scholarly journals Safety and Immunogenicity of a Candidate Bioconjugate Vaccine against Shigella flexneri 2a Administered to Healthy Adults: a Single-Blind, Randomized Phase I Study

2016 ◽  
Vol 23 (12) ◽  
pp. 908-917 ◽  
Author(s):  
Mark S. Riddle ◽  
Robert W. Kaminski ◽  
Claudio Di Paolo ◽  
Chad K. Porter ◽  
Ramiro L. Gutierrez ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Vaccine Development ◽  
Shigella Flexneri ◽  
Protein A ◽  
Age Groups ◽  
Healthy Adults ◽  
Candidate Vaccine ◽  
Content Type ◽  
Single Blind

ABSTRACTSeveral candidate vaccines againstShigellaspp. are in development, but the lack of a clear correlate of protection from challenge with the induction of adequate immune responses among the youngest age groups in the developing world has hamperedShigellavaccine development over the past several decades. Bioconjugation technology, exploited here for anShigella flexneri2a candidate vaccine, offers a novel and potentially cost-effective way to develop and produce vaccines against a major pathogen of global health importance. Flexyn2a, a novelS. flexneri2a bioconjugate vaccine made of the polysaccharide component of theS. flexneri2a O-antigen, conjugated to the exotoxin protein A ofPseudomonas aeruginosa(EPA), was evaluated for safety and immunogenicity among healthy adults in a single-blind, phase I study with a staggered randomization approach. Thirty subjects (12 receiving 10 μg Flexyn2a, 12 receiving Flexyn2a with aluminum adjuvant, and 6 receiving placebo) were administered two injections 4 weeks apart and were followed for 168 days. Flexyn2a was well-tolerated, independently of the adjuvant and number of injections. The Flexyn2a vaccine elicited statistically significantS. flexneri2a lipopolysaccharide (LPS)-specific humoral responses at all time points postimmunization in all groups that received the vaccine. Elicited serum antibodies were functional, as evidenced by bactericidal activity againstS. flexneri2a. The bioconjugate candidate vaccine Flexyn2a has a satisfactory safety profile and elicited a robust humoral response toS. flexneri2a LPS with or without inclusion of an adjuvant. Moreover, the bioconjugate also induced functional antibodies, showing the technology's features in producing a promising candidate vaccine. (This study has been registered at ClinicalTrials.gov under registration no. NCT02388009.)

scholarly journals Shigella Vaccine Development: Finding the Path of Least Resistance

2016 ◽  
Vol 23 (12) ◽  
pp. 904-907 ◽  
Author(s):  
Wilbur H. Chen ◽  
Karen L. Kotloff
Keyword(s):  
Public Health ◽  
Developing Countries ◽  
Phase I ◽  
Phase I Study ◽  
Vaccine Development ◽  
Shigella Flexneri ◽  
Health Concern ◽  
Childhood Diarrhea ◽  
Public Health Concern ◽  
Content Type

ABSTRACTShigellaspp. represent the second most common etiologic pathogen causing childhood diarrhea in developing countries. There are no licensedShigellavaccines, and progress for such vaccines has been limited. In this issue ofClinical and Vaccine Immunology, Riddle and colleagues (M. S. Riddle, R. W. Kaminski, C. Di Paolo, C. K. Porter, R. L. Gutierrez, et al., Clin Vaccine Immunol 23:908–917, 2016,http://dx.doi.org/10.1128/CVI.00224-16) report results from a phase I study of a parenterally administered monovalent O-polysaccharide “bioconjugate” directed againstShigella flexneri2a. Ultimately, the goal is to develop a broad-spectrumShigellavaccine to address this public health concern. A parenteralShigellavaccine capable of eliciting protection in children of developing countries would be an important tool to reach this goal.

