A single birth-dose of Hepatitis B vaccine (HepB) can protect newborns from acquiring Hepatitis B... more A single birth-dose of Hepatitis B vaccine (HepB) can protect newborns from acquiring Hepatitis B infection through vertical transmission, though several follow-up doses are required to induce long-lived protection. In addition to stimulating antibodies, a birth-dose of HepB might also induce polyfunctional CD4+T-cells, which may contribute to initial protection. We investigated whether vaccination with HepB in the first week of life induced detectable antigen-specific CD4+T-cells after only a single dose and following completion of the entire HepB vaccine schedule (3 doses). Using HBsAg- stimulated peripheral blood mononuclear cells from 344 infants, we detected increased populations of antigen-specific polyfunctional CD154+IL-2+TNFα+CD4+T-cells following a single birth-dose of HepB in a proportion of infants. Frequencies of polyfunctional T-cells increased following the completion of the HepB schedule but increases in the proportion of responders as compared to following only one ...
BackgroundHuman adenosine deaminases (ADAs) modulate the immune response: ADA1viametabolizing ade... more BackgroundHuman adenosine deaminases (ADAs) modulate the immune response: ADA1viametabolizing adenosine, a purine metabolite that inhibits pro-inflammatory and Th1 cytokine production, and the multi-functional ADA2, by enhancing T-cell proliferation and monocyte differentiation. Newborns are relatively deficient in ADA1 resulting in elevated plasma adenosine concentrations and a Th2/anti-inflammatory bias compared to adults. Despite the growing recognition of the role of ADAs in immune regulation, little is known about the ontogeny of ADA concentrations.MethodsIn a subgroup of the EPIC002-study, clinical data and plasma samples were collected from 540 Gambian infants at four time-points: day of birth; first week of life; one month of age; and four months of age. Concentrations of total extracellular ADA, ADA1, and ADA2 were measured by chromogenic assay and evaluated in relation to clinical data. Plasma cytokines/chemokine were measured across the first week of life and correlated t...
Clinical research conducted to Good Clinical Practice (GCP) standards is increasingly being under... more Clinical research conducted to Good Clinical Practice (GCP) standards is increasingly being undertaken in resource-constrained low-income and middle-income countries (LMICs) settings. This presents unique challenges that differ from those faced in high-income country (HIC) contexts, due to a dearth of infrastructure and unique socio-cultural contexts. Field experiences by research teams working in these LMIC contexts are thus critical to advancing knowledge on successful research conduct in these settings. The Medical Research Council Unit The Gambia at London School of Hygiene and Tropical Medicine has operated in The Gambia, a resource-constrained LMIC for over 70 years and has developed numerous research support platforms and systems. The unit was the lead clinical collaborator in a recently completed Expanded Program on Immunization Consortium (EPIC) study, involving a multicountry collaboration across five countries including the USA, Canada, Belgium, Papua New Guinea and The G...
Introduction Adenosine is a purine metabolite that acts on its leukocyte receptors to inhibit inf... more Introduction Adenosine is a purine metabolite that acts on its leukocyte receptors to inhibit inflammatory and Th1-polarizing cytokine production. Newborns exhibit lower plasma levels of adenosine deaminase (ADA), an enzyme that metabolizes extracellular adenosine, resulting in elevated plasma adenosine levels and a Th2/anti-inflammatory bias. Humans express two ADA isoforms: ADA1 and ADA2. Characterizing the impact of ontogeny and vaccination on levels of ADA1 and ADA2 may provide insight into mechanisms regulating early life immune development. Methods Newborns were recruited at the MRC Unit-Gambia and randomized to either Hepatitis B (HepB), BCG, or the combination of both vaccines. Plasma was collected at birth (day of life (DOL) 0) and at DOL 1, 3, or 7. Plasma levels of ADA1 and ADA2 were measured by a chromogenic assay. Log-transformed ADA concentrations were compared using ANOVA. Results In this interim analysis, we measured n = 51–53 participants per vaccine group per timep...
The burden of severe Covid-19 has been relatively low in sib-Saharan Africa compared to Europe an... more The burden of severe Covid-19 has been relatively low in sib-Saharan Africa compared to Europe and the Americas. However, SARS-CoV-2 sero-prevalence data has demonstrated that there has been more widespread transmission than can be deduced from reported cases. This could be attributed to under reporting due to low testing capacity or high numbers of asymptomatic SARS-CoV-2 infection in communities. Recent data indicates that prior SARS-CoV-2 exposure is protective against reinfection and that vaccination of previously SARS-CoV-2 infected individuals induces robust cross-reactive antibody responses. Considering these data, calls for a need for a re-think of the COVID-19 vaccination strategy in sub-Saharan African settings with high SARSCoV-2 population exposure but limited available vaccine doses. A potential recommendation would be to prioritize rapid and widespread vaccination of the first dose, while waiting for more vaccines to become available.
