Influenza Vaccine

Mechanism of Action

Influenza viruses express 2 types of antigens: hemagglutinin (HA) and neuraminidase (NA). Influenza A virus has 18 HA and 11 NA subtypes, and these antigens are critical for the organism's virulence. The trimeric hemagglutinin glycoprotein promotes attachment of the virus to the host cell surface, resulting in fusion and thereby releasing virions into the cytoplasm.[1] 

Differently combined HA and NA antigens are seen in influenza A, which undergo antigenic drifts and shifts resulting in antigenic variation and, thereby, the necessity for vaccine strain types to vary accordingly. Antigenic drifts are genetic changes occurring in the virus due to various actions of polymerases leading to gradual antigenic changes in both HA and NA, producing new variant strains. An antigenic shift occurs when the currently circulating virus disappears and is replaced by a new subtype with novel glycoproteins, to which antibodies against the previously circulating subtype do not cross-react.[6]

The influenza vaccine conveys immunity against the influenza virus by stimulating the production of antibodies specific to the disease. Antibodies to NA act by effectively aggregating viruses on the cell surface and reducing the amount of virus released from infected cells. Regarding the induction of immunity, the surface HA protein of the influenza virus contains 2 structural elements, head and stalk, wherein the head is the primary target of antibodies that confer protective immunity against influenza viruses.[1]

Flu shots offer protection against 3 or 4 strains of the flu virus. Trivalent flu vaccines provide protection against 2 influenza A strains, H1N1 and H3N2, and 1 influenza B strain. Quadrivalent flu vaccines protect against the same strains as the trivalent vaccine and an additional strain of influenza B.[7] 

• In the US, mainly, 3 types of influenza vaccines are available: Inactivated Influenza Vaccine (IIV), Recombinant Influenza Vaccine (RIV), and Live Attenuated Influenza Vaccine (LAIV).
• Numerals after letters indicate valency (the number of influenza viruses represented), ie, 3 for trivalent vaccines and 4 for quadrivalent vaccines.
• While prefixes are sometimes used to refer to specific IIVs: a for adjuvanted IIV (eg, aIIV4) and cc for cell culture-based IIV (eg, ccIIV4).

The mechanism of immune protection is more complicated, as while primarily humoral, cell-mediated immunity also plays an essential role in immunity to influenza. After vaccination, it takes 2 weeks to build an immune response against the flu. The effectiveness of a vaccine depends on several host factors such as age, underlying health status, genetic status, and antigenic matches between the vaccine and circulating viruses.[8]

Administration

Timing of Immunization: For most individuals requiring only 1 dose of influenza vaccine for the season, the vaccine should be administered during September or October. However, vaccination should continue as long as influenza viruses are circulating. Vaccination during July and August is not suggested for most individuals. However, an individualized case evaluation is necessary.

• For adults older than 65 years and pregnant women in the first or second trimester, vaccination during July and August is not recommended unless there is concern that subsequent vaccination might not be feasible.
• Administration in July and August can be considered in the third trimester of pregnancy.
• Children aged 6 months through 8 years requiring 2 doses should be administered the first dose as soon as possible.
• Immunization during July and August can be considered for children of any age requiring only 1 dose.

Influenza vaccine administration can vary with both the dose form and the patient's age.

Dosage Forms: Flu shots are available in several forms.[9][10][11] These include the following:

• Intramuscular vaccine 
• High-dose vaccine (age 65 years and older)
• Intradermal vaccine (age 18 to 64 years)
• Egg-free vaccine (age 4 years and older)
• Nasal spray (age 2 to 49 years)
• A needle-free vaccine as a jet injector (age 18 to 64 years)

Dosage: Approved ages and dose volume for IM influenza vaccines (IIV4s and RIV4): Determine the number of doses needed for a child based on the age, the time of the first dose of the current influenza vaccine, and the number of doses of influenza vaccine received in prior seasons.

