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Janine Linden - One of the best experts on this subject based on the ideXlab platform.
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safety and immunogenicity of 26 valent group a Streptococcus Vaccine in healthy adult volunteers
Clinical Infectious Diseases, 2005Co-Authors: Shelly A Mcneil, Scott A Halperin, Joanne M Langley, Bruce Smith, Andrew E Warren, Geoffrey P Sharratt, Darlene M Baxendale, Mark A Reddish, Steven D Stroop, Janine LindenAbstract:BACKGROUND Group A Streptococcus (GAS) causes illness ranging from uncomplicated pharyngitis to life-threatening necrotizing fasciitis, toxic shock, and rheumatic fever. Attempts to develop an M protein-based Vaccine have been hindered by the fact that some M proteins elicit both protective antibodies and antibodies that cross-react with human tissues. New molecular techniques have allowed the previous obstacles to be largely overcome. METHODS The Vaccine is comprised of 4 recombinant proteins adsorbed to aluminum hydroxide that contain N-terminal peptides from streptococcal protective antigen and M proteins of 26 common pharyngitis, invasive, and/or rheumatogenic serotypes. Thirty healthy adult subjects received intramuscular 26-valent GAS Vaccine (400 microg) at 0, 1, and 4 months, with clinical and laboratory follow-up for safety and immunogenicity using assays for tissue cross-reactive antibodies, type-specific M antibodies to 27 Vaccine antigens, and functional (opsonization) activity of M protein antibodies. RESULTS The incidence of local reactogenicity was similar to that for other aluminum hydroxide-adsorbed Vaccines in adults. No subject developed evidence of rheumatogenicity or nephritogenicity, and no induction of human tissue-reactive antibodies was detected. Overall, 26 of 27 antigenic peptides evoked a >4-fold increase in the geometric mean antibody titer over baseline. The mean log2 fold-increase in serum antibody titer (+/- standard error of the mean) for all 27 antigens was 3.67 +/- 0.21. A significant mean log2 reduction in streptococcal bacterial counts in serum samples obtained after immunization was seen in opsonization assays for all M serotypes. CONCLUSIONS On the basis of epidemiological data demonstrating that the majority of cases of pharyngitis, necrotizing fasciitis, and other invasive streptococcal infections are caused by a limited number of serotypes, this 26-valent Vaccine could have significant impact on the overall burden of streptococcal disease.
Shabir A Madhi - One of the best experts on this subject based on the ideXlab platform.
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who consultation on group b Streptococcus Vaccine development report from a meeting held on 27 28 april 2016
Vaccine, 2016Co-Authors: Miwako Kobayashi, Stephanie J Schrag, Mark R Alderson, Shabir A Madhi, Carol J Baker, Ajoke Sobanjoter Meulen, David C Kaslow, Pete Smith, Vasee S Moorthy, Johan VekemansAbstract:Globally, group B Streptococcus (GBS) remains a leading cause of sepsis and meningitis in infants in the first 90days of life. Intrapartum antibiotic prophylaxis (IAP) for women at increased risk of transmitting GBS to their newborns has been effective in reducing part, but not all, of the GBS disease burden in many high income countries (HICs). In low- and middle-income countries (LMICs), IAP use is low. Immunization of pregnant women with a GBS Vaccine represents an alternative strategy to protecting newborns and young infants, through transplacental antibody transfer and potentially by reducing new vaginal colonization. This vaccination strategy was first suggested in the 1970s and several potential GBS Vaccines have completed phase I/II clinical trials. During the 2015 WHO Product Development for Vaccines Advisory Committee meeting, GBS was identified as a high priority for the development of a Vaccine for maternal immunization because of the major public health burden posed by GBS in LMICs, and the high technical feasibility for successful development. Following this meeting, the first WHO technical consultation on GBS Vaccines was held on the 27th and 28th of April 2016, to consider development pathways for such Vaccines, focused on their potential role in reducing newborn and young infant deaths and possibly stillbirths in LMICs. Discussion topics included: (1) pathophysiology of disease; (2) current gaps in the knowledge of global disease burden and serotype distribution; (3) Vaccine candidates under development; (4) design considerations for phase III trials; and (5) pathways to licensure, policy recommendations and use. Efforts to address gaps identified in each of these areas are needed to establish the public health need for, the development and deployment of, efficacious GBS Vaccines. In particular, more work is required to understand the global disease burden of GBS-associated stillbirths, and to develop quality-assured standardized antibody assays to identify correlates of protection.
