ORCID Profile
0000-0002-0769-5242
Current Organisations
Royal College of Paediatrics and Child Health
,
Great Ormond Street Hospital For Children NHS Foundation Trust
,
Great Ormond Street Hospital For Children NHS Trust
,
Royal College of Physicians
,
University College London
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Publications
An Opsonophagocytic Killing Assay for the Evaluation of Group A Streptococcus Vaccine Antisera
Publisher: Springer US
Date: 2020
Safety and immunogenicity of a new Neisseria meningitidis serogroup C-tetanus toxoid conjugate vaccine in healthy adults
Publisher: Elsevier BV
Date: 11-1999
DOI: 10.1016/S0264-410X(99)00276-5
Abstract: We evaluated the safety and immunogenicity of a single dose of a new serogroup C O-deacetylated meningococcal polysaccharide-tetanus toxoid conjugate vaccine in 30 healthy adult volunteers. The vaccine was well tolerated with no serious adverse events and minimal local reactions and systemic symptoms. All subjects developed a fourfold or greater increase in serum bactericidal antibody (SBA) to serogroup C meningococcus. SBA geometric mean titre increased from 11 to 3649 (p<0.001). Serogroup C-specific IgG levels increased postvaccination from 0.65 to 17.02 microg/ml (p<0.001). Bactericidal titres pre- and postimmunisation showed significant correlation with serogroup C-specific IgG (r(2)=0.693). Antibody levels fell by 6 months postvaccination, however, meningococcal C IgG avidity increased indicating the successful induction of a T-cell-dependent antibody response. meningococcal C-tetanus toxoid conjugate vaccine is immunogenic and well tolerated in healthy adults.
Natural and hybrid immunity following four COVID-19 waves: A prospective cohort study of mothers in South Africa
Publisher: Elsevier BV
Date: 11-2022
Standard method for detecting upper respiratory carriage of Streptococcus pneumoniae: Updated recommendations from the World Health Organization Pneumococcal Carriage Working Group
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1016/J.VACCINE.2013.08.062
Abstract: In 2003 the World Health Organization (WHO) convened a working group and published a set of standard methods for studies measuring nasopharyngeal carriage of Streptococcus pneumoniae (the pneumococcus). The working group recently reconvened under the auspices of the WHO and updated the consensus standard methods. These methods describe the collection, transport and storage of nasopharyngeal s les, as well as provide recommendations for the identification and serotyping of pneumococci using culture and non-culture based approaches. We outline the consensus position of the working group, the evidence supporting this position, areas worthy of future research, and the epidemiological role of carriage studies. Adherence to these methods will reduce variability in the conduct of pneumococcal carriage studies undertaken in the context of pneumococcal vaccine trials, implementation studies, and epidemiology studies more generally so variability in methodology does not confound the interpretation of study findings.
Safety, tolerability, and biomarkers of the treatment of mice with aerosolized Toll-like receptor ligands
Publisher: Frontiers Media SA
Date: 2014
Opsonophagocytic Killing Assay to Measure Anti–Group A Streptococcus Antibody Functionality in Human Serum
Publisher: Springer US
Date: 17-11-2021
DOI: 10.1007/978-1-0716-1900-1_20
Abstract: The opsonophagocytic killing assay (OPKA) is designed to measure the functionality of strain-specific antibodies and, therefore, assess protective immunity or the immunogenicity of Group A Streptococcus (GAS) (type A Streptococcus pyogenes) vaccines. Opsonization of GAS for phagocytosis is an important mechanism by which antibodies protect against disease in vivo. The Opsonophagocytic Index or Opsonic Index (OI) is the estimated dilution of antisera that kills 50% of the target bacteria. Here, we describe the protocol of the standardized GAS OPKA developed by Jones et al., 2018.
The Induction of Immunologic Memory after Vaccination withHaemophilus influenzaeType b Conjugate and Acellular Pertussis–Containing Diphtheria, Tetanus, and Pertussis Vaccine Combination
Publisher: Oxford University Press (OUP)
Date: 08-1999
DOI: 10.1086/314901
Abstract: The significance of reduced antibody responses to the Haemophilus influenzae type b (Hib) component of acellular pertussis-containing combination vaccines (DTaP-Hib) is unclear. A DTaP-Hib vaccine evaluated in infants vaccinated at ages 2, 3, and 4 months showed reduced anti-Hib polysaccharide IgG (geometric mean concentration [GMC], 1.23 microgram/mL 57%, >1.0 microgram/mL). Polyribitolribosyl phosphate (PRP) and Hib conjugate (PRP-T) vaccine given as a booster during the second year of life was evaluated for the presence of immunological memory. After boosting, most children achieved anti-PRP IgG >1.0 microgram/mL, although the GMC was higher with PRP-T (88.5 microgram/mL) than with PRP vaccine (7.86 microgram/mL, P<.001). The GMC of the PRP group was higher than anticipated for naive PRP recipients of the same age. PRP-specific IgG avidity was significantly higher after boosting than after priming, providing further evidence for the generation of memory. Despite reduced immunogenicity, DTaP-Hib combination vaccines appear to prime for immunologic memory.
