tetano
Editor, Senior Moderator
Elife
. 2025 Nov 13:14:e107042.
doi: 10.7554/eLife.107042. Repeated vaccination with homologous influenza hemagglutinin broadens human antibody responses to unmatched flu viruses
Yixiang Deng[SUP] #[/SUP][SUP] 1 [/SUP], Melbourne Tang[SUP] #[/SUP][SUP] 2 [/SUP], Ted M Ross[SUP] 3 4 [/SUP], Aaron G Schmidt[SUP] 1 5 [/SUP], Arup K Chakraborty[SUP] 1 2 6 7 8 [/SUP], Daniel Lingwood[SUP] 1 [/SUP]
Affiliations
The ongoing diversification of influenza virus necessitates annual vaccine updating. The vaccine antigen, the viral spike protein hemagglutinin (HA), tends to elicit strain-specific neutralizing activity, predicting that sequential immunization with the same HA strain will boost antibodies with narrow coverage. However, repeated vaccination with homologous SARS-CoV-2 vaccine eventually elicits neutralizing activity against highly unmatched variants, questioning this immunological premise. We evaluated a longitudinal influenza vaccine cohort, where each year the subjects received the same, novel H1N1 2009 pandemic vaccine strain. Repeated vaccination gradually enhanced receptor-blocking antibodies (HAI) to highly unmatched H1N1 strains within individuals with no initial memory recall against these historical viruses. An in silico model of affinity maturation in germinal centers (GCs) integrated with a model of differentiation and expansion of memory cells outside GCs during a recall response provides insight into the potential mechanisms underlying these results and shows how repeated exposure to the same immunogen can broaden the antibody response against diversified targets.
Keywords: B cell; breadth; germinal center; infectious disease; influenza virus; microbiology; physics of living systems; vaccine; viruses.
Plain language summary
Vaccines are the most effective way to prevent many infectious diseases and millions of deaths worldwide every year. They work by training the immune system to react to a protein – the antigen – that is specific to a pathogen. In response, the body produces specific antibodies, large proteins that mark the invaders for destruction. This builds a memory of this particular pathogen, enabling them to fight future infections better. Some vaccines contain antigens, while others contain weakened or inactivated viruses or bacteria. Newer vaccines often contain a blueprint for producing antigens, such as DNA or RNA, instead of an antigen. Each year, the flu vaccine is updated to match the main flu strains in circulation. This is because the vaccine’s key component – the spike protein hemagglutinin (HA) – works best when it triggers antibodies that recognize and neutralize viruses with the same HA sequence. A major obstacle to creating a universal flu vaccine is that influenza viruses constantly mutate, weakening the match between the vaccine and the virus. The problem is made worse because vaccines tend to produce antibodies that target the very parts of HA that change most frequently. Repeated vaccination with the same flu shot (called vaccine boosting) was thought to strengthen the original immune response by increasing the number of antibodies targeting the same variable parts of HA. However, recent findings from studies on SARS-CoV-2 (the virus that causes COVID-19) suggest this is not always the case. Instead, repeated vaccination can both boost existing antibodies and generate new ones that target previously unrecognized regions of the antigen. This broader antibody response can help protect against variant viruses that share these newly recognized regions. Deng, Tang et al. tested whether this antibody broadening also occurs with repeated influenza vaccination. The researchers evaluated data from a group of people who received the same flu vaccine for four consecutive years between 2013 to 2016, which included the new 2009 pandemic strain that many had never encountered before. The analyses showed that over time, their antibody responses became more diverse and capable of recognizing flu viruses spanning almost a century of evolution. To understand how this happens, Deng, Tang et al. built a computational model to trace how a type of immune cell known as the B cells mature and diversify their antibody production after vaccination. The findings suggest that the broad antibody response during vaccination boosting is an inherent feature of the human immune system. The next step and challenge will be to harness the natural ability to broaden antibody responses for designing vaccines that can protect against strains that may emerge in the future. This could involve fine-tuning HA or other vaccine proteins to better guide the immune system toward producing a broadly protective set of antibodies. Importantly, this principle of immune broadening could apply to any vaccine antigen – not just influenza.