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safety and immunogenicity of an investigational maternal trivalent group b Streptococcus Vaccine in healthy women and their infants a randomised phase 1b 2 trial
Lancet Infectious Diseases, 2016Co-Authors: Shabir A Madhi, Ajoke Sobanjoter Meulen, Clare L Cutland, Lisa Jose, Anthonet Koen, Niresha Govender, Frederick Wittke, Morounfolu Olugbosi, Sherryl BakerAbstract:Summary Background Maternal group B Streptococcus (GBS) serotype-specific capsular antibody concentrations are correlated with susceptibility to neonatal GBS invasive disease. Maternal immunisation against GBS during pregnancy might protect infants across the period of susceptibility to invasive disease, but no licensed Vaccine exists. This study assessed the safety and immunogenicity of a CRM 197 -conjugated trivalent GBS Vaccine in non-pregnant and pregnant women, and antibody transfer to their infants. Methods We did a phase 1b/2, randomised, observer-blind single-centre study of an investigational trivalent GBS Vaccine in healthy non-pregnant women (cohort 1), and a dose-ranging study in healthy pregnant women (cohort 2). The study was done at the Chris Hani Baragwanath Academic Hospital in Soweto, South Africa. Participants were healthy non-pregnant or pregnant (28–35 weeks' gestation) women aged 18–40 years. In cohort 1, non-pregnant women were randomly assigned (2:1) to receive the investigational Vaccine (two injections, 1 month apart, of a 20 μg dose [of each serotype] of aluminium hydroxide-adjuvanted investigational Vaccine) or placebo. In cohort 2, pregnant women were randomly assigned (1:1:1:1) to receive one injection at 28–35 weeks' gestation of 0·5 μg, 2·5 μg, or 5·0 μg of the non-adjuvanted investigational Vaccine (for each serotype), or placebo. All study participants and study staff not involved with Vaccine preparation were masked to the randomisation group. The Vaccine contained an equal dose (0·5 μg, 2·5 μg, 5·0 μg, or 20 μg) of each of three glycoconjugates (serotypes Ia, Ib and III). Reactogenicity was monitored to day 7 and unsolicited adverse events (adverse events) and infant safety were recorded throughout the study. The primary outcomes were tolerability and GBS-specific antibody response (measured as geometric mean concentrations [GMCs] in μg/mL) following the two injections for cohort 1, and selection of one Vaccine dose based on analysis of serotype-specific antibody responses at delivery (+72 h) for use in subsequent studies. These outcomes were assessed in participants or infants of participants who correctly received the study Vaccine with no major protocol deviations, and provided evaluable serum samples at day 1 and the scheduled timepoints throughout the study. This study is registered with ClinicalTrials.gov, NCT01193920. Findings Between Oct 5, 2010, and Sept 21, 2011, we screened 75 non-pregnant and 417 pregnant healthy South African women. Of these, 60 non-pregnant women were enrolled in cohort 1 (40 randomly assigned to the GBS 20 μg group and 40 randomly assigned to the placebo group) and 320 pregnant women were enrolled in cohort 2 (80 in each of the four groups). Among the randomised groups of pregnant women, 33–40% experienced at least one local and 54–71% one systemic solicited adverse event, less than 4% of which were severe, and the rate did not differ by study group. Also, 2% of the pregnancies resulted in stillbirth and 3·5% of the liveborn babies died by 12 months age, none of these deaths were attributed to vaccination. There was one death in a GBS-Vaccine recipient, which too was unrelated to vaccination. For cohort 1, serotype-specific antibody concentrations were significantly higher, as evident by no overlap of the 95% CIs of GMCs against all three serotypes in the vaccinated group than the placebo group. For cohort 2, pregnant women in all Vaccine groups had significantly higher GMCs than did those in the placebo group at delivery (eg, GMCs against serotype Ia were 11 μg/mL [95% CI 7·0–18] for the GBS Vaccine 0·5 μg group, 18 μg/mL [11–29] for the GBS Vaccine 2·5 μg group, 22 μg/mL [13–35] for the GBS Vaccine 5·0 μg group, and 0·64 μg/mL [0·42–0·98] for the placebo group) and at all measured timepoints. GMCs did not differ significantly between the Vaccine doses at any of the measured timepoints (p>0·05). Interpretation The Vaccine was well tolerated and induced capsular-specific antibody responses, in non-pregnant and pregnant women. Maternal vaccination led to higher GBS serotype-specific antibody concentrations in infants than did placebo, with both interventions resulting in similar safety profiles. Funding Novartis Vaccines and Diagnostics division, now part of the GlaxoSmithKline group of companies.