Generation of recombinant hyperimmune globulins from diverse B-cell repertoires
Publisher: Springer Science and Business Media LLC
Date: 15-04-2021
Immunogenicity and Boosting After a Reduced Number of Doses of a Pneumococcal Conjugate Vaccine in Infants and Toddlers
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2006
Experimental Human Pneumococcal Colonization in Older Adults Is Feasible and Safe, Not Immunogenic
Publisher: American Thoracic Society
Date: 03-2021
Influence of Prior Meningococcal C Polysaccharide Vaccination on the Response and Generation of Memory after Meningococcal C Conjugate Vaccination in Young Children
Publisher: Oxford University Press (OUP)
Date: 08-2001
DOI: 10.1086/322024
Abstract: To determine whether the immunological hyporesponsiveness induced by meningococcal AC polysaccharide (MACP) vaccines can be overcome by meningococcal C conjugate (MCC) vaccine in young children, serum bactericidal antibody (SBA) serogroup C-specific IgG and IgG avidity indices were measured in young children who received MACP vaccine, followed 7 months later by MCC vaccine, and their responses were compared with those in age-matched MACP-naive control children, who received a single dose of MCC vaccine. For children <1 year of age at MACP vaccination, the SBA geometric mean titer (GMT) after MCC vaccination was lower (P=.022) and proportions with SBA titers <8 (P=.0083) or .5) or in the proportion with SBA titers <8 (P=1.00) or <128 (P=.98). No increase in avidity occurred after MACP vaccination, whereas avidity increased significantly 1 month after MCC vaccination, with a further increase at 6 months, which indicates that the induction of immunological memory was not impaired.
Development of an opsonophagocytic killing assay for group a streptococcus
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.VACCINE.2018.05.056
Abstract: Group A Streptococcus (GAS) or Streptococcus pyogenes is responsible for an estimated 500,000 deaths worldwide each year. Protection against GAS infection is thought to be mediated by phagocytosis, enhanced by bacteria-specific antibody. There are no licenced GAS vaccines, despite many promising candidates in preclinical and early stage clinical development, the most advanced of which are based on the GAS M-protein. Vaccine progress has been hindered, in part, by the lack of a standardised functional assay suitable for vaccine evaluation. Current assays, developed over 50 years ago, rely on non-immune human whole blood as a source of neutrophils and complement. Variations in complement and neutrophil activity between donors result in variable data that is difficult to interpret. We have developed an opsonophagocytic killing assay (OPKA) for GAS that utilises dimethylformamide (DMF)-differentiated human promyelocytic leukemia cells (HL-60) as a source of neutrophils and baby rabbit complement, thus removing the major sources of variation in current assays. We have standardised the OPKA for several clinically relevant GAS strain types (emm1, emm6 and emm12) and have shown antibody-specific killing for each emm-type using M-protein specific rabbit antisera. Specificity was demonstrated by pre-incubation of the antisera with homologous M-protein antigens that blocked antibody-specific killing. Additional qualifications of the GAS OPKA, including the assessment of the accuracy, precision, linearity and the lower limit of quantification, were also performed. This GAS OPKA assay has the potential to provide a robust and reproducible platform to accelerate GAS vaccine development.
