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Influenza immunization elicits antibodies specific for an egg-adapted vaccine strain


For broad protection against infection by viruses such as influenza or HIV, vaccines should elicit antibodies that bind conserved viral epitopes, such as the receptor-binding site (RBS). RBS-directed antibodies have been described for both HIV1,2,3 and influenza virus4,5,6,7,8, and the design of immunogens to elicit them is a goal of vaccine research in both fields. Residues in the RBS of influenza virus hemagglutinin (HA) determine a preference for the avian or human receptor, α-2,3-linked sialic acid and α-2,6-linked sialic acid, respectively9,10. Transmission of an avian-origin virus between humans generally requires one or more mutations in the sequences encoding the influenza virus RBS to change the preferred receptor from avian to human9,11,12, but passage of a human-derived vaccine candidate in chicken eggs can select for reversion to avian receptor preference13,14,15. For example, the X-181 strain of the 2009 new pandemic H1N1 influenza virus, derived from the A/California/07/2009 isolate and used in essentially all vaccines since 2009, has arginine at position 226, a residue known to confer preference for an α-2,3 linkage in H1 subtype viruses13,14; the wild-type A/California/07/2009 isolate, like most circulating human H1N1 viruses, has glutamine at position 226. We describe, from three different individuals, RBS-directed antibodies that recognize the avian-adapted H1 strain in current influenza vaccines but not the circulating new pandemic 2009 virus; Arg226 in the vaccine-strain RBS accounts for the restriction. The polyclonal sera of the three donors also reflect this preference. Therefore, when vaccines produced from strains that are never passaged in avian cells become widely available, they may prove more capable of eliciting RBS-directed, broadly neutralizing antibodies than those produced from egg-adapted viruses, extending the established benefits of current seasonal influenza immunizations.

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Figure 1: B cell clonal lineage CL6515 from Siena patient 7.
Figure 2: Structure of Fab 6639 bound with uncleaved HA (HA0) of the X-181 vaccine strain.
Figure 3: Serum antibody repertoire and analysis of three antibodies from donor 1 of the 2011–12 cohort.

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We thank C.L. Dekker (Department of Pediatrics, Stanford University) and S.R. Quake (Department of Bioengineering and Applied Physics, Stanford University) for the serum samples analyzed in Supplementary Table 1, and the staff members at Advanced Photon Source sector 24 (NE-CAT) and Advanced Light Source beamline 8.2.2 for assistance with X-ray data collection. The NE-CAT beamlines are funded by NIH grant P41 GM103403, and the APS is operated for the DOE Office of Science by Argonne National Laboratory under contract DE-AC02-06CH11357. The research in the authors' laboratories was supported by NIH grants P01 AI089618 (S.C.H.) and 5U19 AI057234 (G.G.), DTRA contract HDTRA 1-12-C-0105 (G.G.), and the Clayton Foundation for Research (G.G.). S.C.H. is an Investigator in the Howard Hughes Medical Institute.

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D.D.R., S.M.S., J.L., J.F., G.B., K.T.D., M.J.E., P.S. and M.A.M. performed experiments and analyzed data; E.C.S., G.G., T.B.K., H.-X.L., A.G.S. and S.C.H. analyzed data; and D.D.R., S.M.S., J.L., J.F., G.B., E.C.S., P.R.D., G.D.G., O.F., T.H.K., G.C.I., G.G., T.B.K., B.F.H., M.A.M., H.-X.L., A.G.S. and S.C.H. wrote, edited or commented on the manuscript.

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Correspondence to Stephen C Harrison.

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J.F., P.S. and E.C.S. are employees of Seqirus; P.R.D. is an employee of Pfizer, Inc.; and G.D.G. and O.F. are employees of GSK Vaccines (Siena, Italy). Each of these companies has research and development programs related to influenza vaccines.

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Raymond, D., Stewart, S., Lee, J. et al. Influenza immunization elicits antibodies specific for an egg-adapted vaccine strain. Nat Med 22, 1465–1469 (2016).

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