A sand fly salivary protein vaccine shows efficacy against vector-transmitted cutaneous leishmaniasis in nonhuman primates

Immunity to sand fly salivary protein correlates to protection against cutaneous leishmaniasis in rhesus macaques. Leishmania vaccine targets the messenger The old adage “Don’t kill the messenger” may not hold true when vaccinating against leishmaniasis. Oliveira et al. demonstrate that a vaccine against sand fly salivary protein can protect nonhuman primate from leishmania infection. Leishmaniasis is transmitted by the bite of infected phlebotomine sand flies, which also transfer some of their saliva with the bite. Most macaques vaccinated against PdSP15, a sand fly salivary protein, had decreased parasite burden after induction of cutaneous leishmaniasis initiated by infected bites. Moreover, people exposed to sand fly bites developed an immune response to PdSP15 as well, suggesting that this approach may be translatable to humans. Currently, there are no commercially available human vaccines against leishmaniasis. In rodents, cellular immunity to salivary proteins of sand fly vectors is associated to protection against leishmaniasis, making them worthy targets for further exploration as vaccines. We demonstrate that nonhuman primates (NHP) exposed to Phlebotomus duboscqi uninfected sand fly bites or immunized with salivary protein PdSP15 are protected against cutaneous leishmaniasis initiated by infected bites. Uninfected sand fly–exposed and 7 of 10 PdSP15-immunized rhesus macaques displayed a significant reduction in disease and parasite burden compared to controls. Protection correlated to the early appearance of Leishmania-specific CD4+IFN-γ+ lymphocytes, suggesting that immunity to saliva or PdSP15 augments the host immune response to the parasites while maintaining minimal pathology. Notably, the 30% unprotected PdSP15-immunized NHP developed neither immunity to PdSP15 nor an accelerated Leishmania-specific immunity. Sera and peripheral blood mononuclear cells from individuals naturally exposed to P. duboscqi bites recognized PdSP15, demonstrating its immunogenicity in humans. PdSP15 sequence and structure show no homology to mammalian proteins, further demonstrating its potential as a component of a vaccine for human leishmaniasis.