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Where to Get Your Flu Vaccination

Some years the flu season can be much more aggressive than others. As soon as one person has it, it seems everyone is coming down with it. Dry coughs can be heard everywhere, complaints of aching muscles and tiredness increase and germs are spreading like wildfire. One way to make sure you don’t fall victim to this illness is by scheduling an appointment for your annual flu vaccination. Here are the different recommended flu dosages, potential side effects from the vaccination and various places where these are administered, such as flu shot clinics and workplaces.

Dosage for Children

It is important that flu shots are given in the correct dosage, which varies depending on age. The Center for Disease Control and Prevention (CDC) recommends that those as young as six months receiving the vaccination and any child between six months and eight years that has never received the influenza vaccination or hasn’t received two doses before July 1, 2016, should be administered two doses in the same season at least four weeks apart.

Those six to 35 months should receive:

.25 mL for Fluzone Quadrivalent
Five mL for FluLaval Quadrivalent

Any child three years and older should receive five mL for all inactivated influenza vaccine products.

Side Effect of Regular Dosage

As with any vaccination, there is a chance of side effects. Common flu shot side effects include anything from soreness and swelling where the shot was administered to nausea and fever. These would usually start appearing within minutes to a few hours after receiving the vaccination. If you start seeing severe allergic reactions such as hives, paleness, difficulty breathing and wheezing, call 9-1-1 immediately.

Dosage for 65+

Fluzone High Dose is specifically aimed at those who are 65 and older. Those in this age category tend to have weaker immune defenses which increase their risk of coming down with the illness and making it much more difficult to recover from. With a higher dosage, the chances that the immune system will respond to the vaccine increases. A study published in the New England Journal of Medicine noted that the high-dose vaccine was 24.2% more effective relative to standard–dose vaccine in those 65 and older.

Side Effects of High Dose

Similar to the regular flu vaccination dosage, a high dose may also lead to side effects. While they are rare, they are usually only mild and temporary. These effects may be muscle aches, headaches and malaise. It is important to note that this high dosage is not recommended to anyone who has a previous record of having a severe reaction to this vaccine.

Where to Get Flu Shots

If you have not received your flu vaccination yet, it is never too late. Flu shots are administered in numerous locations spread out around towns and cities. Www.vaccinefinder.org is a great flu shot location locator that will also search clinics based on what type of vaccination you need and how far you are willing to travel.

The price will vary depending on where you get the shot and what type of insurance coverage you have. If you do not have a regular doctor head to your local clinic, any of the major pharmacies or, for students, your local college health center.

Finding Free Flu Clinics

Those that don’t have medical insurance or a large family can visit a free or low-cost clinic. Check online for the Health and Human Services Office near you.

In every state, there is a high chance that a few clinics or organizations offer shots for little or no cost to the local community. For example, free flu shots happen in St Louis, Missouri, specifically near Barnes Jewish Hospital. For the past 14 years, they have been offering this to their local community. In 2016 they vaccinated over 20,000 people at their clinics. There are also free flu shots in Albuquerque, New Mexico thanks to a Presbyterian Medical group.

Company Flu Shots

Some employers also hire companies that offer on-site flu clinics. This is both convenient for employees as they don’t have to schedule a separate flu vaccination appointment elsewhere, and ideal for the employer as, in theory, there shouldn’t be as many sick days taken by employees.

StatPearls [Internet].

Influenza vaccine.

Saieda M. Kalarikkal ; Gayatri B. Jaishankar .

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Last Update: March 30, 2023 .

Continuing Education Activity

Influenza viruses belong to the Orthomyxoviridae RNA virus family and classify into three distinct types based on their major antigenic differences; influenza A, influenza B, and influenza C. Influenza viruses cause annual human epidemics, seasonal and pandemics. Seasonal influenza epidemics caused by influenza A and B viruses result in 3 to 5 million severe cases and thousands of deaths globally yearly. The influenza A virus will cause epidemics and pandemics because of its spread from migrating birds, pigs, horses, and humans. Transmission can be human to human from fomites, coughing, and sneezing. Influenza B causes only human-to-human spread with a particular emphasis on the fact that no other hosts are involved, therefore, not involved in pandemics. Influenza C is a mild disease. This activity describes the mode of action of influenza vaccine, including modes of administration, formulations, adverse event profiles, eligible patient populations, and monitoring, and highlights the role of the interprofessional team in the management of these patients.

Identify the types of influenza viruses requiring vaccinations.
Summarize the absolute and relative contraindications of the vaccine.
Review the methods of administering influenza vaccination and eligible patients for each type of vaccine.
Explain interprofessional team strategies for improving care coordination and communication to advance influenza vaccination and improve patient outcomes.
Indications

Influenza viruses belong to the Orthomyxoviridae RNA virus family and classify into three distinct types based on their significant antigenic differences; influenza A, influenza B, and influenza C. Influenza viruses cause annual human epidemics, seasonal and pandemics. Seasonal influenza epidemics caused by influenza A and B viruses result in 3 to 5 million severe cases and thousands of deaths globally yearly. Influenza pandemics caused by the influenza A virus emerge at unpredictable intervals. The influenza A virus will cause epidemics and pandemics because of its spread from migrating birds, pigs, horses, and humans. Transmission can be human to human from fomites, coughing, and sneezing. Pandemics are responsible for increased morbidity and mortality compared with seasonal influenza. Four such pandemics have occurred in the past century, 1918, 1957, 1968, and 2009. Influenza B causes only human-to-human spread with a particular emphasis on the fact that no other hosts are involved, therefore, not involved in pandemics. Influenza C is a mild disease. [1] It causes seasonal influenza episodes, such as Northern infections from September to March, while Southern infections occur from May to September. Due to the variation in viruses responsible for infections in these two seasons, it requires two different sets of vaccines. Influenza generally has an incubation period of 2 days, ranging from 1 to 4 days.

FDA-approved Indications for Influenza Vaccines

Prevention of Influenza A in persons aged six months and above
Prevention of Influenza B in persons aged six months and above

The Centers for Disease Control and Prevention (CDC) recommends administering an annual influenza vaccine for all persons older than six months of age who don't have contraindications. Influenza vaccination is the most effective method for preventing and controlling influenza. It is most effective in children over two years old and healthy adults. The efficacy of the seasonal influenza vaccine ranges between 10% and 60%. The lowest efficacy occurs when vaccine strains are not well-matched to circulating strains. Both the trivalent and quadrivalent vaccines are FDA approved. [2]

Regarding immunization in pregnancy, a randomized controlled trial conducted in South Africa has shown that when pregnant women receive the influenza vaccine, it halves their risk of developing influenza while reducing the risk of their infants (up to 24 weeks) contracting the illness. [3]

Data shows the trivalent influenza vaccine provides protection in HIV-infected adults without severe immunosuppression, while the effectiveness in HIV-infected children aged <5 years is somewhat uncertain. In certain groups, including the elderly, immune-compromised individuals, and infants, the influenza vaccine is less effective, but it is beneficial by reducing the incidence of severe diseases, like bronchopneumonia, and reduces hospital admission and mortality. [4]

According to Advisory Committee on Immunization Practices (ACIP) and CDC, routine annual influenza vaccination is suggested for all individuals aged ≥6 months who do not have contraindications.

Indications for vaccination

All children aged 6 through 59 months.
All adults ≥50 years.
Children and adults with chronic pulmonary disease (including asthma), cardiovascular disease (excluding isolated hypertension), renal, hepatic, neurologic, hematologic, or diabetes mellitus.
Patients who are immunocompromised (by medications or HIV infection).
Children and adolescents (6 months to 18 years) who are given aspirin- or medications containing salicylates which increases the risk of developing Reye syndrome after influenza virus infection.
Nursing homes residents and residents of long-term facilities.
Alaska native individuals or American Indian individuals
Individuals with obesity (BMI ≥40 for adults) [5]

COVID-19 Considerations:

Individuals in isolation for COVID-19 or quarantine for suspected exposures should not be vaccinated if vaccination may pose an exposure risk to others.
For patients who are moderate to severely ill due to COVID-19, vaccination should be postponed until patients have recovered.
For patients who are mildly ill or asymptomatic, postponement is suggested to avoid confusing COVID-19 symptoms with postvaccination reactions.
Mechanism of Action

Influenza viruses express two 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 acts by promoting attachment of the virus to the host cell surface resulting in fusion and thereby releasing virions into the cytoplasm. [1]

Differently combined H and N antigens are seen in influenza A, which in turn 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 two 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 three or four strains of the flu virus. Trivalent flu vaccines provide protection against two influenza A strains, H1N1 and H3N2, and one influenza B strain. Quadrivalent flu vaccines protect against the same strains as the trivalent vaccine as well as an additional strain of influenza B. [7]

In the US, mainly, three 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), i.e., 3 for trivalent vaccines and 4 for quadrivalent vaccines.
While prefixes are sometimes used to refer to specific IIVs: a for adjuvanted IIV (e.g., aIIV4) and cc for cell culture-based IIV (e.g., 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 two weeks to build up 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 one 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 (age ≥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 6 months through 8 years requiring two 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 one 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 (> 65 years)
Intradermal vaccine (18 to 64years)
Egg-free vaccine (>4 years)
Nasal spray (2 to 49 years)
A needle-free vaccine as a jet injector (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 2022–23 influenza vaccine, and the number of doses of influenza vaccine received in prior seasons.

Not previously vaccinated/ influenza vaccination history unknown: 2 doses, four weeks apart.
Vaccinated the previous season with two doses four weeks or more apart before July 1, 2022: one dose needed
Not previously vaccinated/influenza vaccination history unknown: 2 doses, four weeks apart.
Age 8 years: 0.5 ml; For a child aged eight years who needs two doses, both doses should be given even if the recipient turns age nine years between dose one and dose two.
Age 9 years and above [12] : Single-dose; 0.5 ml
Age 65 and above Sinle-dose; 0.5 ml - 0.7 ml depending on the vaccine. ACIP recommends that the recipient preferentially receive one of the higher doses (quadrivalent HD-IIV4 or quadrivalent RIV4) or adjuvanted influenza vaccine (quadrivalent aIIV4). If none of these three 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 below ACIP/CDC recommendations.

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 isn't easy to measure the remaining needed volume, inject a repeat of the full dose. A healthy, non-pregnant individual aged 2 to 49 years may alternatively be given 0.2 mL of 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 site for injection.

LAIV4: It is administered intranasally using a single-use sprayer attached to the supplied 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 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 delivery of the content 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. Live Attenuated Influenza Vaccine (LAIV4) should not be used during pregnancy but can be used postpartum. [13]

Persons with Chronic Medical Conditions: 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 be decreased or minimal in individuals on certain medications, chemotherapy, or transplant regimens. Timing of flu vaccine is relative to a specified period before or after an intervention that compromises immunity may be appropriate. Guidance is published by The Infectious Diseases Society of America (IDSA) regarding the timing of vaccination in such cases.

Care Givers and High-Risk Contacts: Any age-appropriate IIV4 or RIV4 is recommended for caregivers and contacts (including those of immunosuppressed persons). LAIV4 may be administered to caregivers/contacts of individuals who are not severely immunocompromised (i.e., who don't require a protected environment). Healthcare personnel/hospital visitors who received LAIV4 should avoid contact with/caring for a severely immunosuppressed individual who requires a protected environment for seven days after vaccination.

Vaccination for Travelers

Travelers who intend to decrease the risk for influenza should consider vaccination≥2 weeks 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 U.S.
Adverse Effects

Adverse events associated with the influenza vaccine include the following:

Injection site reactions
Irritability
Upper respiratory symptoms
Fever, headache, vomiting
Lower respiratory symptoms
Allergic reaction
Urticaria/anaphylaxis [14]
Inactivated flu vaccine and pneumococcal vaccine administered at the same time may show an increased risk for febrile seizures.

Drug Interactions

Influenza antivirals can decrease the efficacy of LAIV4 (Quadrivalent Live Attenuated Influenza Vaccine) 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 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

IIV4s 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.
LAIV4 vaccine may be administered simultaneously with other live or inactivated vaccines. If not given simultaneously, administer ≥4 weeks apart between the administration of LAIV4 and another live vaccine.
The safety and immunogenicity of simultaneous or sequential administration of two 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 less than six months of age

Additionally, LAIV is contraindicated in the following population.

Concomitant aspirin/salicylate-containing medicine in children/adolescents
Children aged 2-4 years age with asthma or reported wheezing/asthma in the preceding 12 months or whose health record of 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 (e.g., due to sickle-cell anemia), or HIV infection
Close contacts/caregivers of severely immunosuppressed persons requiring a protected environment
Individuals with active communication between the CSF and the nasopharynx, oropharynx, nose, ear, or any other cranial CSF leak
Persons with cochlear implants (because of the potential for CSF leak)
Administration of influenza antiviral drugs within the previous 17 days for baloxavir, five 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 six weeks of receipt of influenza vaccine. [15]

LAIV has additional precautions for recipients with asthma aged five years and older. Precautions are warranted for patients with medical conditions that might predispose them to complications from influenza (e.g., 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 an influenza vaccine (i.e., 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 an 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.

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

CDC uses three systems of vaccine safety monitoring:

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

The vaccine does not manifest any dose-dependent toxicity.

The toxicity regarding carcinogenicity and infertility has undergone extensive study and has been shown to be negative.

The components of the influenza vaccine are:

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

Toxicity due to the components of the vaccine is not present due to the inconspicuous amounts present in the vaccine. [17] [18]

Enhancing Healthcare Team Outcomes

Vaccination is the primary strategy for the prevention and control of influenza. The success of the vaccination depends upon the promotion by the health workers, including clinicians (MDs, DOs, NPs, PAs), nurses, pharmacists, and other health care professionals operating as an interprofessional team. A proper understanding of the vaccine's benefits is mandatory. Discouraging vaccination for trivial reasons should be avoided. Encourage health professionals at risk to vaccinate themselves.

