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1 doi:.8/nature76 Abs V gene D gene J gene CDR CDR length Clone Name Origin Year Acc. No. FI7 IGHV-69* IGHD-* IGHJ* AGSATYYESRFDY BC 8 KJ9 FI6 IGHV-69* IGHD-* IGHJ* AGSGTYFVSRFDY BC 8 KJ98 FI7 IGHV-69* IGHD-6* IGHJ* AGSATYYESRFDY BC 8 KJ95 FI8 IGHV-69* IGHD-6* IGHJ* AGSGTYYVSRFDS BC 8 KJ98 FI85 IGHV-69* IGHD-6* IGHJ* AGSATYYESRFDY PC 9 KJ9 FI87 IGHV-69* IGHD-6* IGHJ* AGSATYYESRFDY PC 9 KJ99 FI9 IGHV-69* IGHD-9* IGHJ* ATSATYYISYFDS PC 9 KJ99 FI7 IGHV-69* IGHD-* IGHJ* ATSPTYYISHLDS PC 9 KJ96 FI6 IGHV-69* IGHD-6* IGHJ* AGSATYYESRFDY PC 9 KJ96 FI7 IGHV-69* IGHD-6* IGHJ* AGSGTYFVSRFDY PC 9 KJ9 FI IGHV-69* IGHD-6* IGHJ* AGSATYYESRFDY PC 9 KJ99 FI IGHV-69* IGHD-9* IGHJ* ATSATYYISYFDS PC 9 KJ9 FI IGHV-69* IGHD5/OR5-5a* IGHJ* AGSETYFVSRFDY PC 9 KJ986 FI IGHV-69* IGHD-6* IGHJ* AGSGTYYVSRFDY PC 9 KJ97 FI IGHV-69* IGHD-6* IGHJ* AGSATYYESRFDY PC 9 KJ99 FI7 IGHV-69* IGHD-6* IGHJ* AGSATYYESRFDY PC 9 KJ96 FI59 IGHV-69* IGHD-6* IGHJ* AGSATYYESRFDY PC 9 KJ996 FI67 IGHV-69* IGHD-6* IGHJ* AGSATYYESRFDY PC 9 KJ957 FI99 IGHV-69* IGHD-* IGHJ* ATSATYYISHFDY PC 9 KJ9 FI IGHV-69* IGHD-* IGHJ* ATSGTYYISHFDS PC 9 KJ966 FI59 IGHV-69* IGHD-6* IGHJ* AESGTYFVSRFDN BC KJ9 FI58 IGHV-69* IGHD-* IGHJ* AGSETYYVSRFDH BC KJ97 FI55 IGHV-69* IGHD-6* IGHJ* AESGTYFVSRFDS BC KJ9 FI57 IGHV-69* IGHD-* IGHJ* AGSGTYYVSRFDY PC 9 KJ995 FI58 IGHV-69* IGHD-* IGHJ* ATSPTYYISHLDS PC 9 KJ99 FI5 IGHV-69* IGHD-6* IGHJ* AGSATYYESRFDY PC 9 KJ988 FI555 IGHV-69* IGHD-6* IGHJ* AGSATYYESRFDY PC 9 KJ98 FI89 IGHV-69* IGHD-* IGHJ* AGSATYYVSRFDY BC 9 KJ985 FI5 IGHV-69* IGHD-6* IGHJ* ARDAGYYSGSYYEQ BC 8 KJ985 FI6 IGHV-69* IGHD-6* IGHJ* AREAGYYSGSYYEL BC 8 KJ96 FI7 IGHV-69* IGHD-6* IGHJ* AREAGYYSGSYYEL BC 8 KJ99 FI5 IGHV-69* IGHD-6* IGHJ* AREAGYYSGSYYEL BC KJ96 FI IGHV-69* IGHD-6* IGHJ* AREAGYYSGSYYEL BC KJ9 FI88 IGHV-69* IGHD-6* IGHJ* ARDAGYYSGSYYEQ PC 9 KJ99 FI98 IGHV-69* IGHD-6* IGHJ* ARDAGYYSGSYYEQ PC 9 KJ97 FI8 IGHV-69* IGHD-6* IGHJ* ARDAGYYSGSYYEQ PC KJ96 FI7 IGHV-69* IGHD-6* IGHJ* ARDAGYYSGSYYEQ PC KJ97 FI9 IGHV-69* IGHD-6* IGHJ* ARDAGYYSGSYYEQ PC 9 KJ966 FI5 IGHV-69* IGHD-6* IGHJ* ARDAGYYSGSYYEQ PC 9 KJ999 FI8 IGHV-69*6 IGHD-* IGHJ* AREAAYYTGTYYEQ PC KJ987 FI IGHV-69* IGHD6-9* IGHJ* AKRYSSGWYSFDY 5 PC 8 KJ9 FI8 IGHV-69* IGHD6-9* IGHJ* AKRYNSGWYSFDY 5 BC 8 KJ98 FI9 IGHV-69* IGHD6-9* IGHJ* AKRYNSGWYSFDY 5 BC 8 KJ996 FI IGHV-69* IGHD6-9* IGHJ* AKRYNSGWYSFDY 5 BC 8 KJ9 FI6 IGHV-69* IGHD6-9* IGHJ* AKRYNSGWYSFDY 5 BC 8 KJ9 FI8 