. 2025 Nov 13:14:e107042.
doi: 10.7554/eLife.107042. Repeated vaccination with homologous influenza hemagglutinin broadens human antibody responses to unmatched flu viruses
Yixiang Deng[SUP] #[/SUP][SUP] 1 [/SUP], Melbourne Tang[SUP] #[/SUP][SUP] 2 [/SUP], Ted M Ross[SUP] 3 4 [/SUP], Aaron G Schmidt[SUP] 1 5 [/SUP], Arup K Chakraborty[SUP] 1 2 6 7 8 [/SUP], Daniel Lingwood[SUP] 1 [/SUP]
Affiliations
- PMID: 41231113
- PMCID: PMC12614894
- DOI: 10.7554/eLife.107042
The ongoing diversification of influenza virus necessitates annual vaccine updating. The vaccine antigen, the viral spike protein hemagglutinin (HA), tends to elicit strain-specific neutralizing activity, predicting that sequential immunization with the same HA strain will boost antibodies with narrow coverage. However, repeated vaccination with homologous SARS-CoV-2 vaccine eventually elicits neutralizing activity against highly unmatched variants, questioning this immunological premise. We evaluated a longitudinal influenza vaccine cohort, where each year the subjects received the same, novel H1N1 2009 pandemic vaccine strain. Repeated vaccination gradually enhanced receptor-blocking antibodies (HAI) to highly unmatched H1N1 strains within individuals with no initial memory recall against these historical viruses. An in silico model of affinity maturation in germinal centers (GCs) integrated with a model of differentiation and expansion of memory cells outside GCs during a recall response provides insight into the potential mechanisms underlying these results and shows how repeated exposure to the same immunogen can broaden the antibody response against diversified targets.
Keywords: B cell; breadth; germinal center; infectious disease; influenza virus; microbiology; physics of living systems; vaccine; viruses.
Plain language summary
Vaccines are the most effective way to prevent many infectious diseases and millions of deaths worldwide every year. They work by training the immune system to react to a protein – the antigen – that is specific to a pathogen. In response, the body produces specific antibodies, large proteins that mark the invaders for destruction. This builds a memory of this particular pathogen, enabling them to fight future infections better. Some vaccines contain antigens, while others contain weakened or inactivated viruses or bacteria. Newer vaccines often contain a blueprint for producing antigens, such as DNA or RNA, instead of an antigen. Each year, the flu vaccine is updated to match the main flu strains in circulation. This is because the vaccine’s key component – the spike protein hemagglutinin (HA) – works best when it triggers antibodies that recognize and neutralize viruses with the same HA sequence. A major obstacle to creating a universal flu vaccine is that influenza viruses constantly mutate, weakening the match between the vaccine and the virus. The problem is made worse because vaccines tend to produce antibodies that target the very parts of HA that change most frequently. Repeated vaccination with the same flu shot (called vaccine boosting) was thought to strengthen the original immune response by increasing the number of antibodies targeting the same variable parts of HA. However, recent findings from studies on SARS-CoV-2 (the virus that causes COVID-19) suggest this is not always the case. Instead, repeated vaccination can both boost existing antibodies and generate new ones that target previously unrecognized regions of the antigen. This broader antibody response can help protect against variant viruses that share these newly recognized regions. Deng, Tang et al. tested whether this antibody broadening also occurs with repeated influenza vaccination. The researchers evaluated data from a group of people who received the same flu vaccine for four consecutive years between 2013 to 2016, which included the new 2009 pandemic strain that many had never encountered before. The analyses showed that over time, their antibody responses became more diverse and capable of recognizing flu viruses spanning almost a century of evolution. To understand how this happens, Deng, Tang et al. built a computational model to trace how a type of immune cell known as the B cells mature and diversify their antibody production after vaccination. The findings suggest that the broad antibody response during vaccination boosting is an inherent feature of the human immune system. The next step and challenge will be to harness the natural ability to broaden antibody responses for designing vaccines that can protect against strains that may emerge in the future. This could involve fine-tuning HA or other vaccine proteins to better guide the immune system toward producing a broadly protective set of antibodies. Importantly, this principle of immune broadening could apply to any vaccine antigen – not just influenza.