Prior exposure to one strain of influenza virus may weaken children’s ability to mount an effective antibody response against subsequent exposure to a different flu strain, according to a study led by Weill Cornell Medicine investigators. The analysis focused on the pediatric response to H3N2 and H1N1 influenza A viruses, two of the most common causes of flu, providing insight into the concept of “immune imprinting” and supporting the idea that childhood vaccination, if properly designed, may mitigate its adverse effects.
Immune imprinting, first described in 1960, refers to a long-term bias or skew in the immune response that a first viral exposure can introduce, potentially impairing subsequent responses to closely related viruses. Although imprinting has been challenging to research and remains not fully understood, the study published on March 11 in Nature sheds new light on this phenomenon.
Understanding Immune Imprinting
In the study, researchers analyzed antibodies from participants, including children aged 2 to 6 years, who had their sequential first exposures to the two types of influenza A viruses circulating in humans. They found that following an initial H3N2 exposure, antibodies generated that could bind both H3N2 and H1N1 were ineffective at stopping most H1N1 strains.
Structural analyses and other experiments linked this imprinting effect to a key site on the viral antigen that is similar on H3N2 and H1N1. By first shaping the immune response to the H3N2 virus, the children became unable to properly adapt to this site on the H1N1 virus. However, the researchers also found evidence that simultaneous vaccination in infancy against H3N2 and H1N1 may eliminate this imprinting problem.
“These findings are a reminder that the effectiveness of a vaccine against a given virus may be impacted by a past exposure to a related virus, which can make vaccine design a lot tougher,” said senior author Patrick Wilson, the Anne E. Dyson Professor of Pediatric Research and a member of the Gale and Ira Drukier Institute for Children’s Health at Weill Cornell Medicine.
The Study’s Methodology and Findings
The collaborative study included contributions from many institutions, including Scripps Research, St. Jude Children’s Research Hospital, and the University of Michigan School of Public Health. A first exposure to a virus induces an initial “de novo” B cell response, including secretion of serum antibodies and the creation of a long-lived pool of memory B cells, which can produce antibodies rapidly if they encounter the virus again.
The imprinting problem is thought to arise when a related virus triggers this memory response, creating a surge of antibodies that may not effectively neutralize the new threat and may even hinder the immune system’s ability to mount a robust de novo response. The problem is believed to be directly linked to the immunity elicited by initial exposures in early childhood.
The study covered 40 participants, half of whom were young children with confirmed first exposures to H3N2 then H1N1, or vice versa. Participants came from two larger, clinic-based studies that enrolled children with flu symptoms and analyzed their immune responses—and often those of other household members—over years to better understand the development of immunity to flu viruses.
“This was a really unique cohort of participants providing us an opportunity to study imprinting of influenza virus through a relatively clean analysis,” said first author Jiayi Sun, a postdoctoral associate in pediatrics in the Wilson laboratory.
Implications for Future Vaccinations
As expected, adult participants showed signs of having built stronger and more versatile immunity through a lifetime of exposures. In some children, however, imprinting that impaired immunity was evident. The children who had encountered the two flu subtypes sequentially over time induced “cross-reactive” antibodies capable of binding both subtypes at the stalk region of the flu virus’s main outer envelope protein hemagglutinin—a site almost identical in both subtypes and therefore of major interest to improve future influenza vaccines that might protect against all influenza strains.
In children with H3N2-then-H1N1 exposures, compared to other groups, these cross-reactive antibodies generally bound much better to the H3N2 stalk than to H1N1’s and were relatively ineffective against the encountered H1N1 strain. Experiments also showed that these H3-imprinted antibodies, binding weakly to the H1N1 stalk region, could block binding by an anti-H1 stalk antibody that more potently neutralized the virus.
The H3N2-imprinted antibodies that appeared after H1N1 exposure were also strikingly ineffective against older H1N1 strains, which may pose a future threat. Using cryo-electron microscopy-based analyses, researchers determined that this loss of activity was likely due to a single amino-acid change differing by only an atomic group in the stalk region in older H1N1 strains, compared to more recent H1N1 and H3N2 strains. The impact of such a minute molecular difference on the activity of nearly all antibodies to the shared stalk epitope from seven different children was surprising.
“This shows that it doesn’t take much to render your memory antibody response ineffective,” Wilson said.
B cells from infants vaccinated simultaneously against H1N1 and H3N2—with a seasonal flu vaccine that typically contains both—showed no sign of this deleterious imprinting. Currently, the American Academy of Pediatrics and other public health authorities recommend the seasonal flu vaccine for all children aged 6 months and older.
Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, see the profile for Dr. Patrick Wilson.
Jim Schnabel is a freelance writer for Weill Cornell Medicine.