Pregnant women should be protected by individual vaccination by cocoon protection by vaccinating the surrounding people. Vaccinating pregnant women is preferable. Influenza infection after vaccination tends to be less severe, and complications are also reduced. And it helps to protect the baby against flu during the crucial first six months of life as the mother passes the immune protection to her newborn. [19] [3]

With all 50 states in the USA permitting pharmacists to administer influenza vaccines, patient access to the vaccine has never been more prevalent or easy to obtain. Pharmacists must coordinate their efforts with other interprofessional healthcare team members to ensure patients are appropriate candidates for receiving the vaccine and that the patient's vaccine record is updated so that all team members operate from the same patient data. This information sharing is one example of how interprofessional teamwork can enhance patient outcomes and minimize adverse events. [Level 5]

The real 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 strains of the virus; this will, in turn, minimize the need for frequent vaccination and be the bright future of this vaccination. [20] [21]

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Disclosure: Saieda Kalarikkal declares no relevant financial relationships with ineligible companies.

Disclosure: Gayatri Jaishankar declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

Cite this Page Kalarikkal SM, Jaishankar GB. Influenza Vaccine. [Updated 2023 Mar 30]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.

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Article Contents

Influenza vaccine development—a global achievement, correlates of protection, currently available influenza vaccines, approaches to improve influenza vaccines, conclusions.

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Influenza Vaccines: Successes and Continuing Challenges

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Tanja Becker, Husni Elbahesh, Leslie A Reperant, Guus F Rimmelzwaan, Albert D M E Osterhaus, Influenza Vaccines: Successes and Continuing Challenges, The Journal of Infectious Diseases , Volume 224, Issue Supplement_4, 1 October 2021, Pages S405–S419, https://doi.org/10.1093/infdis/jiab269

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Influenza vaccines have been available for over 80 years. They have contributed to significant reductions in influenza morbidity and mortality. However, there have been limitations in their effectiveness, in part due to the continuous antigenic evolution of seasonal influenza viruses, but also due to the predominant use of embryonated chicken eggs for their production. The latter furthermore limits their worldwide production timelines and scale. Therefore today, alternative approaches for their design and production are increasingly pursued, with already licensed quadrivalent seasonal influenza vaccines produced in cell cultures, including based on a baculovirus expression system. Next-generation influenza vaccines aim at inducing broader and longer-lasting immune responses to overcome seasonal influenza virus antigenic drift and to timely address the emergence of a new pandemic influenza virus. Tailored approaches target mechanisms to improve vaccine-induced immune responses in individuals with a weakened immune system, in particular older adults.

Influenza viruses have been recognized as the causative agents of significant respiratory infections in humans for centuries, with recorded pandemics being described as early as the 16th century [ 1 ]. Over the last century, yearly epidemics and several pandemics that result in heavy health, societal, and economic burdens have highlighted the significant global impact of influenza viruses. Annual epidemics of seasonal influenza result in the deaths of between 291 000 and 645 000 people [ 2 ]. An estimated 3–5 million people suffer from severe respiratory disease caused by seasonal influenza viruses every year. Absenteeism and socioeconomic consequences of the yearly epidemics further cause nonnegligible productivity losses and strain health care capacity.

Influenza viruses are members of the Orthomyxoviridae family. These are enveloped RNA viruses with a segmented genome of 8 single-stranded negative-sense RNA segments. These encode the envelope glycoproteins hemagglutinin (HA) and neuraminidase (NA), the nucleoprotein (NP), the matrix protein (M1) and ion channel protein (M2), the polymerase subunits (PA, PB1, and PB2), the nonstructural protein (NS1), the nuclear export protein (NEP), and the more recently discovered PB1-F2, PB1 N40, PA-X, and M42 proteins [ 3 ]. While influenza B viruses are found in humans only, with some indications of spill-over to pigs and seals [ 4 ], influenza A viruses have a wide distribution in the animal kingdom, with their natural reservoirs in wild water birds. Avian influenza A viruses are classified into subtypes based on their surface glycoproteins, HA and NA. 16 HA and 9 NA subtypes have been identified in avian species and an additional 2 HA and 2 NA subtypes have been recently discovered in bats. Avian influenza viruses from wild birds may sporadically cross the species barrier to domesticated birds and mammals, like poultry, pigs, horses, and dogs. In these species they may become established pathogens. In poultry, such adapted viruses are classified by their pathogenicity in chickens into high- and low-pathogenicity avian influenza viruses (HPAIV and LPAIV, respectively; for review see [ 5 ]).

Zoonotic infections from domestic pigs and poultry have caused numerous human influenza cases, which usually are not or only poorly transmissible between humans. Human infections with H5 HPAIV, H7 LPAIV, H7 HPAIV, and H9 LPAIV of poultry have caused many cases of influenza with high fatality rates in recent years. The further adaptation of these viruses to replication in, and transmission among, humans may lead to the eventual development of a pandemic virus. Four influenza pandemics have emerged in the past century, causing the Spanish flu (1918, H1N1), the Asian flu (1957, H2N2), the Hong Kong flu (1968, H3N2), and the swine-origin flu pandemic of 2009 (H1N1/09). Although these viruses eventually have all originated from wild avian reservoirs, new genetically reassorted viruses typically emerged in domestic pigs and poultry, before initiating pandemics in humans.

Upon their introduction, pandemic viruses can spread rapidly and circulate among a virtually naive and susceptible human population that has not been previously exposed to an antigenically similar influenza A virus, often resulting in devastating morbidity and mortality. Collectively, the 4 pandemics of the last century have resulted in more than 50 million human fatalities. These pandemic viruses all have continued to circulate after their respective pandemics were over and typically replaced one of the previously circulating seasonal influenza A viruses. The new seasonal influenza viruses gradually drift genetically and antigenically, escaping from antibody-mediated virus neutralizing immunity that builds up in the population upon their annual reappearance. The virus neutralizing immunity that drives seasonal influenza genetic and antigenic drift appears predominantly directed against the globular head of the virus HA protein. As a result, this glycoprotein continuously accumulates mutations that eventually affect recognition by the existing neutralizing antibody landscape across the population. The continuous antigenic drift of seasonal influenza viruses requires regular updates of seasonal influenza vaccines in order to correctly match the circulating viruses [ 6 ].

In the interpandemic periods, annual seasonal influenza epidemics, which typically occur in and around winter months in temperate climate zones, collectively have resulted in at least an equivalent number of fatal cases as the 4 past pandemics combined. Severe seasonal influenza infections and complications mainly occur in the so-called high-risk groups, such as older adults, people with chronic disease or impaired immunity, pregnant women, and young children. Therefore, these groups are the first targets of annual influenza vaccination programs, as advised by the World Health Organization (WHO) as well as national and regional public health agencies, such as the US Center for Disease Control and Prevention (CDC), although their response to vaccination is often suboptimal. Because of their contacts with high-risk groups, health care workers also are advised to be annually vaccinated against seasonal influenza.

An estimated 2%–10% of vaccinated, healthy individuals do not produce adequate levels of antibodies following vaccination [ 7 ]. This may be due to their genetic characteristics (eg, human leukocyte antigen [HLA] type or single-nucleotide polymorphisms) [ 8 ] or to the state of their immune system. In apparently healthy vaccinees, the immune response to vaccination can be influenced negatively by lifestyle (eg, stress, nutritional deficiency, or obesity [ 9–15 ]), previous contact with closely related viruses [ 16 ] or age-related changes of the immune system (immunosenescence [ 17–20 ]). Changes in the immune system induced by comorbidities (eg, diabetes), immunosuppression, or medication can further weaken the immune response to vaccination. High-risk group populations are increasing as society ages, diseases of affluence rise, and people with chronic diseases live longer due to better health care, particularly in developed countries. These individuals not only have an increased risk of vaccination failure but also face worse disease outcomes in the event of vaccination failure. Vaccine improvements for these risk groups are therefore direly needed.

Nevertheless, vaccination is the most cost-effective way to prevent influenza virus infections. Until recently, all influenza vaccines were generated in embryonated chicken eggs, based on a technology that was developed in the middle of the 20th century. Although this proved to be a quite efficient method to produce high virus concentrations, it has shown major shortcomings calling for new generation influenza vaccines. Currently available seasonal influenza vaccines are egg- and cell-based inactivated influenza vaccines (IIVs), a live attenuated influenza vaccine (LAIV), and a baculovirus recombinant HA vaccine that is produced in insect cells ( Table 1 ). The development of universal influenza vaccines that would provide both a broad and a long-lasting protection against preferably all circulating and emerging influenza A and B subtypes and variants, including pandemic viruses, with robust responses also induced in high-risk groups, is one of the greatest challenges of modern vaccinology. These will undeniably benefit from current and emerging knowledge of correlates of protection against influenza and of the broad spectrum of novel technologies and technology platforms that are currently used and explored in modern vaccine development, including as part of ongoing responses against the COVID-19 pandemic.

Overview of Currently Used Vaccine Types on the US and European Market

Adapted and modified from [ 21 , 22 ].

Abbreviations: FFU, fluorescent focus units; HA, hemagglutinin.

a Recommended for people aged ≥ 65 years.

The history of influenza vaccination is a success story that started almost a century ago ( Figure 1 ). The first influenza vaccines were a monovalent inactivated influenza A vaccine produced in embryonated chicken eggs and a live-attenuated vaccine in the mid-1930s [ 30 , 31 ], only a few years after the first isolations of influenza viruses from pigs and humans, respectively [ 32 , 33 ]. Influenza B virus was discovered in 1940. The first bivalent vaccine containing 1 influenza A and 1 influenza B strain and was produced and tested by the US army from 1942 onward. It became available for the general population in the United States by 1945. Split and subunit vaccines were subsequently developed beginning in the 1960s. Trivalent vaccines, incorporating 2 influenza A subtypes and 1 influenza B strain, became available in 1978. It was not until 2012 that the first quadrivalent vaccines incorporating 2 influenza A subtypes and 2 influenza B strains was approved by the US Food and Drug Administration (FDA). In the following year, the first recombinant HA vaccine expressed by insect cells was licensed in the United States (for a detailed review of the history of influenza vaccination see [ 23 , 24 ]). The 2009 H1N1 influenza pandemic was the first pandemic for which a specific pandemic influenza vaccine became globally available. Although it came late for the southern hemisphere, the pandemic vaccine was shown to effectively prevent laboratory-confirmed influenza, related hospitalization, and mortality in the northern hemisphere [ 34 ]. Likewise, annual vaccination of the general population and especially of high-risk groups with seasonal vaccines, before the start of the influenza season, has been shown to considerably reduce morbidity, mortality, and economic losses associated with influenza [ 35 ]. Economic losses averted by influenza vaccination are related to reduced health care costs and maintained productivity (eg, [ 36 ]). As a recent example, the CDC estimated for the United States the prevention of an estimated 7.52 million illnesses, 3.69 million medical visits, 105 000 hospitalizations, and 6300 deaths due to influenza, by influenza vaccination during the 2019–2020 season [ 37 ]. Besides direct protective effects of influenza vaccination in the vaccinees, indirect effects in other members of the community may be observed due to reduced virus circulation. For example, a governmental vaccination program for schoolchildren in Japan from 1962 to 1994 was linked to a drop of excess mortality associated with influenza and pneumonia in the elderly, which was not observed after the program was discontinued. The vaccination coverage in adults was reported lower than in children, indicating an indirect protective effect of the vaccination of children on the health of the elderly [ 38 ]. The effectiveness of influenza vaccination in older adults is lower than that in younger adults [ 39 , 40 ]. The efficacy and effectiveness in the elderly was even initially questioned by a Cochrane meta-analysis ([ 41 ]; updated version available [ 42 ]). However, methodologically adjusted meta-analysis resulted in values ranging from 30% to 50% vaccine effectiveness, largely depending on the age of the vaccinees and the matching of the vaccine strains with the circulating influenza viruses [ 43 ]. Furthermore, less severe disease is typically reported in vaccinated patients than in nonvaccinated patients hospitalized with laboratory-confirmed influenza [ 44 ]. Interestingly, influenza vaccination may reduce the impact of other respiratory infections, which can occur as coinfections during influenza, as well as counter the rise of antimicrobial resistance [ 45 ]. Maintaining or increasing influenza vaccination coverage during the currently ongoing COVID-19 pandemic has been recommended by public health agencies to prevent additional seasonal influenza burden on the highly strained health care systems. However, both excess mortality data and viral surveillance have revealed limited cases of other respiratory infections, and in particular influenza, during the COVID-19 pandemic compared to previous seasons [ 46 , 47 ]. The limited circulation of seasonal influenza viruses may be mainly due to the set of nonpharmaceutical public health interventions deployed in most countries since the beginning of the pandemic (eg, increased hygiene measures, face masks, social distancing, and contact reduction). While the effectiveness of such measures against both severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza virus infections is undeniable, their implementation is temporary due to considerable social and economic consequences. Effective vaccination remains the preventive measure of choice against influenza.

Timeline of influenza vaccine history [ 23–29 ]. Abbreviations: IAV, influenza A virus; IIV, inactivated influenza vaccine; LAIV, live attenuated influenza vaccine; WHO, World Health Organization.

Remarkable advances in our understanding of the correlates of immune protection against influenza increasingly point towards the possible development of improved and more broadly protective vaccines against seasonal and pandemic influenza. In addition to animal and cell culture-based models of influenza, human challenge studies have made significant contributions to the identification of correlates of protection (see eg, [ 48 ]). A number of these high-profile induced immunity targets ( Figure 2 ) are actively pursued in current cutting-edge influenza vaccine research and development efforts around the world.

