When is the flu vaccine born?

The 1918-19 influenza pandemic in the early 1933th century stimulated influenza virus research, and in 1936, influenza type A was isolated in ferrets. In XNUMX, type B influenza was isolated, and an Australian scientist discovered that the virus could be grown in embryonic chicken eggs. These findings fueled interest in developing an influenza vaccine that would reduce mortality in future epidemics and pandemics.^(1-2)

The first flu vaccine was developed in 1938 and administered to U.S. soldiers during World War II. A 1944 study of the new influenza vaccine determined that, while it was useful for reducing illness at temperatures above 37.2°C, it did not appear to impact clinical outcomes. In 1947, further evaluation of the influenza vaccine found no difference in health outcomes between those who had been vaccinated and those who had not.^(3-4)

The first influenza vaccines contained only the inactivated influenza type A virus (monovalent), but since 1942 there was a bivalent vaccine containing both type A and type B influenza. This first vaccine caused localized and systemic reactions, especially in children. Despite little evidence of effectiveness, the influenza vaccine was authorized for use in the United States in 1945.^(5-6-7-8)

When the predicted "Asian" influenza pandemic materialized in the 1957–1958 influenza season, production of a vaccine against this pandemic influenza strain was quickly initiated, in the hope that it would limit mortality and reduce the severity of disease in vaccinated people. About 40 million doses of the vaccine were administered to people in the United States. However, due to low efficacy and limited availability, public health officials reported that "the vaccine had no appreciable effect on the progress of the pandemic."⁽⁹⁾ The failure was presumed to be primarily related to lack of availability of the vaccine, and by the 1960s, health officials began recommending routine influenza vaccination each year for the elderly and certain high-risk groups.⁽¹⁰⁾

A review of this "annual flu vaccine" recommendation four years later found little evidence that annual vaccination of older adults and others deemed to be at high risk for influenza had any appreciable impact on influenza-related death rates. A randomized, double-blind study conducted in 1968 by CDC officials and published by the World Health Organization (WHO) reached similar conclusions and even suggested that "attention should be redirected to the search for a more effective means of protection." .⁽¹¹⁾ However, despite studies demonstrating the ineffectiveness of the flu vaccine, government vaccination policy recommendations for the annual vaccine continued.

In early 1976, two cases of H1N1 "swine flu" were confirmed in the United States, and public health officials, in collaboration with the pharmaceutical industry, decided to begin production of a vaccine due to concerns that this new strain of influenza type A could trigger a pandemic similar to that of 1918-19. The US Congress approved $137 million for vaccine production with the goal of vaccinating nearly all Americans before the start of the flu season.⁽¹²⁾

Mass production of the swine flu vaccine did not begin until the U.S. Congress gave in to demands from drug companies pushing for a product liability shield that would block vaccine injury lawsuits caused by the shots of swine flu.⁽¹³⁾ This decision cast doubt on 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 elderly people died after being vaccinated at the same clinic. In December 1976, numerous cases had been reported of people paralyzed due to Guillain-Barre syndrome (GBS), which had developed following vaccinations against swine flu and, as there was no evidence of an imminent influenza pandemic, the vaccination program against swine flu was cancelled.⁽¹⁴⁾

Despite this setback, production of seasonal influenza vaccines continued, and in 1978, the first trivalent influenza vaccine was authorized for use in the United States after scientists identified two different strains of influenza A that were circulating at the same time. The new inactivated trivalent influenza vaccine contained two strains of influenza A virus and one strain of influenza B virus.⁽¹⁵⁾

In 1984, the CDC recommended annual influenza vaccination for high-risk individuals, including adults over age 65, people with chronic illnesses or metabolic disorders, and people living in nursing homes or other long-term care facilities and healthcare workers. At the time, pregnancy was not considered a high risk factor for serious illness or complications from the flu. The 1984 Advisory Committee on Immunization Practices (ACIP) stated: “Pregnancy has not been shown to be a risk factor for severe influenza infection except in the great pandemics of 1918-1919 and 1957-1958.”.

However, in 1997, the CDC updated its flu vaccine recommendations to include pregnant women in their second or third trimester. This recommendation was considered an off-label use of the vaccine because the FDA had not authorized the influenza vaccine for use by pregnant women.⁽¹⁶⁾ The 1997 CDC recommendation was based on information in a small number of documents related to the 1918-1919 and 1957-1958 influenza pandemics, and on a few case reports and small studies reporting an increase in influenza-related hospitalizations in pregnant women.⁽¹⁷⁾

Between 1999 and 2010, the Advisory Committee on Immunization Practices' (ACIP) annual recommendations for seasonal influenza vaccine rapidly expanded to include more and more target populations. In 2004, newborns and children aged between 6 months and 23 months were added.⁽¹⁸⁾ The presence of thimerosal, a mercury-containing preservative found in all multivariant influenza vaccine vials, was discussed by ACIP due to a 1999 recommendation that it be eliminated from all vaccines routinely administered to children.⁽¹⁹⁾ In 2004, however, the CDC stated that "the benefits of influenza vaccination outweigh the theoretical risk, if any, of exposure to thimerosal through vaccination" and no recommendation has been made that infants, children, or pregnant women receive a thimerosal-free flu vaccine.⁽²⁰⁾

On April 26, 2009, public health officials declared a national public health emergency after the discovery of a new strain of influenza A (H1N1) identified first in Mexico and then in the United States.⁽²¹⁾ A new H1N1 pandemic swine flu vaccine was quickly licensed and made available to the public in October 2009, but a 2011 study on the efficacy of the 1 H1N2009 pandemic swine flu vaccine found it to have less efficacy overall of only 56%.⁽²²⁾

The influenza vaccine market has grown substantially since 2009 with the introduction of several new types of influenza vaccines and new delivery methods, including vaccines that use insect and animal cells for production instead of chicken eggs.

