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Long-term studies will track indelible marks of first flu

Immunological imprinting could provide hints to development of better vaccines.

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Child with Flu.

Credit: iStock/Getty

The US National Institutes of Health (NIH) has awarded two major grants to fund the first large-scale, long-term studies of how infants’ first exposures to influenza shape their immune systems. Researchers will follow the children for several years, starting at birth, to decipher how these early imprints affect an individual’s ability to fight off different strains later in life.

The work could also help to explain why a flu vaccine administered in any given year might work well in one person but not in another, and whether a child is better protected if their first encounter is with a wild virus, rather than the weakened forms found in vaccines. It will also feed into efforts to develop a universal flu vaccine that could offer lifelong protection against most seasonal strains.

Paul Thomas, an immunologist at St. Jude Children’s Research Hospital in Memphis, Tennessee, and Aubree Gordon, an epidemiologist at the University of Michigan in Ann Arbor, lead a consortium that will share a 7-year, US$35-million grant from the US National Institute of Allergy and Infectious Diseases (NIAID), part of the NIH. The team will establish infant cohorts — groups to be followed long-term — in Nicaragua, in Los Angeles, California, and in Wellington, New Zealand. A second 7-year award, of $31 million, went to a group led by Mary Allen Staat, an epidemiologist at Cincinnati Children’s Hospital Medical Center in Ohio. This team will establish maternal-infant cohorts in Mexico City and in Cincinnati.

Moving target

Influenza viruses are constantly mutating, with one season’s strains never exactly like the last. A new vaccine has to be developed and administered afresh, with each new flu season. Current seasonal flu vaccines are not very effective, and the protection they offer fades within months.

But the strains to which individuals were first exposed in childhood influences how they respond to the flu strains and vaccines in a given flu season. This is called imprinting: the strains of a pathogen encountered as a child leave an indelible mark on the immune system, protecting a person for life from closely related strains — but not from others that are encountered later. Imprinting also makes people more responsive to vaccines for similar strains than to vaccines for very different ones.

Children born in one flu season will have been exposed to different strains than children born in the previous or following season, and so will have different imprints. As a result, the human population is a vast mosaic of individuals with a range of flu susceptibilities.

Imprinting gives scientists hope that longer-lasting and broader-acting flu vaccines are possible. “I think that it is excellent that NIAID is investing in research to determine how childhood influenza exposures shape immune responses to future influenza-virus encounters,” says Scott Hensley, a viral immunologist at the University of Pennsylvania in Philadelphia. “These studies might reveal why some individuals do not respond effectively to current vaccines, and there is a good chance that this will directly inform the rational development of new and improved influenza vaccines.”

Senior advantage

Scientists don’t have a good understanding of the exact mechanisms behind infant flu imprinting. One theory is that of ‘antigenic seniority’, which says that strains encountered in childhood are given a ‘senior’ position in the immune response, and that subsequent strains are treated as less important. “While it is well accepted that imprinting happens, the mechanisms that govern it essentially remain a black box,” says Matthew Miller, who works on flu immunology at McMaster University in Hamilton, Canada.

The two large infant-cohort studies will provide unparalleled opportunities to unlock the secrets of imprinting. The Nicaraguan site, in particular, already has many of the platforms for enrolling newborns and collecting and analysing samples, because it is home to the NIAID-supported Nicaraguan Pediatric Influenza Cohort Study, which has enrolled infants continuously since 2011 to study the incidence and severity of flu in childhood. As a result, Gordon, who heads the ongoing study, says that she hopes to begin enrolling for the new project at the site by July.

Gordon and Thomas’s three sites will enrol a total cohort of 2,200–3,500 children, says Gordon. That includes 930 infants already enrolled in Nicaragua for whom stored blood samples and histories are available. The California and new Zealand sites will each enrol for three years and follow the children for at least the seven years of the grant, but hope to find further funding to extend the studies until the children reach puberty, or beyond. The Nicaraguan site plans to enrol for all 7 years, and follow children until their 15th birthdays.

The Cincinnati and Mexico City sites each plan to enrol around 1,080 infants, at a pace of 360 per year for 3 years, and follow them up for the duration of the project. Staat also hopes to find further funding to extend follow-up studies.

One at a time

The researchers will take blood and other samples from the infants periodically. Using recently developed technologies that sort hundreds of thousands of single cells from the samples, they will sequence RNA from individual immune-system cells to track patterns of gene activity over time and in response to flu exposures. These techniques allow researchers to profile entire repertoires of immune cells and other components of the immune system at depths impossible until now.

The scientists will be able to analyse samples taken from individual infants repeatedly over years — including before and after the initial imprinting events, during later flu infections and convalescence, and before and after flu vaccinations. Thomas expects the study to generate models of how children’s immune systems respond to flu infections and vaccinations, depending on their history and types of exposure. “The impact of this work is potentially enormous,” says Miller.

The two consortia have begun talks to see how they might best work together. “It is my hope that there will be a great deal of collaboration and complimentary expertise that will improve upon what both groups have proposed,” says Staat.

Nature 569, 464-465 (2019)

doi: 10.1038/d41586-019-01524-9
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