• Age 6 months to 3 years: 0.25 ml-0.5 ml, depending on the vaccine
  • Not previously vaccinated or influenza vaccination history unknown: 2 doses, 4 weeks apart.
  • Vaccinated the previous season with 2 doses 4 weeks or more apart before July 1 of the current season: 1 dose needed                                                                                                             
• Age 3 to 8 years: 0.5 ml
  • Not previously vaccinated or influenza vaccination history unknown: 2 doses, 4 weeks apart.
  • Vaccinated the previous season with 2 doses four weeks or more apart before July 1 of the current season: 1 dose needed                                                                                                                                            
• Age 8 years: 0.5 ml;  for a child aged 8 years who needs 2 doses, both doses should be given even if the recipient turns 9 years of age between dose 1 and dose 2.                                                                               
• Age 9 years and older [12]: Single-dose; 0.5 ml                                                                                              
• Age 65 and older: Single-dose; 0.5 ml-0.7 ml, depending on the vaccine.
  • ACIP recommends that the recipient preferentially receive 1 of the higher doses (quadrivalent HD-IIV4 or quadrivalent RIV4) or adjuvanted influenza vaccine (quadrivalent aIIV4).
  • If none of these 3 options are available at an opportunity for vaccination, then any other age-appropriate influenza vaccine should be used. 

When a dose less than the necessary volume is administered in error, follow the ACIP/CDC recommendations below.

• When an error is found immediately (before the recipient has left the vaccination setting), inject the remaining additional volume needed.
• If the error is discovered after the recipient has left the vaccination setting or it is not easy to measure the remaining needed volume, inject a repeat of the full dose. A healthy, nonpregnant individual aged 2 to 49 years may alternatively be given 0.2 mL of quadrivalent Live Attenuated Influenza Vaccine (LAIV4), 0.1 mL in each nostril, using the supplied intranasal sprayer.

IIVs/RIV4: These vaccines are administered intramuscularly (IM). For adults/older children, the deltoid muscle, and for infants/younger children, the anterolateral thigh is the preferred injection site.

LAIV4: It is administered intranasally using a single-use sprayer prefilled containing 0.2 mL of vaccine. The recipient must be upright, and half of the total sprayer contents must be sprayed into the first nostril. Then, the attached divider clip is removed, and the second half of the dose is administered into the other nostril.

• Recipient sneezing immediately after administration does not warrant dose repetition.
• If a patient has nasal congestion that may interfere with the complete dose delivery to the nasopharyngeal mucosa, deferral should be considered, or another appropriate vaccine should be administered.

Pregnancy Considerations:  Quadrivalent Inactivated Influenza Vaccines (IIV4) or quadrivalent recombinant influenza vaccines (RIV4) may be administered in any trimester. LAIV4 should not be used during pregnancy but can be used postpartum.[13]

Persons with Chronic Medical Conditions: The LAIV4 vaccine is not recommended for individuals with some chronic medical conditions.

Immunocompromised Persons: Age-appropriate IIV4 or RIV4 is recommended for these individuals. LAIV4 should not be administered in these patients. Immune response might decrease or decrease in individuals on certain medications, chemotherapy, or transplant regimens. Adjusting the timing of the flu vaccine relative to a specified period before or after an intervention that compromises immunity may be appropriate. Guidance regarding the timing of vaccination in such cases is published by The Infectious Diseases Society of America (IDSA).

Caregivers and High-Risk Contacts: Any age-appropriate IIV4 or RIV4 is recommended for caregivers and high-risk contacts (including those of immunosuppressed persons). LAIV4 may be administered to caregivers/contacts of individuals not severely immunocompromised (ie, who do not require a protected environment). Healthcare personnel and hospital visitors who received LAIV4 should avoid contact with a severely immunosuppressed individual who requires a protected environment for 7 days after vaccination.

