Creative artwork featuring colorized 3D prints of influenza virus particles (surface glycoprotein hemagglutinin in blue and neuraminidase in orange; the viral membrane is shown in a darker orange). Note: Not to scale. Image credit: NIAID (CC BY 2.0)
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.
