Status of vaccine research and development of vaccines for leishmaniasis.

Tuberculosis (TB) is the leading cause of infectious death worldwide. Development of improved TB vaccines that boost or replace BCG is a major global health goal. ID93 + GLA-SE is a fusion protein TB vaccine candidate combined with the Toll-like Receptor 4 agonist adjuvant, GLA-SE. We conducted a phase 1, randomized, double-blind, dose-escalation clinical trial to evaluate two dose levels of the ID93 antigen, administered intramuscularly alone or in combination with two dose levels of the GLA-SE adjuvant, in 60 BCG-naive, QuantiFERON-negative, healthy adults in the US (ClinicalTrials.gov identifier: NCT01599897). When administered as 3 injections, 28 days apart, all dose levels of ID93 alone and ID93 + GLA-SE demonstrated an acceptable safety profile. All regimens elicited vaccine-specific humoral and cellular responses. Compared with ID93 alone, vaccination with ID93 + GLA-SE elicited higher titers of ID93-specific antibodies, a preferential increase in IgG1 and IgG3 subclasses, and a multifaceted Fc-mediated effector function response. The addition of GLA-SE also enhanced the magnitude and polyfunctional cytokine profile of CD4+ T cells. The data demonstrate an acceptable safety profile and indicate that the GLA-SE adjuvant drives a functional humoral and T-helper 1 type cellular response. A tuberculosis vaccine containing an immunity-potentiating agent stimulated strong immune responses in a first-in-human trial. Tuberculosis (TB) is the world’s foremost cause of infectious disease deaths, yet lacks an effective vaccine for adult humans. Rhea Coler, of the Infectious Disease Research Institute, Seattle, and a team from the United States and South Africa, tested their prophylactic on 60 healthy US adults. The vaccine consisted of ID93, a fusion of TB therapeutic target proteins, and GLA-SE—a supplement to boost immune responses. The candidate proved safe in all participants, with mild-to-moderate adverse effects, and provoked promising immune responses. The formulation was significantly more effective with GLA-SE than without. Further studies will elucidate the therapeutic benefit of this formulation and its ability to combat the pathogenicity of TB.

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The TLR-4 agonist adjuvant, GLA-SE, improves magnitude and quality of immune responses elicited by the ID93 tuberculosis vaccine: first-in-human trial.

Background 
Visceral leishmaniasis (VL or kala azar) is the most serious form of human leishmaniasis, responsible for over 20,000 deaths annually, and post kala azar dermal leishmaniasis (PKDL) is a stigmatizing skin condition that often occurs in patients after successful treatment for VL. Lack of effective or appropriately targeted cell mediated immunity, including CD8+ T cell responses, underlies the progression of VL and progression to PKDL, and can limit the therapeutic efficacy of anti-leishmanial drugs. Hence, in addition to the need for prophylactic vaccines against leishmaniasis, the development of therapeutic vaccines for use alone or in combined immuno-chemotherapy has been identified as an unmet clinical need. Here, we report the first clinical trial of a third-generation leishmaniasis vaccine, developed intentionally to induce Leishmania-specific CD8+ T cells.


Methods 
We conducted a first-in-human dose escalation Phase I trial in 20 healthy volunteers to assess the safety, tolerability and immunogenicity of a prime-only adenoviral vaccine for human VL and PKDL. ChAd63-KH is a replication defective simian adenovirus expressing a novel synthetic gene (KH) encoding two Leishmania proteins KMP-11 and HASPB. Uniquely, the latter was engineered to reflect repeat domain polymorphisms and arrangements identified from clinical isolates. We monitored innate immune responses by whole blood RNA-Seq and antigen specific CD8+ T cell responses by IFNγ ELISPOT and intracellular flow cytometry.


Findings 
ChAd63-KH was safe at intramuscular doses of 1x1010 and 7.5x1010 vp. Whole blood transcriptomic profiling indicated that ChAd63-KH induced innate immune responses characterized by an interferon signature and the presence of activated dendritic cells. Broad and quantitatively robust CD8+ T cell responses were induced by vaccination in 100% (20/20) of vaccinated subjects.


Conclusion 
The results of this study support the further development of ChAd63-KH as a novel third generation vaccine for VL and PKDL.


Trial registration 
This clinical trial (LEISH1) was registered at EudraCT (2012-005596-14) and ISRCTN (07766359).

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A third generation vaccine for human visceral leishmaniasis and post kala azar dermal leishmaniasis: First-in-human trial of ChAd63-KH

Attempts to produce a vaccine to protect against Chlamydia trachomatis-induced trachoma were initiated more than 100 years ago and continued for several decades. Using whole organisms, protective responses were obtained. However, upon exposure to C. trachomatis, disease exacerbation developed in some immunized individuals, precluding the implementation of the vaccine. Evidence of the role of C. trachomatis as a sexually transmitted pathogen started to emerge in the 1960s, and it soon became evident that it can cause acute infections and long-term sequelae in women, men, and newborns. The main focus of this minireview is to summarize recent findings and discuss formulations, including antigens, adjuvants, routes, and delivery systems for immunization, primarily explored in the female mouse model, with the goal of implementing a vaccine against C. trachomatis genital infections.