IGHV-69* IGHD6-9* IGHJ* AKRYNSGWYSFDY 5 BC 8 KJ97 FI88 IGHV-69* IGHD6-9* IGHJ* AKRYNSGWYSFDY 5 BC 8 KJ9 FI97 IGHV-69* IGHD6-9* IGHJ* AKRYNSGWYSFDY 5 BC 8 KJ989 FI IGHV-69* IGHD6-9* IGHJ* AKRYNSGWYSFDY 5 BC 8 KJ98 FI95 IGHV-69* IGHD6-9* IGHJ* AKRYSSGWYSFDY 5 BC KJ99 FI9 IGHV-69* IGHD6-9* IGHJ* AKRYSSGWYFFDY 5 BC 8 KJ975 FI IGHV-69* IGHD6-9* IGHJ* AKRYSSGWYFFDY 5 BC 8 KJ96 FI59 IGHV-69* IGHD6-9* IGHJ* AKRYSSGWYFFDY 5 BC 8 KJ97 FI9 IGHV-69* IGHD6-9* IGHJ* ASRYSSGWYYFDY 5 PC 9 KJ9 FI5 IGHV-69* IGHD5-* IGHJ* ARHSGYHFQSYFDN 9 BC 8 KJ965 FI5 IGHV-69* IGHD5-* IGHJ* AKGSGYHVRDHFDD 9 BC 8 KJ968 FI5 IGHV-69* IGHD-* IGHJ* ARGSGYHVRDYFDL 9 BC 8 KJ97 FI5 IGHV-69* IGHD-* IGHJ* AKGSGYHVRDYFDY 9 BC 8 KJ95 FI69 IGHV-69* IGHD6-5* IGHJ* ARGSGYHVTDYFDL 9 PC 9 KJ96 FI7 IGHV-69* IGHD-5* IGHJ5* ARGQGYCISASCPNYFDP 8 PC 9 KJ98 FI7 IGHV-69* IGHD-5* IGHJ5* ARGQGYCISANCPNWFDP 8 PC 9 KJ9 FI IGHV-69* IGHD-5* IGHJ5* ARGQGYCISPNCPNWFDP 8 PC 9 KJ9 FI57 IGHV-69* IGHD-5* IGHJ5* ARGQGYCISASCPNYFDP 8 PC 9 KJ9 FI66 IGHV-69* IGHD-6* IGHJ* ARGRNYYHTSLEY 9 BC KJ9 FI9 IGHV-69* IGHD-7* IGHJ* ARGGNYYHTSLDY 9 PC 9 KJ99 FI55 IGHV-69* IGHD-7* IGHJ* ARGGNYYHTSLDY 9 PC 9 KJ9 FI58 IGHV-69* IGHD/OR5-a* IGHJ* ARGGKYYHTGLDY 9 PC 9 KJ97 BC, Memory B cells; PC, plasma cells Supplementary Figure. List of clonally-related anti-stem VH-69 antibodies from the FI donor

2 Abs V gene D gene J gene CDR CDR length Clone Name Origin Year Acc. No. FI9 IGHV-* IGHD-9* IGHJ5* VRGEAVLQYFDWQINWFDT 9 BC 8 KJ9 FI IGHV-* IGHD-9* IGHJ5* VRGEAVLQHFDWQINWFDT 9 BC 8 KJ979 FI8 IGHV-* IGHD-9* IGHJ5* ARGEAVLQYFDWQINWFDP 9 BC KJ9 FI IGHV-* IGHD-9* IGHJ5* VRGEAVLQYFDWQINWFDT 9 BC 8 KJ9 FI57 IGHV-* IGHD-9* IGHJ5* VRGEAVLQYFDWQINWFDT 9 BC KJ96 FI IGHV-* IGHD-9* IGHJ5* VRGEAVLQYFDWQINWFDT 9 BC 8 KJ969 FI5 IGHV-* IGHD-9* IGHJ5* VRGEAVLQYFDWQINWFDT 9 PC 8 KJ98 FI57 IGHV-* IGHD-9* IGHJ5* ARGEAVFQYFDWQVNWFDT 9 PC 9 KJ978 FI IGHV-*8 IGHD-9* IGHJ5* AKDSQLRSLLYFEWLSQGSFDP PC KJ95 FI7 IGHV-*8 IGHD-9* IGHJ* AKDSQLRSLLYFDWLSQGYFDH PC 9 JN6 FI IGHV-*8 IGHD-9* IGHJ5* AKDSQLRSLLYFEWLSQGYFDP PC KJ99 FI IGHV-*8 IGHD-9* IGHJ5* AKDSQLRSLLYFEWLSQGYFDP PC KJ9 FI IGHV-*8 IGHD-9* IGHJ5* AKDSQLRSLLYFEWLSQGSFDP PC KJ9 FI IGHV-*8 IGHD-9* IGHJ5* AKDSQLRSLLYFEWLSQGYFDP PC 9 JN FI5 IGHV-*8 IGHD-9* IGHJ5* AKDSQLRSLLYFEWLSQGYFDP PC 9 JN FI68 IGHV-*8 IGHD-9* IGHJ* AKDSLLRSLLYFDWLSQGYFDH BC KJ98 FI6 IGHV-*8 IGHD-9* IGHJ5* AKDSQLRSLLYFEWLSQGYFDP PC 8 JN9 FI8 IGHV-*8 IGHD-9* IGHJ5* AKDSQLRSLLYFEWLSQGYFDP PC JN FI8 IGHV-*8 IGHD-9* IGHJ5* AKDSQLRSLLYFEWLSQGYFDP