic free, 0.5mL dosage, for intramuscular use

CPT codes not covered for indications listed in the CPB:

90660 Influenza virus vaccine, trivalent, live (LAIV3), for intranasal use
90664 Influenza virus vaccine, live (LAIV), pandemic formulation, for intranasal use

Other CPT codes related to the CPB:

87275 Infectious agent antigen detection by immunoflourescent technique; influenza B virus
87276     influenza A virus
87400 Infectious agent antigen detection by enzyme immunoassay technique, qualitative or semi quantitative, multiple step method; influenza A or B, each
90460 Immunization administration through 18 years of age via any route of administration, with counseling by physician or other qualified health care professional; first or only component of each vaccine or toxoid administered
90461     each additional vaccine or toxoid component administered (list separately in addition to code for primary procedure)
90471 Immunization administration (includes percutaneous, intradermal, subcutaneous, intramuscular injections); one vaccine (single or combination vaccine/toxoid)
+ 90472     each additional vaccine (single or combination vaccine/toxoid) (List separately in addition to code for primary procedure)
90473 Immunization administration by intranasal or oral route: one vaccine (single or combination vaccine/toxoid)
+ 90474     each additional vaccine (single or combination vaccine/toxoid) (List separately in addition to code for primary procedure)
90666 Influenza virus vaccine (IIV), pandemic formulation, split virus, preservative free, for intramuscular use
90667 Influenza virus vaccine (IIV), pandemic formulation, split virus, adjuvanted, for intramuscular use
90668 Influenza virus vaccine (IIV), pandemic formulation, split virus, for intramuscular use

HCPCS codes covered if selection criteria are met:

G0008 Administration of influenza virus vaccine
J3530 Nasal vaccine inhalation
Q2034 Influenza virus vaccine, split virus, for intramuscular use (agriflu)
Q2035 Influenza virus vaccine, split virus, when administered to individuals 3 years of age and older, for intramuscular use (Afluria)
Q2036 Influenza virus vaccine, split virus, when administered to individuals 3 years of age and older, for intramuscular use (Flulaval)
Q2037 Influenza virus vaccine, split virus, when administered to individuals 3 years of age and older, for intramuscular use (Fluvirin)
Q2038 Influenza virus vaccine, split virus, when administered to individuals 3 years of age and older, for intramuscular use (Fluzone) [also covered for Fluzone High-Dose for member's age 65 years of age or older when influenza immunization is recommended]
Q2039 Influenza virus vaccine, split virus, not otherwise specified

ICD-10 codes covered if selection criteria are met:

Z23 Encounter for immunization

The above policy is based on the following references:

  1. Bridges CB, Fukuda K, Cox NJ, et al. Prevention and control of influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2001;50(RR-4):1-44. 
  2. American Academy of Pediatrics (AAP). Red Book: 2003 Report of the Committee on Infectious Diseases. 26th ed. Elk Grove Village, IL: AAP; 2003.
  3. Ohmit SE, Arden NH, Monto AS. Effectiveness of inactivated influenza vaccine among nursing home residents during an influenza type A (H3N2) epidemic. J Am Geriatr Soc. 1999;47(2):165-171. 
  4. Minutello M, Senatore F, Cecchinelli G, et al. Safety and immunogenicity of an inactivated subunit influenza virus vaccine combined with MF59 adjuvant emulsion in elderly subjects, immunized for three consecutive influenza seasons. Vaccine. 1999;17(2):99-104. 
  5. Ottolini MG. Influenza update. Pediatr Rev. 1999;20(1):33. 
  6. Reid DW, Bromly CL, Stenton SC, et al. A double-blind placebo-controlled study of the effect of influenza vaccination on airway responsiveness in asthma. Respir Med. 1998;92(8):1010-1011. 
  7. No authors listed. Influenza vaccine, 1999-2000. Med Lett Drugs Ther. 1999;41(1061):282-283. 
  8. Gravenstein S, Drinka P, Duthie EH, et al. Efficacy of an influenza hemagglutinin-diphtheria toxoid conjugate vaccine in elderly nursing home subjects during an influenza outbreak. J Am Geriatr Soc. 1994;42:245-251. 