Michael R. Batzloff - One of the best experts on this subject based on the ideXlab platform.
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erratum for rivera hernandez et al an experimental group a Streptococcus Vaccine that reduces pharyngitis and tonsillitis in a nonhuman primate model
Mbio, 2020Co-Authors: Tania Riverahernandez, Diane G. Carnathan, Scott Jones, Amanda J. Cork, Mark R. Davies, Peter M. Moyle, Istvan Toth, Michael R. BatzloffAbstract:Volume 10, issue 2, e00693-19, 2019, [https://doi.org/10.1128/mBio.00693-19][1]. On PDF page 7, the point mutations for SCPA were incorrectly written as “SCPA (D130A S617A)” and should be “SCPA (D130A S512A)”. [1]: /lookup/doi/10.1128/mBio.00693-19
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An Experimental Group A Streptococcus Vaccine That Reduces Pharyngitis and Tonsillitis in a Nonhuman Primate Model
American Society for Microbiology, 2019Co-Authors: Tania Rivera-hernandez, Diane G. Carnathan, Scott Jones, Amanda J. Cork, Mark R. Davies, Peter M. Moyle, Istvan Toth, Michael R. Batzloff, James Mccarthy, Victor NizetAbstract:GAS-related diseases disproportionally affect disadvantaged populations (e.g., indigenous populations), and development of a Vaccine has been neglected. A recent strong advocacy campaign driven by the World Health Organization and the International Vaccine Institute has highlighted the urgent need for a GAS Vaccine. One significant obstacle in GAS Vaccine development is the lack of a widely used animal model to assess Vaccine efficacy. Researchers in the field use a wide range of murine models of infection and in vitro assays, sometimes yielding conflicting results. Here we present the nonhuman primate pharyngeal infection model as a tool to assess Vaccine-induced protection against colonization and clinical symptoms of pharyngitis and tonsillitis. We have tested the efficacy of an experimental Vaccine candidate with promising results. We believe that the utilization of this valuable tool by the GAS Vaccine research community could significantly accelerate the realization of a safe and effective GAS Vaccine for humans.Group A Streptococcus (GAS) infections account for an estimated 500,000 deaths every year. This bacterial pathogen is responsible for a variety of mild and life-threatening infections and the triggering of chronic autoimmune sequelae. Pharyngitis caused by group A Streptococcus (GAS), but not asymptomatic GAS carriage, is a prerequisite for acute rheumatic fever (ARF). Repeated bouts of ARF may trigger rheumatic heart disease (RHD), a major cause of heart failure and stroke accounting for 275,000 deaths annually. A Vaccine that prevents pharyngitis would markedly reduce morbidity and mortality from ARF and RHD. Nonhuman primates (NHPs) have been utilized to model GAS diseases, and experimentally infected rhesus macaques develop pharyngitis. Here we use an NHP model of GAS pharyngitis to evaluate the efficacy of an experimental Vaccine, Combo5 (arginine deiminase [ADI], C5a peptidase [SCPA], streptolysin O [SLO], interleukin-8 [IL-8] protease [SpyCEP], and trigger factor [TF]), specifically designed to exclude GAS components potentially linked to autoimmune complications. Antibody responses against all Combo5 antigens were detected in NHP serum, and immunized NHPs showed a reduction in pharyngitis and tonsillitis compared to controls. Our work establishes the NHP model as a gold standard for the assessment of GAS Vaccines
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Evaluation of safety and immunogenicity of a group A Streptococcus Vaccine candidate (MJ8VAX) in a randomized clinical trial
2018Co-Authors: Silvana Sekuloski, Michael R. Batzloff, Paul Griffin, William Parsonage, Suzanne Elliott, Jon Hartas, Peter O’rourke, Louise Marquart, Manisha Pandey, Fran A. RubinAbstract:BackgroundGroup A Streptococcus (GAS) is a serious human pathogen that affects people of different ages and socio-economic levels. Although vaccination is potentially one of the most effective methods to control GAS infection and its sequelae, few prototype Vaccines have been investigated in humans. In this study, we report the safety and immunogenicity of a novel acetylated peptide-protein conjugate Vaccine candidate MJ8VAX (J8-DT), when delivered intramuscularly to healthy adults.MethodsA randomized, double-blinded, controlled Phase I clinical trial was conducted in 10 healthy adult participants. Participants were randomized 4:1 to receive the Vaccine candidate (N = 8) or placebo (N = 2). A single dose of the Vaccine candidate (MJ8VAX), contained 50 μg of peptide conjugate (J8-DT) adsorbed onto aluminium hydroxide and re-suspended in PBS in a total volume of 0.5 mL. Safety of the Vaccine candidate was assessed by monitoring local and systemic adverse reactions following intramuscular administration. The immunogenicity of the Vaccine was assessed by measuring the levels of peptide (anti-J8) and toxoid carrier (anti-DT)—specific antibodies in serum samples.ResultsNo serious adverse events were reported over 12 months of study. A total of 13 adverse events (AEs) were recorded, two of which were assessed to be associated with the Vaccine. Both were mild in severity. No local reactogenicity was recorded in any of the participants. MJ8VAX was shown to be immunogenic, with increase in Vaccine-specific antibodies in the participants who received the Vaccine. The maximum level of Vaccine-specific antibodies was detected at 28 days post immunization. The level of these antibodies decreased with time during follow-up. Participants who received the Vaccine also had a corresponding increase in anti-DT serum antibodies.ConclusionsIntramuscular administration of MJ8VAX was demonstrated to be safe and immunogenic. The presence of DT in the Vaccine formulation resulted in a boost in the level of anti-DT antibodies.Trial registrationACTRN12613000030774
Johan Vekemans - One of the best experts on this subject based on the ideXlab platform.
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who ivi global stakeholder consultation on group a Streptococcus Vaccine development report from a meeting held on 12 13 december 2016
Vaccine, 2018Co-Authors: Joshua Osowicki, David C Kaslow, Johan Vekemans, Martin Friede, Jerome H Kim, Andrew C SteerAbstract:While progress towards a Group A Streptococcus (GAS) Vaccine has been stalled by a combination of scientific, regulatory, and commercial barriers, the problem persists. The high and globally-distributed burden of disease attributable to GAS makes vaccination an imperative global public health goal. Advances across a range of scientific disciplines in understanding GAS diseases have made the goal a realistic one and focused attention on the need for coordinated global action. With a view to accelerating GAS Vaccine development, the World Health Organization (WHO) and the International Vaccine Institute (IVI) convened a global stakeholder consultation on the 12th and 13th of December 2016, in Seoul, South Korea. Topics discussed included: (1) gaps in current knowledge of global GAS epidemiology, burden of disease, and molecular epidemiology; (2) contribution of pre-clinical models to candidate Vaccine evaluation and new immunological assays to address GAS immunology knowledge gaps; (3) status and future of the GAS Vaccine development pipeline; and (4) defining a pathway to licensure, policy recommendations and availability of a Vaccine. The meeting determined to establish a GAS Vaccine working group to coordinate preparation of a global Vaccine values proposition, preferred product characteristics, and a technical research and development roadmap. A new global GAS Vaccine consortium will drive strategic planning to anticipate requirements for licensure, prequalification, and policy recommendations.
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who consultation on group b Streptococcus Vaccine development report from a meeting held on 27 28 april 2016
Vaccine, 2016Co-Authors: Miwako Kobayashi, Stephanie J Schrag, Mark R Alderson, Shabir A Madhi, Carol J Baker, Ajoke Sobanjoter Meulen, David C Kaslow, Pete Smith, Vasee S Moorthy, Johan VekemansAbstract:Globally, group B Streptococcus (GBS) remains a leading cause of sepsis and meningitis in infants in the first 90days of life. Intrapartum antibiotic prophylaxis (IAP) for women at increased risk of transmitting GBS to their newborns has been effective in reducing part, but not all, of the GBS disease burden in many high income countries (HICs). In low- and middle-income countries (LMICs), IAP use is low. Immunization of pregnant women with a GBS Vaccine represents an alternative strategy to protecting newborns and young infants, through transplacental antibody transfer and potentially by reducing new vaginal colonization. This vaccination strategy was first suggested in the 1970s and several potential GBS Vaccines have completed phase I/II clinical trials. During the 2015 WHO Product Development for Vaccines Advisory Committee meeting, GBS was identified as a high priority for the development of a Vaccine for maternal immunization because of the major public health burden posed by GBS in LMICs, and the high technical feasibility for successful development. Following this meeting, the first WHO technical consultation on GBS Vaccines was held on the 27th and 28th of April 2016, to consider development pathways for such Vaccines, focused on their potential role in reducing newborn and young infant deaths and possibly stillbirths in LMICs. Discussion topics included: (1) pathophysiology of disease; (2) current gaps in the knowledge of global disease burden and serotype distribution; (3) Vaccine candidates under development; (4) design considerations for phase III trials; and (5) pathways to licensure, policy recommendations and use. Efforts to address gaps identified in each of these areas are needed to establish the public health need for, the development and deployment of, efficacious GBS Vaccines. In particular, more work is required to understand the global disease burden of GBS-associated stillbirths, and to develop quality-assured standardized antibody assays to identify correlates of protection.
