A Comparison of Intramuscular and Subcutaneous Administration of LigA Subunit Vaccine Adjuvanted with Neutral Liposomal Formulation Containing Monophosphoryl Lipid A and QS21

Abstract

Leptospirosis vaccines with higher potency and reduced adverse effects are needed for human use. The carboxyl terminal domain of leptospiral immunoglobulin like protein A (LigAc) is currently the most promising candidate antigen for leptospirosis subunit vaccine. However, LigAc-based vaccines were unable to confer sterilizing immunity against Leptospira infection in animal models. Several factors including antigen properties, adjuvant, delivery system, and administration route need optimization to maximize vaccine efficacy. Our previous report demonstrated protective effects of the recombinant LigAc (rLigAc) formulated with liposome-based adjuvant, called LMQ (neutral liposome combined with monophosphoryl lipid A and Quillaja saponaria fraction 21) in hamsters. This study aimed to evaluate the impact of two commonly used administration routes, intramuscular (IM) and subcutaneous (SC), on immunogenicity and protective efficacy of rLigAc-LMQ administrated three times at 2-week interval. Two IM vaccinations triggered significantly higher levels of total anti-rLigAc IgG than two SC injections. However, comparable IgG titers and IgG2/IgG1 ratio was observed for both routes after the third immunization. The route of vaccine administration did not influence the survival rate (60%) and renal colonization against lethal Leptospira challenge. Importantly, the kidneys of IM group showed no pathological lesions while the SC group showed mild damage. In conclusion, IM vaccination with rLigAc-LMQ not only elicited faster antibody production but also protected from kidney damage following leptospiral infection better than SC immunization. However, both tested routes did not influence protective efficacy in terms of survival rate and the level of renal colonization.

Designing Adjuvant Formulations to Promote Immunogenicity and Protective Efficacy of Leptospira Immunoglobulin-Like Protein A Subunit Vaccine

“…Furthermore, certain formulations of LigAc with alhydrogel failed to induce adequate protection ( Lucas et al., 2011 ; Hartwig et al., 2014 ). LigAc antigen formulated into liposomes or poly-lactic-co-glycolic acid (PLGA) microspheres ( Faisal et al., 2009 ), or formulated with adjuvants including xanthan gum ( Bacelo et al., 2014 ), Salmonella flagellin (FliC) ( Monaris et al., 2015 ), and LMQ, which are neutral liposomes containing a monophosphoryl lipid A (MPL) and a purified saponin fraction from Quillaja saponaria (QS21) ( Techawiwattanaboon et al., 2020 ), showed promoting survival against lethal challenges. However, none of these adjuvanted vaccine formulations completely prevented Leptospira renal colonization ( Faisal et al., 2009 ; Bacelo et al., 2014 ; Monaris et al., 2015 ; Techawiwattanaboon et al., 2020 ).…”

Immunotherapeutic Peptide Vaccine Approaches to Glioma

“…In another study, while comparing intramuscular and subcutaneous vaccination of a recombinant leptospirosis vaccine rLigAc formulated with liposome-based adjuvant (LMQ), it has been demonstrated that intramuscular vaccination did not only elicit faster antibody production but also protected from kidney damage following leptospiral infection with better performance than subcutaneous immunization. However, both tested routes did not influence protective efficacy in terms of survival rate and the level of renal colonization [33]. In another phase II clincal trial of a novel amyloid beta synthetic peptide vaccine UB-311 for Alzheimer's disease (AD), the vaccine comprises two amyloid beta targeting peptides, each peptide synthetically linked to different helper T-cell peptide epitopes and formulated in an alum-containing Th2-biased solution, mixed with polyanionic CpG-ODN to form stable immunostimulatory complexes of microsize particulates.…”

Leptospiral Immunoglobulin-Like Domain Proteins: Roles in Virulence and Immunity

“…In general, PLGA particles cause a Th1 bias in the immune response ( 136 ), although splenic Th1 and Th2 cytokine mRNAs were both increased following immunization with the LigA7’-13/PLGA particles relative to transcript levels from hamsters immunized with LigA7’-13/Al(OH) 3 ( 106 ). In another study, neutral liposomes were mixed with the saponin QS-21 and the TLR4 agonist monophosphoryl lipid A ( 120 , 121 ). 60% of the immunized hamsters survived challenge, whereas no animals immunized with adjuvant alone survived ( 121 ).…”

“…In another study, neutral liposomes were mixed with the saponin QS-21 and the TLR4 agonist monophosphoryl lipid A ( 120 , 121 ). 60% of the immunized hamsters survived challenge, whereas no animals immunized with adjuvant alone survived ( 121 ). Altering the physicochemical properties of the liposome such as its surface charge or size may substantially improve performance of liposome-based vaccines ( 137 ).…”

“…A preliminary determination of the T helper response can be made based on the IgG isotype generated by vaccination. Hamster IgG isotypes involved with immunoprotection have been determined ( 116 , 117 , 119 , 121 ), yet the T helper responses associated with the IgG subsets have not been well characterized in hamsters. Experiments in mice may be more informative due to the well-characterized immune system and the available reagents.…”