Major immunogens of influenza virus. Abbreviations: AB, antibody; bnAB, broadly neutralizing antibody; HA, hemagglutinin; M, matrix protein; NA, neuraminidase; NP, nucleoprotein; P, polymerase; RNP, ribonucleoprotein. Adapted from [ 49 , 50 ] and created with BioRender.com.

Neutralizing HA-Specific Antibodies

It is generally accepted that antibodies directed against the globular head domain of the influenza virus HA are a major correlate of protection. The HA is the viral receptor binding protein allowing attachment of virus particles to cellular targets, before endocytosis, fusion of viral and cellular membranes, and actual infection occur. Antibodies directed to epitopes located in or in close proximity to the receptor-binding site (RBD) can prevent binding of the virus to its receptor, thereby neutralizing the virus before cellular infection takes place. When serum titers of virus strain-specific HA antibodies, induced by vaccination or infection, are high enough, they protect subjects from subsequent (re)infection. The protective effect of virus-neutralizing HA-specific antibodies has been demonstrated both in experimentally infected animals and humans [ 51 ]. The induction of HA-specific antibodies is used as a surrogate of vaccine efficacy. Seasonal influenza vaccines are registered every year provided they fulfill the minimal requirements of national or regional medicine agencies (like the FDA or the European Medicines Agency) on the serological outcome of vaccination and potency of the vaccine (with >15 µg HA per vaccine strain). Most commonly, the serological outcome of vaccination is measured with the hemagglutination inhibition (HI) assay, which is a validated proxy for virus neutralization.

For optimal vaccine efficacy, it is essential that the vaccine strains antigenically match the epidemic strains closely. Because the HA of seasonal influenza virus strains undergo continuous antigenic drift, seasonal influenza viruses eventually evolve to escape from recognition by virus-neutralizing antibodies, necessitating the update of the vaccine strains almost annually [ 6 , 52 ].

NA-Specific Antibodies

The NA is the other major viral envelope protein and functions as a receptor-destroying enzyme, which is crucial for efficient release of virus from infected cells during the last stages of the virus replication cycle. Antibodies directed against the enzymatic site of NA can block its function and can contribute to protective immunity. This has been demonstrated in various in vitro and in vivo systems [ 53–62 ]. In contrast to HA-specific antibodies, NA-specific antibodies cannot prevent infection, but limit the release and further spread of virus from infected cells, and thus improve the clinical outcome of the infection. It is of interest to note that NA-specific antibodies tend to be more cross-reactive than antibodies specific for the HA head domain [ 63 , 64 ], although NA also displays antigenic drift [ 65 , 66 ]. The enzyme-linked lectin assay has emerged as a suitable assay for the detection of NA-specific serum antibodies and the antigenic characterization of NA [ 65 , 67 ].

Other Non-HI Broadly Reactive Antibodies

Other antibodies that may contribute to broadly protective immunity include those directed against conserved proteins like M2 [ 68 ], NP, NA [ 69–71 ], and the stalk region of HA [ 72 , 73 ], which have therefore been considered as potential (universal) influenza vaccine antigens.

The M2 protein is a minor antigen on virus particles but is abundantly expressed on virus-infected cells. Compared to HA and NA, M2 is poorly immunogenic because antisera raised against the virus typically contain few M2-specific antibodies. The protective effect of M2-specific antibodies has been demonstrated after hyperimmunization and passive administration of these antibodies in animal models [ 68 ] and was shown to be dependent on Fcγ receptors [ 74 ]. This indicates that antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells or neutrophils, or antibody-dependent phagocytosis by macrophages likely play a role in conferred protection [ 74 , 75 ].

A protective effect of NP-specific antibodies has been demonstrated in mice [ 76 , 77 ], although the underlying mechanism remains unclear. The effect was dependent on Fc receptors and CD8 + T cells. Therefore, it has been suggested that formation of NP immune complexes and opsonization play a role in protection [ 76 , 77 ], although this could not be confirmed in vitro [ 78 ].

The identification of virus-neutralizing antibodies directed to the stalk region of the trimeric HA molecule, has attracted a lot of attention [ 72 ], because compared to the variable head domain, the stalk region is relatively conserved, opening avenues for strong and broader immune responses. In contrast to virus-neutralizing antibodies specific for the head domain, which defines HA’s antigenic properties and contains the RBD, stalk-specific antibodies fail to inhibit agglutination of erythrocytes and are therefore referred to as non-HI antibodies. Alternative mechanisms independent of blocking receptor binding account for their protective effect. These include preventing HA conformational changes in the endosomes and subsequent fusion of the virus membrane with the endosomal membrane, thus preventing release of the viral genome into the cytosol [ 79 ], effects on virus egress from infected cells [ 80 ], and interference with HA maturation by preventing its cleavage by host proteases [ 72 ]. Interactions between the Fc region of broadly neutralizing HA stalk-specific antibodies and Fcγ receptors were found to be essential in protecting mice from lethal influenza virus challenge. This suggests that ADCC by HA stalk-specific antibodies contributed to protection [ 81 ]. The development of standardized assays for the detection and quantification of unconventional non-HI antibodies is essential and the subject of an active area of research, in order to determine minimal antibody titers required for protection and compare potency between studies.

Mucosal Antibodies IgA

The production of polymeric immunoglobulin A (pIgA) and the subsequent transcytosis across the epithelium after binding to the polymeric Ig receptor (pIgR) yields secretory IgA (sIgA), a complex consisting of dimeric IgA and the secretory component, which is a cleavage product of the pIgR [ 82 ].

sIgA is more efficient than IgG or monomeric IgA for inhibiting influenza virus entry [ 83 ]. Most vaccines are subunit, split virion, or whole inactivated preparations that are administered intramuscularly. These vaccines induce good serum antibody responses but limited local mucosal antibody responses. In contrast, the use of live attenuated vaccines, which are administered topically, induces efficient virus-specific IgA responses, but possibly more limited serum antibody responses. While the clinical effectiveness of both types of vaccines is similar, the immune correlates of protection differ [ 84 ].

Virus-Specific T Cells

It has been demonstrated in various animal models, including mice [ 85–88 ] and nonhuman primates [ 89 ], that virus-specific T lymphocytes, in particular CD8 + T cells, are an important correlate of protection against influenza virus infections and contribute to heterosubtypic immunity (reviewed in [ 88 ]). Because the majority of virus-specific CD8 + cytotoxic T lymphocytes (CTL) recognize conserved internal proteins, like NP and M1 [ 90 , 91 ], they are highly cross-reactive [ 92–95 ]. Indeed, CTL induced after infection with seasonal H1N1 and H3N2 influenza virus cross-react with influenza A viruses of the H5N1 subtype [ 96 , 97 ], H7N9 subtype [ 93 ], H1N1pdm09 viruses [ 94 , 98 ], and swine origin variant H3N2 viruses [ 94 ].

A protective role for cross-reactive virus-specific CTL in humans was first shown after experimental infections [ 99 ]. In the absence of virus-specific antibodies to the challenge virus, the lytic activity of peripheral blood mononuclear cells inversely correlated with the extent of virus shedding. More recently, it was demonstrated that the frequency of preexisting cross-reactive CD8 + T cells inversely correlated with disease severity in patients infected with the pandemic H1N1 virus of 2009 [ 100 , 101 ]. In acutely infected patients, it was demonstrated that the anamnestic cross-reactive virus-specific CD8 + CTL response was very rapid, which may have contributed to accelerated clearance of the virus [ 95 ]. Furthermore, in patients infected with the avian H7N9 virus, positive disease outcome correlated with the magnitude of the virus-specific CD8 + T-cell response [ 102 ]. The observation that CTL epitopes accumulate amino acid substitutions at anchor or T-cell receptor residues that are associated with escape from recognition by CD8 + T cells further support the notion that CTL control influenza virus replication and exert selective pressure on the virus [ 103 ]. In a human challenge study, virus-specific CD4 + T lymphocytes were also shown to correlate with reduced disease severity [ 104 ].

The currently available seasonal influenza vaccines ( Table 1 ) provide protection against circulating virus strains that are closely related to those represented in the vaccine but fail to provide long-lasting and broadly protective immunity against more distantly related drifted influenza viruses. This has led to the development of a procedure of influenza vaccine strain selection that is coordinated by the WHO twice a year in close consultation with an international network of key laboratories and academies to review surveillance, clinical study results, and the availability of vaccine viruses [ 105 ]. For a few decades, this strain selection was used to produce trivalent vaccines that represented the 2 circulating influenza A virus subtypes and 1 influenza B virus lineage. Since 2013–2014, mainly quadrivalent influenza vaccines are administered. They represent 2 circulating influenza A virus subtypes and 2 influenza B virus lineages: the Yamagata and Victoria lineages, which display limited serum cross-reactivity. As cross-B–lineage protection appears to be related to the level of exposure to influenza B virus, which increases with age, protection against the seasonal influenza B virus lineage absent from trivalent vaccines may occasion vaccine failure in children. Quadrivalent vaccines were shown to provide improved protection against influenza B virus in children, which are less likely to have preseasonal immunity in case of a B linage mismatch of a trivalent vaccine [ 106 ].

Nevertheless, these seasonal vaccines provide little or no protection against zoonotic or pandemic influenza viruses. Thus, upon the emergence of a pandemic, an update of the vaccine with the pandemic virus strain is necessary before the deployment of vaccination programs can occur. This requires swift vaccine development, which is hampered by the current production approach used for the vast majority of seasonal influenza vaccines and based on the use of embryonated chicken eggs. While this technology is relatively efficient and cost-effective, it is associated with a number of major disadvantages. First, generating vaccine candidate viruses by reassortment, and to a lesser extent by reverse genetics, that are highly productive in eggs, is highly time-consuming. The development time of seed viruses, using the backbone of an egg-adapted virus and expressing the HA and NA genes of the circulating viruses, and the subsequent vaccine production time may take as long as 6 to 8 months before the first vaccine doses become available. During this time lapse, new drift variants of seasonal and pandemic influenza viruses alike may arise, resulting in vaccine mismatch. Adaptation of the vaccine seed viruses to replication in avian tissue may also lead to adaptive mutations that may result in yet further mismatch with circulating strains. Such changes may severely reduce vaccine-induced protection [ 107 ]. Finally, the capacity of the egg production system requires careful planning, as it cannot be scaled-up within a short period of time for obvious reasons, as it depends on laying chickens. The system is furthermore vulnerable to the risk of avian influenza and other poultry disease outbreaks that may paralyze the supply of embryonated chicken eggs.

Although the relatively cost-effective egg-based vaccine production platform allows the production of more than a billion vaccine doses annually, several vaccine manufacturers are addressing these shortcomings by the use of accredited cell lines, like African green monkey kidney (Vero) cells, Madin-Darby canine kidney (MDCK) cells, and others as new platforms to produce vaccine viruses at yields that are comparable to those obtained in eggs [ 108 , 109 ]. Several of the disadvantages of the egg-based production platform, like lack of scalability, avian mutation-based mismatch, and vulnerability to avian disease outbreaks may at least in part be overcome by using these new production platforms. The price of cell culture-produced IIVs, however, remains considerably higher than that of their egg-based counterparts.

Inactivated Influenza Vaccines

Among the seasonal influenza vaccines that are most frequently used today, are the IIVs produced in embryonated chicken eggs. These vaccines have an excellent safety record. Essentially 3 types of IIVs are being used today, based on whole-virions, split-virions, and HA and NA subunits [ 110 ].

Classically, alum and oil-in-water emulsions (eg, MF59) have been used as adjuvants in some of the nonreplicating seasonal and pandemic human IIVs. These vaccines can profit from the combined use of adjuvants by the resulting increase of the specific immune response upon vaccination, or alternatively by reducing the antigen content in a dose sparing way. The latter may particularly be of interest during an influenza pandemic, when production capacity of vaccine antigen may become a limiting factor for effective vaccination coverage.

In addition to adjuvants, high-dose IIVs are produced to increase vaccine immunogenicity. In contrast to the standard dose IIVs (15 µg HA/strain), high-dose IIVs contain 4-fold HA dose. Trials with individuals aged 65 years and older demonstrated a higher antibody response, a better protection against laboratory-confirmed influenza illness, and a reduced hospitalization rate of nursing home residents when high-dose IIVs instead of the standard vaccine were used [ 111–113 ].

Live Attenuated Influenza Vaccines

LAIVs are based on the use of a cold-adapted virus that replicates well in embryonated chicken eggs and better at temperatures lower than the normal human body temperature. These are largely limited to replication in the upper respiratory tract and are therefore attenuated. LAIVs are generated by reassortment and are composed of the internal genes of a cold- and egg-adapted virus combined with the HA and NA of the respective seasonal influenza viruses identified by the influenza vaccine strain selection. As the immunization is based on replicating vaccine virus administered intranasally, it induces a strong local mucosal IgA response. Importantly, it induces both CD4 + and CD8 + T-cell responses. To what extent the internal proteins of the cold- and egg-adapted vaccine virus at the origin of CD8 + T-cell responses have been subject to escape mutations over time in the circulating viruses is not clear at present [ 114 , 115 ].

The overall level of protection induced by LAIVs in adults is comparable to that induced by IIVs. However, LAIVs appear to be less effective than IIVs in older adults, while they appear more effective in children. Therefore, the recommended age for this type of vaccine is from 24 months to 49 years of age. The exclusion of children under 2 years of age is related to an increased risk of induction of wheezing. Similarly, because LAIV vaccination depends on replication of the attenuated vaccine virus in the upper respiratory tract, which may result in some mild replication-associated symptoms, certain high-risk groups for influenza and pregnant women also have been excluded.