PC JN FI85 IGHV-*8 IGHD-9* IGHJ5* AKDSQLRSLLYFEWLSQGYFDP PC KJ97 FI6 IGHV-6* IGHD-6* IGHJ6* ARAPDRRFTMNIFGGDFAPTGMDV 6 BC 8 KJ99 FI IGHV-6* IGHD-6* IGHJ6* ARAPDRRFSMITFGGGSFAPTGMDV 5 6 PC 9 KJ96 FI68 IGHV-6* IGHD-6* IGHJ6* ARAPDRRFTMNIFGGDFAPTGMDV 6 PC 9 KJ95 FI7 IGHV-6* IGHD-6* IGHJ6* ARAPDRRFTMNMFGGEFAPTGMDV 6 PC 9 KJ989 FI75 IGHV-6* IGHD-6* IGHJ6* ARAPDRRFSMTTFGGGSFAPTGLDV 5 6 PC 9 KJ98 FI5 IGHV-6* IGHD-6* IGHJ6* ARAPDRRFSMITFGGGSFAPTGMDV 5 6 PC 9 KJ97 FI IGHV-*8 IGHD-9* IGHJ* AKERPLRLLRFFDWLSGGANDY 7 BC 9 KJ97 FI8 IGHV-*8 IGHD-9* IGHJ* AKERPLRLLRYFDWLSGGANDY 7 PC 8 KJ98 FI55 IGHV-*8 IGHD-9* IGHJ* AKERPLRLLRYFDWLSGGANDY 7 BC (pre) KJ976 FI6 IGHV-*8 IGHD-9* IGHJ* AKERPLRLLRYFDWLSGGANDY 7 BC KJ99 FI9 IGHV-6* IGHD5-* IGHJ* ARASPAIPPSSRRYTGKVAPHVFDV 5 8 BC 8 KJ97 FI99 IGHV-6* IGHD5-8* IGHJ* ARASPATPPSSRRYTGKVAPHVYDF 5 8 BC 8 KJ96 FI9 IGHV--* IGHD-5* IGHJ6* ARDHLELGFCSGGSCYSGKLNYYYYGM 9 PC 9 KJ977 FI55 IGHV--* IGHD-5* IGHJ6* ARDHLELGFCSGGSCYSGKLNYYYYGM 9 PC 9 KJ96 FI55 IGHV--* IGHD-5* IGHJ6* ARDHLELGFCSGGSCYSGKLNYYYYGM 9 PC 9 KJ98 FI8 IGHV--* IGHD-5* IGHJ6* ARDHLELGFCSGGSCYSGKLNYYYYGM 9 PC KJ98 FI95 IGHV-6* IGHD-* IGHJ* ARALRTGVEAVRYYFDC 7 BC 9 KJ9 FI9 IGHV-6* IGHD/OR5-a* IGHJ* ARVPRTGLDAVRYYFDY 7 BC 9 KJ9 FI9 IGHV-*8 IGHD-9* IGHJ* AKEERARILRYFDWLAHAAFDV 5 BC 9 KJ978 FI IGHV-*8 IGHD-9* IGHJ6* AKEGGARILRYFDWLAHDALDV 5 BC 8 KJ97 FI IGHV-*8 IGHD-9* IGHJ6* AKEGGARILRYFDWLAHDALDV 5 PC KJ9 FI IGHV-*8 IGHD-9* IGHJ* AKEEKARILRYFDWLSHAAFDI 5 PC KJ9 FI87 IGHV-*8 IGHD-9* IGHJ* AKEERARILRYFDWLAHAAFDV 5 BC 9 KJ9 FI78 IGHV-* IGHD-* IGHJ6* ARGAPTDDFWSAYYPNGMDV 6 PC 9 KJ988 FI85 IGHV-* IGHD-* IGHJ6* ARGAPTDDFWSAYYPNGMDV 6 PC 9 KJ956 FI9 IGHV-* IGHD-* IGHJ6* ARGAPTHDFWSAYYPYGMDV 6 PC 9 KJ96 FI9 IGHV-* IGHD-* IGHJ* ARGNPNHDFWSSYYPGSFDC 7 PC KJ95 FI IGHV-* IGHD-* IGHJ* ARGNPNHDFWSSYYPGSFDC 7 BC KJ975 FI6 IGHV-* IGHD-* IGHJ* ARGNPNHDFWSSYYPGSFDC 7 BC KJ95 FI67 IGHV-59* IGHD/OR5-a* IGHJ* ARDRTGINSLNALDV 5 8 BC KJ98 FI66 IGHV-59* IGHD/OR5-a* IGHJ* TRDRTGINSLNALDV 5 8 BC KJ9 BC, Memory B cells; PC, plasma cells; pre, pre-vaccination sample Supplementary Figure. List of clonally-related anti-stem non-vh-69 antibodies from the FI donor