Experimental human pneumococcal colonisation in older adults is feasible and safe, not immunogenic
Publisher: Cold Spring Harbor Laboratory
Date: 29-04-2020
DOI: 10.1101/2020.04.23.20077073
Abstract: Pneumococcal colonisation is key to the pathogenesis of invasive disease, but is also immunogenic in young adults, protecting against re-colonisation. Colonisation is rarely detected in older adults, despite high rates of pneumococcal disease. To establish experimental human pneumococcal colonisation in healthy adults aged 50—84 years, to measure the immune response to pneumococcal challenge, and to assess the protective effect of prior colonisation against autologous strain rechallenge. Sixty-four participants were inoculated with Streptococcus pneumoniae (serotype 6B, 80,000CFU in each nostril). Colonisation was determined by bacterial culture of nasal wash, serum anti-6B capsular IgG responses by ELISA, and anti-protein immune responses by multiplex electrochemiluminescence. Experimental colonisation was established in 39% of participants (25/64) with no adverse events. Colonisation occurred in 47% (9/19) of participants aged 50—59 compared with 21% (3/14) in those aged ≥70 years. Previous pneumococcal polysaccharide vaccination did not protect against colonisation. Colonisation did not confer serotype-specific immune boosting: GMT (95% CI) 2.7μg/mL (1.9—3.8) pre-challenge versus 3.0 (1.9—4.7) four weeks post-colonisation (p = 0.53). Furthermore, pneumococcal challenge without colonisation led to a drop in specific antibody levels from 2.8μg/mL (2.0—3.9) to 2.2μg/mL (1.6—3.0) post-challenge (p = 0.006). Anti-protein antibody levels increased following successful colonisation. Rechallenge with the same strain after a median of 8.5 months (IQR 6.7—10.1) led to recolonisation in 5/16 (31%). In older adults, experimental pneumococcal colonisation is feasible and safe, but demonstrates different immunological outcomes compared with younger adults in previous studies.
Effect of Vaccination with Carrier Protein on Response to Meningococcal C Conjugate Vaccines and Value of Different Immunoassays as Predictors of Protection
Publisher: American Society for Microbiology
Date: 09-2002
DOI: 10.1128/IAI.70.9.4946-4954.2002
Abstract: In order to plan for the wide-scale introduction of meningococcal C conjugate (MCC) vaccine for United Kingdom children up to 18 years old, phase II trials were undertaken to investigate whether there was any interaction between MCC vaccines conjugated to tetanus toxoid (TT) or a derivative of diphtheria toxin (CRM 197 ) and diphtheria-tetanus vaccines given for boosting at school entry or leaving. Children ( n = 1,766) received a diphtheria-tetanus booster either 1 month before, 1 month after, or concurrently with one of three MCC vaccines conjugated to CRM 197 or TT. All of the MCC vaccines induced high antibody responses to the serogroup C polysaccharide that were indicative of protection. The immune response to the MCC-TT vaccine was reduced as a result of prior immunization with a tetanus-containing vaccine, but antibody levels were still well above the lower threshold for protection. Prior or simultaneous administration of a diphtheria-containing vaccine did not affect the response to MCC-CRM 197 vaccines. The immune responses to the carrier proteins were similar to those induced by a comparable dose of diphtheria or tetanus vaccine. The results also demonstrate that, for these conjugate vaccines in these age groups, both standard enzyme-linked immunosorbent assays and those that measure high-avidity antibodies to meningococcal C polysaccharide correlated equally well with assays that measure serum bactericidal antibodies, the established serological correlate of protection for MCC vaccines.
Capturing and Recreating Diverse Antibody Repertoires as Multivalent Recombinant Polyclonal Antibody Drugs
Publisher: Cold Spring Harbor Laboratory
Date: 06-08-2020
DOI: 10.1101/2020.08.05.232975
Abstract: Plasma-derived polyclonal antibodies are polyvalent drugs used for many important clinical indications that require modulation of multiple drug targets simultaneously, including emerging infectious disease and transplantation. However, plasma-derived drugs suffer many problems, including low potency, impurities, constraints on supply, and batch-to-batch variation. In this study, we demonstrated proofs-of-concept for a technology that uses microfluidics and molecular genomics to capture erse mammalian antibody repertoires as multivalent recombinant drugs. These “recombinant hyperimmune” drugs comprised thousands to tens of thousands of antibodies and were derived from convalescent human donors, or vaccinated human donors or immunized mice. Here we used our technology to build a highly potent recombinant hyperimmune for Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2) in less than three months. We also validated a recombinant hyperimmune for Zika virus disease that abrogates antibody-dependent enhancement (ADE) through Fc engineering. For patients with primary immune deficiency (PID), we built high potency polyvalent recombinant hyperimmunes against pathogens that commonly cause serious lung infections. Finally, to address the limitations of rabbit-derived anti-thymocyte globulin (ATG), we generated a recombinant human version and demonstrated in vivo function against graft-versus-host disease (GVHD). Recombinant hyperimmunes are a novel class of drugs that could be used to target a wide variety of other clinical applications, including cancer and autoimmunity.
An Experimental Group A Streptococcus Vaccine That Reduces Pharyngitis and Tonsillitis in a Nonhuman Primate Model
Publisher: American Society for Microbiology
Date: 30-04-2019
Abstract: GAS-related diseases disproportionally affect disadvantaged populations (e.g., indigenous populations), and development of a vaccine has been neglected. A recent strong advocacy c aign 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.
