It is >30 years since HIV discovery and we still don't have vaccine that can protect against it. Billions of dollars spent. And still no one could explain why HIV vaccines developed thus far are failing one after another (RV144 HIV-vaccine trial is one of those).
Here is what I think. Modern vaccinology is based on concept introduced 50 years ago. It is based on assumption that adaptive immune system (canonical B and T cells) is the main driver of protection. 20 years ago, after discovery of TLRs, there was a conceptual shift towards dendritic cell (DCs)-oriented vaccines. Nonetheless, the main focus of vaccine development still remains adaptive immune system (B cells, T cells and DCs). I think it is time to rethink our approach to vaccination. Adaptive immunity is one part of equation. There are growing lists of innate/innate-like cells that could play crucial role in next-generation of vaccines.
For example, following the RV144 HIV-vaccine trial, there was lots of head scratching. Some thought we need to use stronger adjuvants [compared to Alum]. However new study conducted on monkeys showed that "the higher vaccine immunogenicity of MF59 [adjuvant] does not directly translate to higher vaccine efficacy against SIV [monkey HIV] acquisition."
Moreover, this study found that higher percentage of SIV Env-reactive innate NKp44+IL-17+ cells following alum-vaccine "were associated with a reduced risk of acquisition [of SIV in monkeys] in the multivariate analysis" (in other immune parameters MF59 was better than alum).
In summary, we need to acknowledge that the more learn about immune system the more we understand how little we know about it.