Immunization of Humans with Recombinant Pneumococcal Surface Protein A (rPspA) Elicits Antibodies That Passively Protect Mice from Fatal Infection with<i>Streptococcus pneumoniae</i>Bearing Heterologous PspA

Briles, David E.; Hollingshead, Susan K.; King, Janice; Swift, Amy J.; Braun, Patricia A.; Park, Moon K.; Ferguson, L. M.; Nahm, Moon H.; Nabors, Gary S.

doi:10.1086/317602

Cited by 253 publications

(234 citation statements)

References 41 publications

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“…When tested singly, antibodies to such antigens can be protective in animal models; these antibodies seem less potent than capsular antibody, but they can be additive or even synergistic when more than one specificity is used together (38,39). There have been clinical trials of some of these antibodies as purified proteins (40)(41)(42), and attenuated Salmonella typhi engineered to express one such protein (43,44) is currently in phase I testing as an oral vaccine. However, none have yet shown protection in humans, much less in infancy.…”

Section: Noncapsular Components As Immunogensmentioning

confidence: 99%

Serotype-independent pneumococcal experimental vaccines that induce cellular as well as humoral immunity

Malley

Anderson

2012

Proc. Natl. Acad. Sci. U.S.A.

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For prevention of Streptococcus pneumoniae (pneumococcus) infections in infancy, protein-conjugated capsular polysaccharide vaccines provide serotype-specific, antibody-mediated immunity but do not cover all of the 90+ capsule serotypes. Therefore, microbiologists have sought protective noncapsular antigens common to all strains. Alternatively, we investigated killed cells of a noncapsulated strain, which expose many such common antigens. Given to mice intranasally, this vaccine elicits antibody-independent, CD4+ T lymphocyte-dependent accelerated clearance of pneumococci of various serotypes from the nasopharynx mediated by the cytokine IL-17A. Such immunity may reproduce the natural resistance that develops in infants before capsular antibodies arise. Given by injection, the killed cell vaccine induces bifunctional immunity: plasma antibodies protective against fatal pneumonia challenge, as well as IL-17A–mediated nasopharyngeal clearance. Human testing of this inexpensive candidate vaccine by intramuscular injection is planned. Bacterial cellular vaccines are complex—a challenge for reproducibility. However, when several known protective antigens were deleted, the killed pneumococcal vaccine was still protective. This antigenic redundancy may prevent vaccine escape variants by recombinational loss, which is frequent in pneumococcus. Biochemically defined immunogens with bifunctional activity have also been devised. These immunogens are three-component conjugates in which cell wall teichoic acid (a common antigen capable of T cell activation) is coupled to a genetic fusion of two common pneumococcal proteins: a protective surface antigen and a derivative of pneumolysin, which provides TLR4 agonist activity and induces antitoxic immunity. Such constructs induce accelerated clearance when given intranasally and induce both immune mechanisms when injected. The defined composition permits analysis of structure-function activity.

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Section: Noncapsular Components As Immunogensmentioning

confidence: 99%

Serotype-independent pneumococcal experimental vaccines that induce cellular as well as humoral immunity

Malley

Anderson

2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Among the different types of pneumococcal proteins such as pneumococcal surface protein A (PspA), pneumococcal surface protein C (PspC), pneumolysin; PspA is one of the most promising candidates and has been widely investigated by several groups (Briles et al, 2000a;Briles et al, 2000b;Haughney et al, 2013;Moreno et al, 2010;Ogunniyi et al, 2007;Ogunniyi et al, 2001;Vadesilho et al, 2012). The main function of PspA is preventing the deposition of complement on the surface of the bacterium thereby inhibiting opsonization and phagocytosis (Ren et al, 2004a;Ren et al, 2004b).…”

Section: Introductionmentioning

confidence: 99%

“…Vaccination with PspA has shown to induce protective antibodies in humans (Briles et al, 2000b;Nabors et al, 2000). However, recombinant protein based vaccines can be poorly immunogenic generating low antibody responses in the absence of adjuvants or delivery systems.…”