Hospital admissions in children due to pneumococcal pneumonia in England
Publisher: Elsevier BV
Date: 07-1998
DOI: 10.1016/S0163-4453(98)90604-1
Abstract: Hospital records of 116 children under 5 years of age discharged from 11 hospitals in three regions in England with a diagnosis of lobar (pneumococcal) pneumonia were reviewed to estimate the proportion likely to be attributable to infection with Streptococcus pneumoniae. Of these, 100 (86%) had lobar/focal changes on chest X-ray consistent with pneumococcal infection, although only one (1%) had pneumococcus isolated from blood. However, a further 89 (89%) with a lobar/focal picture were considered to be likely or possibly due to pneumococcal infection on the basis of the white cell count, level of C-reactive protein, isolation of the S. pneumoniae from either sputum or nasopharingeal aspirate and failure to identify another responsible pathogen. Of 135 cases with a discharge diagnosis of bronchopneumonia or pneumonia (organism unspecified), two (1%) had S. pneumoniae isolated from blood and a further 95 (70%) had clinical or laboratory features consistent with pneumococcal infection or S. pneumoniae isolated from either sputum or nasopharyngeal aspirate. With the imminent availability of conjugate pneumococcal vaccines, there is a need for improved diagnostic methods for identifying the pathogens responsible for community-acquired pneumonia in young children.
Serotype-specific effectiveness and correlates of protection for the 13-valent pneumococcal conjugate vaccine: A postlicensure indirect cohort study
Publisher: Elsevier BV
Date: 09-2014
Erratum for Rivera-Hernandez et al., “An Experimental Group A Streptococcus Vaccine That Reduces Pharyngitis and Tonsillitis in a Nonhuman Primate Model”
Publisher: American Society for Microbiology
Date: 22-12-2020
Interlaboratory Comparison of the Pneumococcal Multiplex Opsonophagocytic Assays and Their Level of Agreement for Determination of Antibody Function in Pediatric Sera
Publisher: American Society for Microbiology
Date: 25-04-2018
Abstract: When measuring a functional antibody response to pneumococcal immunization, it is imperative that a specific, reproducible, accurate, and standardized assay with acceptable inter- and intra-assay variation be advocated internationally to allow for meaningful comparison of results between laboratories. We report here the results of a collaboration between 3 international laboratories testing 30 pediatric s les against the 13 serotypes in Prevenar13.
Antibodies to Seasonal Coronaviruses Rarely Cross-React With SARS-CoV-2
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 17-09-2021
Assignment of Serotype-Specific IgG1, IgG2, and IgA Weight-Based Antibody Units to the Human Pneumococcal Standard Reference Serum, 007sp
Publisher: American Society for Microbiology
Date: 26-06-2019
Abstract: A well-characterized antibody standard is an indispensable reagent for use in assays designed to measure antibodies with precision and where assays between laboratories need to be comparable. The human pneumococcal standard reference serum, lot 89SF, greatly facilitated the standardization of enzyme-linked immunosorbent assay methodologies during a critical period when the first pneumococcal polysaccharide-conjugate vaccines were being evaluated for licensure. Due to dwindling supplies of lot 89SF, a new reference standard, 007sp, was produced in 2011. Understanding the isotype and subclass composition of either natural or vaccine induced responses to pathogens has assumed increasing importance. In this study, we have assigned IgA, IgG1, and IgG2 values to pneumococcal serotypes 1, 3, 4, 5, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F by bridging to existing values in lot 89SF.
Preparation of human–mouse heterohybridomas against an immunising antigen
Publisher: Elsevier BV
Date: 12-2000
DOI: 10.1016/S0022-1759(00)00293-3
Abstract: The production of murine monoclonal antibodies against specific antigens by hybridomas is a well utilised technique. The production of hybridomas secreting specific human antibodies would have many advantages in therapeutic applications of monoclonal antibodies. The immortalised human lymphocytes themselves would also provide valuable tools in research on lymphocyte development. Preparation of human-human hybridomas has been limited by a lack of suitable fusion partners. This protocol paper describes the production of human-mouse heterohybridomas by two independent laboratories. The purpose of this protocol is to provide a basis for the development of heterohybridoma technology in laboratories with limited hybridoma experience.
