Study Finds Past H1n1 Exposure Shields Animals From Deadly H5n1

Could your erstwhile flu infection protect you from vertebrate flu? Scientists find that immunity to 2009 H1N1 slashes nan consequence of terrible H5N1 illness, moreover aft adjacent interaction exposure.

Study: Preexisting immunity to nan 2009 pandemic H1N1 microorganism reduces susceptibility to H5N1 infection and illness successful ferrets. Image Credit: digicomphoto / Shutterstock

In a caller study published successful nan diary Science Translational Medicine, a group of researchers tested whether infection-elicited immunity to influenza A microorganism (IAV) subtypes hemagglutinin 1 neuraminidase 1 (H1N1) aliases hemagglutinin 3 neuraminidase 2 (H3N2), and nan bid of exposure, lessens ferret susceptibility to and illness from clade 2.3.4.4b hemagglutinin 5 neuraminidase 1 (H5N1), including aft nonstop interaction pinch a dairy cattle isolate.

Background

By property five, astir group person already encountered IAVs, leaving an immune imprint that shapes their responses to later exposures. Since 2020, clade 2.3.4.4b H5N1 has swept done birds and spilled complete into mammals, including an unprecedented outbreak successful United States dairy cows, affecting 989 herds successful 17 states wrong a year, and 41 laboratory-confirmed infections successful workplace workers by June 2025.

Most quality cases person been mild, prompting a cardinal question: tin preexisting immunity to seasonal strains blunt H5N1 disease? Understanding nan reply matters for workers, clinicians, and pandemic planners.

Further investigation is needed to explain really imprinting and cross-reactive antibodies prolong protection complete time.

About nan study

The researchers utilized a well-established ferret exemplary because ferrets recapitulate cardinal features of quality influenza pathogenesis and transmission. They first induced preexisting immunity by infecting animals pinch either B/Brisbane/60/2008 influenza B microorganism (IBV), A/Perth/16/2009 seasonal H3N2 IAV, aliases A/California/07/2009 pandemic H1N1 IAV.

In a abstracted experiment, ferrets received 2 sequential infections, 90 days apart, to trial nan effect of immune imprinting. Ninety days aft nan past seasonal infection, animals were either intranasally challenged pinch 10² insubstantial civilization infectious dose 50% (TCID₅₀) of an A/mink/Spain/2022 highly pathogenic H5N1 microorganism aliases brace housed pinch a naïve cage mate that had been inoculated pinch 10¹⁰ TCID₅₀ of nan A/dairy cattle/Texas/2024 H5N1 microorganism to exemplary nonstop interaction exposure.

Nasal washes were collected each different time and titrated connected Madin-Darby canine kidney cells; assemblage weight, objective scores, and endurance were monitored. Serum immunoglobulin G (IgG) binding, neutralizing, and neuraminidase-inhibiting antibodies were quantified by enzyme-linked immunosorbent assay (ELISA), microneutralization, and enzyme-linked lectin assay (ELLA), respectively.

Predetermined humane endpoints triggered euthanasia. Four ferrets were utilized per group; nan experiments were not randomized aliases blinded. Statistical comparisons utilized study of variance aliases nonparametric tests arsenic appropriate, and endurance was analyzed utilizing nan Mantel-Cox trial successful Prism.

Study results

Preexisting immunity mattered, arsenic compared pinch immunologically naïve aliases IBV-preimmune ferrets, animals antecedently infected pinch nan 2009 pandemic H1N1 IAV shed markedly little microorganism aft situation pinch nan A/mink/Spain/2022 H5N1 strain, maintained assemblage weight, showed nary objective illness, and each survived.

Seasonal H3N2 IAV immunity offered partial protection: viral titers were intermediate, immoderate animals mislaid notable weight, but each survived. Only H1N1 pre-immune ferrets mounted robust IgG responses to H1N1, and these antibodies neutralized H1N1 and inhibited nan neuraminidase activity of H5N1; they besides showed low, non-neutralizing cross-reactivity to H5 hemagglutinin.

When nan squad layered infections to probe immune imprinting, nan shape held. Regardless of whether H1N1 came first aliases second, immoderate group that included nan 2009 H1N1 microorganism shed minimal aliases nary H5N1 and did not create disease. In contrast, ferrets that knowledgeable 2 rounds of IBV infection, aliases nan series H3N2 followed by IBV, shed precocious titers, mislaid astatine slightest 15 percent of assemblage weight, and up to half reached humane endpoints. Thus, bid mattered little than simply having H1N1 successful nan infection history.

Finally, successful a nonstop interaction research modeling nan high-dose exposures seen during dairy milking, naïve philanthropist ferrets infected pinch a dairy cattle H5N1 strain transmitted nan microorganism to 100% of naïve cage mates, causing universally lethal disease. Prior H3N2 immunity did not forestall infection; each interaction shed virus, and only half survived. Prior H1N1 immunity substantially raised nan bar: only half of contacts had low, transient shedding connected a azygous day, nary developed objective disease, and each survived.

Together, these information show that infection-elicited immunity to nan 2009 H1N1 microorganism reduces susceptibility to, replication of, and illness caused by modern clade 2.3.4.4b H5N1 viruses successful ferrets, whereas H3N2 immunity unsocial confers incomplete and adaptable protection.

Mechanistically, H1N1 vulnerability generated precocious titers of cross-reactive N1 neuraminidase–binding antibodies that inhibited nan dairy cattle and mink H5N1 neuraminidases, positive debased titers of group 1 hemagglutinin stem-directed antibodies that bound but did not neutralize H5. Nucleoprotein antibodies, a proxy for responses to conserved soul antigens, were comparable betwixt nan H1N1 and H3N2 groups, suggesting that nan superior protection successful H1N1-primed animals apt reflected hemagglutinin aliases neuraminidase cross-reactivity alternatively than broader immunity to soul proteins. These immunologic patterns reflector caller quality serology against clade 2.3.4.4b H5N1, reported successful independent studies.

Conclusions

To summarize, preexisting, infection-elicited immunity to nan 2009 pandemic H1N1 IAV acted arsenic a beardown obstruction against clade 2.3.4.4b H5N1 infection, replication, and illness successful ferrets, moreover aft high-dose nonstop interaction exposure. Immunity to seasonal H3N2 IAV attenuated but did not reliably forestall infection aliases illness. The bid of earlier infections (immune imprinting) did not erode nan protection conferred by H1N1 exposure.

While nan authors admit definite limitations, specified arsenic nan fixed 90-day infection intervals not reflecting quality timelines and an inability to measure cellular immunity, these findings thief explicate why astir caller quality H5N1 infections linked to dairy cows person been mild and reason that neuraminidase-focused cross-reactivity should beryllium considered successful preparedness strategies, vaccine design, consequence assessment, and objective surveillance policies.