It could be challenging to get anyone to think about another infectious disease besides COVID-19 these days, but flu season is almost upon us, and it could dramatically make the current global pandemic even worse. Now, to add an even greater level of complexity for viral infections in humans, researchers at the University of Pennsylvania’s (UPenn) Perelman School of Medicine have just released findings 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.

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.

“We found that different aged individuals have different H3N2 flu virus antibody specificities,” explained senior study investigator Scott Hensley, PhD, an associate professor of microbiology at Penn Medicine. “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.”

Findings from the new study were published recently in Nature Communications through an article titled, “Middle-aged individuals may be in a perpetual state of H3N2 influenza virus susceptibility.”

In the current study, the UPenn researchers completed a serological survey using serum samples collected in the summer months prior to the 2017–2018 season from 140 children (ages 1 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.

“We completed 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,” the authors wrote. “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.”

Neutralizing antibodies can prevent viral infections, whereas non-neutralizing antibodies can only help after infection takes place. The research team saw that 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,” concluded lead study investigator Sigrid Gouma, PhD, a postdoctoral researcher of microbiology at UPenn.

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