  9. Govaert TME, Thijs CTMCN, Masurel N, et al. The efficacy of influenza vaccination in elderly individuals: A randomized double-blind placebo-controlled trial. JAMA. 1994;272:1661-1665. 
  10. Nichol KL, Margolis KL, Wuorenma J, et al. The efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community. N Engl J Med. 1994;331:778-784. 
  11. Fedson DS, Wajda A, Nicol JP, et al. Clinical effectiveness of influenza vaccination in Manitoba. JAMA. 1993;270:1956-1961. 
  12. Foster DA, Talsma A, Furumoto-Dawson A, et al. Influenza vaccine effectiveness in preventing hospitalization for pneumonia in the elderly. Am J Epidemiol. 1992;136:296-307. 
  13. Treanor JJ, Mattison HR, Dammed G, et al. Protective efficacy of combined live intranasal and inactivated influenza A virus vaccines in the elderly. Ann Intern Med. 1992;117:625-633. 
  14. Nichol KL, Mendelman PM, Mallon KP, et al. Effectiveness of live, attenuated intranasal influenza virus vaccine in healthy, working adults: A randomized controlled trial. JAMA. 1999;282(2):137-144. 
  15. Bridges CB, Fukuda K, Uyeki TM, et al. Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2002;51(RR-3):1-31. 
  16. Wareing MD, Tannock GA. Influenza update: Vaccine development and clinical trials. Curr Opin Pulm Med. 2002;8(3):209-213. 
  17. Gomolin IH, Kathpalia RK. Influenza. How to prevent and control nursing home outbreaks. Geriatrics. 2002;57(1):28-30, 33-34. 
  18. Langley JM, Faughnan M; Canadian Task Force on Preventive Health Care (CTFPHC). Prevention of influenza in the general population: Systematic review and recommendations. CTFPHC Technical Report. London, ON: CTFPHC; 2003.
  19. Zimmerman RK, Middleton DB, Smith NJ. Vaccines for persons at high risk due to medical conditions, occupation, environment, or lifestyle, 2003. J Fam Pract. 2003;52(1 Suppl):S22-S35. 
  20. MedImmune Vaccines, Inc. and Wyeth Vaccines. FluMist influenza virus vaccine live, intranasal. Package Insert (Circular). Gaithersburg, MD: Medimmune Vaccines, Inc.; June 16, 2003.
  21. Centers for Disease Control and Prevention. Using live, attenuated influenza vaccine for prevention and control of influenza. Supplemental recommendations from the Advisory Committee on Immunization Practices. Morbid Mortal Wkly Rep. 2003;52(RR-13):1-8. 
  22. Allsup SJ, Gosney MA. Difficulties of recruitment for a randomized controlled trial involving influenza vaccination in healthy older people. Gerontology. 2002;48(3):170-173. 
  23. Centers for Disease Control and Prevention (CDC). Reasons reported by Medicare beneficiaries for not receiving influenza and pneumococcal vaccinations --- United States, 1996. MMWR Morbid Mortal Wkly Rep. 1999;48(39):886-890. 
  24. Aventis Pasteur Inc. Fluzone influenza virus vaccine USP trivalent types A and B (zonal purified, subvirion) 2001 – 2002 Formula for 6 months and older. Prescribing Information. 4558/4565.  Swiftwater, PA: Aventis; April 2001.
  25. American Academy of Pediatrics (AAP). Thimerosal in vaccines. Joint statement of the American Academy of Family Physicians (AAFP), the American Academy of Pediatrics (AAP), the Advisory Committee on Immunization Practices (ACIP) and the United States Public Health Service (PHS).  AAP Policy Statements. Elk Grove Village, IL: AAP; June 22, 2000.
  26. American Academy of Pediatrics. Joint Statement of the American Academy of Pediatrics (AAP) and the United States Public Health Service (USPHS) (RE9937). AAP Policy Statement. Pediatrics. 1999;104(3 Pt 1):568-569.
