SIV loads are lower in monkeys given both a DNA vaccine and a DC-activating TLR ligand (red).

Because they are cheaper and easier to manufacture than recombinant protein vaccines, successful DNA vaccines are in high demand. So far, however, DNA vaccines targeted against malaria, hepatitis B, and HIV have failed to induce a strong immune response in either monkeys or humans.

For various other types of vaccines, TLR ligands are commonly coinjected to improve the patient's immune response. The ligands activate DCs, which in turn secrete immune-boosting cytokines and enhance the proliferation and activity of T cells. Despite their success in protein vaccines, TLR ligands have not been tested as supplements to DNA vaccines in humans or other primates.

Findings from Kwissa et al. now suggest that TLR ligands may indeed make human DNA vaccines more effective. The authors report that monkeys are better at fighting off SIV infection if their DCs are also activated by a TLR ligand at the time of DNA vaccination. The ligand of choice was TLR-9, which is primarily expressed by a subset of DCs known to boost the numbers of antiviral CD8⁺ T cells.

This dual injection increased the total numbers of SIV-specific T cells. Many of these cells secreted a broader range of protective cytokines than did T cells from monkeys given only the DNA vaccine. However, the mechanism by which the TLR-9–activated DCs instruct T cells to secrete more types of cytokines is unclear.

In humans, survival from HIV infection is correlated with the numbers of CD4⁺ T cells—particularly the precursors of virus-fighting effector cells—in the gut. These precursors were more abundant a few weeks after SIV infection in monkeys that were given the coinjection regimen. Whether this stronger protection is also long lasting remains to be tested.

Related Article

Adjuvanting a DNA vaccine with a TLR9 ligand plus Flt3 ligand results in enhanced cellular immunity against the simian immunodeficiency virus

Marcin Kwissa, Rama R. Amara, Harriet L. Robinson, Bernard Moss, Sefik Alkan, Abdul Jabbar, Francois Villinger, and Bali Pulendran
J. Exp. Med. 2007 204: 2733-2746. [Abstract] [Full Text] [PDF]