Recombinant HA Vaccine

The first purified recombinant HA vaccine FLUBLOK, developed by Protein Sciences and now marketed by Sanofi Pasteur, is formulated into trimer “rosettes,” that are produced in insect cells by a baculovirus expression system. It was shown to be 30% more efficacious than traditional IIVs for adults older than 50 years [ 116 ]. This may at least in part be related to a 3-fold higher HA load than classical IIVs. Until now the price of this first recombinant HA vaccine is relatively high, probably due to the limited scale at which it was originally produced.

Next-Generation Influenza Vaccines

Next-generation influenza vaccines are urgently needed in order to address seasonal influenza antigenic drift and contribute to better pandemic preparedness [ 117 , 118 ]. These aim at inducing broader intra- and intersubtypic as well as longer-lasting protective immune responses. Their production aim at rapid and large-scale capacity, overcoming one of the major shortcomings of the embryonated chickens egg system. Major challenges faced by the research and development community for the successful development of next-generation influenza vaccine candidates therefore include the induction of the desired humoral and T-cell–mediated immune responses against conserved epitopes, as well as the development of large-scale production systems. Mammalian cell lines and baculovirus expression system based on insect cells already offer relevant alternatives to the embryonated egg system, although costs will need to align with the latter for competitiveness [ 119 ].

Significant progress towards these next-generation vaccine candidates has been achieved worldwide [ 48 , 120 , 121 ]. Vaccine candidates in the development pipeline can be divided into 2 categories (for an overview of influenza vaccines in clinical trials see [ 122 ]). The first are designed to elicit broadly neutralizing antibody (bnAb) responses toward highly conserved conformational epitopes in the HA stem [ 123 ] and non-virus–neutralizing (non-VN) antibody responses to structurally conserved regions of influenza virus surface membrane proteins (HA, NA, and matrix protein 2 ectodomain [M2e]). The second are designed to induce cross-protective T-cell responses against predominantly internal proteins, like M1, NP, and PB1 [ 124 ]. The respective immune responses contribute largely to preventing infection on the one hand, and reducing disease severity upon infection on the other.

The recent discovery of bnAbs against influenza viruses indicates that the generation of a broadly protective vaccine may indeed be attainable. The majority of these bnAbs, however, are directed toward highly conserved conformational epitopes in the HA stem, which lack the immunodominance of epitopes displayed by the influenza HA head. A key strategy proposed to avoid or circumvent influenza HA head immunodominance is by generating recombinant headless HA proteins (or HA stems). However, removal of the transmembrane domain on the one hand and HA head on the other without extensive compensatory modifications to stabilize the remaining molecule leads to loss of native conformation of the HA stem, resulting in low if any presence of conformational bnAb-inducing epitopes. This has led to several approaches currently pursued towards stabilization of HA stems [ 125 ].

The HA head is immunodominant, with immune responses naturally targeting the antigenically variable region that surrounds the RBD. However, head-specific bnAbs have also been shown to be induced upon infection. Harnessing HA head immunodominance and steering head-specific immune responses toward more conserved regions of the HA head represents a promising complementary approach. Among explored vaccination strategies to induce reactive antibodies against conserved HA epitopes is the use of sequential vaccination with different chimeric HAs displaying the same HA stem and different HA heads [ 125 ].

In addition to HA, several studies have shown that inclusion of NA into influenza vaccines enhances the protective efficacy of these vaccines [ 126 ]. Serum antibodies that can inhibit NA activity are known to correlate with protection against human influenza independently of HA-specific antibodies [ 127 , 128 ]. M2e also is a safe and broadly protective influenza A vaccine antigen that primarily protects by antibody-dependent effector mechanisms. M2e is naturally a tetramer and thus can present quaternary epitopes to which antibodies with very high affinity may bind. Immune responses directed against M2e are nonetheless very weak following natural infection and virtually absent following vaccination with any of the licensed influenza vaccines [ 129 ]. Several strategies to overcome the inherent problems of M2e limited immunodominance are currently being explored [ 130 ].

The role of MHC class I restricted CD8 + T cells in accelerating virus clearance and limiting disease severity upon reinfection with influenza virus is increasingly recognized to potentially play a significant contribution to vaccine efficacy and breadth of protection. The induction of cellular-mediated immunity is largely dependent on replicating viruses and thus, in addition to LAIVs, viral vectored vaccines, as well as DNA- and RNA-based vaccines and virus-like particles are promising new technology platforms towards broader influenza vaccines [ 131 ]. In particular, the use of viral vectors for the presentation and delivery of (modified) vaccine antigens offer many advantages, in terms of both safety and efficacy (for review see [ 132 , 133 ]). As an example, modified vaccinia Ankara (MVA) is a highly attenuated and replication-deficient strain of vaccinia virus that is increasingly used in biomedicine for vaccine development. The induction of protective humoral and cellular immune responses by MVA against a wide range of viruses [ 133 ], including influenza viruses in animal models [ 134–136 ] and in humans (phase 1/2a clinical trial [ 137 , 138 ]), has been widely demonstrated. The safety and immunogenicity of MVA expressing influenza virus proteins was furthermore confirmed in elderly persons [ 139 ]. MVA vector vaccines rapidly induce strong antigen-specific CD4 + T helper cell as well as CD8 + effector T-cell immunity, leading to robust and durable protective immune responses. The presentation of viral targets of both humoral and cell-mediated immunity by MVA and other viral vectors has strong potential to optimize and synergize the induction of broad immune responses against influenza.

The striking success of mRNA vaccines against COVID-19 including in high-aged individuals [ 140 ] highlights the promise this technology might hold for the development of future influenza vaccines. Indeed, several approaches based on nonreplicating or self-replicating mRNA encoding for influenza HA, NP, and/or M1 have been developed and have demonstrated the general capacity of influenza mRNA vaccines to induce humoral and cellular immune responses and to provide protection against homologous and heterologous strains in animal models [ 141–143 ]. So far, only lipid nanoparticles with nucleoside modified mRNA encoding the full-length, membrane-bound form of HA from H10N8 (A/Jiangxi-Donghu/346/2013; NCT03076385) or H7N9 (A/Anhui/1/2013; NCT03345043) by Moderna Therapeutics have reached clinical trials. While they were well tolerated and induced humoral immune responses, no cell-mediated responses were detected [ 144 ]. Due to the progress and success in the development of mRNA vaccines against SARS-CoV2 as well as several advantages compared to standard egg-based technologies, a further focus on this area can be expected.

New-Generation Adjuvants

Adjuvants can improve the vaccine response by enhancing and modulating the immune response. In general, adjuvants act through different mechanisms or a combination thereof. They can create an antigen depot, activate the innate immune response, induce inflammasomes and cytokines, recruit immune cells, improve antigen uptake, enhance immune cell maturation, and change the activation profile of adaptive immune cells (reviewed in [ 145 ]). Up to now, only 6 adjuvants have been licensed in combination with influenza vaccines (Alum, MF59, AS03, AF03, virosomes and heat labile enterotoxin) but not all are currently in use [ 25 ]. Adjuvanted influenza vaccines were reported to generally improve humoral and cellular responses as well as the immune response in risk groups like the elderly and children [ 146–149 ].

For instance, multiple studies indicate that the addition of the oil-in-water adjuvant MF59 leads to a faster and higher antibody induction and a better cellular immune repose compared to nonadjuvanted influenza vaccines [ 146 , 148 , 150 , 151 ]. MF59 was reported to provoke proinflammatory cytokines and chemokines as well as chemoattractants (eg, CCL2, CCL3, and CXCL8) and to contribute to the recruitment, activation, and maturation of antigen-presenting cells (eg, dendritic cell and macrophages) at the injection site [ 25 , 152 ]. Several human clinical trials have investigated influenza vaccines with experimental adjuvants (reviewed in [ 25 ]). The addition of a suitable adjuvant typically aims at altering the immune response in favor of an immune response type that correlates with protection. For instance, Toll-like receptor (TLR) ligands and agonists (eg, imiquimod [TLR7], resiquimod [TLR7/8], or CpG oligodeoxynucleotids/immunostimulatory sequences [TLR9]) were associated with CTL activation [ 25 , 122 , 153 , 154 ], which might be necessary to improve vaccination outcome in risk groups. Indeed, a topical pretreatment with the TLR7 agonist imiquimod before an intradermal influenza vaccination was shown to significantly increase the immunogenicity of the vaccine in the elderly with chronic diseases [ 155 ] and to induce protection against a heterologous influenza strain in a phase 2b/3 trial [ 156 ].

Immunomodulators

Kinases are one class of biological response modifiers that has been investigated for intervention strategies against influenza viruses. Host kinases not only regulate influenza virus entry and replication, but are also integral components of various antiviral and inflammatory pathways allowing them to shape the immune response (reviewed in [ 157 ] and [ 158 ]). The therapeutic potential of targeting kinases has long been recognized in the field of oncology. While small-molecule kinase inhibitors (SMKIs) have been primarily used in cancer therapy, some are also applied in nonneoplastic diseases such as chronic inflammatory diseases (eg, rheumatic arthritis, Crohn disease, or ulcerative colitis) [ 159 , 160 ]. A large number of SMKIs are FDA approved or in development [ 161 ], many of which have been shown to regulate the immune response. Although immunomodulatory effects of SMKIs have been mainly described in the context of cancer models or patient trials, there is a strong potential that they can also improve immune responses upon vaccination, especially in risk groups. Several studies have described the inhibition and/or inactivation of suppressive immune cells like regulatory T cells (T regs ) and myeloid-derived suppressor cells by different kinase inhibitors [ 162–165 ]. Together with the inhibition of T regs , an increase in the effector T cells has the potential to lead to an improved ratio favoring immune stimulation [ 162 , 166 ]. Some were shown to contribute to the optimal priming of CTLs and NK function by favoring T helper 1 cells.

SMKIs have been successfully used as influenza vaccine adjuvants in several murine vaccination/challenge experiments. Topical application of epidermal growth factor receptor inhibitors (EGFRIs) before intradermal vaccination increased the humoral and cellular vaccination response and led to a reduced viral load in the lungs and improved survival rates in challenged mice [ 147 ]. Systemic EGFRI treatment of cancer patients was correlated with increased cytokine expression, immune cell recruitment, and T reg inhibition in the skin, suggesting a change of the immune homeostasis in favor of enhanced immune reactions to vaccines [ 147 ]. Another study, by Lanna et al, investigated the capacity of mitogen-activated protein kinase inhibitors to overcome immune senescence and improve responses to influenza vaccination in aged mice [ 167 ]. A reversion of immunosenescence by SMKIs was observed and characterized by an upregulation of CD27 and CD28 as well as telomerase reexpression, increased T-cell proliferation, interleukin-2 production, and cytotoxicity, and improved T- and B-cell functions [ 167 ]. These results indicate that SMKIs not only may restore the impaired functions of a senescent immune system, but they can also reverse other immune dysregulations attributed to inflammaging or stress [ 14 ].

Although influenza vaccination is a global achievement and has considerably contributed to reducing morbidity and mortality associated with influenza worldwide, there is an urgent need for novel technologies and strategies to improve influenza vaccine responses towards broader and longer-lasting protective immunity, including in individuals at risk of vaccine failure. The proportion of the population with expected poor vaccine responses is increasing, especially in developed countries. Although there are already strategies to improve vaccine responses for some risk groups, for example the elderly [ 168 , 169 ], additional knowledge of the mechanisms that lead to vaccine failure in risk groups and ways to overcome them through immune modulation may further contribute to improving vaccine design. Such rational approaches to next-generation influenza vaccine development will ultimately help to design new or improved vaccines tailored to induce the range of correlates of protection ensuring broader cross-reactive protection, as well as to address the needs of those most vulnerable to severe disease outcomes.

Financial support . This work was supported by the Alexander von Humboldt Foundation in the framework of the Alexander von Humboldt Professorship endowed by the German Federal Ministry of Education and Research; and by the European Union’s Horizon 2020 Research and Innovation Program (grant numbers 848166 [ISOLDA] and 874650 [ENDFLU]).

Supplement sponsorship. This supplement is sponsored by the Bill and Melinda Gates Foundation.

Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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Mini review article, influenza vaccination: effectiveness, indications, and limits in the pediatric population.

Department of Pediatrics, V. Buzzi Childrens' Hospital, University of Milan, Milan, Italy

Influenza vaccine is considered the most effective way to prevent influenza. Nonetheless, every year vaccine coverage is lower than recommended in the pediatric population. Many factors are supposed to contribute to this phenomenon such as the uncertainty about the indication for vaccination, and the suboptimal vaccine-effectiveness in pediatric age, especially in the youngest children. In this review we discuss the effectiveness, indications, and limits of influenza vaccination in the pediatric population based on the most recent evidences.

Introduction

Human influenza disease is primarily the result of the infection with influenza A and influenza B viruses. Type A virus can be classified using surface antigens hemagglutinin and neuraminidase. In the last years, the main circulating A strains have been the H1N1 pandemic strain and the H3N2 strain ( 1 ). The two major antigenically B viruslineages are B/Victoria and B/Yamagata ( 2 ). Each year both B virus strains co-circulate and are responsible for about 25% of influenza disease cases ( 3 ). However, the proportion of circulating influenza B strains varies by season and countries ( 4 – 6 ) Different strains have different virulence and prefer to infect different age clusters, probably based on previous exposure to antigenically similar viruses ( 1 ). In particular, influenza B virus is likely to affect children, and young adults. Children hospitalizations and fatal influenza cases are mainly associated with B subtypes ( 1 ).

Each year, 15–45% of children are infected with an influenza virus and by the age of 6 most children have been infected with influenza virus at least once ( 7 ). Viremic titers in children are higher than in adults and shedding of virus goes on for longer periods ( 8 , 9 ). Therefore, children represent a critical source in the transmission of influenza and sustain annual epidemics ( 9 ).