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group b Streptococcus Vaccine development present status and future considerations with emphasis on perspectives for low and middle income countries
F1000Research, 2016Co-Authors: Miwako Kobayashi, Carol J Baker, Johan Vekemans, Adam J Ratner, Kirsty Le Doare, Stephanie J SchragAbstract:Globally, group B Streptococcus (GBS) remains the leading cause of sepsis and meningitis in young infants, with its greatest burden in the first 90 days of life. Intrapartum antibiotic prophylaxis (IAP) for women at risk of transmitting GBS to their newborns has been effective in reducing, but not eliminating, the young infant GBS disease burden in many high income countries. However, identification of women at risk and administration of IAP is very difficult in many low and middle income country (LMIC) settings, and is not possible for home deliveries. Immunization of pregnant women with a GBS Vaccine represents an alternate pathway to protecting newborns from GBS disease, through the transplacental antibody transfer to the fetus in utero. This approach to prevent GBS disease in young infants is currently under development, and is approaching late stage clinical evaluation. This manuscript includes a review of the natural history of the disease, global disease burden estimates, diagnosis and existing control options in different settings, the biological rationale for a Vaccine including previous supportive studies, analysis of current candidates in development, possible correlates of protection and current status of immunogenicity assays. Future potential Vaccine development pathways to licensure and use in LMICs, trial design and implementation options are discussed, with the objective to provide a basis for reflection, rather than recommendations.
Shelly A Mcneil - One of the best experts on this subject based on the ideXlab platform.
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safety and immunogenicity of 26 valent group a Streptococcus Vaccine in healthy adult volunteers
Clinical Infectious Diseases, 2005Co-Authors: Shelly A Mcneil, Scott A Halperin, Joanne M Langley, Bruce Smith, Andrew E Warren, Geoffrey P Sharratt, Darlene M Baxendale, Mark A Reddish, Steven D Stroop, Janine LindenAbstract:BACKGROUND Group A Streptococcus (GAS) causes illness ranging from uncomplicated pharyngitis to life-threatening necrotizing fasciitis, toxic shock, and rheumatic fever. Attempts to develop an M protein-based Vaccine have been hindered by the fact that some M proteins elicit both protective antibodies and antibodies that cross-react with human tissues. New molecular techniques have allowed the previous obstacles to be largely overcome. METHODS The Vaccine is comprised of 4 recombinant proteins adsorbed to aluminum hydroxide that contain N-terminal peptides from streptococcal protective antigen and M proteins of 26 common pharyngitis, invasive, and/or rheumatogenic serotypes. Thirty healthy adult subjects received intramuscular 26-valent GAS Vaccine (400 microg) at 0, 1, and 4 months, with clinical and laboratory follow-up for safety and immunogenicity using assays for tissue cross-reactive antibodies, type-specific M antibodies to 27 Vaccine antigens, and functional (opsonization) activity of M protein antibodies. RESULTS The incidence of local reactogenicity was similar to that for other aluminum hydroxide-adsorbed Vaccines in adults. No subject developed evidence of rheumatogenicity or nephritogenicity, and no induction of human tissue-reactive antibodies was detected. Overall, 26 of 27 antigenic peptides evoked a >4-fold increase in the geometric mean antibody titer over baseline. The mean log2 fold-increase in serum antibody titer (+/- standard error of the mean) for all 27 antigens was 3.67 +/- 0.21. A significant mean log2 reduction in streptococcal bacterial counts in serum samples obtained after immunization was seen in opsonization assays for all M serotypes. CONCLUSIONS On the basis of epidemiological data demonstrating that the majority of cases of pharyngitis, necrotizing fasciitis, and other invasive streptococcal infections are caused by a limited number of serotypes, this 26-valent Vaccine could have significant impact on the overall burden of streptococcal disease.