Why making a vaccine against leishmaniasis is taking decades

A deadly parasite hiding in plain sight

Visceral leishmaniasis kills more than 95% of people it infects if left untreated. Each year, it strikes an estimated 50,000 to 90,000 people. At the same time, cutaneous leishmaniasis causes skin sores in 600,000 to over 1 million people across nearly 100 countries. Sandflies spread these tiny single-celled bugs with a bite. The invaders then slip directly into the white blood cells meant to destroy them.

Inside a biting sandfly, the bug lives as a swimming swimmer called a promastigote. Once injected into human flesh, it enters immune clean-up cells called macrophages and turns into an amastigote. Inside this safe space, it multiplies and hides from normal body defences.

Hacking the immune system

To stay alive, the invader acts like a Trojan Horse. It enters the macrophage disguised as harmless waste. Once inside, it switches off the internal alarm and treats the cell as a private nursery. Our body can defeat it, but only if specialised T-cells mount a sharp Th1 response. This releases messenger chemicals like interferon-gamma, ordering macrophages to make nitric oxide to wipe out the bug.

Because beating an infection often gives lasting strength against future attacks, scientists have pursued leishmaniasis vaccine development for decades. Older methods used leishmanization. This meant deliberately scratching live bugs into hidden skin to create a small sore. While this gave lasting defence, it carried major health risks.

Safer modern weapons in clinical trials

Teams are now building safer designs. One path removes specific genes from the bug, such as centrin, p27, FBP, or Kharon-1. These gene deletions leave the bug unable to copy itself inside human cells. This safely alerts the immune system without causing full disease.

Another path uses harmless, altered viruses to carry bug proteins to human immune cells. A jab called ChAd63-KH uses a modified monkey virus carrying blueprints for two target proteins, KMP-11 and HASPB. It became the first third-generation platform to enter human trials, proving safe and sparking strong T-cell activity.

Doctors have also tested a Controlled Human Infection Model (CHIM). In one study, 14 healthy people let infected sandflies bite them under close medical care. The trial saw a 64% take rate, meaning nine people got an infection. Doctors safely stopped sore growth using tissue biopsies, giving a clear look at early human immune defences.

What we still do not know

The central hurdle is that no human vaccine has yet won regulatory approval. More than 20 distinct Leishmania species cause illness in humans. Their surface proteins vary so widely that a jab against one species rarely stops another. Also, standard rodent tests often fail to copy human disease accurately.

Big puzzles also remain in the laboratory. We still do not understand the inner machinery behind resistance to drugs like paromomycin. Doctors must also learn how to spark enough defence without triggering harmful tissue damage, and the exact biological markers of lasting protection in human blood remain unknown.