About 870,000 children aged <5 years and about 300,000 children aged <1 year are hospitalized each year all over the world because of influenza and 10–15% of children need medical care for influenza-related diseases ( 9 , 10 ). It is estimated that between 28,000 and 111,500 children below 5 years of age die each year due to influenza-related causes, most of them in developing countries ( 9 – 11 ) and from 2009, in 8/9 seasons, influenza disease course was reported to be moderate to severe in pediatric population ( 11 ).

It is unquestionable that influenza vaccine (IV) is the most effective way to prevent influenza ( 2 ). The first vaccine, a live-attenuated monovalent vaccine containing virus A, was developed immediately after the isolation of influenza virus in 1933. Fortunately, during the last decades, much has changed in the prevention of influenza in terms of vaccine manufacture, type of vaccines and strain coverage. Nowadays, two types of IVs are mainly used: an inactivated (IIV), and a live attenuated one (LAIV). The IIV can contain three or four virus strains. The trivalent ones (IIV3) are currently targeted against a H1N1 virus, a H3N2 virus, and a B virus, while the quadrivalent ones (IIV4) are targeted against both viruses A, and both viruses B. IIV3 are currently available in three different formulations: whole-virus vaccines, split-virus vaccines, and subunit vaccines. Two IIV4 vaccines have been developed and marked: a split inactivated vaccine and a subunit one. There are also adjuvanted seasonal IVs, but in most countries, they are not still licensed for children use. The LAIV is a quadrivalent vaccine containing both viruses A and B ( 12 – 14 ).

In this review we discuss the effectiveness, indications, limits, and ongoing direction of IVs in the pediatric population based one the most recent evidences.

Indications of Influenza Vaccination

Although seasonal IVs are available since many decades and recommended since 1960, the first practical indications for children immunization were issued in the early two thousand and only for children with high risk conditions.

After 50 years from the first release, the benefit of the vaccination in children with chronic disorders remains unquestioned. However, the vaccination strategy, which is based only on the direct protection of those subjects at highest risk, has not been proven to be very effective in reducing influenza morbidity, and mortality, as well as not being cost-effective ( 15 ). Moreover, children, healthy or chronically ill, –especially those younger than 5 years, are at higher risk for serious influenza-related complications, such as bacterial co-infections (e.g., S. pneumonia e or S. aureus ), seizures, influenza-associated encephalitis/encephalopathies, and fulminant myocarditis and pericarditis ( 16 – 22 ).

The extension of the seasonal IV program to all children aims to reduce the public health impact of influenza by providing direct protection and also lowering transmission rates ( 23 ). Reducing influenza transmission in the community will avert many cases of severe influenza and influenza-related deaths in older adults and in people with clinical risk factors. Additionally, from an economical perspective, IV was shown to be cost-effective for children in all analyses ( 24 , 25 ).

Different types of recommendations have been released worldwide. The World Health Organization (WHO) recommends annual vaccination, prioritizing high risk groups including pregnant women, children under 5 years of age, the elderly, and those with underlying health conditions ( 26 ).

In the United States (US) the Advisory Committee on Immunization Practices included healthy children aged 6–23 months in the target population of influenza vaccine for the first time in 2004 and it included all healthy children aged more than 6 months only in 2010 ( 27 , 28 ).

Many countries suggest vaccinating children older than 6 months of age with high-risk conditions only; just few ones universally recommend the vaccination for the whole pediatric population, from 6 months of age, and offer it for free till the age of 5 years (e.g., Canada, Australia) ( 13 , 29 , 30 ). In Europe, the European Center for Disease Control and Prevention (ECDC) has limited power over national IV policies. Therefore, each country establishes its own strategies in recommending vaccination. Not all member states have a formal national action plan for vaccination and in most countries recommendations for seasonal IV only include target or at-risk groups. During the 2017–18 influenza season, only 6/30 states recommended seasonal IVs to healthy children or adolescents ( 31 – 33 ).

Several reasons may explain these different immunization policies: first of all the availability of economic resources. Implementation of resources allocated to influenza vaccination is not always considered a priority for the National Health Authorities. Several economic evaluations are important to assist policymakers defining the costs of influenza vaccination programs and their financial cost-effectiveness. Secondly, influenza vaccination requires additional work that should be efficiently organized at the light of each national immunization schedules: this is of outstanding importance for the success of the influenza vaccine campaign. Despite the awareness of these economical and organizational barriers, in our opinion, the extension of the recommendation for the whole pediatric age could confer great benefits in terms of social equality.

ECDC, Centers for Disease Control and Prevention (CDC), and American Academy of Pediatrics (AAP) indicate that inactivated vaccines should be the primary choice for all children older than 6 months. However, they do not indicate which one between IIV3 and IIV4 should be preferred. Indeed, the type of the formulation is currently debated considering that the prevalence of B viruses is relatively low and varies between seasons ( 17 , 20 , 33 ). LAIV was not recommended in any setting in the past two influenza seasons based on data demonstrating low effectiveness against influenza A(H1N1) ( 34 , 35 ). However, for the 2018–2019 influenza season, the AAP reintroduced the use of LAIV for healthy children aged older than 2 years who would not otherwise receive an influenza vaccine ( 13 , 35 ). AAP supports the use of LAIV with the aim of achieving the best vaccination coverage and optimal protection in children of all ages ( 13 ).

Concerning IV's schedule, IV should be repeated every year, as recent studies suggested that there was no strong evidence of protection extended for more than one influenza season and vaccine effectiveness seems not to diminish with frequent vaccinations ( 36 – 42 ).

Influenza VACCINE Effectiveness in Pediatric Age

An interesting argument of debate is the vaccine effectiveness (VE) of the available IV. As randomized controlled trials are not suitable for monitoring VE across the seasons, the test-negative design (TND), a modified case-control study, has been introduced since 2004 ( 43 , 44 ). Based on the results of TND studies, the VE appears to vary from season to season, by age group, with vaccination history, and by country. Many theories and factors have been proposed over the years to explain these discrepancies, such as the suboptimal vaccine-strain match, the different types of vaccine (inactivated vs. LAIV), the vaccine manufacturing (e.g., generating egg-induced mutations in the hemagglutinin that affect antigenicity), the age-dependent patterns in protection (e.g., “Original Antigenic Sin”– OAS –and the more recent model of OAS: the “Antigenic Seniority”), the nutritional status, the unresponsiveness of some hosts to influenza vaccine, the vaccination coverage rates in the community, the prior influenza vaccination (e.g., “the antigenic distance hypothesis,” a theoretical framework explaining the variable effect of repeated vaccination) and the difficulty of measuring VE accurately ( 45 – 54 ). A list of possible factors affecting VE is reported in Figure 1 . The contribution and the relative importance of each factor in determining the VE is largely unknown and it is an intriguing field of future research.

Figure 1 . Factors and conditions affecting Influenza Vaccine Effectiveness (VE). OAS, Original Antigenic Sin.

In addition, combining and interpreting differences in VE estimates from available studies is extremely challenging because VE is assessed annually (due to the frequently changing vaccine) and because of the difference in study designs, age of recruited children, influenza seasons, and countries where the studies were conducted.

Given these observations, it is extremely difficult to give data about VE in pediatric age. However, to the best of our knowledge, we summarized the available data as follows:

a) Children older than 2 years: trivalent inactivated IV showed a higher VE against A/H1N1pdm09 (up to 70%) when compared to LAIV (up to 39%). However, they had similar effectiveness against influenza A/H3N2 and B ( 55 , 56 ). Quadrivalent inactivated subunit-antigen vaccine showed a VE in preventing influenza illness ranging from 45 to 65% against any type of influenza, 51–71% against influenza A, and 32–34% against B. According to some authors, for this vaccine the VE seems to be highest in the younger children aged 1–5 years old ( 57 – 59 ).

b) Children between 6 months and 2 years: there are few studies specifically assessing the VE of the inactivated vaccines between 6 and 24 months of age. The great majority of studies performed efficacy analysis or VE pooled analysis considering most often children aged from 2 to 59 months or from 2 to 7–9 years old. Based on the available data, VE in children from 6 to 24 months of age range from 18 to 85% for trivalent inactivated vaccine ( 60 – 64 ).

Efficacy studies showed that the recently quadrivalent split-virion inactivated vaccine was effective against influenza vaccine-like strains (50.9% efficacy against any A or B type and 68.4% against influenza caused by vaccine-like strains) in children aged 6–35 months ( 65 ). VE data are not currently available, however effectiveness is expected to be similar to those reported in efficacy studies.

Limits of Influenza Vaccination in Pediatric Age

One of the major limits of IV in pediatric age is the absence of recommendation in infants younger than 6 months of age. The younger infants have a greater risk of severe influenza infection and a higher rate of hospitalization than older infants ( 66 ). The risk is even greater if they have chronic conditions ( 10 ). Up to now, IV has not been approved by regulators for use in infants and its use is currently off-label and arbitrary. Apart from the well-known cocoon strategy which is extremely difficult to perform, maternal immunization during pregnancy could overcome this limit and is the only measure approved by the health authorities ( 67 ). In this field, evidences about immunogenicity and efficacy are rapidly accumulating. IIV or A(H1N1) MF59-adjuvanted vaccine during pregnancy result in transplacental transfer of the generated antibodies ( 68 ). The efficacy of pregnant women's vaccination in preventing the disease and influenza-related hospitalization in infants was estimated to be around 50–60% according to different studies ( 69 – 71 ). However, several questions remain unanswered as which should be the best time for maternal immunization to ensure the best and the longest protection for the newborn and young infants and which is the immunological role of breastfeeding. In particular some authors reported the absence of protective antibody levels at birth and limited immunological and clinical protection up to the 3rd month of life ( 72 , 73 ). Others showed that clinical protection against influenza and influenza–associated pneumonia persists up to the 6th month of life ( 74 , 75 ). Considering the available data, determining acquired protection duration is imprecise, with few immunological, and effectiveness data between the third and 6th months of infant life. Moreover, long-term adverse effects of maternal immunization on infants have not been reported, and more safety studies are needed. Nonetheless, maternal immunization remains the best practice for protecting children against influenza in the 1st months of life, and should be encouraged.

Another potential limit of IV in pediatric age is the need for 2 shots in the younger naïve children, especially in infants who have a very full immunization schedule. Studies showed that the second dose was not always received or delayed far beyond the recommended interval of 28 days ( 76 , 77 ). There were probably several reasons for incomplete vaccinations, such as schedule complexity, in between-doses frequent infections, difficulties in scheduling a doctor appointment, financial barriers, and lack of provider–parent discussions on the importance of the second dose ( 78 ). Efforts should be made in order to overcome the two shots with just one effective single dose for every age. This change can potentially simplify IV procedures and improve the adherence to IV schedule.

The IVs remain the primary choice for all children, even though LAIV, besides its capacity of inducing mucosal IgA antibodies, providing protection at the site of viral entry against subsequent infection, and eliciting both humoral, and cellular immune responses, may also improve the compliance thanks to its non-invasive administration (endonasal spray) ( 79 ).

Ongoing Discussion and Future Perspectives

The characteristics of the immune system in young children on one side and the presence of an immunosuppressive disease on the other have shown to affect IV response ( 12 , 80 , 81 ). This raised debates about the best approach to enhance the immune response to IV in these two specific different groups. Some strategies have been tested, such as the use of higher doses of antigen, and adjuvants ( 82 ). In 2009 the high-dose (containing four times as much hemagglutinin as in standard-dose vaccines) trivalent inactivated IV was licensed for use in the elderly on the basis of its safety profile and superior immunogenicity ( 83 ). In pediatric population, recent studies showed that the high-dose IV was more immunogenic than the standard one in children with leukemia or solid tumors and in solid organ transplant patients but not in children with HIV ( 84 ), with good reported safety profile ( 84 – 86 ). Given the relatively small studied population, despite the evidences that immunocompromised children generate a lower immune response to standard-dose IV compared to healthy subjects ( 87 ), no definitive recommendation about the use of the high-dose IV can be drawn. Notably, no data about the use of this high dose IV are available in immunocompromised children, and younger than 2 years. Further studies are needed.

Another approach to enhance the immune response was the use of oil-in-water adjuvant MF59 ® , firstly approved in 1990 for adults older than 65 years of age. In 2018, a first trial assessed the relative efficacy, immunogenicity, and safety of an MF59-adjuvanted quadrivalent inactivated subunit IV (aQIV) compared to a US-licensed non-adjuvanted influenza vaccine in a large cohort of children aged between 6 months and 5 years in 2 consecutive seasons ( 88 ). The authors showed that in the youngest children (6–23 months) aQIV provided greater protection against influenza than a non-adjuvanted vaccine. The clinical benefit was demonstrated since the first vaccination in vaccine-naïve children. The efficacy and vaccine safety profiles of aQIV were similar to the non-adjuvanted comparator vaccine, with the exception of major Solicited Adverse Events. Recently, Daily and colleagues assessed the impact of repeated vaccination on immunogenicity and safety of aQIV in children aged between 6 months to 5 years. This study confirmed an enhanced immunogenicity and a similar safety profile after repeated aQIV vaccination compared to repeated non-adjuvanted influenza vaccination ( 89 ). Given the promising results, if confirmed in the ongoing trials, aQIV could be a valid option for the routine use in pediatric population in the near future.

A quadrivalent recombinant vaccine, currently available in adults, was recently studied in children (6–17 years old), and it was found to be comparable to the IIV in terms of safety, and immunogenicity ( 90 ).

The Committee for Medicinal Products for Human Use of the European Medicines Agency and the European Commission (in October 2018 and in January 2019 respectively) approved the inactivated cell-based quadrivalent influenza vaccine (QIVc) for the use in patients older than 9 years. The QIVc is supposed to be used as early as in the next influenza season (2019–2020). The different production process of the vaccine (cell-based vaccine vs. embryonated chicken eggs) represent a step forward in avoiding egg-adapted changes, vast amount of eggs, and long manufacturing time, with a comparative or even better efficacy rate ( 91 ).