Update on Chlamydia trachomatis Vaccinology.

The goal of this review is to summarize the current knowledge of the epidemiology, clinical manifestations, diagnosis, and treatment of cutaneous, mucosal, and visceral leishmaniasis. We will describe the most recent findings and suggest areas of further research in the leishmaniasis field. This article reviews newer leishmaniasis tests (including rapid diagnostic tests using rK39 antibodies), vaccine candidates, and updated treatment recommendations. While leishmaniasis is a complex disease, learning the prominent clinical manifestations and major parasite species can guide the recommendations for diagnosis and treatment.

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A Review of Leishmaniasis: Current Knowledge and Future Directions.

Key antigens of Leishmania species identified in the context of host responses in Leishmania-exposed individuals from disease-endemic areas were prioritized for the development of a subunit vaccine against visceral leishmaniasis (VL), the most deadly form of leishmaniasis. Two Leishmania proteins—nucleoside hydrolase and a sterol 24-c-methyltransferase, each of which are protective in animal models of VL when properly adjuvanted— were produced as a single recombinant fusion protein NS (LEISH-F3) for ease of antigen production and broad coverage of a heterogeneous major histocompatibility complex population. When formulated with glucopyranosyl lipid A-stable oil-in-water nanoemulsion (GLA-SE), a Toll-like receptor 4 TH1 (T helper 1) promoting nanoemulsion adjuvant, the LEISH-F3 polyprotein induced potent protection against both L. donovani and L. infantum in mice, measured as significant reductions in liver parasite burdens. A robust immune response to each component of the vaccine with polyfunctional CD4 TH1 cell responses characterized by production of antigen-specific interferon-γ, tumor necrosis factor and interleukin-2 (IL-2), and low levels of IL-5 and IL-10 was induced in immunized mice. We also demonstrate that CD4 T cells, but not CD8 T cells, are sufficient for protection against L. donovani infection in immunized mice. Based on the sum of preclinical data, we prepared GMP materials and performed a phase 1 clinical study with LEISH-F3+GLA-SE in healthy, uninfected adults in the United States. The vaccine candidate was shown to be safe and induced a strong antigen-specific immune response, as evidenced by cytokine and immunoglobulin subclass data. These data provide a strong rationale for additional trials in Leishmania-endemic countries in populations vulnerable to VL.

https://onlinelibrary.wiley.com/doi/pdf/10.1038/cti.2015.6

From mouse to man: safety, immunogenicity and efficacy of a candidate leishmaniasis vaccine LEISH-F3+GLA-SE.

Vaccine development for vector-borne pathogens may be accelerated through the use of relevant challenge models, as has been the case for malaria. Because of the demonstrated biological importance of vector-derived molecules in establishing natural infections, incorporating natural challenge models into vaccine development strategies may increase the accuracy of predicting efficacy under field conditions. Until recently, however, there was no natural challenge model available for the evaluation of vaccine candidates against visceral leishmaniasis. We previously demonstrated that a candidate vaccine against visceral leishmaniasis containing the antigen LEISH-F3 could provide protection in preclinical models and induce potent T-cell responses in human volunteers. In the present study, we describe a next generation candidate, LEISH-F3+, generated by adding a third antigen to the LEISH-F3 di-fusion protein. The rationale for adding a third component, derived from cysteine protease (CPB), was based on previously demonstrated protection achieved with this antigen, as well as on recognition by human T cells from individuals with latent infection. Prophylactic immunization with LEISH-F3+formulated with glucopyranosyl lipid A adjuvant in stable emulsion significantly reduced both Leishmania infantum and L. donovani burdens in needle challenge mouse models of infection. Importantly, the data obtained in these infection models were validated by the ability of LEISH-F3+/glucopyranosyl lipid A adjuvant in stable emulsion to induce significant protection in hamsters, a model of both infection and disease, following challenge by L. donovani–infected Lutzomyia longipalpis sand flies, a natural vector. This is an important demonstration of vaccine protection against visceral leishmaniasis using a natural challenge model. A research collaboration between the United States and Bangladesh has improved its own vaccine candidate and demonstrated it to be effective. The vaccine’s target, visceral leishmaniasis, is a deadly parasitic disease transmitted via the bites of sandflies. The collaboration, led by Steven Reed of the United States’ Infectious Disease Research Institute, previously developed a vaccine that presents two parasite-derived proteins (antigens) to a host’s immune system, allowing it to build a defense. The new vaccine candidate contains three antigens and has shown to confer disease resistance to hamsters who were subsequently exposed to infected sandflies. This is the first time a vaccine for visceral leishmaniasis has stood up in tests where the host has been infected through natural methods, which inspires confidence in the vaccine’s capacity to work in the wild.

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Jeffery Guderian

Papers

From mouse to man: safety, immunogenicity and efficacy of a candidate leishmaniasis vaccine LEISH-F3+GLA-SE.

A defined subunit vaccine that protects against vector-borne visceral leishmaniasis.

Multi-epitope proteins for improved serological detection of Trypanosoma cruzi infection and Chagas Disease