3 Abs V gene D gene J gene CDR CDR length Clone Name Origin Year Acc. No. FI9 IGHV-69* IGHD-6* IGHJ6* ASGRDFYYYGMDV N/A BC 9 KJ95 FI IGHV-69* IGHD-* IGHJ* ARAENYHGSGSYYRH 5 N/A BC 8 KJ97 FI95 IGHV-69* IGHD-5* IGHJ* ASPPAKTVVVSHAEYFQY 8 N/A BC 8 KJ968 FI5 IGHV-69* IGHD-* IGHJ* ARDPYFYDSSGYYTYSLDV 9 N/A PC KJ96 FI6 IGHV-69*6 IGHD-6* IGHJ* ARNREGSFDF N/A PC KJ9 FI96 IGHV-69* IGHD-* IGHJ6* AKAQYYDSPRDAADFYFYAMDV N/A BC KJ9 FI IGHV-69* IGHD-6* IGHJ* ARSLASLTGDY N/A BC KJ96 FI57 IGHV-69* IGHD-6* IGHJ* ARGKNYYEDYFDT N/A BC KJ99 FI IGHV-69* IGHD5-8* IGHJ5* ARGRGYHFGDLVS N/A PC KJ977 FI IGHV-69* IGHD-* IGHJ* ATSPTYYESSLDF N/A PC 9 KJ97 FI IGHV-69* IGHD5-* IGHJ* ARDGFSKSWLD N/A PC KJ98 FI5 IGHV-69* IGHD-6* IGHJ* ARGKNYYEDYFDT N/A PC 9 KJ95 FI5 IGHV-69* IGHD-6* IGHJ6* ARRYGSTSGVNTGGVSGFYYYGMDV 5 N/A BC KJ9 FI5 IGHV-69* IGHD-* IGHJ* ARGPHYYLNYFDY N/A PC 9 KJ9 FI5 IGHV-69* IGHD5-* IGHJ* ARTKSTIYPPYYFDY 5 N/A PC 9 KJ9 FI8 IGHV-69* IGHD-* IGHJ6* ATDGRQIFGASNRSGMDV 8 N/A PC 8 KJ965 FI7 IGHV-6* IGHD-5* IGHJ5* ARALGYCSGGTCSGASSVWFDT N/A BC 9 KJ97 FI7 IGHV-6* IGHD-* IGHJ* ARGRFHYDSSGFYGLSDY 8 N/A BC 9 KJ96 FI75 IGHV-* IGHD-9* IGHJ6* ATGANILTGPASRPYSYYGLDV N/A BC 8 KJ9 FI57 IGHV-* IGHD-* IGHJ* ARGNANSDFWSSYHPGTFDY N/A BC 8 KJ9 FI8 IGHV-6* IGHD-6* IGHJ* ARSWGIVGVTLHTSFDY 7 N/A BC 8 KJ97 FI67 IGHV-* IGHD-* IGHJ* ARGHYYGSGSYFPPWAH 7 N/A BC KJ998 FI85 IGHV-* IGHD-8* IGHJ5* ARVTRYWSPFFGS N/A BC KJ95 FI7 IGHV-6* IGHD-8* IGHJ* ARGGEIVQFREHGDLDY 7 N/A BC KJ987 FI6 IGHV-8* IGHD-* IGHJ6* ARFGLGTTIVEVPYYYYGMDV N/A BC KJ97 FI IGHV-6* IGHD-* IGHJ5* AREGTYYYDSSGLNWFDS 8 N/A BC 8 KJ95 FI5 IGHV-6* IGHD-* IGHJ5* AREGTYYYDSSGLNWFDS 8 N/A BC 8 KJ986 FI8 IGHV-8* IGHD-6* IGHJ5* VREREHLTVSGMLSETVKLHRHFDP 5 N/A PC 9 KJ9 FI IGHV-* IGHD-5* IGHJ* ARDYEHCTGGSCLGY 5 N/A PC 9 KJ997 FI5 IGHV-6* IGHD-* IGHJ* AKVQNDYSNYGPFDY 5 N/A PC 9 KJ99 FI68 IGHV-6* IGHD-* IGHJ6* ARAGPFFFGSGTYYRSSYGLDV N/A BC 8 (pre) KJ955 FI868 IGHV-* IGHD-* IGHJ6* ARDRMELRFLEWLNYGMDV 9 N/A BC 9 KJ967 FI9 IGHV-8* IGHD-* IGHJ5* AREEGTYYDFWSANNWFDP 9 N/A PC 8 KJ9 FI75. IGHV-5* IGHD-* IGHJ* ALNVPPRPFDH N/A BC KJ9 FI IGHV-9* IGHD5-* IGHJ* AKAFSGGDAYNWGLWDYFDY N/A BC 9 KJ98 FI9 IGHV-9*5 IGHD-* IGHJ* ARVGRNNWNARHAFDV 6 N/A BC 9 KJ95 FI8 IGHV-9* IGHD-* IGHJ* VKDGGMGSSGYLYWHFDL 8 N/A BC 9 KJ99 FI5 IGHV-8* IGHD5-* IGHJ6* ARAITPGIRHALDV N/A BC 9 KJ9 FI7 IGHV-8* IGHD-6* IGHJ* ARDSKGWRRVTRGSYDY 7 N/A BC 9 KJ98 FI78 IGHV--* IGHD-* IGHJ* ARDRATADTTFEF N/A BC 9 KJ9 FI5 IGHV-* IGHD-* IGHJ6* AKDKWRCDGDCSSNYYGMDV N/A BC 9 KJ96 FI68 IGHV-* IGHD6-9* IGHJ* ARGQQWHTPTSVNWYFDL 8 N/A BC 8 KJ976 FI5 IGHV-7* IGHD-7* IGHJ* ARDGRLGWITGTTWS 5 N/A BC 8 KJ997 FI6 IGHV-* IGHD-* IGHJ* VRAPDHYGSGTVVEAFDY 8 N/A BC 8 KJ98 FI IGHV-* IGHD-* IGHJ* AKAGAGYYPRLERRASRHFYFDS N/A BC 8 KJ9 FI7 IGHV-9* IGHD-8* IGHJ5* TKDRLLRAARTRGPPRGFDP N/A BC 8 KJ96 FI IGHV-*8 