Safety and immunogenicity of a candidate bioconjugate vaccine against Shigella dysenteriae type 1 administered to healthy adults: A single blind, partially randomized Phase I study

Vaccine ◽  
2015 ◽  
Vol 33 (36) ◽  
pp. 4594-4601 ◽  
Author(s):  
Christoph F.R Hatz ◽  
Bettina Bally ◽  
Susanne Rohrer ◽  
Robert Steffen ◽  
Stefanie Kramme ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Healthy Adults ◽  
Shigella Dysenteriae ◽  
Single Blind ◽  
Shigella Dysenteriae Type

scholarly journals CD4 T Cell Antigens from Staphylococcus aureus Newman Strain Identified following Immunization with Heat-Killed Bacteria

2012 ◽  
Vol 19 (4) ◽  
pp. 477-489 ◽  
Author(s):  
Paulraj K. Lawrence ◽  
Bachra Rokbi ◽  
Nadège Arnaud-Barbe ◽  
Eric L. Sutten ◽  
Junzo Norimine ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
T Cell ◽  
Reverse Genetics ◽  
Vaccine Development ◽  
Protein A ◽  
Cd4 T Cell ◽  
Content Type ◽  
Intramammary Infections ◽  
T Cell Antigens ◽  
Ifn Γ

ABSTRACTStaphylococcus aureusis a commensal bacterium associated with the skin and mucosal surfaces of humans and animals that can also cause chronic infection. The emergence of antibiotic-resistant strains such as methicillin-resistantS. aureus(MRSA) and strains causing chronic intramammary infections (IMI) in cows results in severe human and livestock infections. Conventional approaches to vaccine development have yielded only a few noneffective vaccines against MRSA or IMI strains, so there is a need for improved vaccine development. CD4 T lymphocytes are required for promoting gamma interferon (IFN-γ) mediated immunoglobulin isotype switching in B lymphocytes to produce high-affinity IgG antibodies and IFN-γ-mediated phagocyte activation for an effective resolution of bacterial infection. However, the lack of known CD4 T cell antigens fromS. aureushas made it difficult to design effective vaccines. The goal of this study was to identifyS. aureusproteins recognized by immune CD4 T cells. Using a reverse genetics approach, 43 antigens were selected from theS. aureusNewman strain. These included lipoproteins, proteases, transcription regulators, an alkaline shock protein, conserved-domain proteins, hemolysins, fibrinogen-binding protein, staphylokinase, exotoxin, enterotoxin, sortase, and protein A. Screening of expressed proteins for recall T cell responses in outbred, immune calves identified 13 proteins that share over 80% sequence identity among MRSA or IMI strains. These may be useful for inclusion in a broadly protective multiantigen vaccine against MRSA or IMI.

scholarly journals Development, Interlaboratory Evaluations, and Application of a Simple, High-ThroughputShigellaSerum Bactericidal Assay

mSphere ◽  
2018 ◽  
Vol 3 (3) ◽  
Author(s):  
Moon H. Nahm ◽  
Jigui Yu ◽  
Hailey P. Weerts ◽  
Heather Wenzel ◽  
Chitradevi S. Tamilselvi ◽  
...  
Keyword(s):  
Vaccine Development ◽  
Shigella Flexneri ◽  
Binding Activity ◽  
Serum Samples ◽  
Bacterial Killing ◽  
Content Type ◽  
Bactericidal Assay ◽  
Serum Bactericidal Assay ◽  
Reference Serum

ABSTRACTShigellais an important cause of diarrhea worldwide, with serotypesShigella flexneri2a,S. flexneri3a, andShigella sonneidemonstrating epidemiological prevalence. Many development efforts are focused onShigellalipopolysaccharide (LPS)-based vaccines, as O antigen-specific conjugate vaccines are immunogenic and efficacious. Immunization withShigellavaccines containing LPS can elicit antibodies capable of killingShigellain a serotype-specific manner. Thus, to facilitateShigellavaccine development, we have developed a serum bactericidal assay (SBA) specific for threeShigellaserotypes that measures killing of target bacteria at multiple serum dilutions and in the presence of exogenous complement. The SBA has a high analytical throughput and uses simple technologies and readily available reagents. The SBA was characterized with human sera with bactericidal antibodies againstS. flexneri2a,S. flexneri3a, andS. sonnei. Purified LPS of a homologous serotype, but not a heterologous serotype, inhibited bacterial killing. Assessment of precision found median intra-assay precision to be 13.3% and median interassay precision to be 19 to 30% for the three serotypes. The SBA is linear, with slight deviations for samples with low (~40) killing indices. The SBA was sensitive enough to allow about 100-fold predilution of serum samples. Repeat assays yielded results with less than 2-fold deviations, indicating the robustness of the assay. Assay results from four different laboratories were highly comparable when normalized with a reference serum. TheShigellaSBA, combined with a reference serum, should facilitate the development ofShigellavaccines across the field.IMPORTANCEShigellais an important cause of diarrhea worldwide, and efforts are ongoing to produce a safe and effectiveShigellavaccine. Although a clear immune correlate of protection has not been established, antibodies with bactericidal capacity may provide one means of protecting against shigellosis. Thus, it is important to measure the functional capacity of antibodies, as opposed to only binding activity. This article describes a simple, robust, and high-throughput serum bactericidal assay capable of measuringShigella-specific functional antibodiesin vitro. We show for the first time that this assay was successfully performed by multiple laboratories and generated highly comparable results, particularly when SBA titers were normalized using a reference standard. The serum bactericidal assay, along with a reference serum, should greatly facilitateShigellavaccine development.

