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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 increased the survival of mice after S. aureus infection. BALB/c mice were immunized with 4C-Staph, 4C-Staph/MF59, 4C-Staph/alum, and respective controls (PBS, MF59, and alum) once or twice 2 weeks apart, and challenged 2 weeks after the last immunization with ~5 × 108 CFU S. aureus. Animals were monitored for 7 days post-infection for health status. Graphs represent the merge of at least two separate experiments (n = 32). Statistical analyses were 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 1: 4C-Staph formulations increased the survival of mice after S. aureus infection. BALB/c mice were immunized with 4C-Staph, 4C-Staph/MF59, 4C-Staph/alum, and respective controls (PBS, MF59, and alum) once or twice 2 weeks apart, and challenged 2 weeks after the last immunization with ~5 × 108 CFU S. aureus. Animals were monitored for 7 days post-infection for health status. Graphs represent the merge of at least two separate experiments (n = 32). Statistical analyses were 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: Efficacy of 4C-Staph vaccine was evaluated in the peritonitis model by immunizing mice once with 4C-Staph antigens alone, or in combination with MF59 or alum, or as control with saline or adjuvant alone. Two weeks after immunization, mice were infected i.p. with ~5 × 108 CFU S. aureus and then monitored for up to 2 weeks. 4C-Staph/MF59- and 4C-Staph/alum-immunized mice showed significantly improved survival rates 7 days post-challenge compared to MF59 and alum adjuvant control, respectively (Figure 1 left panel). The increased survival induced by 4C-Staph/MF59 and 4C-Staph/alum was similar, while 4C-Staph alone showed lower efficacy with no statistical difference compared to control mice immunized with saline. As expected, neither MF59 nor alum adjuvant alone conferred protection against S. aureus challenge. Similarly, an increased survival was measured after two immunizations with 4C-Staph/MF59 and 4C-Staph/alum, while mice immunized with 4C-Staph alone did not show statistically significant differences with control mice immunized with saline (Figure 1 right panel). In the second week of observation, the survival decreased from 56 to 50% for 4C-Staph/MF59, from 46 to 40% for 4C-Staph/alum, and from 21 to 15% for 4C-Staph in the two immunizations regime (data not shown). In the single immunization regime, the survival decreased from 62 to 56% for 4C-Staph/MF59, from 56 to 53% for 4C-Staph/alum, and remained at about 10% for 4C-Staph. The protection for both adjuvanted vaccine formulations and schedules of immunization remained statistically significant compared to controls receiving adjuvant alone. These data suggest that one immunization is sufficient to induce a protective immune response against S. aureus infection, but only when the 4C-Staph antigens are adjuvanted with MF59 or alum. Since a longer time of observation did not add value to the results, survival data will be reported at 1 week post-infection for all the subsequent challenge experiments.


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 increased the survival of mice after S. aureus infection. BALB/c mice were immunized with 4C-Staph, 4C-Staph/MF59, 4C-Staph/alum, and respective controls (PBS, MF59, and alum) once or twice 2 weeks apart, and challenged 2 weeks after the last immunization with ~5 × 108 CFU S. aureus. Animals were monitored for 7 days post-infection for health status. Graphs represent the merge of at least two separate experiments (n = 32). Statistical analyses were 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
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getmorefigures.php?uid=PMC4561515&req=5

Figure 1: 4C-Staph formulations increased the survival of mice after S. aureus infection. BALB/c mice were immunized with 4C-Staph, 4C-Staph/MF59, 4C-Staph/alum, and respective controls (PBS, MF59, and alum) once or twice 2 weeks apart, and challenged 2 weeks after the last immunization with ~5 × 108 CFU S. aureus. Animals were monitored for 7 days post-infection for health status. Graphs represent the merge of at least two separate experiments (n = 32). Statistical analyses were 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: Efficacy of 4C-Staph vaccine was evaluated in the peritonitis model by immunizing mice once with 4C-Staph antigens alone, or in combination with MF59 or alum, or as control with saline or adjuvant alone. Two weeks after immunization, mice were infected i.p. with ~5 × 108 CFU S. aureus and then monitored for up to 2 weeks. 4C-Staph/MF59- and 4C-Staph/alum-immunized mice showed significantly improved survival rates 7 days post-challenge compared to MF59 and alum adjuvant control, respectively (Figure 1 left panel). The increased survival induced by 4C-Staph/MF59 and 4C-Staph/alum was similar, while 4C-Staph alone showed lower efficacy with no statistical difference compared to control mice immunized with saline. As expected, neither MF59 nor alum adjuvant alone conferred protection against S. aureus challenge. Similarly, an increased survival was measured after two immunizations with 4C-Staph/MF59 and 4C-Staph/alum, while mice immunized with 4C-Staph alone did not show statistically significant differences with control mice immunized with saline (Figure 1 right panel). In the second week of observation, the survival decreased from 56 to 50% for 4C-Staph/MF59, from 46 to 40% for 4C-Staph/alum, and from 21 to 15% for 4C-Staph in the two immunizations regime (data not shown). In the single immunization regime, the survival decreased from 62 to 56% for 4C-Staph/MF59, from 56 to 53% for 4C-Staph/alum, and remained at about 10% for 4C-Staph. The protection for both adjuvanted vaccine formulations and schedules of immunization remained statistically significant compared to controls receiving adjuvant alone. These data suggest that one immunization is sufficient to induce a protective immune response against S. aureus infection, but only when the 4C-Staph antigens are adjuvanted with MF59 or alum. Since a longer time of observation did not add value to the results, survival data will be reported at 1 week post-infection for all the subsequent challenge experiments.

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