Influenza has been one of the most common viral infections for centuries. Perhaps the most destructive and well-remembered outbreak occurred in 1918 when approximately 500 million people world-wide were infected with what became known as the Spanish Flu.1

The first influenza vaccine was developed in the 1933 for Influenza A, as Influenza B was not isolated until the 1940s. The first bivalent influenza vaccination was developed shortly thereafter in 1942.1

Due to the rapidly evolving nature of influenza, an annual flu vaccination is developed to protect against infection from the most prevalent strains of the virus that experts anticipate will be circulating during the upcoming season, including 2 subtypes of Influenza A (H1N1 and H3N2) and 2 lineages of Influenza B (Victoria and Yamagata). A new vaccine is annually developed based on scientific modeling and testing to determine which strains will be most prevalent in the upcoming influenza season.2

Vaccination timing depends on geographic location. The Northern Hemisphere’s flu season lasts from approximately October to March, but it is possible to contract influenza at any time. After vaccination, there is approximately a 2-week window where a vaccinated individual is still susceptible while the body forms an immune response due to the vaccine.3

Because influenza has a long seasonal cycle, the question regarding whether multiple influenza vaccinations, spaced throughout the season, could provide added protection has arisen. There is validity to this question as previous studies have shown decreasing influenza vaccine protection with increasing time since vaccination.4 The vaccine’s efficacy (VE) against strains of H3N2 (VE 0% 111 days after vaccination) and Influenza B (VE 21.4% at season end) in particular decreased compared to its efficacy against H1N1 (VE 50.3% at season end).5

A study by Ferdinands et al. showed a consistent rate of decline in vaccination effectiveness, about 7% decrease per month, in H3N2, H1N1, and Influenza B.4 Several studies agree that vaccination effectiveness declines significantly by 5 to 6 months after vaccination depending on the influenza strain.4,5

Additionally, studies show that in some patient populations a 2-dose regimen of the seasonal influenza vaccination can induce greater seroprotection against influenza.6,7,8 A 2-dose regimen is given because a singular dose in these patients does not stimulate the immune system enough to produce a protective number of antibodies.9

The first dose of the 2-dose regimen serves to prime the immune system by activating antigen-specific helper T-cells, while the second dose provides the immunity by causing the primed cells to differentiate into effector or memory cells that can mount a stronger response to the vaccine.15 While there is a large amount of consistent evidence for young, vaccine-naïve children receiving a 2-dose regimen, the data for a 2-dose regimen in other patient populations is conflicting. For example, some studies have shown benefit in patients with solid organ transplant, while other studies did not indicate added benefit.6,10,11 However, in these studies the vaccinations were given as contiguous doses with only 2-4 weeks between the 2 doses.

In the past, it has been thought that older adults lost seroprotection associated with influenza vaccination more quickly than younger patients.13 However, recent studies have shown that there is not as much decrease in seroprotection as previously thought.

A study conducted by Skowronski et al. indicates that older adults who achieved seroprotection rates of 70-100% with initial vaccination maintained immunity for 5-6 months, which is comparable to other age demographics.13 A second dose of the influenza vaccine, given 4 weeks after the initial dose, does not significantly improve seroprotective rates overall in geriatrics in studies.12,13 However, it may have the potential to lengthen the duration of immunity.

A study by Matsushita et al. showed that when given a 2-dose regimen, with doses given 4 weeks apart, seroprotection rates against H3N2 (-4.9%) and Influenza B (-8.8%) did not decline between 4 and 22 weeks after vaccination in older adults; however protection against strain H1N1 (-19.3%) did decline significantly, which should be a consideration in years when H1N1 is the predominant strain circulating.14 Similarly, overall seroprotection rates did not decline significantly differently in adults > 75 years (-20.8%) when compared to adults < 75 years (-17.1%).14

Considering the conflicting evidence of these studies, a multi-dose regimen of the yearly influenza vaccine is not recommended at this time except in influenza vaccine naïve children aged 6 months to 8 years old, and in select solid organ transplant patients. A 2-dose regimen for older adults has been explored, but additional data is needed before a conclusive recommendation can be made on whether or not a second dose is warranted. Other specialized patient populations may benefit from a multi-dose regimen, but as with older adults, more studies should be done to determine the efficacy before such a regimen is implemented into practice.

For now, optimizing influenza vaccine coverage is often best addressed with immunization timing. Patients should wait until the recommended time to be vaccinated to ensure immunity will last throughout influenza season.

 
Marilyn Bulloch PharmD, BCPS, FCCM is an inpatient pharmacist in Tuscaloosa, Alabama, and a faculty member with Auburn University in Arkansas.

Chad Hartley II is a 2022 PharmD candidate at Auburn University, Harrison School of Pharmacy in Arkansas.