Vaccination for Travelers:

• Travelers who intend to decrease the risk of influenza should consider vaccination 2 weeks or more before departure.
• Individuals at higher risk for complications of influenza who were not vaccinated during the prior fall or winter should be considered for influenza vaccination administration before departure if planning to travel to the tropics, on cruise ships, organized tourist groups, or to the Southern Hemisphere during April-September.
• It is important to note that Southern Hemisphere influenza vaccines may differ in viral composition from Northern Hemisphere vaccine formulations.
• Immunization with the Southern Hemisphere influenza vaccine before Southern Hemisphere travel might be acceptable; however, these vaccine formulations are usually unavailable in the US.

Adverse Effects

Adverse Events:

• Injection site reactions
• Fever
• Irritability
• Drowsiness
• Myalgia
• Upper and lower respiratory symptoms, headache, and vomiting are specific to the nasal spray 

Rare effects of the influenza vaccine include allergic reactions and urticaria/anaphylaxis.[14]

Inactivated flu and pneumococcal vaccines administered simultaneously may increase the risk for febrile seizures.

Drug Interactions

Influenza antivirals can decrease the efficacy of LAIV4  if administered before or after LAIV4. Therefore, individuals who have been prescribed antivirals should be revaccinated with an age-appropriate RIV4 or IIV4. Recommendations for the use of antivirals are given below. It is important to note that the period may be prolonged in the presence of renal insufficiency, which delays the clearance of the drug.[5]

• Oseltamivir and zanamivir 48 hours before to 2 weeks following LAIV4
• Baloxavir 17 days before to 2 weeks following LAIV4
• Peramivir 5 days before to 2 weeks following LAIV4

Administration with Other Vaccines

• IIV4 and RIV4 may be administered concurrently/sequentially with other inactivated/live vaccines. However, injectable vaccines given at the same time should be administered at separate anatomic sites.
• Clinicians should refer to the latest CDC/ACIP recommendations/guidance for COVID-19 vaccines and administering influenza vaccines.
• The LAIV4 vaccine may be administered simultaneously with other live or inactivated vaccines. If not given simultaneously, administer 4 weeks or more apart between the administration of LAIV4 and another live vaccine.
• The safety and immunogenicity of simultaneous or sequential administration of 2 vaccines containing non-aluminum adjuvants have not yet been studied.

Contraindications

The following are contraindications to receiving the influenza vaccine. However, clinicians should check the prescribing information of the vaccine before administration. 

• History of severe allergic reactions (anaphylaxis) to any component of the vaccine
• Infants younger than 6 months of age

Additionally, LAIV is contraindicated in the following populations:

• Children or adolescents on concomitant aspirin/salicylate-containing medicine
• Children aged 2 to 4 years age with asthma or reported wheezing/asthma in the preceding 12 months or whose health record  notes wheezing episodes in the preceding 12 months
• Children/adults who are immunocompromised due to any cause, including but not limited to medications, anatomic asplenia, congenital or acquired immunodeficiency states, functional asplenia (eg, due to sickle-cell anemia), or HIV infection
• Close contacts/caregivers of severely immunosuppressed persons requiring a protected environment
• Pregnant women
• Individuals with active communication between the cerebrospinal fluid (CSF) and the nasopharynx, oropharynx, nose, ear, or any other cranial CSF leak
• Persons with cochlear implants (due to the potential for CSF leak)
• Administration of influenza antiviral drugs within the previous 17 days for baloxavir, 5 days for peramivir, and 48 hours for oseltamivir/zanamivir

Precautions

• Moderate/severe acute illness with or without fever• History of Guillain-Barré syndrome(GBS) within 6 weeks of receipt of influenza vaccine [15]

LAIV has additional precautions for recipients with asthma aged 5 years and older. Precautions are warranted for patients with medical conditions that might predispose them to complications from influenza (eg, cardiovascular [except isolated hypertension], chronic pulmonary, hepatic, renal, neurologic, metabolic [including diabetes mellitus], or hematologic disorders).

Egg Allergy

• Individuals who have experienced only hives after exposure to eggs may get the influenza vaccine (ie, any IIV4, RIV4, or LAIV4) appropriate for their health status and age.
• Persons reporting angioedema, respiratory distress, lightheadedness, or recurrent emesis or who require epinephrine or another emergency medical intervention may also get the influenza vaccine that is otherwise recommended. If a vaccine other than RIV4 or ccIIV4 is selected, it should be administered in an outpatient/inpatient medical setting, supervised by a clinician to recognize and manage severe allergic reactions.