Phase I study on safety and pharmacokinetics of a novel influenza endonuclease inhibitor, AL-794 (JNJ-64155806), following single- and multiple-ascending doses in healthy adults

2018 ◽  
Vol 23 (7) ◽  
pp. 555-566 ◽  
Author(s):  
Thomas N Kakuda ◽  
Jeysen Yogaratnam ◽  
Jennifer Rito ◽  
Malcolm Boyce ◽  
Toni Mitchell ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Healthy Adults

Clinical testing of pre-pandemic live attenuated A/H5N2 influenza candidate vaccine in adult volunteers: Results from a placebo-controlled, randomized double-blind phase I study

Vaccine ◽  
2015 ◽  
Vol 33 (39) ◽  
pp. 5110-5117 ◽  
Author(s):  
Larisa Rudenko ◽  
Irina Kiseleva ◽  
Marina Stukova ◽  
Marianna Erofeeva ◽  
Anatoly Naykhin ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Candidate Vaccine ◽  
Clinical Testing ◽  
Double Blind ◽  
Adult Volunteers

scholarly journals Monoclonal Antibodies to Shigella Lipopolysaccharide Are Useful for Vaccine Production

2016 ◽  
Vol 23 (8) ◽  
pp. 681-688 ◽  
Author(s):  
Jisheng Lin ◽  
Mark A. Smith ◽  
William H. Benjamin ◽  
Robert W. Kaminski ◽  
Heather Wenzel ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Vaccine Development ◽  
Shigella Flexneri ◽  
High Sensitivity ◽  
Epidemiological Data ◽  
Enzyme Linked Immunosorbent Assay ◽  
Content Type ◽  
Bacterial Surface ◽  
Bactericidal Assay

ABSTRACTThere is a significant need for an effective multivalentShigellavaccine that targets the most prevalent serotypes. MostShigellavaccines under development utilize serotype-specific lipopolysaccharides (LPSs) as a major component based on protection and epidemiological data. As vaccine formulations advance from monovalent to multivalent, assays and reagents need to be developed to accurately and reproducibly quantitate the amount of LPSs from multiple serotypes in the final product. To facilitate this effort, we produced 36 hybridomas that secrete monoclonal antibodies (MAbs) against the O antigen on the LPS fromShigella flexneri2a,Shigella flexneri3a, andShigella sonnei. We used six of these monoclonal antibodies for an inhibition enzyme-linked immunosorbent assay (iELISA), measuring LPSs with high sensitivity and specificity. It was also demonstrated that theShigellaserotype-specific MAbs were useful for bacterial surface staining detected by flow cytometry. These MAbs are also useful for standardizing the serum bactericidal assay (SBA) forShigella. Functional assays, such as thein vitrobactericidal assay, are necessary for vaccine evaluation and may serve as immunological correlates of immunity. AnS. flexneri2a-specific monoclonal antibody killedS. flexneri2b isolates, suggesting thatS. flexneri2a LPS may induce cross-protection againstS. flexneri2b. Overall, theShigellaLPS-specific MAbs described have potential utility to the vaccine development community for assessing multivalent vaccine composition and as a reliable control for multiple immunoassays used to assess vaccine potency.

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