Immunization of healthy adults with a single recombinant pneumococcal surface protein A (PspA) variant stimulates broadly cross-reactive antibodies to heterologous PspA molecules

Nabors, Gary S.; Braun, Patricia A.; Herrmann, Diane J.; Heise, Martha L.; Pyle, Derek J.; Gravenstein, Stefan; Schilling, Margo; Ferguson, L. M.; Hollingshead, Susan K.; Briles, David E.; Becker, Robert S.

doi:10.1016/s0264-410x(99)00530-7

Cited by 196 publications

(189 citation statements)

References 23 publications

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“…In addition, it has been shown the clinical dose required for pneumococcal polysaccharide vaccine administered via nebulized inhalation is estimated to be about 25 µg (Menzel et al, 2005;Meyer et al, 2006). Furthermore, intramuscular administration of rPspA achieved antibody responses at 25 µg (Nabors et al, 2000). Although the mechanisms of immune response between polysaccharide and PspA are different, if we assume a similar dose is required for dry powder pulmonary delivery, then using PGA-co-PDL NPs/NCMPs we are able to deliver 60.02±8.56 ug of PspA (FPD per capsule of 12.5 mg).…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

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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“…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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“…Cells from each spleen were assayed by ELISPOT in triplicate wells as previously described (31). A brief summary of this procedure can be found in SI Materials and Methods.…”

Section: Il-4 and Ifn-␥ Elispotsmentioning

confidence: 99%

Evaluation of new generationSalmonella entericaserovar Typhimurium vaccines with regulated delayed attenuation to induce immune responses against PspA

Wang

Scarpellini

et al. 2009

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

112

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Increasing the immunogenicity to delivered antigens by recombinant attenuated Salmonella vaccines (RASV) has been the subject of intensive study. With this goal in mind, we have designed and constructed a new generation of RASV that exhibit regulated delayed attenuation. These vaccine strains are phenotypically wild type at the time of immunization and become attenuated after colonization of host tissues. The vaccine strains are grown under conditions that allow expression of genes required for optimal invasion and colonization of host tissues. Once established in the host, these virulence genes are turned off, fully attenuating the vaccine strain. In this study, we compared 2 of our newly developed regulated delayed attenuation Salmonella enterica serovar Typhimurium strains 9088 and 9558 with the ⌬cya ⌬crp ⌬asd strain 8133, for their abilities to express and present a secreted form of the ␣-helical region of pneumococcal surface protein A (PspA) to the mouse immune system. All 3 strains induced high levels of serum antibodies specific for PspA as well as to Salmonella antigens in orally immunized mice. However, both RASVs expressing delayed attenuation elicited significantly greater anti-PspA immune responses, including serum IgG and T cell secretion of IL-4 and IFN-␥, than other groups. Also, vaccination with delayed attenuation strains resulted in a greater degree of protection against Streptococcus pneumoniae challenge than in mice vaccinated with 8133 (71-86% vs. 21% survival, P < 0.006). Together, the results demonstrate that the regulated attenuation strategy results in highly immunogenic antigen delivery vectors for oral vaccination.Streptococcus pneumoniae ͉ bacterial vectors G enerating a safe and immunogenic vaccine strain is the biggest challenge in the development of live Salmonella vaccines (1). An ideal Salmonella vaccine strain should exhibit wild-type abilities to withstand stresses (enzymatic, acid, osmotic, ionic, etc.) and host defenses (bile, antibacterial peptides, etc.) encountered after oral or intranasal immunization, and should exhibit wild-type ability to colonize and invade host lymphoid tissues while remaining avirulent. Various attenuated Salmonella strains have been used as live vaccines to induce mucosal and systemic immunity against either the carrier itself or to a vectored antigen (2). Salmonella vaccine strains typically carry defined deletion mutations affecting either metabolic functions or virulence factors (3). Various attenuating mutations have been investigated in the pursuit to develop optimal immune responses (4, 5). Many attenuating mutations were found to either reduce Salmonella survival due to host-induced stresses and/or reduce colonization of lymphoid effector tissues leading to less than ideal immunogenicity (6, 7). To circumvent these problems, we explored ways to achieve regulated delayed attenuation in vivo (8, 9) to create vaccine strains that are phenotypically wild-type at the time of immunization and become attenuated after colonization of host tissues.O...

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Immunization of healthy adults with a single recombinant pneumococcal surface protein A (PspA) variant stimulates broadly cross-reactive antibodies to heterologous PspA molecules

Cited by 196 publications

References 23 publications

Pulmonary dry powder vaccine of pneumococcal antigen loaded nanoparticles

Pulmonary dry powder vaccine of pneumococcal antigen loaded nanoparticles

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

Evaluation of new generationSalmonella entericaserovar Typhimurium vaccines with regulated delayed attenuation to induce immune responses against PspA

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