IGHD-* IGHJ* AKVASRYCITTSCYRSGRTVDY N/A BC 8 KJ9 FI8 IGHV-*8 IGHD-5* IGHJ* AKDQTVVSVAAALFDY 6 N/A BC KJ9 FI5 IGHV-9* IGHD-5* IGHJ* SGRYCSGSRCFDY N/A BC 8 KJ9 FI58 IGHV-*8 IGHD-6* IGHJ* ANDDVVGGSIRFGSSSRPPVGLKAFEI 7 N/A BC 8 KJ9 FI77 IGHV-* IGHD-* IGHJ* AREANYQRFTTYEPFDV 7 N/A PC 9 KJ97 FI9 IGHV-9* IGHD6-9* IGHJ* AKDVRSAGLAVAGFES 6 N/A PC 9 KJ9 FI IGHV-* IGHD/OR5-a* IGHJ5* VRNLGGRYSFGLYDRFDS 8 N/A PC KJ9 FI8 IGHV--* IGHD-* IGHJ6* ATGSGYYKRDYDYGMDV 7 N/A PC 9 KJ995 FI6 IGHV-5*7 IGHD-* IGHJ6* TTSMVRGVIRTADSSYYGMDV N/A PC 9 KJ95 FI IGHV-7* IGHD-* IGHJ* AREDEWNAGAD N/A PC 8 KJ95 FI IGHV-7* IGHD-* IGHJ* VRDYLTSYYSSSGDDFDY 8 N/A PC 9 KJ999 FI6 IGHV-9* IGHD-9* IGHJ* TRDLYRGEAYYFDS N/A PC 8 KJ98 FI85 IGHV--* IGHD-5* IGHJ* ARDMRDCVTTRSCYRGPFDY N/A BC 9 KJ99 FI898 IGHV-* IGHD/OR5-a* IGHJ* ARGPFGLLDY N/A BC 9 KJ99 FI IGHV--* IGHD-6* IGHJ6* ARAGGGYSGRSSHYYSYGMDV N/A BC 9 KJ959 FI55 IGHV-* IGHD-* IGHJ* ARSIGSGTYYNPRRVFDY 8 N/A BC 9 KJ958 FI7 IGHV-9* IGHD-* IGHJ* ARRIRLPHYFDY N/A BC 9 KJ95 FI8 IGHV--* IGHD-6* IGHJ* ARLWGTGYDYVWGSFRYHAFDI N/A BC 9 KJ9 FI IGHV-59* IGHD-* IGHJ* ARDLTTLTMFQGVSYFDY 8 N/A BC 9 KJ99 FI7 IGHV-59* IGHD-* IGHJ* AREDGTVTSGGGHYFDL 7 N/A PC KJ95 FI7 IGHV-* IGHD-* IGHJ6* AKLLVWFGTQIPNYYYAMDV N/A PC KJ99 FI7 IGHV-* IGHD-* IGHJ* ARFNWYYDFLPGQSPDDF 8 N/A BC KJ9 FI6 IGHV-* IGHD5-* IGHJ5* ARHYGGYDWFDP N/A BC KJ9 FI IGHV-* IGHD-6* IGHJ5* ARDRGYYDNIWGYNRPTQNWFDP N/A PC 9 KJ969 FI6 IGHV-* IGHD-6* IGHJ* ATGADGEYSGDGLLAGSDY 9 N/A PC 9 KJ97 FI IGHV--* IGHD-* IGHJ5* ARRPNIFGYNWFDP N/A PC 8 KJ9 FI95 IGHV--* IGHD-6* IGHJ6* ARILSADYYYGMDV N/A PC 9 KJ98 FI58 IGHV-* IGHD-5* IGHJ6* SRPGDSSLYYGMDV N/A PC 9 KJ99 FI587 IGHV-9* IGHD-* IGHJ* SRHRDYSSGWGFDQ N/A PC 9 KJ998 FI867 IGHV-9* IGHD6-* IGHJ* ARLVNQMAAAGSLPGKRRFDS N/A BC 9 KJ967 FI869 IGHV-59* IGHD/OR5-a* IGHJ6* ARIITEAPGFRWGPKERYNGMDV N/A BC 9 KJ979 FI6 IGHV5-5* IGHD-* IGHJ* ARHEGFYDRSGYTKIPDF 8 N/A PC 8 KJ98 FI9 IGHV6-* IGHD-* IGHJ* ARGQHLWMTYWYFDV 5 N/A BC 8 KJ95 BC, Memory B cells; PC, plasma cells; pre, pre-vaccination sample Supplementary Figure. List of unique anti-stem antibodies from the FI donor

4 b FC Clone (FI) FE FC6 FE5 FB FE 6 8 FE FB9 Mutated UCA 6 8 Clone (FI7) Clone 5 (FI88) Clone 9 (FI5) CR9 6 8 CR F 6 8 Supplementary Figure. Binding of UCA and wild type VH-69 antibodies to H HA as measured by SPR. Binding of 5 mutated and UCA antibodies to H CA9 HA as measured by SPR ( nm antibody, nm H CA9 HA). Red lines indicate the mutated antibody and blue lines their UCA counterpart.