Monitoring

The CDC and FDA continuously monitor vaccine safety and will inform health officials, clinicians, and the public when necessary.

The CDC uses 3 systems of vaccine safety monitoring:

1. The Vaccine Adverse Event Reporting System (VAERS): an early warning system that helps the CDC and FDA monitor problems following vaccination.  Anyone can report possible vaccine side effects to VAERS.                     
2. The Vaccine Safety Datalink (VSD): a collaborative effort between the CDC and 9 other healthcare organizations that allows ongoing monitoring and proactive searches of vaccine-related data.                            
3. The Clinical Immunization Safety Assessment (CISA) Project: a partnership between the CDC and several medical centers conducting clinical research on vaccine-associated health risks.[16]

Toxicity

The vaccine does not manifest any dose-dependent toxicity.

Despite extensive studies, no toxicity regarding carcinogenicity and infertility has been found. 

The components of the influenza vaccine are the following: 

• Formaldehyde which is used to inactivate toxins from viruses and bacteria.                                                       
• Thimerosal which safeguards against contamination and is only present in multi-dose vials.                                   
• Aluminum salts which act as adjuvants and impart a more robust immune response.                                   
• Gelatin which is present as a stabilizer.                                                                                                                
• Antibiotics, such as gentamicin or neomycin, which are present in the flu vaccine to keep bacteria from growing.

Toxicity does not exist due to the inconspicuous amounts of these components in the vaccine.[17][18]

Enhancing Healthcare Team Outcomes

Vaccination is the primary strategy for the prevention and control of influenza. Vaccination success depends upon its promotion by health professionals, including physicians, advanced care practitioners,  nurses, pharmacists, and others working as an interprofessional team. A proper understanding of the vaccine's benefits is mandatory. Discouraging vaccination for trivial reasons should be avoided. Healthcare professionals should be encouraged to be vaccinated themselves.

Physicians, advanced practitioners, nurses, and pharmacists need refined skills in assessing patient eligibility, administering vaccines, and addressing potential adverse events. Proficient injection techniques and communication skills enhance patient experience and adherence to vaccination recommendations. Developing comprehensive vaccination strategies is crucial. This includes targeted outreach to high-risk populations, effective communication campaigns, and integrating influenza vaccination into routine healthcare practices. Strategies should be adaptable to evolving recommendations and public health priorities.

Vaccinating pregnant women is advised. Influenza infection during pregnancy after vaccination tends to be less severe, and complications are reduced. It helps to protect the infant against flu during the crucial first 6 months of life as the mother passes the immune protection to her newborn.[19][3] Individual vaccination of pregnant women should be complemented by cocoon protection, achieved through the vaccination of those in close proximity. This approach provides a protective barrier, reducing the risk of influenza transmission to pregnant individuals and safeguarding maternal and fetal health.  

With all 50 states in the US permitting pharmacists to administer influenza vaccines, patient access to the vaccine has never been more available. Pharmacists must coordinate their efforts with other interprofessional healthcare team members to ensure patients are appropriate candidates for the vaccine and that the patient's vaccine record is updated so that all team members benefit from the same patient data. Interprofessional collaboration ensures shared understanding, coordinated efforts, and efficient information exchange, ultimately benefiting patient care and safety. 

The real scientific challenge in the primary strategy for preventing and controlling the influenza virus is antigenic drifts and shifts. Annual vaccination is the current recommendation due to waning immunity. A universal influenza vaccine is undergoing trials and serves the purpose of building a single vaccine that targets all virus strains, which will, in turn, minimize the need for frequent vaccination.[20][21] Pursuing a universal flu vaccine promises to provide lasting and comprehensive protection against diverse influenza strains, potentially revolutionizing global influenza prevention efforts.