Safety and immunogenicity of the pneumococcal pneumolysin derivative PlyD1 in a single-antigen protein vaccine candidate in adults

Kamtchoua, Thierry; Bologa, Monica; Hopfer, Robert; Neveu, David; Hu, Branda; Sheng, Xinjun; Corde, Nicolas; Pouzet, Catherine; Zimmermann, G L; Gurunathan, Sanjay

doi:10.1016/j.vaccine.2012.11.005

Cited by 87 publications

(54 citation statements)

References 36 publications

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“…We investigated a range of antigen dosages around those previously determined to be optimal in CB mice (personal communication from Sanofi Pasteur) and found the optimal doses (maximal IgG titers) to be similar, but not identical, in infant and adult mice for all three proteins. Alum was included as an adjuvant in all experiments described here because it is approved for use in humans and clinical trials and is included in current clinical trials with these proteins (19,24).…”

Section: Vaccination Dosage Optimizationmentioning

confidence: 99%

“…Recent development of a highly detoxified genetic mutant of Ply (PlyD1) has shown limited protection in mice against challenge with S. pneumoniae and lung injury (17). Phase I studies have demonstrated that PlyD1 is safe and immunogenic in adults (19). Natural S. pneumoniae colonization leads to lower Ply-specific plasma IgG levels in infants and young children than other S. pneumoniae proteins or in older children (9).…”

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confidence: 99%

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Contributions to Protection from Streptococcus pneumoniae Infection Using the Monovalent Recombinant Protein Vaccine Candidates PcpA, PhtD, and PlyD1 in an Infant Murine Model during Challenge

Verhoeven

Perry

Pichichero

2014

Clin. Vaccine Immunol.

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A vaccine consisting of several conserved proteins with different functions directing the pathogenesis of pneumonia and sepsis would be preferred for protection against infection by Streptococcus pneumoniae. Infants will be the major population targeted for nextgeneration pneumococcal vaccines. Here, we investigated the potential efficacy provided by three recombinant pneumococcal vaccine candidate proteins-pneumococcal histidine triad D (PhtD), detoxified pneumolysin derivative (PlyD1), and pneumococcal choline-binding protein A (PcpA)-for reducing pneumonia and sepsis in an infant mouse vaccine model. We found vaccination with PhtD and PcpA provided high IgG antibody titers after vaccination in infant mice, similar to adult mice comparators. PlyD1-specific total IgG was significantly lower in infant mice, with minimal boosting with the second and third vaccinations. Similar isotypes of IgG for PhtD and PlyD1 were generated in infant compared to adult mice. Although lower total specific IgG to all three proteins was elicited in infant than in adult mice, the infant mice were protected from bacteremic pneumonia and sepsis mortality (PlyD1) and had lower lung bacterial burdens (PcpA and PhtD) after challenge. The observed immune responses coupled with bacterial reductions elicited by each of the monovalent proteins support further testing in human infant clinical trials.

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Section: Vaccination Dosage Optimizationmentioning

confidence: 99%

mentioning

confidence: 99%

Contributions to Protection from Streptococcus pneumoniae Infection Using the Monovalent Recombinant Protein Vaccine Candidates PcpA, PhtD, and PlyD1 in an Infant Murine Model during Challenge

Verhoeven

Perry

Pichichero

2014

Clin. Vaccine Immunol.

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“…Ply, a cholesteroldependent cytolysin, is an important factor in pneumococcal pathogenicity, interfering in the cellular immune response and in the activation of the complement system during pneumococcal infection (11,12). PspA and pneumolysoids have been studied in preclinical and clinical trials, showing an ability to induce a protective antibodydependent response (13)(14)(15)(16)(17).…”

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confidence: 99%

A Combination of Recombinant Mycobacterium bovis BCG Strains Expressing Pneumococcal Proteins Induces Cellular and Humoral Immune Responses and Protects against Pneumococcal Colonization and Sepsis

Goulart

Rodríguez

Kanno

et al. 2017

Clin Vaccine Immunol

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Pneumococcal diseases remain a substantial cause of mortality in young children in developing countries. The development of potentially serotypetranscending vaccines has been extensively studied; ideally, such a vaccine should include antigens that are able to induce protection against colonization (likely mediated by interleukin-17A [IL-17A]) and invasive disease (likely mediated by antibody). The use of strong adjuvants or alternative delivery systems that are able to improve the immunological response of recombinant proteins has been proposed but poses potential safety and practical concerns in children. We have previously constructed a recombinant Mycobacterium bovis BCG strain expressing a pneumococcal surface protein A (PspA)-PdT fusion protein (rBCG PspA-PdT) that was able to induce an effective immune response and protection against sepsis in a prime-boost strategy. Here, we constructed two new rBCG strains expressing the pneumococcal proteins SP 0148 and SP 2108, which confer IL-17A-dependent protection against pneumococcal colonization in mouse models. Immunization of mice with rBCG 0148 or rBCG 2108 in a prime-boost strategy induced IL-17A and gamma interferon (IFN-␥) production. The combination of these rBCG strains with rBCG PspA-PdT (rBCG Mix), followed by a booster dose of the combined recombinant proteins (rMix) induced an IL-17A response against SP 0148 and SP 2108 and a humoral response characterized by increased levels of IgG2c against PspA and functional antibodies against pneumolysin. Furthermore, immunization with the rBCG Mix prime/rMix booster (rBCG Mix/ rMix) provides protection against pneumococcal colonization and sepsis. These results suggest the use of combined rBCG strains as a potentially serotype-transcending pneumococcal vaccine in a prime-boost strategy, which could provide protection against pneumococcal colonization and sepsis.KEYWORDS protection, Streptococcus pneumoniae, cytokines, recombinant BCG N asopharynx colonization is the first step in the establishment of pneumococcal disease. This colonization process, which affects virtually 100% of young children, can either remain asymptomatic or lead to pathogenic conditions, such as otitis, sinusitis, pneumonia, meningitis, or sepsis (1). Indeed, epidemiologic evidence suggests that in response to pneumococcal carriage, both serotype-specific and -independent immunity to subsequent carriage develop (2, 3).Pneumococcal vaccines available are based on pure polysaccharides or polysaccha-

