LigB subunit vaccine confers sterile immunity against challenge in the hamster model of leptospirosis

Abstract

Neglected tropical diseases, including zoonoses such as leptospirosis, have a major impact on rural and poor urban communities, particularly in developing countries. This has led to major investment in antipoverty vaccines that focus on diseases that influence public health and thereby productivity. While the true, global, impact of leptospirosis is unknown due to the lack of adequate laboratory diagnosis, the WHO estimates that incidence has doubled over the last 15 years to over 1 million cases that require hospitalization every year. Leptospirosis is caused by pathogenic Leptospira spp. and is spread through direct contact with infected animals, their urine or contaminated water and soil. Inactivated leptospirosis vaccines, or bacterins, are approved in only a handful of countries due to the lack of heterologous protection (there are > 250 pathogenic Leptospira serovars) and the serious side-effects associated with vaccination. Currently, research has focused on recombinant vaccines, a possible solution to these problems. However, due to a lack of standardised animal models, rigorous statistical analysis and poor reproducibility, this approach has met with limited success. We evaluated a subunit vaccine preparation, based on a conserved region of the leptospiral immunoglobulin-like B protein (LigB(131–645)) and aluminium hydroxide (AH), in the hamster model of leptospirosis. The vaccine conferred significant protection (80.0–100%, P < 0.05) against mortality in vaccinated animals in seven independent experiments. The efficacy of the LigB(131–645)/AH vaccine ranged from 87.5–100% and we observed sterile immunity (87.5–100%) among the vaccinated survivors. Significant levels of IgM and IgG were induced among vaccinated animals, although they did not correlate with immunity. A mixed IgG1/IgG2 subclass profile was associated with the subunit vaccine, compared to the predominant IgG2 profile seen in bacterin vaccinated hamsters. These findings suggest that LigB(131–645) is a vaccine candidate against leptospirosis with potential ramifications to public and veterinary health.

A Live Attenuated Vaccine Model Confers Cross-Protective Immunity Against Different Species ofLeptospiraspp.

“…Given the limitations of the whole-cell vaccines currently in use, identifying the perfect protein candidate has been a major effort in the field of vaccine development for leptospirosis 3 . Immunization with Lig proteins or LipL32 2,38,39 has been shown to confer protection, albeit not cross-protective immunity, against experimental infection. However, efficacy results have been proven difficult to replicate 2,40 .…”

Two Piscan Aeromonas Vaccine Strategies

“…The two vaccine strategies have shown decline of agglutinin titers at the day 60 of the experiment thought the test fish in aquaria being normal till termination of experiment. This may be due to the phenomenon of sterile immunity , Table 6, were the antibody prevents pathogens from expressing their pathological effect [24,25],decline effector and/ or memory B cell functions or due the interplay of cellular immune factors in immune efficacy of these vaccine strategies. Though the latter possibility is far from being the case.…”

Comparative screening of recombinant antigen thermostability for improved leptospirosis vaccine design

“…While these results suggest a possible link between domain stability and protection consistency, leptospirosis challenge experiments have many notable issues, including the animal model (Gomes‐Solecki, Santecchia, & Werts, ), the challenge strain (Fouts et al, ), the delivery method (Coutinho et al, ), and the use of adjuvants, that can each cause variability between vaccine trials (Vernel‐Pauillac & Werts, ). Comparing two recent LigB studies that used different adjuvants, the trial that incorporated the potent Alum adjuvant provided sterilizing immunity (Conrad et al, ), whereas the other trial used mycobacterial‐derived Freund adjuvant and did not provide complete protection (Evangelista et al, ). The best adjuvants should improve immune response kinetics thereby reducing the importance of antigen stability (Liang & Lore, ).…”

“…The results of previous Lig protein studies should be considered in the context of domain thermostability. Vaccine trials utilizing recombinant Lig protein‐based antigens have shown results ranging from sterile immunity to only partial protection (Adler, ; Cao et al, ; Conrad et al, ; Evangelista et al, ; Yan et al, ). Variable handling and storage procedures could easily affect vaccine trial outcomes with a bias against domains with poor thermostability.…”

“…Proteins displayed on the leptospiral surface during host infection provide an optimal target for recombinant vaccines (Chang et al, ; Dellagostin et al, ; Lessa‐Aquino et al, ). Currently, antigens derived from Leptospira immunoglobulin‐like (Lig) proteins are the most promising vaccine candidates but concerns about formulation consistency have hampered development (Conrad et al, ; Evangelista, Lourdault, Matsunaga, & Haake, ; Palaniappan et al, ; Santos & Nascimento, ; Yan et al, ).…”