A prime-and-trap vaccination strategy to evaluate minimal requirements for malaria liver stage protection in mice

The Plasmodium liver stage is an attractive prophylactic vaccine target since blocking parasites in the liver has the potential to prevent both clinical disease and transmission. However, immunity to Plasmodium liver stages is difficult to study, and highly efficacious liver stage vaccines have been difficult to develop. Prime-and-trap vaccination induces liver CD8⁺ T cells that can provide complete liver stage protection in mice. However, the minimal vaccine requirements for complete liver stage protection remain unclear.

In this study, a prime-and-trap vaccination strategy was used to evaluate minimal vaccine requirements for malaria liver stage protection in mice. Here, Prime-and-trap pulls and traps primed Plasmodium yoelii circumsporozoite protein (CSP)-specific CD8⁺ T cells in the liver via liver expression of DNA-encoded CSP delivered by hydrodynamic transfection (HDT). HDT-CSP trapping doses were progressively de-escalated to define the minimal requirements for inducing CSP-specific CD8⁺ T cells in the liver.

Prime-and-HDT trap induced sterile protection against sporozoite challenge with CSP-HDT doses as low as 5 ng DNA. However, protection was lost at an ultra-low CSP-HDT dose of 50 pg, which was associated with a similarly low level of CSP-specific CD8⁺ T cells in the liver. These results suggest that there is a threshold of CSP-specific CD8⁺ T cells required in the liver to achieve sterile protection.

Overall, these studies indicate that prime-and-HDT trap vaccination offers a tractable new strategy to study immunity to liver stage malaria in mice that is inexpensive, reproducible, and accessible.