In 2012, the FDA approved the first quadrivalent influenza vaccine, containing two type A and two type B influenza viruses.⁽²³⁾ FluMist Quadrivalent, the live attenuated influenza vaccine, was made available for the 2013-2014 flu season, and several quadrivalent inactivated injectable vaccines followed soon after. Quadrivalent vaccines add another strain of influenza B virus to traditional trivalent vaccines, which contain two strains of influenza A virus and one strain of influenza B virus, with the goal of improving the effectiveness of the influenza vaccine .

The first cell-based flu vaccine, Flucelvax, was approved by the FDA in 2012, using canine kidney cells⁽²⁴⁾ instead of chicken embryos for vaccine production.⁽²⁵⁾ In 2013, Flublok, a recombinant flu vaccine that uses armyworm caterpillar cells instead of chicken embryos for production, was approved for use in adults ages 18 to 49.^(26-27-28) Flublok Quadrivalent received FDA approval for use in adults 18 years of age and older in July 2016.⁽²⁹⁾

On June 26, 2014, the CDC recommended that FluMist be given to healthy children ages 2 to 8 in place of inactivated injectable flu vaccines, but two years later, in June 2016, the CDC withdrew the recommendation on the basis of data that determined the total ineffectiveness of the vaccine in preventing influenza.^(30-32) On February 21, 2018, the CDC reinstated a new formulation of FluMist ahead of the 2018-2019 flu season. Vaccine efficacy studies on this new formulation of FluMist have not been completed, so it is not known whether the vaccine offers protection against influenza. The CDC voted against recommending FluMist over available injectable inactivated flu vaccines, but said it could be considered as an option if appropriate.⁽³²⁾

In 2015, the FDA approved FLUAD, a trivalent flu vaccine containing MF59, a squalene oil-based adjuvant that hyperstimulates the immune system to produce more antibodies, for use in adults 65 and older.⁽³³⁾ FLUAD's clearance was fast-tracked by the FDA despite concerns about the use of the squalene adjuvant and its association with immune and neurological disorders.⁽³⁴⁾

In addition to the increase in the types of flu vaccines available, manufacturers have also added new delivery methods. In 2012, the first intradermal (administered between the skin layers rather than into the muscle) flu vaccine was approved.⁽³⁵⁾ In 2014, the first jet injector (vaccine delivery device that uses high pressure) was made available to administer the flu vaccine.⁽³⁶⁾

As the influenza vaccine market has expanded, recommendations for use by the CDC's Advisory Committee on Immunization Practices (ACIP) have also increased.

In 2010, ACIP voted to recommend that every person over the age of six months, including pregnant women at any stage of pregnancy, receive an annual flu vaccine. The only contraindications were for people with a history of hypersensitivity or anaphylaxis to eggs or any other ingredient in the flu vaccine, or with a history of Guillain-Barre syndrome (GBS).⁽³⁸⁾

In 2011, however, the CDC began recommending the flu vaccine even to people who had previously developed hives following exposure to eggs.⁽³⁹⁾ In 2016, egg allergy was no longer considered a contraindication to receiving the influenza vaccine.⁽⁴⁰⁾

Currently, a severe allergy to a component of the vaccine or a history of a life-threatening allergic reaction to a previous influenza vaccine are the only CDC-approved official contraindications (medical reasons for not getting vaccinated) to receiving the influenza vaccine. A history of Guillain-Barre within 6 weeks of a previous influenza vaccine, a severe egg allergy (i.e., respiratory distress, recurrent vomiting, angioedema, lightheadedness, epinephrine treatment), or a "moderate or severe acute illness with or without fever" they are now considered only vaccination precautions. According to the CDC, individuals with a history of severe egg allergy can receive any flu vaccine indicated for their age without additional safety measures beyond those recommended for receiving any vaccine.⁽⁴¹⁾

Despite the ever-increasing number of flu vaccines available on the market, the effectiveness of flu vaccines has not improved much over the years. In 2003-2004, the CDC stepped up research efforts to determine the effectiveness of the seasonal influenza vaccine in preventing cases of influenza in vaccinated people.

Since 2004, the seasonal flu vaccine has failed to prevent flu in vaccinated people more than half the time, with a low of 10% effectiveness in 2004/2005 and a high of 60% effectiveness in 2010 /2011. The average effectiveness of flu vaccines over the past 19 flu seasons has been less than 40%.⁽⁴²⁾

The Cochrane Collaboration's 2014 review of the medical literature on the flu vaccine found a bias in the publication of research on the effectiveness and safety of the flu vaccine:

“A previous review of 274 influenza vaccine studies across all age groups (including most of the studies in this review) showed an inverse relationship between the risk of bias and the direction of the studies' conclusions. The favorable conclusions 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 not supported by the data presented. Additionally, industry-funded studies are more likely to have favorable conclusions, to be published in journals with a significantly higher impact factor and to have higher citation rates than studies not funded by industry. This difference is explained neither by size nor by methodological quality (Jefferson 2009a). Any interpretation of the This review's body of evidence should be done with these findings in mind."⁽⁴³⁾

The Cochrane review also concluded that recommendations for the routine use of influenza vaccine as a routine public health measure are not supported by published evidence and stated that:

“The findings of this review provide no evidence for the use of influenza vaccination in healthy adults as a routine public health measure. Because healthy adults have a low risk of complications from respiratory disease, the use of the vaccine can only be recommended as an individual protective measure."⁽⁴⁴⁾

The 2018 Cochrane review of influenza vaccination in healthy adults found that the influenza vaccine may have only 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 a impact on days of work missed or reduction of serious flu complications during flu season.⁽⁴⁵⁾