What is the History of Influenza Vaccine Use in America?
The 1918-19 influenza pandemic at the beginning of the 20th century stimulated research on the influenza virus and, in 1933, influenza type A was isolated in ferrets. In 1936, influenza type B was isolated and an Australia scientist discovered that the virus could be grown in embryonic hen eggs. These discoveries fueled an interest in the development of an influenza vaccine that would reduce mortality in future epidemics and pandemics.1 2
The first vaccine for influenza was developed in 1938 and given to U.S. soldiers during World War II. A 1944 study of the new influenza vaccine determined that, while helpful in reducing illness with a temperature above 99 degrees F, it did not appear to have an impact on clinical outcomes. In 1947, further evaluation of the influenza vaccine found no difference in health outcomes between those who were vaccinated and those who were not vaccinated.3 4
Early flu vaccines contained only inactivated influenza virus type A (monovalent) but, by 1942, there was a bivalent vaccine containing both Influenza type A and influenza type B. This early vaccine caused localized and systemic reactions, especially in children. Despite little evidence of its effectiveness, the influenza vaccine was licensed for use in the U.S. in 1945.5 6 7 8
When the predicted “Asian” flu pandemic materialized in the 1957-1958 flu season, production of a vaccine against this pandemic influenza strain was initiated quickly in hopes it would limit mortality and reduce severity of the illness for vaccinated persons. Approximately 40 million doses of the vaccine were administered to people in the U.S.
However, due to the lack of effectiveness and limited availability, public health officials reported “the vaccine had no appreciable effect on the trend of the pandemic.”9 The failure was presumed to be primarily related to the lack of availability of the vaccine and, by 1960, health officials started recommending routine flu shots every year for the elderly and certain high risk groups. 10
A review of this “annual flu shot” recommendation four years later found little evidence that annual vaccination of seniors and others thought to be at high risk for influenza had any appreciable impact on influenza-related mortality rates. A 1968 double-blind randomized study conducted by CDC officials and published by the World Health Organization came to similar conclusions and even suggested that “attention should be redirected towards finding a more efficacious means of protection.”11 Yet, despite studies demonstrating that the influenza vaccine was ineffective, government vaccine policy recommendations for annual flu shots continued.
In early 1976, two cases of H1N1 “swine flu” were confirmed in the U.S. and public health officials working with the pharmaceutical industry made the decision to start manufacturing a vaccine out of concerns that this new strain of type A influenza could start a pandemic similar to the 1918-19 influenza pandemic. The U.S. Congress approved $137 million dollars for vaccine production with the goal that nearly all Americans would be vaccinated before the flu season started.12
Mass production of the swine flu vaccine did not start until the U.S. Congress gave in to demands from drug companies lobbying for a product liability shield to block vaccine injury lawsuits for any harm caused by swine flu shots.13 This decision called into question the safety of the swine flu vaccine and public support for the mass vaccination program began to wane.
The swine flu vaccination program began in October 1976 and, within two weeks public concerns about safety were highlighted when three senior citizens died after getting vaccinated at the same clinic. By December 1976, there had been numerous reports of people becoming paralyzed from Guillain-Barre Syndrome (GBS) that developed after getting swine flu shots and, with no evidence of an impending influenza pandemic, the swine flu vaccination program was cancelled.14
Despite this setback, seasonal flu vaccine production continued and, in 1978, the first trivalent influenza vaccine was licensed for use in the U.S. after scientists identified two different influenza A strains circulating simultaneously. The new inactivated trivalent influenza vaccine contained two strains of influenza A and one strain of influenza B virus.15
The first live attenuated influenza vaccine (LAIV), FluMist, was approved by the FDA in 2003. A trivalent vaccine administered as a nasal spray, FluMist was approved for use in healthy children and adults ages five to 49 years of age.16 This live virus flu vaccine was not recommended for individuals with a history of asthma or other respiratory illness, any underlying chronic illness, including those with immune or metabolic dysfunction, persons with a history of Guillain-Barre Syndrome, children or adolescents on aspirin therapy, pregnant women, or anyone with an egg allergy.