  27. American Academy of Pediatrics (AAP), Department of Community Pediatrics. Vaccine implementation information for 2003-2004. AAP Immunization Initiatives. Elk Grove Village, IL: AAP; October 1, 2003.
  28. Allsup S, Gosney M, Haycox A, Regan M. Cost-benefit evaluation of routine influenza immunisation in people 65-74 years of age. Health Technol Assess. 2003;7(24):1-78.
  29. Smith SA, Poland GA, American Diabetes Association. Immunization and the prevention of influenza and pneumococcal disease in people with diabetes. Diabetes Care. 2003;26 Suppl 1:S126-S128.
  30. Centers for Disease Control and Prevention (CDC). Interim influenza vaccination recommendations, 2004--05 influenza season. MMWR Morbid Mortal Wkly Rep. 2004;53(39):923-924.
  31. Jordan R, Wake B, Hawker J, et al. Influenza vaccination of health care workers (HCW) to reduce influenza-related outcomes in high risk patients: A systematic review of clinical and cost-effectiveness. DPHE Report No. 48. Birmingham, UK: West Midlands Health Technology Assessment Collaboration, Department of Public Health and Epidemiology, University of Birmingham (WMHTAC); 2004.
  32. Centers for Disease Control and Prevention (CDC). Tiered use of inactivated influenza vaccine in the event of a vaccine shortage. MMWR Morb Mortal Wkly Rep. 2005;54(30):749-750.
  33. Harper SA, Fukuda K, Uyeki TM, et al. Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2005;54(RR-8):1-40.
  34. Bueving HJ, Thomas S, Wouden JC. Is influenza vaccination in asthma helpful? Curr Opin Allergy Clin Immunol. 2005;5(1):65-70.
  35. Ljungman P, Nahi H, Linde A. Vaccination of patients with haematological malignancies with one or two doses of influenza vaccine: A randomised study. Br J Haematol. 2005;130(1):96-98.
  36. Centers for Disease Control and Prevention (CDC), Office of Communication. CDC’s advisory committee recommends expanded influenza vaccinations for children. Press Release. Atlanta, GA: CDC; February 23, 2006. Available at: http://www.cdc.gov/od/oc/media/pressrel/r060223.htm. Accessed March 9, 2006.
  37. Kay E, Ng K, Salmon A, Del Mar C. Influenza vaccine for preventing acute otitis media in infants and children. Cochrane Database Syst Rev. 2005;(3):CD005438.
  38. Poole PJ, Chacko E, Wood-Baker RWB, Cates CJ. Influenza vaccine for patients with chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2006;(1):CD002733.
  39. Bueving HJ. Is influenza vaccination in asthmatic children helpful? Clin Exp Allergy. 2006;36(1):21-25.
  40. Smith S, Demicheli V, Di Pietrantonj C, et al. Vaccines for preventing influenza in healthy children. Cochrane Database Syst Rev. 2006;(1):CD004879.
  41. Smith NM, Bresee JS, Shay DK, et al.; Advisory Committee on Immunization Practices.  Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006;55(RR-10):1-42.
  42. Chang CC, Morris PS, Chang AB. Influenza vaccine for children and adults with bronchiectasis. Cochrane Database Syst Rev. 2007;(3):CD006218.
  43. Jefferson T. Influenza. In: BMJ Clinical Evidence. London, UK: BMJ Publishing Group; April 2007.
  44. Loeb M. Community acquired pneumonia. In: BMJ Clinical Evidence. London, UK: BMJ Publishing Group; April 2007.
  45. Fiore AE, Shay DK, Haber P, et al; Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention (CDC). Prevention and control of influenza. Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2007. MMWR Recomm Rep. 2007;56(RR-6):1-54.
  46. U.S. Food and Drug Administration (FDA). FDA approves nasal influenza vaccine for use in younger children. FDA News. Rockville, MD: FDA; September 19, 2007.
  47. U.S. Food and Drug Administration (FDA). Additional influenza vaccine approved for upcoming influenza season. Approval increases number of available doses to record level. FDA News. Rockville, MD: FDA; September 28, 2007.
  48. Lewis EN, Griffin MR, Szilagyi PG, et al. Childhood influenza: Number needed to vaccinate to prevent 1 hospitalization or outpatient visit. Pediatrics. 2007;120(3):467-472.
