A Universal Vaccine against Leptospirosis: Are We Going in the Right Direction?

Abstract

Leptospirosis is the most widespread zoonosis in the world and a neglected tropical disease estimated to cause severe infection in more than one million people worldwide every year that can be combated by effective immunization. However, no significant progress has been made on the leptospirosis vaccine since the advent of bacterins over 100 years. Although protective against lethal infection, particularly in animals, bacterin-induced immunity is considered short term, serovar restricted, and the vaccine can cause serious side effects. The urgent need for a new vaccine has motivated several research groups to evaluate the protective immune response induced by recombinant vaccines. Significant protection has been reported with several promising outer membrane proteins, including LipL32 and the leptospiral immunoglobulin-like proteins. However, efficacy was variable and failed to induce a cross-protective response or sterile immunity among vaccinated animals. As hundreds of draft genomes of all known Leptospira species are now available, this should aid novel target discovery through reverse vaccinology (RV) and pangenomic studies. The identification of surface-exposed vaccine candidates that are highly conserved among infectious Leptospira spp. is a requirement for the development of a cross-protective universal vaccine. However, the lack of immune correlates is a major drawback to the application of RV to Leptospira genomes. In addition, as the protective immune response against leptospirosis is not fully understood, the rational use of adjuvants tends to be a process of trial and error. In this perspective, we discuss current advances, the pitfalls, and possible solutions for the development of a universal leptospirosis vaccine.

Recent findings related to immune responses against leptospirosis and novel strategies to prevent infection

“…This technique has recently been implemented for leptospires (for comprehensive recent reviews see Refs. [75] and [76]). In 2006, the Yang group obtained the first results using bioinformatics and analysis based on the theory of reverse vaccinology.…”

“…Among these proteins, the conserved orthologs present in all the pathogenic serovars, harboring outer membrane b barrel domains, were further modeled in 3D. Peptides predicted to be surface exposed epitopes of major histocompatibility complex of class II molecules were mapped on the proteins, giving information about their potential immunogenicity [80,76]. This study identified 18 outer membrane proteins, including 8 outer membrane lipoproteins, TolC efflux pumps and several TonB-dependent transporters, that bind and transport siderophores, metals, and vitamins [80].…”

Extended low-resolution structure of a Leptospira antigen offers high bactericidal antibody accessibility amenable to vaccine design

“…The exploration of recombinant strategies can be particularly fruitful when classical vaccine strategies provide weak protection. Currently available inactivated vaccines against leptospirosis, the most common bacterial zoonosis ( Picardeau, 2017 ), are inadequate because of the severe side-effects and lack of cross-protection among pathogenic Leptospira species ( Grassmann et al, 2017 ; Adler, 2015 ). Because the estimated worldwide burden of leptospirosis is over 1 million severe cases and ~60,000 deaths per year, advances in recombinant leptospiral vaccines are desperately needed and are likely to benefit from a structure-based antigen design strategy ( Picardeau, 2017 ; Costa et al, 2015 ).…”

“…While several leptospiral antigens have been explored for use in vaccines, the most promising candidates have been derived from the Leptospira immunoglobulin-like (Lig) protein family ( Ko et al, 2009 ; Grassmann et al, 2017 ; Cao et al, 2011 ; Yan et al, 2009 ; Chang et al, 2007 ). Lig proteins are present in only pathogenic species with LigB (but not LigA or LigC) being found in all pathogenic Leptospira genomes ( McBride et al, 2009 ; Matsunaga et al, 2003 ), LigB’s expression during host invasion further suggests an important role in virulence ( Lessa-Aquino et al, 2017 ; Choy et al, 2007 ).…”

Comparative screening of recombinant antigen thermostability for improved leptospirosis vaccine design

“…Existing commercial vaccines rely on inactivated or fragmented Leptospira spp. bacteria and have a high potential for severe side effects (Adler, ; Grassmann, Souza, & McBride, ). 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, ).…”