Conclusions

Influenza immunization is the best available strategy to reduce influenza-related morbidity, and mortality and virus spread. Nonetheless, questions and limits about influenza vaccine in pediatric population remain open ( Table 1 ). Firstly, the vaccine effectiveness in children is variable and suboptimal, with reported differences according to vaccine types, seasons, and child age. Estimating the mean effectiveness remains challenging. Secondly, influenza vaccine is currently the only vaccine requiring yearly immunization, with two shots in naïve children which could influence the vaccine uptake especially in younger children. Thirdly, there is no influenza vaccine that directly protects infants <6 months of age. The most promising strategy to protect children that are too young to be vaccinated is the maternal immunization, with estimated efficacy of 50–60%. Finally, the promising recombinant, adjuvanted, and high-dose vaccines are still not universally approved in pediatric population. Addressing these issues, together with better understanding the complex immune responses induced by natural influenza infection, will be of outstanding importance to finally design future universal vaccine.

Table 1 . Visual summary.

Author Contributions

CM, IC, and MF wrote the paper. GZ revised the manuscript. All authors read and approved the final manuscript.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Keywords: influenza vaccine, influenza, children, effectiveness, pediatric population

Citation: Mameli C, Cocchi I, Fumagalli M and Zuccotti G (2019) Influenza Vaccination: Effectiveness, Indications, and Limits in the Pediatric Population. Front. Pediatr. 7:317. doi: 10.3389/fped.2019.00317

Received: 14 April 2019; Accepted: 12 July 2019; Published: 30 July 2019.

Reviewed by:

Copyright © 2019 Mameli, Cocchi, Fumagalli and Zuccotti. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Chiara Mameli, chiara.mameli@unimi.it

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The journal Medicina Universitaria is aimed at students and teachers of the School of Medicine of the Universidad Autónoma de Nuevo León. It seeks to promote medical-scientific writing and thereby support research and creativity in Medicine. The journal aims as well to support the medical-biological sciences related to health as to have a space for history, philosophy and ethics. Medical writing without relation to science is promoted: anecdotes, stories and short stories of doctors and patients. Dirigida a estudiantes y docentes de la Facultad de Medicina de la Universidad Autónoma de Nuevo León, la revista Medicina Universitaria busca fomentar el escrito medico-científico y con ello apoyar la investigación y la creatividad en la medicina. La revista pretende apoyar a las ciencias medicobiológicas relacionadas con la salud y tener un espacio para la historia, la filosofía y la ética. Se fomenta el escrito médico sin relación con la ciencia: anécdotas, historias y relatos de médicos y pacientes.

Immunization -whether from polio, typhoid, flu or whooping cough- is never absolute. A shot in the arm may save your life -but you can't always rely on it... Nor is any immunization absolutely safe . 1

Influenza is a major cause of morbidity and mortality; current estimates by the World Health Organization (WHO) are 3 to 5 million cases and 250,000 to 500,000 deaths worldwide every year. 2 Most deaths associated with it occur among people age 65 or older, as well as among persons suffering a chronic debilitating disease regardless of age. The recent 2009 pandemic served to foster interest in this disease. 3

An inactivated virus vaccine has been available since the late 1940´s but it only began to be used extensively when the influenza virus antigenic variability was taken into account. Aside from such variability, influenza viruses are capable of infecting a wide variety of vertebrates, 4 including many avian species, both wild and domestic, thus it is essential to monitor the antigenic characteristics of influenza virus strains currently circulating, and so the vaccine formula has to be evaluated and modified accordingly every year.

Vaccine indications

The efficacy of influenza vaccine is relatively low (70%-90%) 5 and vaccinated persons could have insufficient protection even to homologous virus strains, not to mention those viruses that have undergone antigenic changes, either drift or shift. Furthermore, other respiratory viruses such as parainfluenza, adenoviruses or respiratory syncytial virus could cause a similar illness, frequent anecdotal comments of acute respiratory illness (ARI) coincident with vaccine application is therefore not too surprising.

The risk of complications during an influenza episode, leading to hospitalization and death is higher in older people (≥ 65 years) and in those patients undergoing any of a well-known list of chronic debilitating diseases, 6 yet the benefit of the influenza vaccine should be weighted in different situations. In Mexico, the Ministry of Health ( Secretaría de Salud ) recommends vaccine application to people belonging to certain groups 7 (Table 1).

Additional information to make better particular recommendations for influenza vaccine use is available from WHO, 8 as well as from the Advisory Committee on Immunization Practices 9 in the United States of America:

• Healthy individuals : vaccination may be recommended from age 50 onwards.

• Adults and children with health conditions such as chronic pulmonary disease (including asthma) or cardiovascular (except isolated hypertension), renal, hepatic, neurological, hematologic, or metabolic disorders (including diabetes mellitus).

• Persons who have immunosuppression , including compromised immune systems caused by medications or human immunodeficiency virus (HIV) infection.

• Women who are or will be pregnant during the influenza season.

• Children and adolescents (aged 6 months-18 years) who are receiving long-term aspirin therapy and who might be at risk for experiencing Reye's syndrome after influenza virus infection.

• Residents of nursing homes and other long-term care facilities.

• Persons who are morbidly obese , with a body mass index (BMI) over 39.

Vaccine use and its public perception

Annual vaccination should take place ideally before the "flu season" starts, that is, the months of September-October of each year; if uptake in this period is missed however, later vaccination is always encouraged, especially for persons at risk.

Although influenza vaccine is recommended by the WHO and is firmly established worldwide as an effective measure for influenza control, the number of persons who receive influenza vaccine each year is very low even in countries with good health systems. 6,9 Fear of adverse effects has discouraged public vaccine acceptance ever since Edward Jenner first proposed systematic smallpox prevention through cowpox immunization. The roots of this universal phenomenon are myths and misinformation such as beliefs of vaccine being the cause of disease, lack of vaccine efficacy, refusal to get medical care, or plain mistrust of the health care system. A combination of these factors results in deficient vaccine coverage.

Data on factors influencing vaccine uptake, such as age, gender, co-morbidity, educational level, income and area of residence are important. However, recent research provides an insight on the reasons for vaccination acceptance or rejection; an improvement on vaccine acceptance requires a significant level of knowledge and understanding of health beliefs, attitudes, perceptions and subjective experiences both on individual and collective levels. This is particularly evident in older people, who decide to be vaccinated based on the interpretation and evaluation of beliefs about whether it could cause or prevent colds and influenza, and the importance of side effects. Older people's subjective assessment of their own health is often incongruent with objective assessment. 10

A group of police, fire fighters and prison workers in Spain, regarded as essential community workers, surveyed by Caballero et al. 11 showed that the vaccine was better accepted by those who never had doubts about vaccine safety.

In 2009, the Ministry of Health in France purchased 94 million vaccine doses to ensure the vaccination of 65 million citizens. Yet, there was a low uptake of the vaccine that could have been related to a lack of high quality advice about the benefits of getting vaccinated; the same study also postulated that media and social networks may have contributed to raise undue concerns in the population. Participation of general practitioners may help to improve vaccine perception by providing face-to-face professional advice and information. 12

Considerations for improvement

Many countries show vaccine uptake rates less than 50% in health care workers (HCW). Livni et al. found the overall vaccination rate among a group of pediatric HCW in Israel was 46.8%. Their data show that knowledge about the influenza vaccine by health care personnel leads to better vaccination rates. 13

Blasi et al. suggest improving communication between health authorities, scientific societies, HCW and general population through simple, clear, honest and straightforward messages to ensure unbiased information about the vaccine is the basis for a person to accept it. 14

Septimus et al. established a mandatory vaccination program for HCW aimed to foster patient safety, including categories for professional employees with patient care (clinical) duties as well as any other person who could be in the premises. The basis to establish these categories are: 1) access to clinical areas, and 2) work area within a 2 meter distance from the patient. 15

Influenza vaccination rates are particularly low among marginalized, hard-to-reach urban populations, so intervention activities are to be designed with a high degree of inter-institutional cooperation, taking into account neighborhood particularities, strong community organization, and individual orientation. 16

Probabilistic models have the power to handle large amounts of data; these models are also suited to analyze factors such as weather (low temperature, humidity, and rainfall), which has been widely anecdotically considered as associated with seasonal variation of ARI and influenza, and to enable better decision making, vaccination campaign planning and resource allocation during epidemics. 17

American Indians and Alaskan natives are also groups targeted for influenza vaccination in the United States of America, so we propose to study the benefits of preventing influenza in Mexican and other Meso-American ethnic groups.

As we know from the past, fear and concern about vaccine safety have been present from the beginning of vaccination during the 19 th Century (Fig. 1). With an ever-increasing amount of internet and social network users, anti-vaccination messages lacking scientific foundation may keep the public at large ill-informed and scared. HCW should be the best-informed group, with a solid knowledge of vaccination benefits and side effects. Vaccine perception should not be a black and white picture, but rather a balance between the many benefits obtained contrasted with a number of known and expected adverse effects. We have long postulated that a sound application of any vaccine has to be a carefully crafted benefit vs. risk evaluation, in other words, adverse reactions are to be considered the lesser evil 18 given the higher hospitalization and death rates among high-risk groups.

Figure 1 Graphic depiction of fear elicited by smallpox vaccination in 1802. Painting by James Gillray (1756-1815). Image downloaded from the United States library of Congress's prints and Photographs division under the digital ID cph.3g03147. This artistic work belongs in the public Domain according to World Trade Organization Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS), 1994.

Conflicts of interest

The authors have no conflicts of interest to declare.

No financial support was provided.

Received: March 2014; Accepted: April 2014

• Corresponding author: Centro de Investigación y Desarrollo en Ciencias de la Salud, (CIDICS) Universidad Autónoma de Nuevo León. Carlos Canseco s/n and Av. Gonzalitos, Mitras Centro, C.P. 64460, Monterrey, N. L., Mexico. Telephone: 1340 4370 (J. G. Velasco-Castañón).

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Peer-reviewed

Research Article

Examining the potential benefits of the influenza vaccine against SARS-CoV-2: A retrospective cohort analysis of 74,754 patients

Roles Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Resources, Software, Validation, Visualization, Writing – original draft, Writing – review & editing

¶ ‡ Denotes equal contribution as co-first authors.

Affiliation Division of Plastic & Reconstructive Surgery, University of Miami Miller School of Medicine, Miami, Florida, United States of America

Roles Project administration, Resources, Software, Supervision, Writing – review & editing

Affiliation Anne Arundel Medical Center, Annapolis, Maryland, United States of America

Roles Conceptualization, Investigation, Methodology, Project administration, Supervision, Writing – review & editing

* E-mail: [email protected]

Susan M. Taghioff,
Benjamin R. Slavin,
Tripp Holton,
Devinder Singh

Published: August 3, 2021
https://doi.org/10.1371/journal.pone.0255541
Reader Comments

Introduction

Recently, several single center studies have suggested a protective effect of the influenza vaccine against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). This study utilizes a continuously updated Electronic Medical Record (EMR) network to assess the possible benefits of influenza vaccination mitigating critical adverse outcomes in SARS-CoV-2 positive patients from 56 healthcare organizations (HCOs).

The de-identified records of 73,346,583 patients were retrospectively screened. Two cohorts of 37,377 patients, having either received or not received influenza vaccination six months–two weeks prior to SARS-CoV-2 positive diagnosis, were created using Common Procedural Terminology (CPT) and logical observation identifiers names and codes (LOINC) codes. Adverse outcomes within 30, 60, 90, and 120 days of positive SARS-CoV-2 diagnosis were compared between cohorts. Outcomes were assessed with stringent propensity score matching including age, race, ethnicity, gender, hypertension, diabetes, hyperlipidemia, chronic obstructive pulmonary disease (COPD), obesity, heart disease, and lifestyle habits such as smoking.

SARS-CoV-2-positive patients who received the influenza vaccine experienced decreased sepsis (p<0.01, Risk Ratio: 1.361–1.450, 95% CI:1.123–1.699, NNT:286) and stroke (p<0.02, RR: 1.451–1.580, 95% CI:1.075–2.034, NNT:625) across all time points. ICU admissions were lower in SARS-CoV-2-positive patients receiving the influenza vaccine at 30, 90, and 120 days (p<0.03, RR: 1.174–1.200, 95% CI:1.003–1.385, NNT:435), while approaching significance at 60 days (p = 0.0509, RR: 1.156, 95% CI:0.999–1.338). Patients who received the influenza vaccine experienced fewer DVTs 60–120 days after positive SARS-CoV-2 diagnosis (p<0.02, RR:1.41–1.530, 95% CI:1.082–2.076, NNT:1000) and experienced fewer emergency department (ED) visits 90–120 days post SARS-CoV-2-positive diagnosis (p<0.01, RR:1.204–1.580, 95% CI: 1.050–1.476, NNT:176).

Our analysis outlines the potential protective effect of influenza vaccination in SARS-CoV-2-positive patients against adverse outcomes within 30, 60, 90, and 120 days of a positive diagnosis. Significant findings favoring influenza vaccination mitigating the risks of sepsis, stroke, deep vein thrombosis (DVT), emergency department (ED) & Intensive Care Unit (ICU) admissions suggest a potential protective effect that could benefit populations without readily available access to SARS-CoV-2 vaccination. Thus further investigation with future prospective studies is warranted.

