Memory bias to Flu virus globular head explains rational for universal stem[stalk]-only Flu immunogen design

Few days ago Science Translational Medicine published interesting study explaining hurdles for creating universal Flu vaccine. Universal Flu vaccine refers to a "hypothetical" Flu vaccine that can induce cross-strain neutralizing antibody response. 

There are dozen of Flu viruses that differ from each other in H and N antigen composition. However, multiple studies that followed 2009 H1N1 Flu pandemic revealed that the most Flu viruses share conservative region called stem [or stalk] region located below their globular head [main target of anti-Flu antibodies]. Antibody response to Flu stem/stalk region is not common but when induced it has potential to cross-neutralize almost every human-specific Flu viruses. Such vaccine, obviously, has a huge medical application and carries huge marketing potential too.

So why are these anti-Flu stem/stalk antibodies so rare? First clue came from serial analysis of serum samples harvested from individuals immunized second time with H1N1 vaccine [that included both globular head ad stem/stalk regions]. Unlike primary immunization, secondary vaccination re-directed immune response towards Flu globular head at the expense of flu stem/stalk region. Basically, anti-globular head antibody memory response could easily out-compete anti-Flu stem/stalk region antibody memory response [thus reducing cross-neutralizing potency].

Second and more puzzling clue came from observation that unlike anti-Flu globular head antibodies, anti-Flu stem/stalk antibodies displayed excessive non-specific binding [in an in vitro assay] to irrelevant antigens. This raises basic question whether human immune system had been "intentionally" keeping away from Flu stem/stalk response to avoid any potential cross-reactivity to self antigens. However, so far there is no evidence to suggest that this in vitro "sticky" character of anti-Flu stem/stalk antibodies plays any clinically relevant role in vivo.  

In summary, this study shows that conventional Flu vaccine design that incorporates both Flu virus globular head as well as its stem/stalk region wouldn't work to induce long-lasting cross-neutralizing universal antibodies. However, Flu stem/stalk only immunogens could work as reported earlier in two independent studies. 

Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection.

A stable trimeric influenza hemagglutinin stem as a broadly protective immunogen.

David Usharauli