BACKGROUND: 7-Valent pneumococcal conjugate vaccine (PCV7 [Prevnar, Wyeth Pharmaceuticals Inc, Ph... more BACKGROUND: 7-Valent pneumococcal conjugate vaccine (PCV7 [Prevnar, Wyeth Pharmaceuticals Inc, Philadelphia, PA], serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) is effective in preventing vaccine-serotype pneumococcal disease. 13-Valent pneumococcal conjugate vaccine (PCV13) (PCV7 serotypes plus 1, 3, 5, 6A, 7F, and 19A) was designed to provide broader pneumococcal disease coverage. We evaluated the immunogenicity and safety of PCV13 compared with PCV7. METHODS: Infants received PCV13 or PCV7 at ages 2, 4, 6, and 12 to 15 months with routine pediatric vaccinations. Pneumococcal anticapsular polysaccharide-binding immunoglobulin G responses and functional antipneumococcal opsonophagocytic activity were assessed 1 month after dose 3, before the toddler dose, and 1 month after the toddler dose. Safety and tolerability were also assessed. RESULTS: For the 7 common serotypes, PCV13-elicited immunoglobulin G titers were noninferior to those elicited by PCV7, although PCV13 responses were gen...
Neonatal administration of BCG vaccine rapidly increases neutrophil production to reduce mortalit... more Neonatal administration of BCG vaccine rapidly increases neutrophil production to reduce mortality from sepsis.
ABSTRACTA meningococcal group A polysaccharide (PS) conjugate vaccine (PsA-TT) has been developed... more ABSTRACTA meningococcal group A polysaccharide (PS) conjugate vaccine (PsA-TT) has been developed for African countries affected by epidemic meningitis caused byNeisseria meningitidis. Complement-mediated serum bactericidal antibody (SBA) assays are used to assess protective immune responses to meningococcal vaccination. Human complement (hC′) was used in early studies demonstrating antibody-mediated protection against disease, but it is difficult to obtain and standardize. We developed and evaluated a method for sourcing hC′ and then used the SBA assay with hC′ (hSBA) to measure bactericidal responses to PsA-TT vaccination in 12- to 23-month-old African children. Sera with active complement from 100 unvaccinated blood donors were tested for intrinsic bactericidal activity, SBA titer using rabbit complement (rSBA), and anti-group A PS antibody concentration. Performance criteria and pooling strategies were examined and then verified by comparisons of three independently prepared hC′...
A single birth-dose of Hepatitis B vaccine (HepB) can protect newborns from acquiring Hepatitis B... more A single birth-dose of Hepatitis B vaccine (HepB) can protect newborns from acquiring Hepatitis B infection through vertical transmission, though several follow-up doses are required to induce long-lived protection. In addition to stimulating antibodies, a birth-dose of HepB might also induce polyfunctional CD4+T-cells, which may contribute to initial protection. We investigated whether vaccination with HepB in the first week of life induced detectable antigen-specific CD4+T-cells after only a single dose and following completion of the entire HepB vaccine schedule (3 doses). Using HBsAg- stimulated peripheral blood mononuclear cells from 344 infants, we detected increased populations of antigen-specific polyfunctional CD154+IL-2+TNFα+CD4+T-cells following a single birth-dose of HepB in a proportion of infants. Frequencies of polyfunctional T-cells increased following the completion of the HepB schedule but increases in the proportion of responders as compared to following only one ...
BackgroundHuman adenosine deaminases (ADAs) modulate the immune response: ADA1viametabolizing ade... more BackgroundHuman adenosine deaminases (ADAs) modulate the immune response: ADA1viametabolizing adenosine, a purine metabolite that inhibits pro-inflammatory and Th1 cytokine production, and the multi-functional ADA2, by enhancing T-cell proliferation and monocyte differentiation. Newborns are relatively deficient in ADA1 resulting in elevated plasma adenosine concentrations and a Th2/anti-inflammatory bias compared to adults. Despite the growing recognition of the role of ADAs in immune regulation, little is known about the ontogeny of ADA concentrations.MethodsIn a subgroup of the EPIC002-study, clinical data and plasma samples were collected from 540 Gambian infants at four time-points: day of birth; first week of life; one month of age; and four months of age. Concentrations of total extracellular ADA, ADA1, and ADA2 were measured by chromogenic assay and evaluated in relation to clinical data. Plasma cytokines/chemokine were measured across the first week of life and correlated t...
Clinical research conducted to Good Clinical Practice (GCP) standards is increasingly being under... more Clinical research conducted to Good Clinical Practice (GCP) standards is increasingly being undertaken in resource-constrained low-income and middle-income countries (LMICs) settings. This presents unique challenges that differ from those faced in high-income country (HIC) contexts, due to a dearth of infrastructure and unique socio-cultural contexts. Field experiences by research teams working in these LMIC contexts are thus critical to advancing knowledge on successful research conduct in these settings. The Medical Research Council Unit The Gambia at London School of Hygiene and Tropical Medicine has operated in The Gambia, a resource-constrained LMIC for over 70 years and has developed numerous research support platforms and systems. The unit was the lead clinical collaborator in a recently completed Expanded Program on Immunization Consortium (EPIC) study, involving a multicountry collaboration across five countries including the USA, Canada, Belgium, Papua New Guinea and The G...
