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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

4C-Staph formulations induced antigen-specific functional antibody and antibody-secreting B cells. (A) IgG titers specific to each 4C-Staph component (HlaH35L, EsxAB, FhuD2, and Csa1A) were determined in sera of mice after one (Post-1) or two (Post-2) immunizations (n = 10–16). (B) Correlation between Hla-specific neutralization and antibody titers. (C) HlaH35L-specific antibody-secreting B cells were detected in spleen of mice 2 weeks after the second immunization (n = 4–8). Graphs show mean ± SD, and represent the merge of a 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.
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Figure 2: 4C-Staph formulations induced antigen-specific functional antibody and antibody-secreting B cells. (A) IgG titers specific to each 4C-Staph component (HlaH35L, EsxAB, FhuD2, and Csa1A) were determined in sera of mice after one (Post-1) or two (Post-2) immunizations (n = 10–16). (B) Correlation between Hla-specific neutralization and antibody titers. (C) HlaH35L-specific antibody-secreting B cells were detected in spleen of mice 2 weeks after the second immunization (n = 4–8). Graphs show mean ± SD, and represent the merge of a 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.

Mentions: To characterize the immunogenicity of 4C-Staph formulations in term of antibody responses in mice, serum levels of IgG and IgM specific for each 4C-Staph antigen were measured after one or two vaccine administrations of 4C-Staph, 4C-Staph/MF59, and 4C-Staph/alum. HlaH35L-specific IgG titers were readily detectable after one immunization in all groups of vaccinated mice, and IgG titers in the 4C-Staph/MF59 group reached a significant difference versus control mice that received MF59 alone (Figure 2A). In contrast, low (EsxAB) to undetectable (FhuD2 and Csa1A) levels of antigen-specific IgG were observed in all 4C-Staph-vaccinated groups after a single immunization. The second dose boosted HlaH35L and EsxAB-specific antibody titers in all groups, however, the difference in IgG titers after one and two immunizations reached statistical significance only for 4C-Staph/MF59 and 4C-Staph/alum. IgG isotypes were investigated for HlaH35L 2 weeks after the second immunization. MF59- and alum-adjuvanted 4C-Staph vaccines elicited predominantly IgG1 (81 and 74%, respectively), followed by IgG2b (17 and 23%, respectively), and IgG2a (2 and 3%, respectively) (data not shown).


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)

4C-Staph formulations induced antigen-specific functional antibody and antibody-secreting B cells. (A) IgG titers specific to each 4C-Staph component (HlaH35L, EsxAB, FhuD2, and Csa1A) were determined in sera of mice after one (Post-1) or two (Post-2) immunizations (n = 10–16). (B) Correlation between Hla-specific neutralization and antibody titers. (C) HlaH35L-specific antibody-secreting B cells were detected in spleen of mice 2 weeks after the second immunization (n = 4–8). Graphs show mean ± SD, and represent the merge of a 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.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4561515&req=5

Figure 2: 4C-Staph formulations induced antigen-specific functional antibody and antibody-secreting B cells. (A) IgG titers specific to each 4C-Staph component (HlaH35L, EsxAB, FhuD2, and Csa1A) were determined in sera of mice after one (Post-1) or two (Post-2) immunizations (n = 10–16). (B) Correlation between Hla-specific neutralization and antibody titers. (C) HlaH35L-specific antibody-secreting B cells were detected in spleen of mice 2 weeks after the second immunization (n = 4–8). Graphs show mean ± SD, and represent the merge of a 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.
Mentions: To characterize the immunogenicity of 4C-Staph formulations in term of antibody responses in mice, serum levels of IgG and IgM specific for each 4C-Staph antigen were measured after one or two vaccine administrations of 4C-Staph, 4C-Staph/MF59, and 4C-Staph/alum. HlaH35L-specific IgG titers were readily detectable after one immunization in all groups of vaccinated mice, and IgG titers in the 4C-Staph/MF59 group reached a significant difference versus control mice that received MF59 alone (Figure 2A). In contrast, low (EsxAB) to undetectable (FhuD2 and Csa1A) levels of antigen-specific IgG were observed in all 4C-Staph-vaccinated groups after a single immunization. The second dose boosted HlaH35L and EsxAB-specific antibody titers in all groups, however, the difference in IgG titers after one and two immunizations reached statistical significance only for 4C-Staph/MF59 and 4C-Staph/alum. IgG isotypes were investigated for HlaH35L 2 weeks after the second immunization. MF59- and alum-adjuvanted 4C-Staph vaccines elicited predominantly IgG1 (81 and 74%, respectively), followed by IgG2b (17 and 23%, respectively), and IgG2a (2 and 3%, respectively) (data not shown).

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