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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

B cells and CD4 T cells contribute to protection conferred by 4C-Staph formulations. Mice were immunized once or twice with 4C-Staph/MF59 or MF59 and challenged with S. aureus 10 days after the last immunization. Animals were monitored for 7 days post-infection for health status. (A,B) CD4 T cells were depleted in immunized BALB/c mice by i.p. injection of anti-CD4 or isotype control antibodies (n = 48) (A) 1–3 days before challenge, or (B) 1 day before each immunization. (C) Survival of B-cell knock-out Jh mice (n = 15). Graphs represent the merge of three separate experiments. Statistical analyses were performed using Mantel–Cox test, *p < 0.05.
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Figure 4: B cells and CD4 T cells contribute to protection conferred by 4C-Staph formulations. Mice were immunized once or twice with 4C-Staph/MF59 or MF59 and challenged with S. aureus 10 days after the last immunization. Animals were monitored for 7 days post-infection for health status. (A,B) CD4 T cells were depleted in immunized BALB/c mice by i.p. injection of anti-CD4 or isotype control antibodies (n = 48) (A) 1–3 days before challenge, or (B) 1 day before each immunization. (C) Survival of B-cell knock-out Jh mice (n = 15). Graphs represent the merge of three separate experiments. Statistical analyses were performed using Mantel–Cox test, *p < 0.05.

Mentions: CD4 T cells may have a dual role: as (i) effector cells through the release of cytokines and/or (ii) providers of cognate help to B cells for the production of antigen-specific functional IgG. To evaluate a possible role for any of these two CD4 T-cell populations in 4C-Staph/MF59-mediated protection against S. aureus, we depleted CD4 T cells by treating mice with anti-CD4 antibody or an IgG2b isotype control before or after immunization (Figure S2A in Supplementary Material). Mice immunized once with 4C-Staph/MF59 and depleted of CD4 T cells after vaccination shortly prior to S. aureus challenge showed a significantly decreased survival compared to isotype control-treated mice, while no differences in survival were seen between anti-CD4 and isotype treatments in mice immunized twice (Figure 4A). These data suggest that effector CD4 T cells may have a prominent role in protecting mice against rapid death by S. aureus in the presence of low 4C-Staph-specific IgM and IgG titers (single immunization), while they might be dispensable at high antibody titers (two immunizations).


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)

B cells and CD4 T cells contribute to protection conferred by 4C-Staph formulations. Mice were immunized once or twice with 4C-Staph/MF59 or MF59 and challenged with S. aureus 10 days after the last immunization. Animals were monitored for 7 days post-infection for health status. (A,B) CD4 T cells were depleted in immunized BALB/c mice by i.p. injection of anti-CD4 or isotype control antibodies (n = 48) (A) 1–3 days before challenge, or (B) 1 day before each immunization. (C) Survival of B-cell knock-out Jh mice (n = 15). Graphs represent the merge of three separate experiments. Statistical analyses were performed using Mantel–Cox test, *p < 0.05.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 4: B cells and CD4 T cells contribute to protection conferred by 4C-Staph formulations. Mice were immunized once or twice with 4C-Staph/MF59 or MF59 and challenged with S. aureus 10 days after the last immunization. Animals were monitored for 7 days post-infection for health status. (A,B) CD4 T cells were depleted in immunized BALB/c mice by i.p. injection of anti-CD4 or isotype control antibodies (n = 48) (A) 1–3 days before challenge, or (B) 1 day before each immunization. (C) Survival of B-cell knock-out Jh mice (n = 15). Graphs represent the merge of three separate experiments. Statistical analyses were performed using Mantel–Cox test, *p < 0.05.
Mentions: CD4 T cells may have a dual role: as (i) effector cells through the release of cytokines and/or (ii) providers of cognate help to B cells for the production of antigen-specific functional IgG. To evaluate a possible role for any of these two CD4 T-cell populations in 4C-Staph/MF59-mediated protection against S. aureus, we depleted CD4 T cells by treating mice with anti-CD4 antibody or an IgG2b isotype control before or after immunization (Figure S2A in Supplementary Material). Mice immunized once with 4C-Staph/MF59 and depleted of CD4 T cells after vaccination shortly prior to S. aureus challenge showed a significantly decreased survival compared to isotype control-treated mice, while no differences in survival were seen between anti-CD4 and isotype treatments in mice immunized twice (Figure 4A). These data suggest that effector CD4 T cells may have a prominent role in protecting mice against rapid death by S. aureus in the presence of low 4C-Staph-specific IgM and IgG titers (single immunization), while they might be dispensable at high antibody titers (two immunizations).

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