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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 persistent protection against S. aureus. CD1 mice were immunized once or twice with 4C-Staph, 4C-Staph/MF59, and 4C-Staph/alum (n = 10) and challenged with S. aureus 0.5, 1, or 4 months after immunization. Animals were monitored for 7 days post-infection for health status. (A) Survival and (B) protective efficacy (PE) calculated (as described in Materials and Methods) on day 7 post-infection. Graphs represent the merge of at least two separate experiments (n = 16–24). Statistical analysis was performed using Mantel–Cox test; survival in the groups receiving the formulated 4C-Staph vaccines were compared to their respective control. *p < 0.05.
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Figure 6: 4C-Staph formulations induced persistent protection against S. aureus. CD1 mice were immunized once or twice with 4C-Staph, 4C-Staph/MF59, and 4C-Staph/alum (n = 10) and challenged with S. aureus 0.5, 1, or 4 months after immunization. Animals were monitored for 7 days post-infection for health status. (A) Survival and (B) protective efficacy (PE) calculated (as described in Materials and Methods) on day 7 post-infection. Graphs represent the merge of at least two separate experiments (n = 16–24). Statistical analysis was performed using Mantel–Cox test; survival in the groups receiving the formulated 4C-Staph vaccines were compared to their respective control. *p < 0.05.

Mentions: Finally, to evaluate whether the immune responses observed at later time point from vaccination were still protective, mice immunized once or twice with 4C-Staph/MF59 or 4C-Staph/alum were challenged 1 month or 4 months after vaccination with S. aureus and their survival was monitored for 7 days. 4C-Staph/MF59- and 4C-Staph/alum-immunized mice were still protected when challenged 1 or 4 months post-vaccination (Figure 6A). Protective efficacy (calculated as described in Materials and Methods) was higher at 1 month than 2 weeks after vaccination and sustained at least up to 4 months with both 4C-Staph/MF59 and 4C-Staph/alum formulations (Figure 6B). Moreover, 4C-Staph/MF59 outperformed 4C-Staph/alum at late time points. Similar results were observed if mice were infected after one or two vaccine injections. Altogether, these data suggest that 4C-Staph vaccine formulations induced levels of protective immune responses sustained at least for 4 months after immunization.


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 persistent protection against S. aureus. CD1 mice were immunized once or twice with 4C-Staph, 4C-Staph/MF59, and 4C-Staph/alum (n = 10) and challenged with S. aureus 0.5, 1, or 4 months after immunization. Animals were monitored for 7 days post-infection for health status. (A) Survival and (B) protective efficacy (PE) calculated (as described in Materials and Methods) on day 7 post-infection. Graphs represent the merge of at least two separate experiments (n = 16–24). Statistical analysis was performed using Mantel–Cox test; survival in the groups receiving the formulated 4C-Staph vaccines were compared to their respective control. *p < 0.05.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 6: 4C-Staph formulations induced persistent protection against S. aureus. CD1 mice were immunized once or twice with 4C-Staph, 4C-Staph/MF59, and 4C-Staph/alum (n = 10) and challenged with S. aureus 0.5, 1, or 4 months after immunization. Animals were monitored for 7 days post-infection for health status. (A) Survival and (B) protective efficacy (PE) calculated (as described in Materials and Methods) on day 7 post-infection. Graphs represent the merge of at least two separate experiments (n = 16–24). Statistical analysis was performed using Mantel–Cox test; survival in the groups receiving the formulated 4C-Staph vaccines were compared to their respective control. *p < 0.05.
Mentions: Finally, to evaluate whether the immune responses observed at later time point from vaccination were still protective, mice immunized once or twice with 4C-Staph/MF59 or 4C-Staph/alum were challenged 1 month or 4 months after vaccination with S. aureus and their survival was monitored for 7 days. 4C-Staph/MF59- and 4C-Staph/alum-immunized mice were still protected when challenged 1 or 4 months post-vaccination (Figure 6A). Protective efficacy (calculated as described in Materials and Methods) was higher at 1 month than 2 weeks after vaccination and sustained at least up to 4 months with both 4C-Staph/MF59 and 4C-Staph/alum formulations (Figure 6B). Moreover, 4C-Staph/MF59 outperformed 4C-Staph/alum at late time points. Similar results were observed if mice were infected after one or two vaccine injections. Altogether, these data suggest that 4C-Staph vaccine formulations induced levels of protective immune responses sustained at least for 4 months after immunization.

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