Ability of 3 Different Meningococcal C Conjugate Vaccines to Induce Immunologic Memory after a Single Dose in UK Toddlers
Publisher: Oxford University Press (OUP)
Date: 2001
DOI: 10.1086/317646
Abstract: To test for immunologic memory after a single dose of meningococcal C conjugate (MCC) vaccine in toddlers, 226 children 12-18 months old were randomized to receive 1 of 3 MCC vaccines, with a C polysaccharide booster 6 months later. The protein conjugate was diphtheria mutant toxoid in 2 vaccines (MCC-CRM(197)) and was tetanus toxoid in the third (MCC-TT). One month after the MCC vaccines, 91%-100% of children had serum bactericidal antibody (SBA) titers > or =8, and 89%-100% had a > or =4-fold increase. Geometric mean titer (GMT) increased from <4 to 215 (95% confidence interval [CI], 166-279). MCC-TT induced higher SBA GMTs (P or =8 (P=.02) than did the MCC-CRM(197) vaccines. By 6 months, GMTs had decreased to 55.1 (95% CI, 40-76), but IgG antibody avidity increased (P<.001). Induction of immunologic memory was confirmed by a GMT of 1977 (range, 1535-2547) after the polysaccharide booster and a further increase in avidity. This evidence justified the use of a single dose in a catch-up immunization program for children 1-18 years old.
When to update COVID-19 vaccine composition
Publisher: Springer Science and Business Media LLC
Date: 20-02-2023
Vaccine-Induced Th1-Type Response Protects against Invasive Group A Streptococcus Infection in the Absence of Opsonizing Antibodies
Publisher: American Society for Microbiology
Date: 28-04-2020
Abstract: Availability of a group A Streptococcus vaccine remains an unmet public health need. Here, we tested different adjuvant formulations to improve the protective efficacy of non-M protein vaccine Combo5 in an invasive disease model. We show that novel adjuvants can dramatically shape the type of immune response developed following immunization with Combo5 and significantly improve protection. In addition, protection afforded by Combo5 is not mediated by opsonizing antibodies, believed to be the main correlate of protection against GAS infections. Overall, this report highlights the importance of adjuvant selection in raising protective immune responses against GAS invasive infection. Adjuvants that can provide a more balanced Th1/Th2-type response may be required to optimize protection of GAS vaccines, particularly those based on non-M protein antigens.
Functional anti-polysaccharide IgG titres induced by unadjuvanted pneumococcal-conjugate vaccine when delivered by microprojection-based skin patch
Publisher: Elsevier BV
Date: 11-2015
DOI: 10.1016/J.VACCINE.2015.10.081
Abstract: Adequate access to effective and affordable vaccines is essential for the prevention of mortality due to infectious disease. Pneumonia--a consequence of Streptococcus pneumoniae infection--is the world's leading cause of death in children aged under 5 years. The development of a needle-free, thermostable pneumococcal-conjugate vaccine (PCV) could revolutionise the field by reducing cold-chain and delivery constraints. Skin patches have been used to deliver a range of vaccines, with some inducing significantly higher vaccine-specific immunogenicity than needle-injected controls in pre-clinical models, though they have yet to be used to deliver a PCV. We dry-coated a licensed PCV onto a microprojection-based patch (the Nanopatch) and delivered it to mouse skin. We analysed resulting anti-polysaccharide IgG responses. With and without adjuvant, anti-polysaccharide IgG titres induced by Nanopatch immunisation were significantly higher than dose-matched intramuscular controls. These improved responses were primarily obtained against pneumococcal serotypes 4 and 14. Importantly, capsule-specific IgG correlated with functionality in an opsonophagocytic killing assay. We demonstrate enhanced anti-PCV immunogenicity when delivered by Nanopatch over intramuscular injection. As the first study of a PCV delivered by a skin vaccination technology, this report indicates the potential for reduced costs and greater global distribution of such a vaccine.
Establishment of the first International Standard for human anti-typhoid capsular Vi polysaccharide IgG
Publisher: Elsevier BV
Date: 11-2018
Related Organisations
Royal College Of Paediatrics And Child Health
Location: United Kingdom of Great Britain and Northern Ireland
Great Ormond Street Hospital For Children NHS Foundation Trust
Location: United Kingdom of Great Britain and Northern Ireland
Great Ormond Street Hospital For Children NHS Trust
Location: United Kingdom of Great Britain and Northern Ireland
Royal College Of Physicians
Location: United Kingdom of Great Britain and Northern Ireland
University College London
Location: United Kingdom of Great Britain and Northern Ireland
University Of London
Location: United Kingdom of Great Britain and Northern Ireland
Related Funding Activities
No related grants have been discovered for David Goldblatt.