Natural and Synthetic Saponins as Vaccine Adjuvants

Abstract

Saponin adjuvants have been extensively studied for their use in veterinary and human vaccines. Among them, QS-21 stands out owing to its unique profile of immunostimulating activity, inducing a balanced Th1/Th2 immunity, which is valuable to a broad scope of applications in combating various microbial pathogens, cancers, and other diseases. It has recently been approved for use in human vaccines as a key component of combination adjuvants, e.g., AS01b in Shingrix^® for herpes zoster. Despite its usefulness in research and clinic, the cellular and molecular mechanisms of QS-21 and other saponin adjuvants are poorly understood. Extensive efforts have been devoted to studies for understanding the mechanisms of QS-21 in different formulations and in different combinations with other adjuvants, and to medicinal chemistry studies for gaining mechanistic insights and development of practical alternatives to QS-21 that can circumvent its inherent drawbacks. In this review, we briefly summarize the current understandings of the mechanism underlying QS-21's adjuvanticity and the encouraging results from recent structure-activity-relationship (SAR) studies.

Keywords: QS-21; SAR; VSA-1; VSA-2; adjuvant; mechanism; saponin.

Figure 1

Natural saponin adjuvant QS-21.

Figure 2

Natural QS saponins QS-7, QS-17, and QS-18.

Figure 3

Immunostimulating natural saponins.

Figure 4

Groups of female BALB/c mice were immunized by the subcutaneous route (s.c.) with OVA (20 µg) alone or with QS-21 (20 µg), or a synthetic saponin (50 μg). IgG2a/IgG1 ratios are expressed as mean ± SEM. Statistical significance was evaluated by t tests (with unpaired, nonparametric, and Mann-Whitney test). ** p < 0.01 compared with the group of OVA alone, and # p < 0.05 compared between the indicated groups.

Figure 5

Synthesized QS analogs.

Figure 6

Structural similarity between Momordica saponins (MS) and de-acylated QS-17/18 and MS derivatization.

Figure 7

Serum IgG, IgG1, and IgG2a anti-OVA response in mice immunized by the s.c. route with OVA alone or with GPI-0100 or a saponin adjuvant. Mice were immunized on days 0, 14, and 28. Serum samples were collected prior to each immunization and at 6 weeks following the initial immunization. Values are expressed as mean ± SEM. * p < 0.05, ** p < 0.01, and *** p < 0.001 compared with mice immunized with OVA alone.

Figure 7

Serum IgG, IgG1, and IgG2a anti-OVA response in mice immunized by the s.c. route with OVA alone or with GPI-0100 or a saponin adjuvant. Mice were immunized on days 0, 14, and 28. Serum samples were collected prior to each immunization and at 6 weeks following the initial immunization. Values are expressed as mean ± SEM. * p < 0.05, ** p < 0.01, and *** p < 0.001 compared with mice immunized with OVA alone.

Figure 8

Semi-synthetic MS derivative VSA-2. Mice were immunized by the s.c. route with rHagB alone or with GPI-0100 or a saponin adjuvant on days 0, 14, and 28. Serum samples were collected prior to each immunization and at 6 weeks after the initial immunization. IgG2a/IgG1. Values are expressed as mean ± SD. Statistical significance compared with rHagB + VSA-2 (21). Statistical significance was evaluated by t tests (with unpaired, nonparametric, and Mann−Whitney test). * p < 0.05; ** p < 0.01.

Figure 8

Semi-synthetic MS derivative VSA-2. Mice were immunized by the s.c. route with rHagB alone or with GPI-0100 or a saponin adjuvant on days 0, 14, and 28. Serum samples were collected prior to each immunization and at 6 weeks after the initial immunization. IgG2a/IgG1. Values are expressed as mean ± SD. Statistical significance compared with rHagB + VSA-2 (21). Statistical significance was evaluated by t tests (with unpaired, nonparametric, and Mann−Whitney test). * p < 0.05; ** p < 0.01.

Figure 9

Synthetic QS isomeric analogs having different stereocenters.