Limits...
MF59- and Al(OH)3-Adjuvanted Staphylococcus aureus (4C-Staph) Vaccines Induce Sustained Protective Humoral and Cellular Immune Responses, with a Critical Role for Effector CD4 T Cells at Low Antibody Titers.

Monaci E, Mancini F, Lofano G, Bacconi M, Tavarini S, Sammicheli C, Arcidiacono L, Giraldi M, Galletti B, Rossi Paccani S, Torre A, Fontana MR, Grandi G, de Gregorio E, Bensi G, Chiarot E, Nuti S, Bagnoli F, Soldaini E, Bertholet S - Front Immunol (2015)

Bottom Line: Due to the increasing antibiotic resistance, the development of an effective vaccine against S. aureus is needed.However, the role of CD4 T cells seemed more evident in the presence of low-antibody responses.This study provides preclinical data further supporting the use of the adjuvanted 4C-Staph vaccines against S. aureus diseases, and provides critical insights on the correlates of protective immunity necessary to combat this pathogen.

View Article: PubMed Central - PubMed

Affiliation: Research Center, Novartis Vaccines and Diagnostics S.r.l. , Siena , Italy.

ABSTRACT
Staphylococcus aureus (S. aureus) is an important opportunistic pathogen that may cause invasive life-threatening infections, like sepsis and pneumonia. Due to the increasing antibiotic resistance, the development of an effective vaccine against S. aureus is needed. Although a correlate of protection against staphylococcal diseases is not yet established, several findings suggest that both antibodies and CD4 T cells might contribute to optimal immunity. In this study, we show that adjuvanting a multivalent vaccine (4C-Staph) with MF59, an oil-in-water emulsion licensed in human vaccines, further potentiated antigen-specific IgG titers and CD4 T-cell responses compared to alum and conferred protection in the peritonitis model of S. aureus infection. Moreover, we showed that MF59- and alum-adjuvanted 4C-Staph vaccines induced persistent antigen-specific humoral and T-cell responses, and protected mice from infection up to 4 months after immunization. Furthermore, 4C-Staph formulated with MF59 was used to investigate which immune compartment is involved in vaccine-induced protection. Using CD4 T cell-depleted mice or B cell-deficient mice, we demonstrated that both T and B-cell responses contributed to 4C-Staph vaccine-mediated protective immunity. However, the role of CD4 T cells seemed more evident in the presence of low-antibody responses. This study provides preclinical data further supporting the use of the adjuvanted 4C-Staph vaccines against S. aureus diseases, and provides critical insights on the correlates of protective immunity necessary to combat this pathogen.

No MeSH data available.


Related in: MedlinePlus

Persistence of IgG and CD4 T-cell responses induced by 4C-Staph formulations. BALB/c mice were immunized with 4C-Staph, 4C-Staph/MF59 and 4C-Staph/alum (n = 10), and immune responses were determined 0.5, 1, and 4 months after immunization. (A) IgG titers specific to each 4C-Staph component (HlaH35L, EsxAB, FhuD2, and Csa1A) (n = 10–16). (B) Hla-specific neutralization titers. Number of (C) Edu+ proliferating and frequency of (D) cytokine+ CD4 T cells in response to in vitro stimulation with 4C-Staph antigens. (E) Pie charts representing polyfunctional CD4 CD44hi T cells. (F) Frequencies of CD4 T cells expressing one or more cytokines. Graphs show mean ± SD, and are the merge of at least two separate experiments. Data were analyzed using one-way ANOVA and Tukey’s multiple comparison test, p < 0.05, *4C-Staph formulation versus its respective formulation without 4C-Staph; #adjuvanted-4C-Staph versus 4C-Staph alone; $4C-Staph/MF59 versus 4C-Staph/alum; †1 month or 4 months versus 0.5 month time point.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4561515&req=5

Figure 5: Persistence of IgG and CD4 T-cell responses induced by 4C-Staph formulations. BALB/c mice were immunized with 4C-Staph, 4C-Staph/MF59 and 4C-Staph/alum (n = 10), and immune responses were determined 0.5, 1, and 4 months after immunization. (A) IgG titers specific to each 4C-Staph component (HlaH35L, EsxAB, FhuD2, and Csa1A) (n = 10–16). (B) Hla-specific neutralization titers. Number of (C) Edu+ proliferating and frequency of (D) cytokine+ CD4 T cells in response to in vitro stimulation with 4C-Staph antigens. (E) Pie charts representing polyfunctional CD4 CD44hi T cells. (F) Frequencies of CD4 T cells expressing one or more cytokines. Graphs show mean ± SD, and are the merge of at least two separate experiments. Data were analyzed using one-way ANOVA and Tukey’s multiple comparison test, p < 0.05, *4C-Staph formulation versus its respective formulation without 4C-Staph; #adjuvanted-4C-Staph versus 4C-Staph alone; $4C-Staph/MF59 versus 4C-Staph/alum; †1 month or 4 months versus 0.5 month time point.

Mentions: 4C-Staph-specific antibody titers were sustained in 4C-Staph-, 4C-Staph/MF59-, and 4C-Staph/alum-immunized mice up to 4 months after vaccination (Figure 5A). Titers remained higher in the two 4C-Staph-adjuvanted formulations at all time points evaluated. The magnitude of IgG responses of each vaccine formulation was antigen-dependent: alum formulation was more immunogenic than MF59 for Csa1A and FhuD2, MF59 was more immunogenic for EsxAB, while alum- and MF59-adjuvanted vaccines were equally immunogenic against Hla. Hla-neutralizing antibody titers were detected in all vaccinated groups 1 month after the second vaccine administration, and were sustained up to 4 months with no significant differences among non-adjuvanted and adjuvanted-4C-Staph formulations (Figure 5B).