  49. Kerzner B, Murray AV, Cheng E, et al. Safety and immunogenicity profile of the concomitant administration of ZOSTAVAX and inactivated influenza vaccine in adults aged 50 and older. J Am Geriatr Soc. 2007;55(10):1499-1507.
  50. Nichol KL, Nordin JD, Nelson DB, et al. Effectiveness of influenza vaccine in the community-dwelling elderly. N Engl J Med. 2007;357(14):1373-1381.
  51. Treanor JD. Influenza -- The goal of control. N Engl J Med. 2007;357(14):1439-1441.
  52. Centers for Disease Control and Prevention (CDC), Division of Media Relations. CDC's advisory committee recommends influenza vaccination for children 6 months through 18 years of age. Press Release. Atlanta, GA; CDC; February 27, 2008.
  53. 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.
  54. U.S. Food and Drug Administration (FDA). FDA Approves vaccine for 2009-2010 seasonal influenza. FDA News Release. Rockville, MD: FDA; July 20, 2009.
  55. Ciszewski A, Bilinska ZT, Brydak LB, et al. Influenza vaccination in secondary prevention from coronary ischaemic events in coronary artery disease: FLUCAD study. Eur Heart J. 2008;29(11):1350-1358.
  56. Zaman K, Roy E, Arifeen SE, et al. Effectiveness of maternal influenza immunization in mothers and infants. N Engl J Med. 2008;359(15):1555-1564.
  57. Cates CJ, Jefferson T, Rowe BH. Vaccines for preventing influenza in people with asthma. Cochrane Database Syst Rev. 2008;(2):CD000364.
  58. Keller T, Weeda VB, van Dongen CJ, Levi M. Influenza vaccines for preventing coronary heart disease. Cochrane Database Syst Rev. 2008;(3):CD005050.
  59. Jefferson T, Rivetti A, Harnden A, et al. Vaccines for preventing influenza in healthy children. Cochrane Database Syst Rev. 2008;(2):CD004879.
  60. Dharmaraj P, Smyth RL. Vaccines for preventing influenza in people with cystic fibrosis. Cochrane Database Syst Rev. 2009;(4): CD001753.
  61. Goossen GM, Kremer L, van de Wetering MD. Influenza vaccination in children being treated with chemotherapy for cancer. Cochrane Database Syst Rev. 2009;(2):CD006484.
  62. Centers for Disease Control and Prevention (CDC). Novel H1N1 vaccination recommendations. Atlanta, GA: CDC; July 30, 2009. Available at: http://www.cdc.gov/h1n1flu/vaccination/acip.htm. Accessed August 11, 2009.
  63. Fiore AE, Shay DK, Broder K, et al. Prevention and control of seasonal influenza with vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2009. MMWR Recomm Rep. 2009;58(RR-8):1-52.
  64. Centers for Disease Control and Prevention (CDC), National Center for Immunization and Respiratory Diseases. Use of influenza A (H1N1) 2009 monovalent vaccine. Recommendations of the advisory committee on immunization practices (ACIP), 2009. MMWR Morb Mortal Wkly Rep. August 21, 2009/58 (early release):1-8.
  65. U.S. Food and Drug Administration (FDA). FDA approves vaccines for 2009 H1N1 influenza virus. Approval provides important tool to fight pandemic. FDA News Release. Rockville, MD: FDA; September 15, 2009.
  66. U.S. Food and Drug Administration (FDA). FDA approves agriflu seasonal influenza vaccine. FDA News Release. Rockville, MD: FDA; November 27, 2009.
  67. U.S. Food and Drug Administration (FDA). FDA approves a high dose seasonal influenza vaccine specifically intended for people ages 65 and older. FDA News Release. Rockville, MD: FDA; December 23, 2009.
  68. Ljungman P, Cordonnier C, Einsele H, et al. Vaccination of hematopoietic cell transplant recipients. Bone Marrow Transplant. 2009;44(8):521-526.