5 FC Clone FE FC6 FE5 FB FE FE FB Clone Clone 5 Clone CR CR F Supplementary Figure. Binding of UCA VH-69 antibodies to H HA as measured by SPR. Binding of the UCA antibodies to H CA9 HA as measured by SPR, using more sensitive conditions ( nm antibody, nm H CA9 HA). 5

6 FC Clone (FI) FE FC6 FE5 FB79 UCA H UCA ctrl H ctrl FE FE5 FB Clone (FI99) Clone 5 (FI88) Clone 9 (FI5) CR66 CR9 F Supplementary Figure. Binding of UCA and wild type VH-69 antibodies to H HA as measured by ELISA. Binding of the antibodies to H HA as measured by ELISA. Red and white symbols indicate the binding of the mutated and UCA antibodies, respectively. Circles, binding to H CA9; squares, binding to control antigen. 6

7 a b fold change (k(uca)/k(mutated)) - ka kd ka kd KD UCA-9.9E+5.7E-.9E- FI5.E+5.5E-5.E- FI5.8E+5 ND ND FI5.7E+5.7E-5.55E- FI5.8E E-5.E- UCA-5.E+5.58E-.9E-9 FI88.77E+5 ND ND FI6.9E+5.E-5.5E- FI.5E+5 6.E-5 5.5E- FI95.7E+5 ND ND FC-UCA.5E+6.E-.E- FC.E+5 8.9E-5.68E- FE-UCA.E E- 5.6E-9 FE.9E+5.7E-6 6.7E- FE5-UCA 6.6E+5 7.7E-5.8E- FE5.6E+5.58E- 5.59E- FE5-UCA.E+.7E- 6.75E-9 FE5.66E+5.68E-5 9.E- UCA-.E+5.8E-.79E- FI99.E+5 ND ND FI6.55E+5 ND ND FI7.E+5 9.6E-6.9E- UCA- 9.88E+ 5.5E- 6.9E-9 FI.E+5.88E-5 9.E- FE5-UCA 5.55E+5.9E- 6.69E- FE5.9E+5.5E-5.97E- FB79-UCA.9E+5 5.7E-5.9E- FB79.8E+5.97E E- CR66-UCA.9E+5.E-.E-9 CR66 7.9E+5.5E-5.E- F 7.E+5.7E-.E- CR9-UCA 6.9E+5.E-.5E-9 CR9.87E+5.E-.E- FB9-UCA 5.7E+.6E-.8E-9 FB9.E E E- ND indicates values that could not be calculated from the analysis, due to the lack of significant dissociation. Supplementary Figure 5. Somatic mutations increase binding affinity by decreasing dissociation rates. a, Shown are the fold changes of the ka and kd values between UCA and mutated antibodies as determined by SPR using H CA9 HA. b, List of ka, kd and KD values of antibodies tested by SPR shown in panel a. 7

8 Abbreviation Full name NC/99 H HN A/Caledonia//99 SD/7 H HN A/South Dakota/6/7 CA/9 HN A/California/7/9 WSN/ HN A/Wilson Smith N/ BJ/95 HN ca A/Beijing/6/95 SI/6 HN A/Solomon Islands//6 FM/7 HN A/Fort Monmouth//7 PR/ HN A/Puerto Rico/8/ TX/9 HNca A/Texas/6/9 SZ/95 HN ca A/Shenzhen/7/95 KW/86 HN ca A/Kawasaki/9/86 BS/ HN A/Brisbane// JAP/57 HN ca A/Japan/57 Swine/MO/6 HN ca A/swine/Missouri/96/6 HK/ H5N ca A/Hong Kong// VN/ H5N ca A/Vietnam// Teal/HK/97 H6N ca A/Hong Kong/W/97 MD/AB/86 H6N ca A/mallard/Alberta/89/85 Chic/HK/97 H9N ca A/chicken/Hong Kong/G9/97 Supplementary Figure 6. List of virus strains used for neutralization experiments shown in Fig., and Extended Data Fig.. 8

9 CDR CDR CDR CDR Supplementary Figure 7. Alignment of HCDR and HCDR from all anti-stem VH-69 antibodies analyzed. Alignment of the HCDR and HCDR residues from 9 antistem VH-69 antibodies by ClustalW ( Tools/msa/clustalw/). UCA residues on the top. Dots indicate identical residues. 9

