It has been almost a decade since the 2009 influenza A virus pandemic hit the globe causing significant morbidity and mortality. Nonetheless, annual influenza vaccination, which elicits antibodies mainly against the head region of influenza hemagglutinin (HA), remains as the mainstay to combat and reduce symptoms of influenza infection. Influenza HA is highly antigenically variable, thus limiting vaccine efficacy.


In addition, the variable HA head occupies the upper strata of the immunodominance hierarchy, thereby clouding the antibody response toward subdominant epitopes, which are usually conserved across different influenza strains. Isolation of monoclonal antibodies from individuals recognizing such epitopes has facilitated the development of recombinant vaccines that focus the adaptive immune response toward conserved, protective targets. Here, we review some significant leaps in recombinant vaccine development, which could possibly help to overcome B cell and antibody immunodominance and provide heterosubtypic immunity to influenza A virus.Copyright © 2020 Mathew and Angeletti.

…Know What We Do Not Know

Bioengineering and design of epitope-focused immunogens is proceeding at an incredible speed in influenza and other fields. Several promising immunogens are now in clinical trials and, hopefully, will be available to the public soon, as long-lasting universal vaccines. It is, however, crucial to understand more about the basics of B cell responses to interpret results and inform on vaccination policies.

Introduction of pandemic H1N1 2009 virus showed that most individuals, with low serological anti-stem antibodies, were able to mount a stem-directed response, but repeated vaccinations skewed the immune response back to the immunodominant head (21). It will be critical to understand when, in which order and how often give universal vaccines to appropriately boost stem response. Andrews et al. demonstrated that novel B cells specific for variable epitopes have a different phenotype compared to reactivated Bmem specific for stem (142). To maximize success, efforts will need to be put in understanding how B-cell specificity can influence their programming and differentiation. Furthermore, it is still unclear how much of stem-specific antibodies are required for optimal protection from a drifted or heterologous virus. Table 1 summarizes what we know about antibody responses to the major targets on IAV and how seasonal vaccination is able to boost those responses.