  69. Centers for Disease Control and Prevention (CDC). Division of Media Relations. CDC's Advisory Committee on Immunization Practices (ACIP) recommends universal annual influenza vaccination.  Press Release. Atlanta, GA; CDC; February 24, 2010. 
  70. U.S. Food and Drug Administration (FDA). FDA approves vaccines for the 2010 – 2011 influenza season. FDA News. Rockville, MD: FDA; July 30, 2010.
  71. U.S. Department of Health and Human Services (HHS). H1N1 influenza public health emergency determination expired on June 23. Washington, DC: HHS; 2010. Available at: http://www.flu.gov/news/h1n1pheexpiration.html. Accessed on August 10, 2010.
  72. Centers for Disease Control and Prevention (CDC). Prevention and control of influenza with vaccines. Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. Morbid Mortal Wkly Rep. 2010;59(RR08):1-62.
  73. Pollyea DA, Brown JM, Horning SJ. Utility of influenza vaccination for oncology patients. J Clin Oncol. 2010;28(14):2481-2490.
  74. Jefferson T, Di Pietrantonj C, Rivetti A, et al. Vaccines for preventing influenza in healthy adults. Cochrane Database Syst Rev. 2010;(7):CD001269.
  75. American Academy of Pediatrics. Committee on Infectious Diseases. Policy statement -- recommendations for prevention and control of influenza in children, 2010-2011. Pediatrics. 2010;126(4):816-826.
  76. Sanofi Pasteur. 390 Fluzone® Intradermal. Prescribing Information. Swiftwater, PA: Sanofi Pasteur; May 25, 2011.
  77. Frenck RW Jr, Belshe R, Brady RC, et al. Comparison of the immunogenicity and safety of a split-virion, inactivated, trivalent influenza vaccine (Fluzone(®)) administered by intradermal and intramuscular route in healthy adults. Vaccine. 2011;29(34):5666-5674.
  78. Jefferson T, Di Pietrantonj C, Al-Ansary LA, et al. Vaccines for preventing influenza in the elderly. Cochrane Database Syst Rev. 2010;(2);CD004876.
  79. Thomas RE, Jefferson T, Lasserson TJ. Influenza vaccination for healthcare workers who work with the elderly. Cochrane Database Syst Rev. 2010:(2):CD005187.
  80. Ansaldi F, Durando P, Icardi G. Intradermal influenza vaccine and new devices: A promising chance for vaccine improvement. Expert Opin Biol Ther. 2011;11(3):415-427.
  81. Centers for Disease Control and Prevention (CDC). Prevention and control of influenza with vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2011. MMWR Morb Mortal Wkly Rep. 2011;60(33):1128-1132.
  82. Cheuk DK, Chiang AK, Lee TL, et al. Vaccines for prophylaxis of viral infections in patients with hematological malignancies. Cochrane Database Syst Rev. 2011;(3):CD006505.
  83. Martin ST, Torabi MJ, Gabardi S. Influenza in solid organ transplant recipients. Ann Pharmacother. 2012;46(2):255-264.
  84. Jefferson T, Rivetti A, Di Pietrantonj C, et al. Vaccines for preventing influenza in healthy children. Cochrane Database Syst Rev. 2012;8:CD004879.
  85. Centers for Disease Control and Prevention (CDC). Prevention and control of influenza with vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP) -- United States, 2012-13 influenza season. MMWR Morb Mortal Wkly Rep. 2012;61(32):613-618.
  86. Hibberd, PL. Seasonal influenza vaccination in adults. UpToDate. Waltham, MA: January 21, 2013.
  87. U.S. Food and Drug Administration (FDA). Highlights of prescribing information: Fluarix quadrivalent influenza virus vaccine. FDA Prescribing Information. Rockville, MD: FDA; 2012.
  88. U.S. Food and Drug Administration (FDA). FDA approves new seasonal influenza vaccine made using novel technology. FDA News Release. Rockville, MD: FDA; January 16, 2013a.
  89. Lardy B, Korba C, Slaughter N. ACIP Influenza Update and Vote. America’s Health Insurance Plans (AHIP). Washington, DC. (written communication, June 28, 2013).