Importantly, FluMist was not recommended for people coming in close contact with immunocompromised individuals “because of the theoretical risk that a live, attenuated vaccine virus could be transmitted to the immunosuppressed person and cause disease.”17 There are documented cases in the medical literature of vaccine virus infection, shedding and transmission with FluMist and other live attenuated virus vaccines.18 19
On April 26, 2009, public health officials declared a national public health emergency after the discovery of a new Influenza A (H1N1) strain was first identified in Mexico and then in the U.S.20 A new pandemic H1N1 swine flu vaccine was quickly licensed and made available to the public in October of 2009, but a 2011 study of the effectiveness of the 2009 pandemic H1N1 swine flu vaccine found it had an overall effectiveness of only 56%.21
The influenza vaccine market has grown considerably since 2009 with the introduction of several new types of influenza vaccines along with new delivery methods, including vaccines than use insect and animal cells for production instead of chicken eggs.
A “high-dose” influenza vaccine targeting those over age 65 years was approved by the FDA in 2009 and became available in the U.S. for the 2010-2011 flu season.22 This vaccine contains four times the amount of antigen as other flu vaccines and is supposed to stimulate a stronger immune response that will produce more antibodies and, theoretically, give the elderly better protection from getting sick with influenza.23
In 2012, the FDA approved the first quadrivalent influenza vaccine, containing two type A and two type B influenza viruses.24 FluMist Quadrivalent, the live attenuated influenza vaccine, became available for the 2013-2014 flu season, and several quadrivalent inactivated injectable vaccines followed soon afterward. Quadrivalent vaccines add another strain of type B influenza B virus to the traditional trivalent vaccines, which contain two strains of type A influenza virus and one strain of type B influenza virus, with the goal of improving flu vaccine effectiveness.
The first cell-based influenza vaccine, Flucelvax, was approved by the FDA in 2012, using canine (dog) kidney cells25 instead of chicken embryos to produce the vaccine.26 In 2013, Flublok, a recombinant influenza vaccine using armyworm caterpillar cells instead of chicken embryos for production, was approved for use in adult over 18 years of age.27
On June 26, 2014, the CDC recommended giving FluMist to healthy children between two and eight years of age instead of inactivated injectable influenza vaccines but, two years later, in June 2016, the CDC withdrew its recommendation based on data that showed the vaccine was very ineffective in preventing influenza.28 29 On February 21, 2018, the CDC reinstated a new formulation of FluMist in advance of the 2018-2019 flu season. Vaccine efficacy studies on this new formulation of FluMist have not been completed and it is unknown whether it will offer any protection from influenza. The CDC voted against recommending FluMist over the available inactivated injectable influenza vaccines and would be considered an option if appropriate.30
In 2015, the FDA approved FLUAD, a trivalent influenza vaccine containing MF 59, a squalene oil adjuvant that hyper-stimulates the immune system to produce more antibodies. FLUAD is approved for adults over the age of > 65.31 The licensing of FLUAD was fast-tracked by the FDA despite concerns over the use of the squalene adjuvant and its association with immune and neurological disorders.32
Methods of how influenza vaccines are administered to people have also changed, as well. In 2012, the first intradermal influenza vaccine (administered between skin layers rather than into the muscle) was approved for use.33 In 2014, the first jet injector (vaccine delivery device using high-pressure) to administer influenza vaccine became available.34
As the influenza vaccine market expanded, so did recommendations for use by the CDC’s Advisory Committee on Immunization Practices (ACIP).