10 Abs V gene D gene J gene CDR CDR length Reference F IGHV-69* IGHD-* IGHJ* ARGPYYYGNSHLDF US/9699 A IGHV-69* IGHD-* IGHJ6* ARDSDAYYYGSGGMDV 6 US/895 B5 IGHV-69*6 IGHD-7* IGHJ* ATSAGGIVNYFLLFDI 6 US/9699 E6 IGHV-69*6 IGHD-* IGHJ* ATSAGGIVNYYLSFNI 6 US/9699 5B IGHV-69* IGHD-6* IGHJ* ASSSGSYYGDYFDY US/9699 A66 IGHV-69* IGHD-* IGHJ* ARTLSSYQPNNDAFAI 6 US/895 CR66 IGHV-69* IGHD-* IGHJ6* AKHMGYQVRETMDV US 8,9,97 CR66 IGHV-69* IGHD-* IGHJ6* ARGPKYYSEYMDV US 8,9,97 CR6 IGHV-69* IGHD-* IGHJ* ARSSGYYPAYLPH US 8,9,97 CR67 IGHV-69* IGHD-* IGHJ* ARGSGYHISTPFDN US 8,9,97 CR69 IGHV-69* IGHD5-* IGHJ* ARGSGYTTRNYFDY US 8,9,97 CR6 IGHV-69* IGHD-* IGHJ* ARGNYYYESSLDY US 8,9,97 CR6 IGHV-69* N/A IGHJ6* ARGPHYYSSYMDV US 8,9,97 CR6 IGHV-69* N/A IGHJ6* ARGPTYYYSYMDV US 8,9,97 CR6 IGHV-69* IGHD-* IGHJ5* ARLNYHDSGTYYNAPRGWFDP US 8,9,97 CR6 IGHV-69* IGHD-* IGHJ* ARSSNYYDSVYDY US 8,9,97 CR6 IGHV-69* IGHD-* IGHJ* ARIPHYNFGSGSYFDY 6 US 8,9,97 CR9 IGHV-69*6 IGHD-* IGHJ6* ARHGNYYYYSGMDV Dreyfus et al., Science, D7 IGHV-69* IGHD-* IGHJ* ARSSGYHFRSHFDS US/895 D8 IGHV-69* IGHD-* IGHJ* ARGLYYYESSLDY US/895 E88 IGHV-69* IGHD-* IGHJ* ARTLSSYQPNNDAFAI 6 US/895 F IGHV-69* IGHD-8* IGHJ* ARSPSYICSGGTCVFDH 7 US/895 FB8.5 IGHV-69* IGHD5-* IGHJ6* ARGNGYSFAYGMDV Corti et al., JCI, FB79.9 IGHV-69* IGHD-* IGHJ6* ARRGFGDKYYYYGMDV 6 Corti et al., JCI, FB5.9 IGHV-69*6 IGHD-* IGHJ5* ARAGTTLTRFNWFDP 5 Corti et al., JCI, FB79. IGHV-69*6 IGHD-* IGHJ5* ARLGSGSYHNGPNWFDP 7 Corti et al., JCI, FC.5 IGHV-69*6 IGHD-6* IGHJ* ARGGRYYVDYFDY Corti et al., JCI, FC6. IGHV-69* IGHD-* IGHJ6* ARGQRYYYDRDGMDV 5 Corti et al., JCI, FB9. IGHV-69*6 IGHD-* IGHJ5* ARAGTTVTRFNWFDP 5 Corti et al., JCI, FB86.8 IGHV-69* IGHD-* IGHJ5* ARAGTTVTRFNWFDP 5 Corti et al., JCI, FE5. IGHV-69* IGHD-6* IGHJ* ARGGGSYYGGEYFQH 5 Corti et al., JCI, FE5.7 IGHV-69*6 IGHD-8* IGHJ* ARGKRPGYCSGGVCSSDY 8 Corti et al., JCI, FE5 IGHV-69*6 IGHD-5* IGHJ6* ASSPGGFCSGGTCHYYYGMDV Corti et al., JCI, FE9B IGHV-69*6 IGHD-5* IGHJ6* ASSPGGFCSGGTCHYYYGMDV Corti et al., JCI, FG.5 IGHV-69*6 IGHD-* IGHJ6* ASGLPSMVYGLDV Corti et al., JCI, G7 IGHV-69*6 IGHD/OR5-a* IGHJ* AREPGYYVGKNGFDV 5 US/895 Supplementary Figure 8. List of anti-stem VH-69 antibodies from the literature

11 O N M L K J I H G F E D C B A O N M L K J I H G F E D C B A Supplementary Figure 9. Alignment of HCDR from all anti-stem VH-69 antibodies analyzed. Alignment of the HCDR regions from 9 anti-stem VH-69 antibodies, listed according to the order of their HCDR and HCDR alignment shown in Supplementary Figure 7. Dots indicate identical residues.