  90. U.S. Food and Drug Administration (FDA). FluMist Quadrivalent. Rockville, MD: March 9, 2013b. Available at: http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm293952.htm. Accessed July 9, 2013.
  91. U.S. Food and Drug Administration (FDA). Fluzone Quadrivalent. Vaccines, Blood & Biologics. Rockville, MD: June 11, 2013c. Available at: http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm356091.htm. Accessed July 9, 2013.
  92. Marra F, Young F, Richardson K, Marra CA. A meta-analysis of intradermal versus intramuscular influenza vaccines: Immunogenicity and adverse events. Influenza Other Respir Viruses. 2013;7(4):584-603.
  93. Centers for Disease Control and Prevention (CDC). Prevention and control of seasonal influenza with vaccines. Recommendations of the Advisory Committee on Immunization Practices -- United States, 2013-2014. MMWR Recomm Rep. 2013;62(RR-07):1-43.
  94. Centers for Disease Control and Prevention (CDC). Fluzone high-dose seasonal influenza vaccine. Seasonal Influenza (Flu) Questions and Answers. Atlanta, GA: CDC; updated September 3, 2014.
  95. Committee on Obstetric Practice and Immunization Expert Work Group; Centers for Disease Control and Prevention’s Advisory Committee on Immunization, United States; American College of Obstetricians and Gynecologists.. Committee opinion no. 608: Influenza vaccination during pregnancy. Obstet Gynecol. 2014;124(3):648-651.
  96. Madhi SA, Cutland CL, Kuwanda L, et al; Maternal Flu Trial (Matflu) Team. Influenza vaccination of pregnant women and protection of their infants. N Engl J Med. 2014;371(10):918-931.
  97. Prutsky GJ, Domecq JP, Elraiyah T, et al. Assessing the evidence: Live attenuated influenza vaccine in children younger than 2 years. A systematic review. Pediatr Infect Dis J. 2014;33(4):e106-e115.
  98. Dharmaraj P, Smyth RL. Vaccines for preventing influenza in people with cystic fibrosis. Cochrane Database Syst Rev. 2014;3:CD001753.
  99. Rubin LG, Levin MJ, Ljungman P, et al. 2013 IDSA clinical practice guideline for vaccination of the immunocompromised host. Clin Infect Dis. 2014;58(3):e44-e100.
  100. Pileggi C, Lotito F, Bianco A, et al. Immunogenicity and safety of intradermal influenza vaccine in immunocompromized patients: A meta-analysis of randomized controlled trials. BMC Infect Dis. 2015;15(1):427.
  101. Remschmidt C, Wichmann O, Harder T. Vaccines for the prevention of seasonal influenza in patients with diabetes: Systematic review and meta-analysis. BMC Med. 2015;13:53.
  102. Norhayati MN, Ho JJ, Azman MY. Influenza vaccines for preventing acute otitis media in infants and children. Cochrane Database Syst Rev. 2015;3:CD010089.
  103. CDC. Media statement: Advisory Committee on Immunization Practices (ACIP) recommends a preference for using the nasal spray flu vaccine. Atlanta, GA: CDC; June 25, 2014.
  104. Afluria (influenza vaccine) Prescribing Information. Parkville, Victoria: CSL Limited; August 2014.
  105. Agriflu (influenza vaccine) Prescribing Information. Novartis Vaccines and Diagnostics Inc. Cambridge, MA. May 2015.
  106. Flublok (influenza vaccine) Prescribing Information. Protein Sciences Corporation. Meriden CT. April 2015.
  107. Flucelvax (influenza vaccine) Prescribing Information. Novartis Vaccines and Diagnostics, Inc. Cambridge, MA. May 2015.
  108. Fluarix (influenza vaccine) Prescribing Information. Research Triangle Park; Glaxo Smith Kline; 2015.
  109. Flulaval (influenza vaccine) Prescribing Information. Research Triangle Park; Glaxo Smith Kline; 2015.
  110. FluMist (influenza vaccine) Prescribing Information. Gaithersburg, MD; July 2014.
  111. Fluvirin (influenza vaccine) Prescribing Information. Liverpool, UK; February 2015.
  112. Fluzone, Fluzone High Dose, and Fluzone Intradermal (influenza vaccine) Prescribing Information. Swiftwater, PA: Sanofi Pasteur Inc.; February 2015.