In 1984, the CDC recommended annual flu shots for high risk individuals, which included adults over the age of 65; any person with a chronic illness or a metabolic disorder; persons living in nursing homes or other long term care facilities, as well as health care personnel. At that time, pregnancy was not considered to be a high risk factor for severe illness or complications from influenza. The ACIP committee stated in 1984 that, “Pregnancy has not been demonstrated to be a risk factor for severe influenza infection, except in the largest pandemics of 1918-1919 and 1957-1958.”35
However, in 1997, the CDC updated influenza vaccine recommendations to include pregnant women in their second or third trimester, which was considered an off-label use of the vaccine because the FDA had not licensed influenza vaccine for use by pregnant women.36 The CDC’s recommendation in 1997 was based on information contained in a small number of documents from the 1918-1919 and 1957-1958 influenza pandemics, along with a few case reports and small studies reporting an increase in influenza-related hospitalizations in pregnant women.37
Between 1999 and 2010, the ACIP annual recommendations for the seasonal flu vaccine quickly expanded to include more and more target populations. Infants and children, aged six months to 23 months, were added in 2004.38 The presence of thimerosal, a mercury-containing preservative present in all multi-vial flu vaccine vials, was discussed by the ACIP due to a 1999 recommendation for removal from all vaccines routinely administered to children.39 However, in 2004 the CDC stated that, “the benefits of influenza vaccination outweigh the theoretical risk, if any, for thimerosal exposure through vaccination,” and there was no recommendation made for infants, children or even pregnant women to receive a thimerosal-free influenza vaccine.40
By 2010, the ACIP’s recommendation was that every person six months and older, including pregnant women at any stage of pregnancy, should get an annual flu shot. The only contraindications were for persons with a history of hypersensitivity or anaphylaxis to eggs or any other influenza vaccine ingredient, or history of Guillain-Barre Syndrome (GBS).41
In 2011, the CDC began recommending that individuals who had previously developed hives following exposure to eggs should get influenza vaccine.42 By 2016, egg allergies were no longer considered a contraindication to flu vaccine.43
Currently, a history of GBS or a severe allergy to a vaccine component or history of a life threatening allergic reaction to a previous flu shot are the only CDC approved official contraindications (medical reasons for not getting vaccinated) to receiving influenza vaccine.44 However, the CDC also states that influenza vaccination should be postponed if a child or adult has “moderate or severe acute illness with or without a fever,” which is listed as a “precaution” for receipt of any vaccine.45
Despite the ever-growing number of influenza vaccines available in the U.S. market, influenza vaccination rates have not improved very much over the years. In 2003-2004, the CDC increased research efforts to determine just how well seasonal flu vaccine works in preventing cases of influenza in vaccinated persons.
Since 2004, the seasonal influenza vaccine has failed to prevent influenza in vaccinated persons more than half the time, demonstrating a low of 10 percent effectiveness in 2004/20015 to a high of 60 percent effectiveness in 2010/2011. The average effectiveness of influenza vaccines over the past 14 flu seasons was less than 41 percent.46
The Cochrane Collaboration’s 2014 review of the medical literature on influenza vaccine noted bias in the publication of influenza vaccine research on effectiveness and safety:
“An earlier review of 274 influenza vaccine studies in all age groups (including most of the studies in this review) showed an inverse relationship between risk of bias and the direction of study conclusions. Conclusions favourable to the use of influenza vaccines were associated with a higher risk of bias. In these studies, the authors made claims and drew conclusions that were unsupported by the data they presented. In addition, industry-funded studies are more likely to have favourable conclusions, to be published in significantly higher-impact factor journals and to have higher citation rates than non-industry-funded studies. This difference is not explained by either their size or methodological quality (Jefferson 2009a). Any interpretation of the body of evidence in this review should be made with these findings in mind.”47
The Cochrane review also concluded that recommendations for routine use of influenza vaccine as a routine public health measure was not supported by the published evidence base and stated,
“The results of this review provide no evidence for the utilisation of vaccination against influenza in healthy adults as a routine public health measure. As healthy adults have a low risk of complications due to respiratory disease, the use of the vaccine may only be advised as an individual protective measure.” 48
The 2018 Cochrane review of influenza vaccination in healthy adults found that the flu vaccine may only have a modest impact on reducing the number of cases of influenza and influenza-like illness but the data was insufficient to determine whether vaccination had any impact on working days lost or on reducing serious complications of the flu during influenza season.49
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2 CDC. Influenza. Epidemiology and Prevention of Vaccine-Preventable Diseases (The Pink Book). 13th ed. 2015.
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4 Biondi E.A , Aligne A.C. Flu Vaccine for All: A Critical Look at the Evidence. Medscape Pediatrics Dec. 21, 2015.
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8 Biondi E.A , Aligne A.C. Flu Vaccine for All: A Critical Look at the Evidence. Medscape Pediatrics Dec. 21, 2015.
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10 Langmuir AD, Henderson DA, Serfling RE. The epidemiological basis for the control of influenza. Am J Public Health 1964; 54:563-571.
11 Schoenbaum SC, Mostow SR et al. Studies with inactivated influenza vaccines purified by zonal centrifugation. 2. Efficacy. Bull World Health Organ 1969; 41:531-535.
12 Sencer DJ, Millar JD. Reflections on the 1976 Swine Flu Vaccination Program. Emerg Infect Dis 2006; 12(1): 29–33.
13 Neustadt RE, Fineberg HV. The Swine Flu Affair: Decision-Making on a Slippery Disease. Washington (DC): National Academies Press (US) 1978.