Citation: Taghioff SM, Slavin BR, Holton T, Singh D (2021) Examining the potential benefits of the influenza vaccine against SARS-CoV-2: A retrospective cohort analysis of 74,754 patients. PLoS ONE 16(8): e0255541. https://doi.org/10.1371/journal.pone.0255541

Editor: Corstiaan den Uil, Erasmus Medical Centre: Erasmus MC, NETHERLANDS

Received: April 29, 2021; Accepted: July 17, 2021; Published: August 3, 2021

Copyright: © 2021 Taghioff et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the paper.

Funding: The authors received no specific funding for this work.

Competing interests: Dr. Holton serves as a consultant for Acelity/3M and Stryker. Dr. Slavin, Ms. Taghioff, and Dr. Singh have no relevant disclosures. The authors have not received any consulting fees, stock options, research funding, capital equipment, or educational grants from TriNetX.

With cases in excess of 140 million and a death toll over 3 million, COVID-19 has greatly impacted the global community [ 1 ]. In the nascency of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), demand for rapid, yet accurate data was voracious [ 2 ]. As the world continues to attempt to overcome the current pandemic and readies itself to combat a future one, the need for expeditious clinical answers remains paramount.

Federated electronic medical record (EMR) networks, such as TriNetX (TriNetX Inc, Cambridge, MA), aggregate the de-identified records of millions of patients from participating healthcare organizations (HCOs) into an accessible and searchable database in real-time [ 3 , 4 ]. Several publications have already demonstrated the utility of federated EMR networks in addressing research questions regarding the implications of SARS-CoV-2 on maladies including obesity, rheumatological disease, gastrointestinal bleeding, and psychiatric illness [ 5 – 8 ]. The efficiency and speed with which these previous retrospective studies were able to examine topics of interest, using real-time EMRs, allows for the collective advancement of COVID-19 knowledge in hopes of optimizing prevention and management.

Recently, several studies have suggested a possible protective effect of the influenza vaccine against SARS-CoV-2 [ 9 – 12 ]. Although no cross-reactivity between influenza-induced antibodies and SARS-CoV-2 protection has been demonstrated, several theorized mechanisms of the potential protective effect of influenza vaccination have been proposed in the recent literature [ 9 , 13 , 14 ]. The first hypothesis centers around the presence of MF59 in the influenza vaccine: an oil-in-water squalene emulsion that has been shown to assist in potentiating an immune response to SARS-CoV variants [ 14 ]. Alternatively, influenza vaccination’s potential protective effect may be explained by its ability to stimulate the activation of natural killer cells, the levels of which have been found to be considerably decreased in moderate and severe SARS-CoV-2 cases [ 15 , 16 ]. Another proposed mechanism was described in a recent case-control study of 261 healthcare workers. The authors noted several prior studies that suggested both coronaviruses and influenza viruses engage with the angiotensin-converting enzyme 2 (ACE-2) and tetraspanin antibodies. Thus, there is belief that ACE-2 and tetraspanin antibodies may inhibit both coronavirus and low-pathogenic influenza A virus infections. Outcomes of this study pointed to a potential protective effect in those with influenza vaccination [ 11 ]. Additional studies reported that the influenza vaccine may lead to decreased risk of cardiovascular events due to potential interaction with immune and inflammatory systems to promote plaque stabilization [ 17 , 18 ]. It has also been recently reported that influenza vaccine-induced antibodies may interact with the bradykinin 2 receptor, leading to an anti-inflammatory effect secondary to increasing nitric oxide [ 18 , 19 ].

In a single-center study of 2,005 patients, Yang et al. were the first to perform a retrospective review highlighting a potential protective effect of influenza vaccination against adverse outcomes associated with SARS-CoV-2. Only 10.7% of patients in this study were considered up to date on their influenza immunization. The authors reported a 2.44 greater odds ratio (OR) for hospitalization and 3.29 greater OR for intensive care unit (ICU) admission indicating a protective effect for SARS-CoV-2 positive patients who were up to date on their influenza immunization [ 9 ].

This investigation seeks to explore the potential protective effects of influenza vaccination against SARS-CoV-2 using the TriNetX database. Specifically, this study aims to assess the possible benefit of influenza vaccination in mitigating critical adverse outcomes in SARS-CoV-2 positive patients using 73 million deidentified EMRs from 56 HCOs provided by a continuously updated network.

At the time of our search in January 2021, the analytics subset contained EMRs from 56 HCOs distributed predominantly throughout the United States of America, but also with participating institutions in the United Kingdom, Italy, Germany, Israel, and Singapore. Within the US, the geographic distribution of HCOs is 6% in the Northwest, 33% in the Midwest, 42% in the South, and 19% in the West [ 3 ]. The deidentified records of 73,346,583 patients were retrospectively screened using the TriNetX platform ( Fig 1 ).

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https://doi.org/10.1371/journal.pone.0255541.g001

In order to ensure accuracy, logical observation identifiers names and codes (LOINCs), the universal standard for identification of medical laboratory data, were used to identify patients positive for SARS-CoV-2 (LOINC 94500–6). CPT codes were used to identify patients who had received either the trivalent live intranasal (90660) or inactivated intramuscular influenza vaccine (90653) within a timeframe of six months–two weeks prior to receiving a SARS-CoV2-positive diagnosis. Additionally, Medicare patients receiving either the intranasal or intramuscular influenza vaccine were captured using the corresponding healthcare common procedure coding system (HCPCS) code (G0008). Any EMRs belonging to patients that were pregnant, incarcerated, experienced an outcome outside of a 120-day post-SARS-CoV-2 diagnosis window, or not meeting all of the aforementioned criteria by CPT code were excluded. Following application of inclusion and exclusion criteria, a cohort of 2,814,377 patients who had not received the influenza vaccine six months–two weeks prior to a positive SARS-CoV-2 diagnosis was compared to a second cohort of 37,377, patients who had received the influenza vaccine six months–two weeks prior to a positive SARS-CoV-2 diagnosis. We selected two weeks as the minimum end of our study’s timespan as it takes approximately two weeks for the immune system to fully develop antibodies following influenza vaccination. Conversely, six months was chosen as the maximum end of the timespan between influenza vaccination and SARS-CoV-2-positive diagnosis because the accepted standard for adequate protection without a waning effect is six months [ 20 ].

Following the creation of these two cohorts, we used the TriNetX platform to facilitate propensity score matching between cohorts with ICD-10 codes for numerous factors including age, race, gender, ethnicity, diabetes mellitus (E08-E13), elevated BMI status (E65-E68), hypertension (I10-I16), chronic ischemic heart disease (I25), heart failure (I50), COPD (J44), musculoskeletal disease (M00-M99), and factors influencing health status and contact with human services (Z00-Z99) which includes factors influencing health status including tobacco use, body mass index (BMI), and socioeconomic status. After propensity score matching, a cohort of 37,377 SARS-CoV-2 positive patients without influenza vaccination was paired with a second cohort of 37,377 SARS-CoV-2 positive patients, comparable in demographics and co-morbidities, that had received influenza vaccination within the aforementioned time frame.

Propensity score 1:1 balancing was completed within the TriNetX platform via logistic regression utilizing version 3.7 of Python Software Foundation’s Scikit-Learn package (Python Software Foundation, Delaware, USA). A greedy nearest neighbor matching algorithm approach was used, setting standard differences to a value of less than 0.1 to indicate appropriate matching. To eliminate record order bias, randomization of the record order in a covariate matrix occurs before matching. Baseline characteristics with a standardized mean difference between cohorts lower than 0.1 were considered well balanced.

Following optimization of the two cohorts for direct comparison, adverse outcomes were identified with ICD-10 or CPT codes as sepsis (A41.9), deep vein thrombosis (DVT) (I82.220, I82.40-I82.89, I82.A19), pulmonary embolism (I26), acute myocardial infarction (I21), stroke(I63), arthralgia(M25.5), ICU admission (99291, 1013729, 1014309), ED visits (1013711), hospital admission (1013659, 1013660, 1013699), renal failure (N19), acute respiratory distress syndrome (J80), acute respiratory failure (J96), anorexia (R63), pneumonia (J18), and death. Following identification, adverse outcomes within 30, 60, 90, and 120 days of SARS-CoV-2-positive diagnosis were analyzed and compared between the two cohorts. 120 days was made the maximum endpoint of our study window to account for the presence of the poorly understood Post-Acute Covid Syndrome (PACS), an autonomic dysfunction phenomenon observed in many patients after recovering from SARS-CoV-2 [ 17 ].

Using the TriNetX platform’s Analytics function, statistical analysis and logistical regression were performed by comparing indices and relative risks of outcomes following the successful matching of cohorts with a p-value greater than 0.05. Outcomes for all measures were calculated using 95% confidence intervals (CIs). All p-values were two-sided and the alpha level was set at 0.05. Risk ratio was defined in this study as the ratio of the probability of an adverse SARS-CoV-2-related event occurring without history of up-to-date influenza vaccination versus the probability of the same adverse SARS-CoV-2-related event occurring in a patient with history of up-to-date influenza vaccination [ 21 ].

Subsequently, Absolute Risk Reduction (ARR), defined as the difference in risk of an adverse SARS-CoV-2-related outcome between the influenza-vaccinated group and non-influenza-vaccinated group, was calculated for each adverse outcome. The reciprocal of ARR was then obtained to determine number needed to treat, henceforth referred to in this study as number needed to vaccinate (NNV), for all statistically significant variables. The NNV is a calculation specifying the average number of patients who needed to be up-to-date on their influenza vaccination in order to have prevented one adverse SARS-CoV-2-related outcome [ 22 , 23 ].

Propensity score matching resulted in 37,377 patients in each cohort. Prior to matching, all between-groups factors were found to be significantly different (p<0.0001). However, following matching, all demographic and diagnostic factors were no longer significant (p>0·05) ( Table 1 ), indicating successful balancing.

https://doi.org/10.1371/journal.pone.0255541.t001

Following propensity score matching by the TriNetX system, statistical analysis was performed for all adverse outcomes of interest at 4 time points: 30, 60, 90, and 120 days following a SARS-CoV-2-positive diagnosis (Tables 2 – 5 ).

https://doi.org/10.1371/journal.pone.0255541.t002

https://doi.org/10.1371/journal.pone.0255541.t003

https://doi.org/10.1371/journal.pone.0255541.t004

https://doi.org/10.1371/journal.pone.0255541.t005

SARS-CoV-2-positive patients who received the influenza vaccine experienced significantly decreased sepsis (p = 0.0001–0.0020, Risk Ratio: 1.361–1.450, 95% CI: 1.123–1.699) and stroke (p = 0.0003–0.0154, Risk Ratio: 1.451–1.580, 95% CI: 1.075–2.034) across all time points. ICU admissions were significantly lower in SARS-CoV-2-positive patients receiving the influenza vaccine at 30, 90, and 120 days (p = 0.0073–0.0240, Risk Ratio: 1.174–1.200, 95% CI: 1.003–1.385), while approaching significance at 60 days (p = 0.0509, Risk Ratio: 1.156, 95% CI: 0.999–1.338) ( Fig 2A ).

Significant adverse outcome trends 30–120 days (a), 60–120 days (b) & 90–120 days (c) (p<0.05). ** ICU Admissions Within 60 Days approaching significance (p = 0.0509, 95%).

https://doi.org/10.1371/journal.pone.0255541.g002

Patients who received influenza vaccination experienced significantly fewer DVTs 60–120 days after positive SARS-CoV-2 diagnosis (p = 0.0058–0.0108, Risk Ratio: 1.411–1.530, 95% CI: 1.082–2.076) ( Fig 2B ) and experienced significantly fewer ED visits 90–120 days post SARS-CoV-2-positive diagnosis (p = 0.0001–0.0076, Risk Ratio: 1.204–1.580, 95% CI: 1.050–1.476) ( Fig 2C ).

Additional findings included patients up-to-date on their influenza vaccination experiencing significantly less anorexia within 90 days of SARS-CoV-2-positive diagnosis (p = 0.0486, Risk Ratio: 1.276, 95% CI: 1.001–1.627) as well as decreased arthralgia within 120 days of SARS-CoV-2-positive diagnosis (p = 0.0041, Risk Ratio: 1.218, 95% CI: 1.064–1.395).

NNV with influenza vaccination to prevent one adverse SARS-CoV-2-related outcome calculations for significant findings for sepsis, stroke, and ICU Admission within 30, 60, 90, and 120 days of positive SARS-CoV-2 diagnosis are illustrated in Fig 3 , along with NNV to prevent DVT within 60–120 days, and NNV to prevent ED Visits within 90–120 days ( Fig 3 ).

https://doi.org/10.1371/journal.pone.0255541.g003

This study underscores the utility of federated EMR networks as a potential solution for the need for urgent clinical data, particularly during health crises such as pandemics. While the work of retrospective single-center studies continues to have advantages such as detailed historical patient information that deidentified EMR networks cannot provide, the ability to scan, in minutes, the charts of 73 million patients from 56 HCOs in real-time to guide clinical decision-making is invaluable.

EMRs included in our study monitored patients with positive SARS-CoV-2 diagnoses for adverse outcomes during a period of 120 days. This time window was chosen intentionally to account for the possible presence of PACS. Although poorly understood, previous studies of PACS have reported orthostatic intolerance, often without objective hemodynamic abnormalities upon testing, as well as new illness-related fatigue to be the most common presentations. Development of these symptoms was found to occur between 0–122 days and 29–71 days post-SARS-CoV-2 diagnosis respectively [ 24 , 25 ].

