Ability to Produce immunity to Influenza A H3N2 Called Into Question for Certain Adults

Marilyn Bulloch, PharmD, BCPS

While the exact reason for the decreased immune response in middle-aged adults remains unclear, these findings suggest that this patient population may be continuously susceptible to the 3c2A H3N2 infection, even with immunization.

Protection against circulating influenza viruses is dependent on antibody titers to antigenically similar strains obtained via natural, or vaccine induced immunity.1 Most humans have high antibody titers against strains of influenza viruses encountered in early childhood and exposures at young ages influence how an individual reacts to antigenically distinct strains later on in life.2,3 A recent study published in Nature Communications indicates that adults born in the 1960s and 1970s may be less able to produce neutralizing antibodies to modern H3N2 strains, and subsequently middle aged patients may be continuously susceptible to Influenza A (H3N2) viruses.3

Influenza A (H3N2) first infected humans in the late 1960s.4 They have evolved significantly in the past 5 decades. Since 2014, an antigenically drifted descendant of the first 1968 H3N2 strain known as clade 3c2.A H3N2 viruses has circulated in high levels globally. These viruses uniquely contain a key glycosylation site that shields HA antigenic site B, the major target of neutralizing antibodies. They are also capable of producing a high flu-related morbidity and mortality burden. In the 2017-18 flu season alone, these influenza viruses were responsible for more than 800,000 hospitalizations and more than 60,000 deaths in the United States.5 The fact that 2c2.A H3N2 viruses were dominate in the 2017-18 season may seem surprising because they also were the most common strains in the 2014-15 and 2016-17 seasons, and it would be reasonably expected that many people would have developed immunity against them.

The study authors collected serological samples from different aged individuals in the summer months prior to the 2017-18 influenza season.3 These investigators then characterized antibodies from patients with confirmed 3c2.A H3N2 infections prior to the 2017-18 flu season to see if antibodies would be effective in neutralizing H3N2 viruses circulating in the subsequent 2017-18 season (referred to as 3c2.A2). There were 3 amino acid substitutions seen on the HA of the 3c2.A2 H3N2 viruses compared to the HA of the 3c2.A H2N2 viruses. Over 89% of study patients aged 4 years and older had HA ELISA-reactive antibodies to 3c2.A and 3c2.A2. All but 3 of those who did not were under the age of 4 years and were thought not to have been previously exposed to H3N2 virus.

The study found that children aged 3-10 years had the highest levels of neutralizing antibodies for the viruses. It also showed that most middle-aged adults did not have detectable neutralizing antibody titers against 3c2.A or 3c2.A2 H3N2 viruses. In fact, the lowest titers were measured in patients born in 1967, a year before H3N2 introduction into human circulation. It should also be noted that there did not seem to be any significant HA antigenic changes between the 2014-15 3c2.A and 2017-18 3c2.A2 strains, which usually results in at least some immunity after exposure.

The authors contend that childhood infections that current middle-aged adults experienced in the 1960s and 1970s primed antibody responses that are reactive, but not neutralizing against modern 3c2.A H3N2 viruses. In short, people could produce non-neutralizing antibodies that could bind to the viruses’ HA but did not prevent infection.

The authors followed up on their findings by measuring HA and NA antibodies in a small sample of adults born between 1963 and 1979 before and after confirmed 3c2A H3N2 infection in the 2014-15 season.3 They found that HA ELISA antibody titers increased in serum 4-8 months after infection in most individuals, but neutralizing titers remained low. They also found that 3c2A neuraminidase (NA) antibodies increased but did not respond well to the antigenically drifted 3c2A2 NA from the 2017-18 season.

While the exact reason for the decreased immune response in middle-aged adults remains unclear, these findings suggest that this patient population may be continuously susceptible to the 3c2A H3N2 infection, even with immunization. It also provides some insight into the high infection rates of adults during seasons when H3N2 is the dominant circulating strain and why 3c2A viruses continue to circulate despite minimal to no antigenic drift. The study also raises questions about the existence of other age-related immune responses.

Further and larger studies are needed to fully evaluate immunity among different aged groups and birth years. Data from such studies could lead to a significant breakthrough in our understanding of immunity and subsequently change our influenza prevention approach.


1. Centers for Disease Control and Prevention. Immunogenicity, efficacy, and effectiveness of influenza vaccines. Accessed May 25, 2021. https://www.cdc.gov/flu/professionals/acip/immunogenicity.htm

2. Fonville JM et al. Antibody landscapes after influenza virus infection or vaccination. Science.2014;346:996-1000

3. Gouma S, Kim K, Weirick ME, et al. Middle-aged individuals may be in a perpetual state of H3N2 influenza virus susceptibility. Nature Communications.2020;11:4566

4. Allen JD, Ross TM. H3N2 influenza viruses in humans: viral mechanisms, evolution, and evaluation. Hum Vaccin Immunother.2018;14:1840-47

5. Centers for Disease Control and Prevention. Estimated influenza illnesses, medical visits, hospitalizations, and deaths in the United states – 2017-2018 influenza season. Accessed May 25, 2021. https://www.cdc.gov/flu/about/burden/2017-2018.html