  113. Fluzone Intradermal (influenza vaccine) Prescribing Information. Swiftwater, PA: Sanofi Pasteur Inc.; 2015.
  114. Grohskopf LA, Sokolow LZ, Olsen SJ, et al. Prevention and Control of Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices, United States, 2015-16 Influenza Season. MMWR Morb Mortal Wkly Rep. 2015;64(30):818-825.
  115. Flu vaccines: CDC says FluMist ‘nasal spray’ should not be used this upcoming flu season. Outbreak News Today, June 23, 2016. Available at: http://outbreaknewstoday.com/flu-vaccines-cdc-says-flumist-nasal-spray-should-not-be-used-this-upcoming-flu-season-72228/. Accessed June 23, 2016.
  116. Barnes M, Heywood AE, Mahimbo A, et al. Acute myocardial infarction and influenza: A meta-analysis of case-control studies. Heart. 2015;101(21):1738-1747.
  117. Clar C, Oseni Z, Flowers N, et al. Influenza vaccines for preventing cardiovascular disease. Cochrane Database Syst Rev. 2015;(5):CD005050.
  118. Liao Z, Tang H, Xu X, et al. Immunogenicity and safety of influenza vaccination in systemic lupus erythematosus patients compared with healthy controls: A meta-analysis. PLoS One. 2016;11(2):e0147856.
  119. Liao Z, Xu X, Liang Y, et al. Effect of a booster dose of influenza vaccine in patients with hemodialysis, peritoneal dialysis and renal transplant recipients: A systematic literature review and meta-analysis. Hum Vaccin Immunother. 2016;12(11):2909-2915.
  120. Ramsay LC, Buchan SA, Stirling RG, et al. The impact of repeated vaccination on influenza vaccine effectiveness: A systematic review and meta-analysis. BMC Med. 2017;15(1):159.
  121. Grohskopf LA, Sokolow LZ, Broder KR, et al. Prevention and control of seasonal influenza with vaccines: Recommendations of the Advisory Committee on Immunization Practices - United States, 2017-18 Influenza Season. MMWR Recomm Rep. 2017;66(2):1-20.
  122. Committee on Infectious Diseases. Recommendations for prevention and control of influenza in children, 2017 - 2018. Pediatrics. 2017;140(4).
  123. U.S. Food and Drug Administration (FDA). FDA Information Regarding FluMist Quadrivalent Vaccine. Silver Spring, MD: FDA; January 26, 2018. Available at: https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm590004.htm.
  124. Grohskopf LA, Sokolow LZ, Fry AM, et al. Update: ACIP Recommendations for the Use of Quadrivalent Live Attenuated Influenza Vaccine (LAIV4) — United States, 2018–19 Influenza Season. MMWR Morb Mortal Wkly Rep 2018;67:643–645.
  125. No authors listed. Flucelvax. Prescribing Information. Seqirus, Inc. Holly Springs, NC. April 2016. Available at: https://www.fda.gov/downloads/biologicsbloodvaccines/vaccines/approvedproducts/ucm329134.pdf. Accessed September 19, 2018
  126. Demicheli V, Jefferson T, Di Pietrantonj C, et al. Vaccines for preventing influenza in the elderly. Cochrane Database Syst Rev. 2018;2:CD004876.
  127. Bitterman R, Eliakim-Raz N, Vinograd I, et al. Influenza vaccines in immunosuppressed adults with cancer. Cochrane Database Syst Rev. 2018;2:CD008983.
  128. Grohskopf LA, Sokolow LZ, Fry AM, et al. Update: ACIP recommendations for the use of quadrivalent live attenuated influenza vaccine (LAIV4) - United States, 2018-19 influenza season. MMWR Morb Mortal Wkly Rep. 2018;67(22):643-645.
  129. Kopsaftis Z, Wood-Baker R, Poole P. Influenza vaccine for chronic obstructive pulmonary disease (COPD). Cochrane Database Syst Rev. 2018;6:CD002733.