Effects on Immunogenicity by Formulations of Emulsion-Based Adjuvants for Malaria Vaccines

Abstract

bNew malaria vaccines are urgently needed to improve vaccine protective efficacy. PfCelTOS is a recombinant malaria vaccine antigen that has shown protective efficacy in a small-animal challenge model when combined with a water-in-oil emulsion adjuvant (Montanide ISA 720). In this report, we show that PfCelTOS vaccines containing GLA-SE (a stable oil-in-water emulsion combined with a Toll-like receptor 4 [TLR4] agonist) elicit strong Th1-type immune responses in BALB/c mice. These responses include higher antigen-specific IgG2a antibody titers and more gamma interferon (IFN-␥) production than those seen with a PfCelTOS vaccine containing Montanide ISA 720. Furthermore, reducing the emulsion dose from 2% to 1% or 0.5% (vol/vol) squalene in GLA-SE did not compromise immunogenicity. Emulsion dose titration in the absence of formulated GLA caused some reduction in humoral and cellular immune responses compared to those with the 2% squalene emulsion dose. Oil-in-water (o/w) emulsions have been used safely and successfully as adjuvants in modern vaccines. The most notable o/w emulsions are MF59 and AS03, which are produced by Novartis and GSK Biologicals, respectively. Both of these adjuvants contain squalene at ϳ2.5% (vol/vol) in the final vaccine formulation (13). However, until recently, only a few reports regarding the motivation for selecting this squalene concentration were published (9,21,25). Moreover, a recent study showed that dilution of MF59 did not compromise the immune response in a pandemic influenza vaccine clinical trial (20). If adjuvant activity can be maintained with a reduction of the squalene dose, then the local reactogenicity of o/w emulsions can potentially be reduced. Furthermore, the vaccine cost could decrease while the available adjuvant supply would increase, thus making vaccine and adjuvant production in resource-poor countries more achievable.The recombinant malaria antigen PfCelTOS (Plasmodium falciparum cell traversal protein for ookinetes and sporozoites) combined with an emulsion adjuvant (Montanide ISA 720) protected 60% of mice in a heterologous challenge model (8). PfCelTOS inhibits sporozoite motility and hepatocyte infectivity and could be an important component of new malaria vaccines. Both cellular and humoral immune responses are important for protective efficacy directed against this antigen (7,8).In this work, we evaluated squalene-based stable emulsion (SE) adjuvant dose effects on humoral and cellular immune responses to PfCelTOS. Moreover, we investigated the effect of including a formulated synthetic Toll-like receptor 4 (TLR4) agonist, glucopyranosyl lipid adjuvant (GLA), in the vaccine formulation. We show that squalene concentrations of Ͻ2% (vol/vol) in GLA-SE may induce adjuvant responses equivalent to those seen with a 2% (vol/vol) squalene concentration. This finding has important implications for vaccine adjuvant production and dosing as well as for novel routes of administration (such as intradermal routes), which may be more sensitive to oil concentrations. Mo...

Adeno-Associated Virus-Like Particles as New Carriers for B-Cell Vaccines: Testing Immunogenicity and Safety in BALB/c Mice

“…Alum is administered mostly in the context of infectious disease and allergy (8), while Montanide is used in vaccines against HIV and cancer, as well as infectious diseases (6,17,18). Our hypothesis was that the Th1 adjuvant would counterbalance an ongoing Th2 response.…”

Protection and Long-Lived Immunity Induced by the ID93/GLA-SE Vaccine Candidate against a Clinical Mycobacterium tuberculosis Isolate

“…When formulated in an oil-in-water stable emulsion (SE), GLA induces in vivo innate immune responses as well as Th1-skewed cellular immunity to coadministered vaccine antigens (27,28). GLA adjuvant formulations have been used with experimental vaccines for influenza, HIV (29), respiratory syncytial virus (RSV) (30), leishmaniasis (31), malaria (32), and leprosy (33) in addition to TB (34,35). Many of these vaccines using GLA formulations have also resulted in protection in preclinical animal models, including mice (34)(35)(36), ferrets (37,38), guinea pigs (34,35,39), cotton rats (30), and hamsters (40), against infectious challenge.…”

Particle-based platforms for malaria vaccines

“…Indeed, GLA-SE has a demonstrated capacity to elicit strong Th1 type immune responses. Pb CSP and Pf CelTOS formulated with GLA-SE induced higher level of IgG2 antibodies and more INFγ-producing cells in mice [56, 57]. GLA-SE also has a broad safety profile in humans: It has been injected in hundreds of humans in multiple Phase 1 trials evaluating vaccine candidates against various diseases.…”