14 Dowdle WR. The 1976 Experience. J Infect Dis 1997; 176 (Supplement 1): S69-S72.
15 Hannoun C. The Evolving History of Influenza Viruses and Influenza Vaccines. Expert Rev Vaccines 2013;12(9):1085-1094.
16 FDA. June 17, 2003 Approval Letter - Influenza Virus Vaccine Live, Intranasal. June 2003.
17 CDC. Using Live, Attenuated Influenza Vaccine for Prevention and Control of Influenza: Supplemental Recommendations of the Advisory Committee on Immunization Practices (ACIP) MMWR Sept. 26, 2003, 52(RR13);1-8
18 Mallory RM, Yi T, Ambrose CS. Shedding of Ann Arbor strain live attenuated influenza vaccine virus in children 6-59 months of age. Vaccine 2011; 29(26): 4322-4327.
19 Fisher BL. The Emerging Risk of Live Virus and Virus Vectored Vaccines: Vaccine Strain Virus Infection, Shedding and Transmission. National Vaccine Information Center November 2014.
20 The White House. Press Briefing On Swine Influenza. Apr. 26, 2009.
21 Griffen MR, Monto AS et al. Effectiveness of Non-Adjuvanted Pandemic Influenza A Vaccines for Preventing Pandemic Influenza Acute Respiratory Illness Visits in 4 U.S. Communities. PloS One2011; 6(8): e23085.
22 FDA. Approval Letter - Fluzone High-Dose. Dec. 23, 2009.
23 CDC. Fluzone High-Dose Seasonal Influenza Vaccine. Dec. 14, 2017.
24 Lowes R. First Quadrivalent Flu Vaccine Approved, Debuts Fall 2013. Medscape Medical News Mar 1, 2012.
25 FDA. Flucelvax Package Insert – Seqiris, Inc. April 2016.
26 CDC. Cell-Based Flu Vaccines. Nov 7, 2016.
27 CDC. Flublok Seasonal Influenza (Flu) Vaccine. Oct. 3, 2017.
28 Stobbe M. Ouch! Flu spray fails again, panel urges shot instead. Associated Press June 22, 2016.
29 CDC. ACIP votes down use of LAIV for 2016-2017 flu season. June 22, 2016.
30 Walker, M. ACIP Reinstates FluMist for 2018-2019 Flu Season. MEDPAGE TODAY Feb. 21, 2018
31 CDC. FLUAD™ Flu Vaccine With Adjuvant. July 11, 2016.
32 NVIC Questions FDA Fast Tracking of Squalene Adjuvanted Flu Vaccine The Vaccine Reaction Sept. 16, 2016.
33 CDC. Intradermal Influenza (Flu) Vaccination. Dec. 14, 2017
34 CDC. Flu Vaccination by Jet Injector. Oct. 12, 2017
35 CDC. Recommendation of the Immunization Practices Advisory Committee (ACIP) Prevention and Control of Influenza MMWR May 18, 1984; 33(19).
36 Fisher BL. Vaccination During Pregnancy: Is It Safe? National Vaccine Information Center Nov. 9, 2013.
37 CDC. Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Apr. 25, 1997; 46(RR-9):1-25.
38 CDC. Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR May 28, 2004; 53(RR06);1-40.
39 CDC. Recommendations Regarding the Use of Vaccines That Contain Thimerosal as a Preservative. MMWR Nov. 5, 1999; 48(43):996-998.
40 CDC. Prevention and Control of Influenza: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR May 28, 2004; 53(RR06);1-40.
41 CDC. Prevention and Control of Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Aug. 6, 2010; 59(RR08):1-62.
42 CDC. Prevention and Control of Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization Practices (ACIP), 2011. MMWR Aug. 26, 2011; 60(33):1128-1132.
43 CDC. Flu Vaccine and People with Egg Allergies. Dec. 28, 2017
44 CDC. Seasonal Influenza Vaccine Safety - A Summary for Clinicians: Contraindications and Precautions. Oct. 3, 2017.
45 CDC. Vaccine Recommendations and Guidelines of the ACIP: Contraindications and Precautions. July 18, 2018
46 CDC. Seasonal Influenza Vaccine Effectiveness 2005-2018. Feb. 15, 2018.
47 Demicheli V, Jefferson T et al. Vaccines for preventing influenza in healthy adults. Cochrane Database of Systematic Reviews Mar. 13, 2014.
49 Demicheli V, Jefferson T et al. Vaccines for preventing influenza in healthy adults. Cochrane Database of Systematic Reviews. Feb 1, 2018