MF59- and Al(OH)3-Adjuvanted Staphylococcus aureus (4C-Staph) Vaccines Induce Sustained Protective Humoral and Cellular Immune Responses, with a Critical Role for Effector CD4 T Cells at Low Antibody Titers.

Monaci E, Mancini F, Lofano G, Bacconi M, Tavarini S, Sammicheli C, Arcidiacono L, Giraldi M, Galletti B, Rossi Paccani S, Torre A, Fontana MR, Grandi G, de Gregorio E, Bensi G, Chiarot E, Nuti S, Bagnoli F, Soldaini E, Bertholet S - Front Immunol (2015)

Persistence of IgG and CD4 T-cell responses induced by 4C-Staph formulations. BALB/c mice were immunized with 4C-Staph, 4C-Staph/MF59 and 4C-Staph/alum (n = 10), and immune responses were determined 0.5, 1, and 4 months after immunization. (A) IgG titers specific to each 4C-Staph component (HlaH35L, EsxAB, FhuD2, and Csa1A) (n = 10–16). (B) Hla-specific neutralization titers. Number of (C) Edu+ proliferating and frequency of (D) cytokine+ CD4 T cells in response to in vitro stimulation with 4C-Staph antigens. (E) Pie charts representing polyfunctional CD4 CD44hi T cells. (F) Frequencies of CD4 T cells expressing one or more cytokines. Graphs show mean ± SD, and are the merge of at least two separate experiments. Data were analyzed using one-way ANOVA and Tukey’s multiple comparison test, p < 0.05, *4C-Staph formulation versus its respective formulation without 4C-Staph; #adjuvanted-4C-Staph versus 4C-Staph alone; $4C-Staph/MF59 versus 4C-Staph/alum; †1 month or 4 months versus 0.5 month time point.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4561515&req=5

Figure 5: Persistence of IgG and CD4 T-cell responses induced by 4C-Staph formulations. BALB/c mice were immunized with 4C-Staph, 4C-Staph/MF59 and 4C-Staph/alum (n = 10), and immune responses were determined 0.5, 1, and 4 months after immunization. (A) IgG titers specific to each 4C-Staph component (HlaH35L, EsxAB, FhuD2, and Csa1A) (n = 10–16). (B) Hla-specific neutralization titers. Number of (C) Edu+ proliferating and frequency of (D) cytokine+ CD4 T cells in response to in vitro stimulation with 4C-Staph antigens. (E) Pie charts representing polyfunctional CD4 CD44hi T cells. (F) Frequencies of CD4 T cells expressing one or more cytokines. Graphs show mean ± SD, and are the merge of at least two separate experiments. Data were analyzed using one-way ANOVA and Tukey’s multiple comparison test, p < 0.05, *4C-Staph formulation versus its respective formulation without 4C-Staph; #adjuvanted-4C-Staph versus 4C-Staph alone; $4C-Staph/MF59 versus 4C-Staph/alum; †1 month or 4 months versus 0.5 month time point.
Mentions: 4C-Staph-specific antibody titers were sustained in 4C-Staph-, 4C-Staph/MF59-, and 4C-Staph/alum-immunized mice up to 4 months after vaccination (Figure 5A). Titers remained higher in the two 4C-Staph-adjuvanted formulations at all time points evaluated. The magnitude of IgG responses of each vaccine formulation was antigen-dependent: alum formulation was more immunogenic than MF59 for Csa1A and FhuD2, MF59 was more immunogenic for EsxAB, while alum- and MF59-adjuvanted vaccines were equally immunogenic against Hla. Hla-neutralizing antibody titers were detected in all vaccinated groups 1 month after the second vaccine administration, and were sustained up to 4 months with no significant differences among non-adjuvanted and adjuvanted-4C-Staph formulations (Figure 5B).

Bottom Line: Due to the increasing antibiotic resistance, the development of an effective vaccine against S. aureus is needed.However, the role of CD4 T cells seemed more evident in the presence of low-antibody responses.This study provides preclinical data further supporting the use of the adjuvanted 4C-Staph vaccines against S. aureus diseases, and provides critical insights on the correlates of protective immunity necessary to combat this pathogen.

View Article: PubMed Central - PubMed

Affiliation: Research Center, Novartis Vaccines and Diagnostics S.r.l. , Siena , Italy.

ABSTRACT
Staphylococcus aureus (S. aureus) is an important opportunistic pathogen that may cause invasive life-threatening infections, like sepsis and pneumonia. Due to the increasing antibiotic resistance, the development of an effective vaccine against S. aureus is needed. Although a correlate of protection against staphylococcal diseases is not yet established, several findings suggest that both antibodies and CD4 T cells might contribute to optimal immunity. In this study, we show that adjuvanting a multivalent vaccine (4C-Staph) with MF59, an oil-in-water emulsion licensed in human vaccines, further potentiated antigen-specific IgG titers and CD4 T-cell responses compared to alum and conferred protection in the peritonitis model of S. aureus infection. Moreover, we showed that MF59- and alum-adjuvanted 4C-Staph vaccines induced persistent antigen-specific humoral and T-cell responses, and protected mice from infection up to 4 months after immunization. Furthermore, 4C-Staph formulated with MF59 was used to investigate which immune compartment is involved in vaccine-induced protection. Using CD4 T cell-depleted mice or B cell-deficient mice, we demonstrated that both T and B-cell responses contributed to 4C-Staph vaccine-mediated protective immunity. However, the role of CD4 T cells seemed more evident in the presence of low-antibody responses. This study provides preclinical data further supporting the use of the adjuvanted 4C-Staph vaccines against S. aureus diseases, and provides critical insights on the correlates of protective immunity necessary to combat this pathogen.

No MeSH data available.


Related in: MedlinePlus