12 Abs A B C D E F G H I J K L M N O P Specificity Reference BNC A R A Q G D I L T E G Y F D Y HIV- Env Scheid et al. Science B8 A R D H G D P R T G Y Y F D Y HIV- Env Scheid et al. Science BNC8 A R G Q T D L N D D L W S D Y S T P G F D Y HIV- Env Scheid et al. Science HCF A R I F P I I V G S P G V I G Y F D Y HCV E Unpublished D5 A R D N P T L L G S D Y HIV- Env Miller et al. PNAS 5 CBHB A R E A D I V V G G S S Y F D S HCV E Chan et al, Blood, HCF8 A R E V R I T F G G V S G D N W L D P HCV Unpublished HGD65 V R D G D D G D H HIV- Env Corti et al PLoS One X5 A R D F G P D W E D G D S Y D G S G R G F F - - D F HIV- Env PDB ID RHH, Darbha et al, Biochemistry, RVC69 A R G D G Y N Y K W Y F D T Rabies G protein Unpublished 5F A R S G D G Y N Y Y F P L H5N HA Simmons et al. PLoS Med 7 RSD6 A R V M D A Y D S N G Y N Y R S F D I RSV F Corti et al. Nature RSB A R V E D T A L D H Y F D Y RSV F Corti et al. Nature RSB A R V E D T A L D H Y F D Y RSV F Corti et al. Nature RSB A R V E D R A L D H Y F D Y RSV F Corti et al. Nature D5 A T E T A L V V S T T Y L P H Y F D N RSV F Kwakkenbos et al Nat Med 8 (PCT/NL8/) CBH A R V P G S G T Y A Y F D Y HCV E Chan et al, Blood, D A S P Y P N D Y N D Y A P E E G M S W Y F D L HIV- Env Huang et al., Science, 7 A79 A R G F R G S P F S S G S L Y F D S HIV- Env Scheid et al. Science 8M A R V G G E W G S G R Y Y L D H H HA Krause et al., J. Virol, B7 A R A T G Y S Y G Y L D A F D I HIV- Env Scheid et al. Science BNC A R A T G Y S Y G Y L D A F D I HIV- Env Scheid et al. Science FLD9 A R A G G D S S G Y Y G A L G R F F Q H H5N HA Unpublished CBH5 A R P H G D S S G I Y R R P L D Y HCV E Unpublished RHD8 A I K P R Y C S S S G C Y D Y HRV capsid Unpublished HH55 A T D P G Y C S G V G C Y S G G V H HIV- Env Unpublished 8ANC6 A R D R S S A I G Y C S S I S C Y K G S F D I HIV- Env Scheid et al. Science HCM76 A R E S I G Y C R G G S C S T T F D F HCV E Unpublished CBH8E A R D W L G S C R G G S C Y S A F D I HCV E Chan et al, Blood, HR A R E A F C G G D C N S R P F K F D Y HIV- Env Corti et al PLoS One HR5 A R E T Y C G G D C Y S R P F K F D Y HIV- Env Corti et al PLoS One N A R G I L A Y C G G D C Y N T P Y G M D V HCMV UL-A Macagno JV B55 A R G L C R G G N C R L G P S G W L D P HIV- Env Scheid et al. Science G A R G I S G S Y G W F D P H HA Krause et al., J. Virol, -6D5 A R V F G G T R L Y Y A L N V Tetanus Toxoid Poulsen et al., JI, 7-6A A R V L G G T R L Y Y A L N V Tetanus Toxoid Poulsen et al., JI, 7-6F9 A R V V G G T R S Y Y A L G F Tetanus Toxoid Poulsen et al., JI, 7-6C7 A R D Y G G T R H Y Y A L D A Tetanus Toxoid Poulsen et al., JI, 7-6H7 A R D R G G T R H H Y Y M D V Tetanus Toxoid Poulsen et al., JI, 7 8ANC7 A R D R G D T R L L D Y G D Y E D E R Y Y Y G M D V HIV- Env Scheid et al. Science CBHD A R D S G D F G A V I I G N H Y Y Y G M D V HCV E Chan et al, Blood, CBHG A R A T G Q G L E L H G S Y Y Y Y A M D V HCV E Chan et al, Blood, B8 A R G R Q T F R A I W S G P P V V F D I HIV- Env Scheid et al. Science NC5 A R G R Q T F R A I W S G P P V V F D I HIV- Env Scheid et al. Science B A R E I L Q S P P F A V D V HCMV gb Macagno JV HK A R A S Y S S S S P Y A F D I HIV- Env Sabin et al Plos Path. A8 A R D P Q V E V R G N A F D I HIV- Env Scheid et al. Science A8 A R A V I T D L H T F G D Y E L E D P S Y Y Y M D V HIV- Env Scheid et al. Science GCA A R V S S R D D H T L D A F D L GM-CSF Unpublished A A R D V H N Y D F L T G Y P L H L Y G M D V H5N HA Simmons et al. PLoS Med 7 5A A R D F L S G P M E M P G G Y Y G L D V H5N HA Simmons et al. PLoS Med 7 CBH7 A R R G Y I Y G S P F D Y HCV E Chan et al, Blood, HCL A S R S T Y Y G S G F D H HCV E Unpublished BNC9 A R G E F D S S G F D Y E S W Y P Y Y M D V HIV- Env Scheid et al. Science F-6 A R P S I N E S P Y C L D C A A K D Y Y Y G L - D V HN Oshima et al, J. Virol 8ANC9 A R S S G N Y D F A Y D I HIV- Env Scheid et al. Science HIC5 A T D G R Q I F G A S N R S G M D V HIV- Env Unpublished HCF6 A K E Q G G L W F G E S G P V S P G R Y F D S HCV E Unpublished HP A T D R G W D V L R L P L D Y HIV- Env Corti et al PLoS One E A R E G T T G W G W L G K P I G A F A H HIV- Env Zwick et al. JV HCF A S G L K Y Y D I L R G H F S D Y D F G V D V HCV E Unpublished HGK9 V R R Q K Y S V I T D D A P F D Y HIV- Env Corti et al PLoS One 7B A G V Y E G E A D E G E Y D N N G F L K H HIV- Env Kwong et al Structure Fold Des. 8ANC A R T S T Y D Q W S G L H H D G V M A F S S HIV- Env Scheid et al. Science Supplementary Figure. List of the VH-69 antibodies specific for antigens other than the HA-stem that were used in the analysis presented in Fig..