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“…The conserved pneumococcal proteins PhtD and dPly have both been shown in earlier studies to elicit functional antibodies (21,(31)(32)(33)(34)(35) and provide protection against pneumococcal infection in animal models (21,26,(35)(36)(37)(38). This phase I study evaluated six different experimental formulations of pneumococcal vaccines containing PhtD and dPly as free or conjugated proteins, as well as with AS02 V or alum adjuvant.…”

Section: Discussionmentioning

confidence: 99%

Randomized Controlled Study of the Safety and Immunogenicity of Pneumococcal Vaccine Formulations Containing PhtD and Detoxified Pneumolysin with Alum or Adjuvant System AS02 _V in Elderly Adults

Pauksens

Nilsson

Caubet

et al. 2014

Clin Vaccine Immunol

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Six vaccine formulations containing AS02 V or alum (aluminum phosphate [AlPO 4 ]) adjuvant with pneumococcal proteins, pneumococcal histidine triad D (PhtD), and/or detoxified pneumolysin (dPly), either as a polysaccharide carrier in an 8-valent pneumococcal conjugate vaccine (8PCV) or as free (unconjugated) proteins, were evaluated in adults -65 to 85 years of age. In this phase I observer-blind study, 167 healthy subjects were randomized to receive two doses (days 0 and 60) of 10 or 30 g PhtD-dPly plus AS02 V or alum, 8PCV plus AS02 V or alum, or one dose (day 0) of 23-valent polysaccharide pneumococcal vaccine (23PPV) as a control (placebo on day 60). The safety, reactogenicity, and antibody-specific responses to these vaccines were evaluated. No vaccine-related serious adverse events were reported. The incidences of solicited local and specific general (fatigue and myalgia) symptoms tended to be higher in the AS02 V groups than in other groups. Anti-PhtD and anti-Ply antibody responses were observed in all groups except the control group. One month post-dose 2, the anti-PhtD and anti-Ply antibody geometric mean concentrations tended to be higher with AS02 V than with alum, higher with a dose of 30 g than with 10 g for PhtD-dPly and higher with 30-g PhtD-dPly formulations than with conjugated PhtD and dPly (8PCV) formulations. Functional antibody responses, measured by an opsonophagocytic activity assay, tended to be higher with 8PCV than with 23PPV. In conclusion, vaccine formulations containing free or conjugated PhtD and dPly had acceptable reactogenicity and safety profiles in elderly adults. Immune responses were enhanced with an AS02 V -adjuvanted formulation containing free 30-g PhtD-dPly compared to those with alum adjuvant and conjugated proteins. (This study has been registered at ClinicalTrials.gov under registration no. NCT00756067.)

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Safety and immunogenicity of the pneumococcal pneumolysin derivative PlyD1 in a single-antigen protein vaccine candidate in adults

Cited by 87 publications

References 36 publications

Contributions to Protection from Streptococcus pneumoniae Infection Using the Monovalent Recombinant Protein Vaccine Candidates PcpA, PhtD, and PlyD1 in an Infant Murine Model during Challenge

Contributions to Protection from Streptococcus pneumoniae Infection Using the Monovalent Recombinant Protein Vaccine Candidates PcpA, PhtD, and PlyD1 in an Infant Murine Model during Challenge

A Combination of Recombinant Mycobacterium bovis BCG Strains Expressing Pneumococcal Proteins Induces Cellular and Humoral Immune Responses and Protects against Pneumococcal Colonization and Sepsis

Randomized Controlled Study of the Safety and Immunogenicity of Pneumococcal Vaccine Formulations Containing PhtD and Detoxified Pneumolysin with Alum or Adjuvant System AS02 _V in Elderly Adults

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Safety and immunogenicity of the pneumococcal pneumolysin derivative PlyD1 in a single-antigen protein vaccine candidate in adults

Cited by 87 publications

References 36 publications

Contributions to Protection from Streptococcus pneumoniae Infection Using the Monovalent Recombinant Protein Vaccine Candidates PcpA, PhtD, and PlyD1 in an Infant Murine Model during Challenge

Contributions to Protection from Streptococcus pneumoniae Infection Using the Monovalent Recombinant Protein Vaccine Candidates PcpA, PhtD, and PlyD1 in an Infant Murine Model during Challenge

A Combination of Recombinant Mycobacterium bovis BCG Strains Expressing Pneumococcal Proteins Induces Cellular and Humoral Immune Responses and Protects against Pneumococcal Colonization and Sepsis

Randomized Controlled Study of the Safety and Immunogenicity of Pneumococcal Vaccine Formulations Containing PhtD and Detoxified Pneumolysin with Alum or Adjuvant System AS02 V in Elderly Adults

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Randomized Controlled Study of the Safety and Immunogenicity of Pneumococcal Vaccine Formulations Containing PhtD and Detoxified Pneumolysin with Alum or Adjuvant System AS02 _V in Elderly Adults