Section: Introductionmentioning

confidence: 99%

Pulmonary dry powder vaccine of pneumococcal antigen loaded nanoparticles

Kunda

Alfagih

Miyaji

et al. 2015

International Journal of Pharmaceutics

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Pneumonia, caused by Streptococcus pneumoniae, mainly affects the immune compromised, the very young and the old, and remains one of the leading causes of death.A steady rise in disease numbers from non-vaccine serotypes necessitates a new vaccine formulation that ideally has better antigen stability and integrity, does not require cold-chain and can be delivered non-invasively. In this study, a dry powder vaccine containing an important antigen of S. pneumoniae, pneumococcal surface protein A (PspA) that has shown cross-reactivity amongst serotypes to be delivered via the pulmonary route has been formulated. The formulation contains the antigen PspA adsorbed onto the surface of polymeric nanoparticles encapsulated in L-leucine microparticles that can be loaded into capsules and delivered via an inhaler. We have successfully synthesized particles of ~150 nm and achieved ~ 20 µg of PspA adsorption per mg of NPs. In addition, the spray-dried powders displayed a FPF of 74.31±1.32% and MMAD of 1.70±0.03 μm suggesting a broncho-alveolar lung deposition facilitating the uptake of the nanoparticles by dendritic cells. Also, the PspA released from the dry powders maintained antigen stability (SDS-PAGE), integrity (Circular dichroism) and activity (lactoferrin binding assay). Moreover, the released antigen also maintained its antigenicity as determined by ELISA.

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“…Furthermore, it remains unclear whether serotype replacement will result in significant increases in non-vaccine-type disease in the face of widespread conjugate vaccine use (16). Streptococcus pneumoniae vaccines based on conserved pneumococcal protein antigens such as pneumococcal surface protein A (PspA), pneumolysin, and pneumococcal surface adhesin A (PsaA) are currently under study (4,5) and, if proven effective, may provide an alternative that is less expensive while affording greater coverage.…”

mentioning

confidence: 99%

Age-Specific Immunoglobulin G (IgG) and IgA to Pneumococcal Protein Antigens in a Population in Coastal Kenya

et al. 2004

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Streptococcus pneumoniae is the primary etiological agent of community-acquired pneumonia and a major cause of meningitis and bacteremia. Three conserved pneumococcal proteins-pneumolysin, pneumococcal surface adhesin A (PsaA), and pneumococcal surface protein A (PspA)-are currently being investigated as vaccine candidates. Such protein-based vaccines, if proven effective, could provide a cheaper alternative to conjugate vaccine formulae. Few data from sub-Saharan Africa exist concerning the development of natural antibody to these antigens, however. To investigate the age-specific development of antiprotein immunoglobulin G (IgG) and IgA antibody responses, the sera of 220 persons 2 weeks to 84 years of age from coastal Kenya were assayed using enzyme-linked immunosorbent assays. IgG and IgA antibody responses to each antigen were observed in all age groups. Serum concentrations of IgG and IgA antibody responses to PspA and PdB (a recombinant toxoid derivative of pneumolysin), but not to PsaA, increased significantly with age (P < 0.001). No decline was observed in the sera of the elderly. Anti-protein IgG concentrations were only weakly correlated (0.30 < r < 0.56; P < 0.0001), as were IgA concentrations (0.24 < r < 0.54; P < 0.0001).In Kenya, as in other developing countries, invasive pneumococcal disease (IPD) is responsible for substantial morbidity and mortality (6, 8). In populations for which incidence data are available, the risk of IPD peaks at the end of the first and beginning of the second year of life, declining sharply thereafter. Disease incidence remains low through puberty and early adulthood, rises gradually through middle age, and increases dramatically for individuals over 65 (15,18,23). Recent largescale efficacy trials have shown that a 7-valent pneumococcal conjugate vaccine is effective against IPD and, to a lesser extent, against pneumonia caused by vaccine types (3,12,17). Unfortunately, the price of this vaccine will likely preclude its inclusion in national immunization programs for many countries with the greatest burden of pneumococcal disease. Recent studies also suggest that coverage for such multivalent vaccines may not be universally optimal across the developing world (7, 9). Furthermore, it remains unclear whether serotype replacement will result in significant increases in non-vaccine-type disease in the face of widespread conjugate vaccine use (16). Streptococcus pneumoniae vaccines based on conserved pneumococcal protein antigens such as pneumococcal surface protein A (PspA), pneumolysin, and pneumococcal surface adhesin A (PsaA) are currently under study (4, 5) and, if proven effective, may provide an alternative that is less expensive while affording greater coverage.Immunity to PspA, pneumolysin, and PsaA in European adults and children with and without pneumococcal disease has been studied extensively (20)(21)(22). To the best of our knowledge, the development of naturally acquired immunity to these three antigens in an African population has not yet been described. In...

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Immunization of Humans with Recombinant Pneumococcal Surface Protein A (rPspA) Elicits Antibodies That Passively Protect Mice from Fatal Infection withStreptococcus pneumoniaeBearing Heterologous PspA

Cited by 253 publications

References 41 publications

Serotype-independent pneumococcal experimental vaccines that induce cellular as well as humoral immunity

Serotype-independent pneumococcal experimental vaccines that induce cellular as well as humoral immunity

Pulmonary dry powder vaccine of pneumococcal antigen loaded nanoparticles

Age-Specific Immunoglobulin G (IgG) and IgA to Pneumococcal Protein Antigens in a Population in Coastal Kenya

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