Introduction Adenosine is a purine metabolite that acts on its leukocyte receptors to inhibit inf... more Introduction Adenosine is a purine metabolite that acts on its leukocyte receptors to inhibit inflammatory and Th1-polarizing cytokine production. Newborns exhibit lower plasma levels of adenosine deaminase (ADA), an enzyme that metabolizes extracellular adenosine, resulting in elevated plasma adenosine levels and a Th2/anti-inflammatory bias. Humans express two ADA isoforms: ADA1 and ADA2. Characterizing the impact of ontogeny and vaccination on levels of ADA1 and ADA2 may provide insight into mechanisms regulating early life immune development. Methods Newborns were recruited at the MRC Unit-Gambia and randomized to either Hepatitis B (HepB), BCG, or the combination of both vaccines. Plasma was collected at birth (day of life (DOL) 0) and at DOL 1, 3, or 7. Plasma levels of ADA1 and ADA2 were measured by a chromogenic assay. Log-transformed ADA concentrations were compared using ANOVA. Results In this interim analysis, we measured n = 51–53 participants per vaccine group per timep...
The burden of severe Covid-19 has been relatively low in sib-Saharan Africa compared to Europe an... more The burden of severe Covid-19 has been relatively low in sib-Saharan Africa compared to Europe and the Americas. However, SARS-CoV-2 sero-prevalence data has demonstrated that there has been more widespread transmission than can be deduced from reported cases. This could be attributed to under reporting due to low testing capacity or high numbers of asymptomatic SARS-CoV-2 infection in communities. Recent data indicates that prior SARS-CoV-2 exposure is protective against reinfection and that vaccination of previously SARS-CoV-2 infected individuals induces robust cross-reactive antibody responses. Considering these data, calls for a need for a re-think of the COVID-19 vaccination strategy in sub-Saharan African settings with high SARSCoV-2 population exposure but limited available vaccine doses. A potential recommendation would be to prioritize rapid and widespread vaccination of the first dose, while waiting for more vaccines to become available.
BACKGROUND: 7-Valent pneumococcal conjugate vaccine (PCV7 [Prevnar, Wyeth Pharmaceuticals Inc, Ph... more BACKGROUND: 7-Valent pneumococcal conjugate vaccine (PCV7 [Prevnar, Wyeth Pharmaceuticals Inc, Philadelphia, PA], serotypes 4, 6B, 9V, 14, 18C, 19F, and 23F) is effective in preventing vaccine-serotype pneumococcal disease. 13-Valent pneumococcal conjugate vaccine (PCV13) (PCV7 serotypes plus 1, 3, 5, 6A, 7F, and 19A) was designed to provide broader pneumococcal disease coverage. We evaluated the immunogenicity and safety of PCV13 compared with PCV7. METHODS: Infants received PCV13 or PCV7 at ages 2, 4, 6, and 12 to 15 months with routine pediatric vaccinations. Pneumococcal anticapsular polysaccharide-binding immunoglobulin G responses and functional antipneumococcal opsonophagocytic activity were assessed 1 month after dose 3, before the toddler dose, and 1 month after the toddler dose. Safety and tolerability were also assessed. RESULTS: For the 7 common serotypes, PCV13-elicited immunoglobulin G titers were noninferior to those elicited by PCV7, although PCV13 responses were gen...
Neonatal administration of BCG vaccine rapidly increases neutrophil production to reduce mortalit... more Neonatal administration of BCG vaccine rapidly increases neutrophil production to reduce mortality from sepsis.
ABSTRACTA meningococcal group A polysaccharide (PS) conjugate vaccine (PsA-TT) has been developed... more ABSTRACTA meningococcal group A polysaccharide (PS) conjugate vaccine (PsA-TT) has been developed for African countries affected by epidemic meningitis caused byNeisseria meningitidis. Complement-mediated serum bactericidal antibody (SBA) assays are used to assess protective immune responses to meningococcal vaccination. Human complement (hC′) was used in early studies demonstrating antibody-mediated protection against disease, but it is difficult to obtain and standardize. We developed and evaluated a method for sourcing hC′ and then used the SBA assay with hC′ (hSBA) to measure bactericidal responses to PsA-TT vaccination in 12- to 23-month-old African children. Sera with active complement from 100 unvaccinated blood donors were tested for intrinsic bactericidal activity, SBA titer using rabbit complement (rSBA), and anti-group A PS antibody concentration. Performance criteria and pooling strategies were examined and then verified by comparisons of three independently prepared hC′...
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