tetano
Editor, Senior Moderator
Immunity
. 2026 Mar 26:S1074-7613(26)00113-5.
doi: 10.1016/j.immuni.2026.03.002. Online ahead of print.
Genetically diverse influenza antibodies highlight the role of IG germline gene variation and inform population-comprehensive vaccine strategies
Alexandra A Fischer[SUP] 1 [/SUP], Martin Corcoran[SUP] 2 [/SUP], Philip J M Brouwer[SUP] 3 [/SUP], Mark Chernyshev[SUP] 1 [/SUP], Rebecca A Gillespie[SUP] 4 [/SUP], Andrea Nicoletto[SUP] 1 [/SUP], Johannes R Loeffler[SUP] 3 [/SUP], James A Ferguson[SUP] 3 [/SUP], Ioannis Zygouras[SUP] 1 [/SUP], Pradeepa Pushparaj[SUP] 1 [/SUP], Alesandra J Rodriguez[SUP] 3 [/SUP], Sanjana Narang[SUP] 1 [/SUP], Marit J van Gils[SUP] 5 [/SUP], Xaquin Castro Dopico[SUP] 1 [/SUP], Masaru Kanekiyo[SUP] 4 [/SUP], Andrew B Ward[SUP] 3 [/SUP], Julianna Han[SUP] 6 [/SUP], Gunilla B Karlsson Hedestam[SUP] 7 [/SUP]
Affiliations
The regular emergence of influenza strains with pandemic potential necessitates vaccines that elicit protective immune responses across genetically diverse human populations. A critical but understudied factor is how germline-encoded variation in immunoglobulin genes shapes the development of neutralizing antibodies. Here, by combining personalized immunoglobulin genotyping with high-throughput paired-chain antibody sequencing from influenza A hemagglutinin (HA)-binding B cells across four donors, using a technique we developed called individualized single-cell analysis of paired expressed antigen receptors (ISCAPE), we demonstrate that B cell responses to HA are highly individual. We identified a common IGHV2-70 polymorphism that impaired the function of a class of neutralizing HA head-directed antibodies. Furthermore, we described HA central stem-targeting broadly neutralizing antibodies that utilize IGHD3-3 recombined with diverse IGHV genes, expanding the known repertoire of stem antibodies and highlighting antibody gene usage population restrictions. We suggest that multi-donor repertoire studies, coupled with personalized immunoglobulin genotyping, can uncover germline-encoded functional variations and help mitigate population vulnerabilities in vaccine design.
Keywords: central stem; cryo-EM structures; epitope; germline-targeting; hemagglutinin; influenza; monoclonal antibodies; neutralizing activity; personalized IG genotyping; population vulnerabilities.
. 2026 Mar 26:S1074-7613(26)00113-5.
doi: 10.1016/j.immuni.2026.03.002. Online ahead of print.
Genetically diverse influenza antibodies highlight the role of IG germline gene variation and inform population-comprehensive vaccine strategies
Alexandra A Fischer[SUP] 1 [/SUP], Martin Corcoran[SUP] 2 [/SUP], Philip J M Brouwer[SUP] 3 [/SUP], Mark Chernyshev[SUP] 1 [/SUP], Rebecca A Gillespie[SUP] 4 [/SUP], Andrea Nicoletto[SUP] 1 [/SUP], Johannes R Loeffler[SUP] 3 [/SUP], James A Ferguson[SUP] 3 [/SUP], Ioannis Zygouras[SUP] 1 [/SUP], Pradeepa Pushparaj[SUP] 1 [/SUP], Alesandra J Rodriguez[SUP] 3 [/SUP], Sanjana Narang[SUP] 1 [/SUP], Marit J van Gils[SUP] 5 [/SUP], Xaquin Castro Dopico[SUP] 1 [/SUP], Masaru Kanekiyo[SUP] 4 [/SUP], Andrew B Ward[SUP] 3 [/SUP], Julianna Han[SUP] 6 [/SUP], Gunilla B Karlsson Hedestam[SUP] 7 [/SUP]
Affiliations
- PMID: 41895293
- DOI: 10.1016/j.immuni.2026.03.002
The regular emergence of influenza strains with pandemic potential necessitates vaccines that elicit protective immune responses across genetically diverse human populations. A critical but understudied factor is how germline-encoded variation in immunoglobulin genes shapes the development of neutralizing antibodies. Here, by combining personalized immunoglobulin genotyping with high-throughput paired-chain antibody sequencing from influenza A hemagglutinin (HA)-binding B cells across four donors, using a technique we developed called individualized single-cell analysis of paired expressed antigen receptors (ISCAPE), we demonstrate that B cell responses to HA are highly individual. We identified a common IGHV2-70 polymorphism that impaired the function of a class of neutralizing HA head-directed antibodies. Furthermore, we described HA central stem-targeting broadly neutralizing antibodies that utilize IGHD3-3 recombined with diverse IGHV genes, expanding the known repertoire of stem antibodies and highlighting antibody gene usage population restrictions. We suggest that multi-donor repertoire studies, coupled with personalized immunoglobulin genotyping, can uncover germline-encoded functional variations and help mitigate population vulnerabilities in vaccine design.
Keywords: central stem; cryo-EM structures; epitope; germline-targeting; hemagglutinin; influenza; monoclonal antibodies; neutralizing activity; personalized IG genotyping; population vulnerabilities.