Table 1.

Overview of HA stalk-based influenza vaccine approaches

Candidate	Development stage	Key points	References
Headless HA	pre-clinical	removal of globular head domain allows the immune system to focus on the stalk domain; must be expressed recombinantly and cannot be produced using traditional influenza vaccine production platforms	[15–24], reviewed in [13]
Chimeric HA (cHA)	pre-clinical, clinical phase in preparation	sequential presentation of the same stalk domain in combination with exotic head domains breaks the immunodominance of the head domain and refocuses the immune response to the stalk; can be produced using traditional influenza virus vaccine production platforms	[27,29–33,35,36]
Glycan shielding	pre-clinical	hyperglycosylation of the globular head domain shields it from the immune system	[58,59]
Prime-boost strategies	clinical	have been developed to increase the efficacy of seasonal, H5 and H7 influenza virus vaccines but have also been shown to broaden the immune response	[45,60,61,63,64]
Peptides	pre-clinical	allow the immune response to focus on the epitope of choice without distraction by the globular head domain; might not capture the right conformation of complex structural epitopes	[56,57]
VLP-based approaches	pre-clinical	present key epitopes on the surface of immunogenic VLPs, might not capture the right conformation of complex structural epitopes	[54,55]