Table 1.

Pathway to eliciting broadly neutralizing antibodies through vaccination: recent developments

	Challenges	Proposed solutions
Kickstart bNAb precursors	Rare, frequently autoreactive, and may not bind HV Env	Engineer germline-reactive immunogens
		Screen for germline-reactive natural Env
		Measure early indicators of success (e.g. antibody allele, angle of approach)
Elicit Tier-2 nAbs and drive them towards breadth	Native-like HIV Env immunogens needed, off-target responses to glycan holes are common, breadth may require extensive SHM and tolerance of epitope diversity/glycans	SOSIP and other trimer platforms (e.g. NFL-trimers and trimer-enriched VLPs)
		Immunogen redesign to reduce off-target neutralization
		B cell-lineage based immunogens
		Cocktails
		Replicating vectors for persisting antigen