By focusing on rates of hospitalization and ICU admission, the study of Yang et al., garnered a sizable amount of media coverage [ 23 , 24 ]. This study most closely mirrors this study’s aim of appraising the potential impact of influenza vaccination on adverse outcomes associated with SARS-CoV-2. Prior to comparing findings between these two studies, it is important to note several key differences in methodology [ 9 ]. While both studies relied on medical coding to identify SARS-CoV-2 positivity and influenza vaccination status, the timeframes were different, with this study encompassing the first full year of SARS-CoV-2 cases globally from January 2020-January 2021 [ 1 , 25 ]. This timespan enabled our study to include data from the 2019–2020 influenza vaccine formulation as well as the most recent 2020–2021 influenza season formulation. This contrasts with the timespan of the previously mentioned study, as well as the recently published retrospective review of 27,000 patients by Conlon et al. Both of these studies analyzed SARS-CoV-2 cases between March-August 2020, a period overlapping between two different influenza vaccinations and seasons which excludes peak influenza season, and did not set a 2 week– 6 month time limit for influenza vaccine being “current/active” [ 9 , 12 ]. Additionally, the Yang and Conlon study timeframes began 6 months after the CDC’s recommended influenza vaccination time in October, therefore the vaccine antibodies were likely already waning [ 9 , 12 , 20 ].

Our study found no association between influenza vaccination and risk of death in SARS-CoV-2-positive patients. This confirms the previous findings of Umasabor-Bubu et al., Pedote et al. and Ragni et al., which found that a history of influenza vaccination did not confer protection against death in reviews of 558, 664, and 17,600 patients respectively [ 26 – 28 ].

Alternatively, two macro-scale studies have found there to be conflicting relationships between influenza vaccination and mortality in the elderly population. In a large scale study of over 2,000 counties in the United States, Zanettini et al. demonstrated a potential protective effect of influenza vaccination on SARS-CoV-2 mortality [ 29 ]. Conversely, Wehenkel et al. performed a macro-scale study of association between influenza vaccination rate and SARS-CoV-2 deaths in an examination of over 500,000 patients across 39 countries [ 30 ]. This study showed a positive association between COVID-19 deaths and influenza vaccination rates in elderly people 65 years of age and older. The conflicting findings of these studies may be attributable to their large scale nature and lack of analysis of individual patient EMRs, thereby further increasing the need for prospective randomized control studies to better define the potential protective effect of influenza vaccination against SARS-CoV-2.

In light of the over 140 million confirmed positive cases worldwide 1 , the use of NNV calculations allows for a deeper appreciation of the potential benefit of influenza vaccination. In addition to guarding against a possible “twindemic” of simultaneous outbreaks of influenza and SARS-CoV-2 [ 31 ], the NNV trends observed within 30–120 days of SARS-CoV-2 diagnosis for sepsis, stroke, ICU admission, DVT, and ED visits further strengthen the case in favor of a protective effect of influenza vaccination ( Fig 3 ). Specifically, in order to prevent one individual from visiting the ED, developing sepsis, being admitted to the ICU, suffering a stroke, or having a DVT within 120 days of positive SARS-CoV-2 diagnosis, 176, 286, 435, 625, and 1,000 people respectively would need to have been up-to-date with their influenza vaccination. When considered on a global scale, the NNVs calculated in this study may serve to benefit not only those that will be infected with SARS-CoV-2, a diagnosis that has already affected over 140 million to date, but also the finances and resources of the health systems responsible should patients suffer these adverse outcomes [ 32 ]. Even more encouraging, apart from DVT for which NNV remained stable, the NNVs for sepsis, stroke, ICU Admissions, and ED Visits were down trending at the 120-day mark, implying that the NNV and thus potential protective benefit of influenza vaccination may be even stronger than observed in the present study.

Expanding upon our prospective understanding of the relationship between influenza vaccination and protection against adverse outcomes during SARS-CoV-2 is the work of Pawlowski et al. This retrospective review found that a history of eight different vaccines including Polio, H. influenzae type-B, measles-mumps-rubella, and Varicella, amongst others, within the past one, two, or five years is associated with decreased SARS-CoV-2 infection rates, even after cohort balancing [ 33 ]. This suggests that the protective effect observed by our group and others against SARS-CoV-2 may not be unique to influenza vaccination.

This study has the benefits of large cohort size and a tightly matched patient population, however reliance on a global database also introduces limitations that must be acknowledged. These limitations include our study’s retrospective nature, absence of detailed historical patient data, and lack of ability to follow up regarding new symptoms. Our search query’s reliance on the CPT, ICD-10, and LOINC coding of individual HCOs is another potential source of confounding as the accuracy of these factors is inherent to the EMRs comprising the database. This statement is particularly of interest as relates to false positive and false negative cases of SARS-CoV-2, which relies on the specificity and sensitivity of PCR and rapid antigen testing.

Federated EMR networks, such as TriNetX, have vast potential to challenge or verify scientific findings using sample sizes and turnaround times unachievable by individual centers, particularly during health crises such as pandemics. Our study was able to verify and challenge the relatively large difference in the potential protective effect of influenza vaccination observed by the previous study with a much more modest effect backed by nearly 75,000 global EMRs [ 9 ]. The potential protective effects of the vaccine against sepsis, stroke, DVT, ED visits, and ICU admissions at 30, 60, 90, and 120 days following SARS-CoV-2-positive diagnosis reaffirms the importance of annual influenza immunization.

While this observed potential protective effect is relatively small, the stringently matched cohort balancing and sample size afforded by TriNetX substantially increases our confidence in the fidelity of our findings. In the context of over 140 million cases globally, the potential protective benefits further elucidated by the NNV calculations for these same adverse outcomes suggests that a concerted effort to continue ramping up influenza vaccination in parallel with SARS-CoV-2 vaccination is strongly worth consideration. Although production and distribution of SARS-CoV-2 vaccines continues to increase daily, the fact remains that certain populations in the global community may still have to wait a long period of time before they are vaccinated and could therefore benefit from a more readily available source of even marginally increased protection [ 34 ]. That being said, less than half of US adults receive influenza vaccination each year, with Non-Hispanic Black, Hispanic, and American Indian/Alaskan Native individuals having had the lowest influenza vaccination coverage while also being disproportionately affected by SARS-CoV-2 [ 35 ].

The influenza vaccine may be a viable option to attenuate the adverse effects of SARS-CoV-2 worldwide, with a specific potential to benefit populations struggling with access to or distribution of SARS-CoV-2 vaccination. Even patients who have already received SARS-CoV-2 vaccination may stand to benefit given that the SARS-CoV-2 vaccine does not convey complete immunity, although further research into the relationship and potential interaction between influenza vaccination and SARS-CoV-2 vaccination should be performed.

Using a federated EMR network of over 73 million patients across 56 global HCOs, this analysis examines the potential protective effect of the influenza vaccine against various adverse outcomes at 30, 60, 90, and 120 days of SARS-CoV-2-positive diagnosis. Significant findings in favor of the influenza vaccine in mitigating the risks of sepsis, stroke, DVT, ED visits, and ICU admissions suggest a protective effect that merits further investigation. Limitations include this study’s retrospective nature and its reliance on the accuracy of medical coding. Future prospective controlled studies to validate these findings and determine if an increased emphasis on influenza vaccination will improve adverse outcomes in SARS-CoV-2-positive patients will be beneficial.

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CDC Seasonal Flu Vaccine Effectiveness Studies

CDC conducts studies each flu season to help determine how well flu vaccines are working. These vaccine effectiveness (VE) studies help regularly assess the value of flu vaccination as a public health intervention. The results of vaccine effectiveness studies can vary based on the study design, the outcome(s) measured, the population studied, and the season studied.

Figure. Effectiveness of Seasonal Flu Vaccines from the 2009-2023 Flu Seasons

Table. Adjusted vaccine effectiveness estimates for influenza seasons from 2004-2023
Supporting Research

U.S. Flu Vaccine Effectiveness Networks

CDC has been working with researchers at universities and hospitals since the 2003-2004 flu season to estimate how well flu vaccines work through observational studies using laboratory-confirmed flu as the outcome. Over the past few years, CDC has conducted VE studies using multiple vaccine effectiveness networks. More information on CDC’s vaccine effectiveness networks and studies is available at CDC’s Influenza Vaccine Effectiveness Networks .

Results from Prior Flu Seasons

The overall, adjusted vaccine effectiveness estimates for flu seasons from 2004-2023 are noted in the chart below. (Estimates are typically adjusted for study site, age, sex, underlying medical conditions, and days from illness onset to enrollment.)

Download Vaccine Effectiveness PowerPoint Presentation Slides [PPT – 1 MB]

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The vaccine effectiveness estimates included in the chart and tables below are vaccine effectiveness estimates from the U.S. Flu VE Network.

graph Effectiveness of Seasonal Flu Vaccines from the 2005 – 2023 Flu Seasons

*2020-2021 flu vaccine effectiveness was not estimated due to low flu virus circulation during the 2020-2021 flu season.

**In a Wisconsin study among patients aged 6 months to 64 years, VE was 54% against medically attended outpatient acute respiratory illness (ARI) associated with laboratory-confirmed influenza A.

Table. Adjusted vaccine effectiveness estimates for flu seasons from 2004-2023

*From 2004-2005 through 2010-2011, the Flu VE Network also enrolled inpatients.

**2020-2021 flu vaccine effectiveness was not estimated due to low flu virus circulation during the 2020-2021 flu season.

***In a Wisconsin study among patients aged 6 months to 64 years, VE was 54% against medically attended outpatient acute respiratory illness (ARI) associated with laboratory-confirmed influenza A.

† Vaccine effectiveness (VE) estimates for the 2008-2009 flu season have not been published.

‡ Number of patients used in VE calculation.

Belongia EA, Kieke BA, Donahue JG, et al. Effectiveness of inactivated influenza vaccines varied substantially with antigenic match from the 2004-2005 season to the 2006-2007 season. J Infect Dis. 2009 Jan 15;199(2):159-67. doi:10.1086/595861. PubMed PMID: 19086915.

Belongia EA, Kieke BA, Donahue JG,et al. Influenza vaccine effectiveness in Wisconsin during the 2007-08 season: comparison of interim and final results. Vaccine. 2011 Sep 2;29(38):6558-63. doi: 10.1016/j.vaccine.2011.07.002. Epub 2011 Jul 19. PubMed PMID: 21767593.

Ferdinands JM, Gaglani M, Martin ET, Middleton D, Monto AS, Murthy K, Silveira FP, Talbot HK, Zimmerman R, Alyanak E, Strickland C, Spencer S, Fry AM; HAIVEN Study Investigators. Prevention of influenza hospitalization among adults in the US, 2015-16: Results from the US Hospitalized Adult Influenza Vaccine Effectiveness Network (HAIVEN). J Infect Dis. 2018 Dec 14. doi:10.1093/infdis/jiy723. [Epub ahead of print] PubMed PMID: 30561689.external

Flannery B, Clippard J, Zimmerman RK, Norwalk MP, Jackson ML, Jackson LA, Monto AS, Petrie JG, McLean HQ, Belongia EA, Gaglani M, Berman L, Foust A, Sessions W, Thaker SN, Spencer S, Fry AM. Early Estimates of Seasonal Influenza Vaccine Effectiveness – United States, January 2015. MMWR Morb Mortal Wkly Rep. 2015 Jan 13;64(1);10-15.

Flannery 2019 Influenza Vaccine Effectiveness in the United States During the 2016-2017 Season – PubMed (nih.gov)

Flannery 2020 Spread of Antigenically Drifted Influenza A(H3N2) Viruses and Vaccine Effectiveness in the United States During the 2018-2019 Season – PubMed (nih.gov)

Gaglani 2016 Influenza Vaccine Effectiveness Against 2009 Pandemic Influenza A(H1N1) Virus Differed by Vaccine Type During 2013-2014 in the United States – PubMed (nih.gov)

Griffin MR, Monto AS, Belongia EA, et al. Effectiveness of non-adjuvanted pandemic influenza A vaccines for preventing pandemic influenza acute respiratory illness visits in 4 U.S. communities. PLoS One. 2011;6(8):e23085. doi: 10.1371/journal.pone.0023085. Epub 2011 Aug 12. PubMed PMID: 21857999.

Jackson ML, Chung JR, Jackson LA, Phillips CH, Benoit J, Monto AS, Martin ET, Belongia EA, McLean HQ, Gaglani M, Murthy K, Zimmerman R, Nowalk MP, Fry AM, Flannery B. N Engl J Med. 2017 Aug 10;377(6):534-543. doi: 10.1056/NEJMoa1700153. PMID: 2879286

McLean HQ, Thompson MG, Sundaram ME, Kieke BA, Gaglani M, Murthy K, Piedra PA, Zimmerman RK, Nowalk MP, Raviotta JM, Jackson ML, Jackson L, Ohmit SE, Petrie JG, Monto AS, Meece JK, Thaker SN, Clippard JR, Spencer SM, Fry AM, Belongia EA. Influenza Vaccine Effectiveness in the United States During 2012-2013: Variable Protection by Age and Virus Type. J Infect Dis. 2014 Nov 18. pii: jiu647. [Epub ahead of print] PubMed PMID: 25406334.

Ohmit SE, Thompson MG, Petrie JG, et al. Influenza vaccine effectiveness in the 2011-2012 season: protection against each circulating virus and the effect of prior vaccination on estimates. Clin Infect Dis. 2014 Feb;58(3):319-27. doi: 10.1093/cid/cit736. Epub 2013 Nov 13.

Rolfes 2019 Effects of Influenza Vaccination in the United States During the 2017-2018 Influenza Season – PubMed (nih.gov)

Tenforde 2020 Effect of antigenic drift on influenza vaccine effectiveness in the United States – 2019-2020 – PubMed (nih.gov)

Treanor JJ, Talbot HK, Ohmit SE, et al. Effectiveness of seasonal influenza vaccines in the United States during a season with circulation of all three vaccine strains. CID 2012; 55(7):951-959. Epub 2012 Jul 25. PubMed PMID: 22843783.

Zimmerman 20162014-2015 Influenza Vaccine Effectiveness in the United States by Vaccine Type – PubMed (nih.gov)

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