All human influenza A viruses over the past 130 years have belonged to H1, H2, or H3 subtypes - and until 1977 - only one influenza A subtype circulated at a time. Each time a pandemic virus emerged (H1N1 in 1918, H2N2 in 1957, H3N2 in 1968) the new virus quickly supplanted the old influenza A virus.
This viral monarchy ended in 1977 when - for the first time on record - a second influenza A virus (H1N1) began to co-circulate with the existing (H3N2) virus. This surprise return of H1N1, after a 20 year absence - sparked a pseudo-pandemic in those born after 1957 (see Pseudo Pandemics And Viral Interlopers).
Descendants of the 1977 H1N1 virus were supplanted in 2009 by the pandemic H1N1 virus, and once again - H3N2 survived the transition - making it the longest-lived (52 years and counting) continually circulating influenza A subtype on record.
But as we've discussed often, H3N2 has continually evolved, and diversified over the years making it antigenically quite different from the virus that first circulated in the late 1960s and 1970s (see The Enigmatic, Problematic H3N2 Influenza Virus).
While counter-intuitive, this susceptibility is believed to be due to OAS (Original Antigenic Sin) - a term coined in 1960 by Thomas Francis, Jr. in the article On the Doctrine of Original Antigenic Sin).So different in fact, that those born during that time may be at greater risk of H3N2 infection today, than those born before or since.
Francis postulated that when the body’s immune system is exposed to and develops an immunological memory to a specific virus, it may be less able to mount a defense against a subsequent exposure to a second slightly different version of the virus.
We recently revisited the topic in Scripps Research: Study Suggests Some Flu Viruses May Be Less Susceptible To A `Universal' Flu Vaccine.
I've posted a link, and a brief excerpt, from the study, followed by a press release from Penn Medicine at the University of Pennsylvania. Follow the link to read the study in its entirety. I'll have a brief postscript when you return.
Open Access
Published: 11 September 2020
Middle-aged individuals may be in a perpetual state of H3N2 influenza virus susceptibility
Sigrid Gouma, Kangchon Kim, Madison E. Weirick, Megan E. Gumina, Angela Branche, David J. Topham, Emily T. Martin, Arnold S. Monto, Sarah Cobey & Scott E. Hensley
Nature Communications volume 11, Article number: 4566 (2020) Cite this article
Abstract
Influenza virus exposures in childhood can establish long-lived memory B cell responses that can be recalled later in life. Here, we complete a large serological survey to elucidate the specificity of antibodies against contemporary H3N2 viruses in differently aged individuals who were likely primed with different H3N2 strains in childhood.
We find that most humans who were first infected in childhood with H3N2 viral strains from the 1960s and 1970s possess non-neutralizing antibodies against contemporary 3c2.A H3N2 viruses. We find that 3c2.A H3N2 virus infections boost non-neutralizing H3N2 antibodies in middle-aged individuals, potentially leaving many of them in a perpetual state of 3c2.A H3N2 viral susceptibility.
Introduction
Most humans are infected with influenza viruses by 3–4 years of age1 and have high antibody titers against viral strains encountered early in life2. Early childhood influenza exposures can leave lifelong immunological imprints that affect how an individual responds to antigenically distinct viral strains later in life3,4. H3N2 influenza viruses began circulating in humans in 1968 and have evolved substantially over the past 51 years5. Therefore, an individual’s birth year largely predicts which specific type of H3N2 virus they first encountered in childhood.
Individuals’ immunological imprint from early childhood infection likely lessens severity but does not prevent infection
September 11, 2020PHILADELPHIA — Penn Medicine researchers have found that middle-aged individuals — those born in the late 1960s and the 1970s — may be in a perpetual state of H3N2 influenza virus susceptibility because their antibodies bind to H3N2 viruses but fail to prevent infections, according to a new study led by Scott Hensley, PhD, an associate professor of Microbiology at the Perelman School of Medicine at the University of Pennsylvania. The paper was published today in Nature Communications.“We found that different aged individuals have different H3N2 flu virus antibody specificities,” Hensley said. “Our studies show that early childhood infections can leave lifelong immunological imprints that affect how individuals respond to antigenically distinct viral strains later in life.”Most humans are infected with influenza viruses by three to four years of age, and these initial childhood infections can elicit strong, long lasting memory immune responses. H3N2 influenza viruses began circulating in humans in 1968 and have evolved substantially over the past 51 years. Therefore, an individual’s birth year largely predicts which specific type of H3N2 virus they first encountered in childhood.Researchers completed a serological survey — a blood test that measures antibody levels — using serum samples collected in the summer months prior to the 2017-2018 season from 140 children (ages one to 17) and 212 adults (ages 18 to 90). They first measured the differences in antibody reactivity to various strains of H3N2, and then measured for neutralizing and non-neutralizing antibodies. Neutralizing antibodies can prevent viral infections, whereas non-neutralizing antibodies can only help after an infection takes place. Samples from children aged three to ten years old had the highest levels of neutralizing antibodies against contemporary H3N2 viruses, while most middle-aged samples had antibodies that could bind to these viruses but these antibodies could not prevent viral infections.Hensley said his team’s findings are consistent with a concept known as “original antigenic sin” (OAS), originally proposed by Tom Francis, Jr. in 1960. “Most individuals born in the late 1960s and 1970s were immunologically imprinted with H3N2 viruses that are very different compared to contemporary H3N2 viruses. Upon infection with recent H3N2 viruses, these individuals tend to produce antibodies against regions that are conserved with older H3N2 strains and these types of antibodies typically do not prevent viral infections.”According to the research team, it is possible that the presence of high levels of non-neutralizing antibodies in middle-aged adults has contributed to the continued persistence of H3N2 viruses in the human population. Their findings might also relate to the unusual age distribution of H3N2 infections during the 2017-2018 season, in which H3N2 activity in middle-aged and older adults peaked earlier compared to children and young adults.The researchers say that it will be important to continually complete large serological surveys in different aged individuals, including donors from populations with different vaccination rates. A better understanding of immunity within the population and within individuals will likely lead to improved models that are better able to predict the evolutionary trajectories of different influenza virus strains.“Large serological studies can shed light on why the effectiveness of flu vaccines varies in individuals with different immune histories, while also identifying barriers that need to be overcome in order to design better vaccines that are able to elicit protective responses in all age groups,” said Sigrid Gouma, PhD, a postdoctoral researcher of Microbiology and first author on the paper.Other Penn authors include Madison Weirick and Megan E. Gumina. Additional authors include Angela Branche, David J. Topham, Emily T. Martin, Arnold S. Monto, and Sarah Cobey.This work was supported by the National Institute of Allergy and Infectious Diseases (1R01AI113047, S.E.H.; 1R01AI108686, S.E.H.; 1R01AI097150, A.S.M.; CEIRS HHSN272201400005C, S.E.H., S.C., E.T.M., A.S.M. A.B., D.J.T.) and Center for Disease Control (U01IP000474, A.S.M.). Scott E. Hensley holds an Investigators in the Pathogenesis of Infectious Disease Awards from the Burroughs Wellcome Fund.
Four years ago, in Science: Protection Against Novel Flu Subtypes Via Childhood HA Imprinting, we looked at new research which suggested the influenza HA Group type you are first exposed to also makes a significant, and lasting, impression on your immune system.
And that the resultant immune response may carry over to other - similarly grouped - subtypes.
While more theoretical than proven, this suggests if your first influenza exposure was to H1N1 or H2N2 (group1), you may carry some degree of immunity to the H5 viruses (H5N1, H5N6, etc.), while if your first exposure was to H3N2 (group 2), you may carry some protection against H7 viruses instead.
