A vaccine could work
There are several unanswered questions concerning the development of vaccines for leishmaniasis. First, for which form of leishmaniasis is it most urgent to develop a vaccine? Ideally, a vaccine for leishmaniasis should be broadly protective against all the species of the parasite causing the different variants of clinical disease, but this has so far proven difficult. However, in theory, it should be possible. When selecting antigens for a recombinant, vector or nucleic acid vaccine, antigens that are highly conserved among different species of the pathogen are typically selected. Even if two species are relatively distant in evolutionary terms, a vaccine based on conserved antigens could give protection against several species. Intuitively, it may be most pressing to develop a vaccine for the potentially fatal visceral form, commonly caused by only two species – L. donovani or L. infantum.
Second, Leishmania has a complex digenetic life cycle between the mammalian host and the vector sand fly. The host-vector-reservoir relationship is only partly understood – making vaccine development more difficult. For example, when developing new vaccines, antigens that might enhance the susceptibility of the host to the infection have to be avoided (13). Likewise, a vaccine has to be tested for adverse effects among already infected individuals, such as what has been reported for the Q-fever vaccine (14, 15). Another example is the role of the sand fly and how it may affect the immune response in humans. This is only partly understood and may affect the efficacy of a vaccine (11). Furthermore, antibodies against Leishmania may facilitate infection rather than limit it (13, 16), also potentially complicating vaccine development.
Third, there is a debate about how the vaccine should work. Traditionally vaccines work prophylactically. But a vaccine could also work therapeutically, alone or in combination with drug therapy (3, 17). For leishmaniasis, it is unclear which approach is most viable and most important to prioritise.
Fourth, which type of vaccine is most likely to be effective against leishmaniasis? (See Table 1 for a brief overview of potential vaccine strategies and their pros and cons.) First generation vaccines include killed or live attenuated pathogens. Such vaccines have the potential to closely mimic natural infection. In the Middle East, so-called leishmanisation has been practised, whereby pus from cutaneous lesions and parasites from culture were used to induce a local infection (10). Leishmanisation was discontinued because of problems with reproducibility and safety issues. Furthermore, a leishmanisation strategy involving a viscerotropic strain, such as L. donovani, is highly unlikely.
Table 1
Potential vaccine strategies for leishmaniasis and their pros and cons
| Vaccine approach | Inducing antibody production | Inducing cellular immunity | Allows diagnostic testing1 | Safe for immuno- suppressed individuals |
| Inactivated pathogen | Yes | No | No | Yes |
| Live attenuated pathogen | Yes | Yes | No | No |
| Recombinant antigens | Yes | No | Yes | Yes |
| Vector- based vaccines2 | Yes | Yes | No | No |
| Nucleic acid vaccine3 | Weak | Yes | Yes | Yes |
Moreover, ill-defined mutants may lack important epitopes necessary for protective immune responses, while at the same time carrying wild-type alleles that could potentially cause disease. The live attenuated approach is especially unattractive because endemic areas for leishmaniasis are also endemic for HIV and those infected with the latter are thereby also immunosuppressed. Another path would be to inactivate the parasite. However, there have been issues with standardisation of the culture from which the vaccine would be produced, and initial tests show that these vaccines give limited protection in humans (10).
Second generation vaccines are purified or recombinant proteins expressed in bacteria or eukaryotic cells. Such vaccines usually require an adjuvant to induce a good T-cell response (18). The Infectious Disease Research Institute in Seattle has developed a vaccine where several proteins conserved across several species of Leishmania are expressed in a single vaccine using a toll-like-receptor agonist as an adjuvant to induce a strong T-cell response (18, 19). This vaccine has shown promising results (19).
Third generation vaccines are nucleic acid vaccines where expression vectors encoding for a protein antigen are introduced. Here not the antigen itself, but the information required to produce it, is introduced. The recipient’s cells produce and present the antigens to immune cells (20). This vaccine strategy has obvious attractions, such as the fact that the vaccine can be rapidly and cheaply produced. The DNA-vaccine approach has been tested with several antigens against Leishmania-infected mice, but its effect remains unconvincing. Also, to the best of our knowledge, there are currently no pre-clinical or clinical trials using RNA-based vaccine technology for Leishmania. Vectors such as Adenovirus, expressing recombinant antigens, can also be used as vaccines. A novel vaccine uses this approach by expressing a gene encoding for two Leishmania proteins, and initial results are promising (17). But this is only in the phase I clinical trial stage, and there are significant challenges ahead.
It takes great effort to develop vaccines. So far, vaccine development has been carried out with limited information on the pathophysiological and immunological complexity of Leishmania infection.
Over the years, several vaccine targets and vaccination routes have been proposed and tested (21). Some of them have shown great potential in protecting animals against leishmaniasis (2). Remarkably few have been able to proceed to a clinical trial. This lack of progress is partly due to lack of a small-animal model that reflects human disease, and to the fact that many vaccines are tested with cutaneous strains where the testing has been undertaken by injections instead of sand fly bites (18).