Route of administration of attenuated sporozoites is instrumental in rendering immunity against Plasmodia infection.

Whole sporozoite vaccine (WSV) approach has been shown to induce efficient CD8(+) T cell response, critical for developing of long-lasting sterile protection against Plasmodium. Although WSV was initiated over four decades ago, we still do not fully understand about the absolute requirements for the generation of liver-stage specific CD8(+) T memory cells. For more than a decade intravenous (IV) route of immunization has been shown to be protective in pre-clinical studies. However, the intradermal (ID) route is preferred over IV route by many researchers as it is perceived to mimic the natural route of parasite delivery through mosquito bite. Various clinical studies have shown that ID route provokes poor protective responses compared to those seen with IV route of administration. The present study highlights the importance of circumsporozoite (CS) protein in preventing sporozoite entry to the hepatocytes, which however, it is not necessarily sufficient to ensure sterile protection. Instead, this article favors the idea that liver-stage development is a prime requirement for generation of antigen specific CD8(+) T cells and suggests the conditions favored by IV inoculation of sporozoite.