Highlights • Intranasal immunisation with ChAdOx1.85A induces strong T-cell responses. • ChAdOx1.85A boosted with MVA85A significantly improves the protective efficacy of BCG. • MVA85A boost is ...protective both after mucosal and systemic administration.
BCG, the only vaccine licensed against tuberculosis, demonstrates variable efficacy in humans. Recent preclinical studies highlight the potential for mucosal BCG vaccination to improve protection. ...Lung tissue-resident memory T cells reside within the parenchyma, potentially playing an important role in protective immunity to tuberculosis. We hypothesised that mucosal BCG vaccination may enhance generation of lung tissue-resident T cells, affording improved protection against Mycobacterium tuberculosis. In a mouse model, mucosal intranasal (IN) BCG vaccination conferred superior protection in the lungs compared to the systemic intradermal (ID) route. Intravascular staining allowed discrimination of lung tissue-resident CD4
T cells from those in the lung vasculature, revealing that mucosal vaccination resulted in an increased frequency of antigen-specific tissue-resident CD4
T cells compared to systemic vaccination. Tissue-resident CD4
T cells induced by mucosal BCG displayed enhanced proliferative capacity compared to lung vascular and splenic CD4
T cells. Only mucosal BCG induced antigen-specific tissue-resident T cells expressing a PD-1
KLRG1
cell-surface phenotype. These cells constitute a BCG-induced population which may be responsible for the enhanced protection observed with IN vaccination. We demonstrate that mucosal BCG vaccination significantly improves protection over systemic BCG and this correlates with a novel population of BCG-induced lung tissue-resident CD4
T cells.
Highlights • Histopathology can be used as a novel parameter of protection in bovine TB. • Multiple cytokine-producing T-cells relate more to an on-going immune response than to protection in bovine ...TB. • Ad5-85A is a promising BCG-boosting vaccine candidate against tuberculosis in cattle.
The wide spectrum of clinical outcomes following infection with Mycobacterium tuberculosis is largely determined by the host immune response; therefore, we studied several clinically defined groups ...of individuals (n = 120) that differ in their ability to contain the bacillus. To quantitate M. tuberculosis-specific T cells directly ex vivo, we enumerated IFN-gamma-secreting CD4 T cells specific for ESAT-6, a secreted Ag that is highly specific for M. tuberculosis, and a target of protective immune responses in animal models. We found that frequencies of circulating ESAT-6 peptide-specific IFN-gamma-secreting CD4 T cells were higher in latently infected healthy contacts and subjects with minimal disease and low bacterial burdens than in patients with culture-positive active pulmonary tuberculosis (p = 0.009 and p = 0.002, respectively). Importantly, the frequency of these Ag-specific CD4 T cells fell progressively in all groups with treatment (p = 0.005), suggesting that the lower responses in patients with more extensive disease were not due to tuberculosis-induced immune suppression. This population of M. tuberculosis Ag-specific Th1-type CD4 T cells appears to correlate with clinical phenotype and declines during successful therapy; these features are consistent with a role for these T cells in the containment of M. tuberculosis in vivo. Such findings may assist in the design and evaluation of novel tuberculosis vaccine candidates.
Objective
Paediatric laboratory reference intervals used in Africa and Asia may be derived from historical intervals of predominantly Caucasian infants in Europe or North America. These intervals may ...therefore not be compatible with the range of normality for developing country populations. We aimed to compare haematology and biochemistry parameters in healthy South African infants with local laboratory reference intervals.
Methods
We compared the baseline haematology and biochemistry results of 634 (316 male and 318 female) HIV‐unexposed infants, aged 3–6 months, living in a rural area of the Western Cape Province, South Africa, against laboratory reference intervals supplied by the South African National Health Laboratory Services (NHLS). We calculated the percentage of observed values out of bound (in terms of lower and upper limits) compared to laboratory reference intervals.
Results
Of the 634 healthy infants screened, 316 (49.84%) were male and 318 (50.16%) female. A majority (91.05%) had platelet counts above the laboratory reference interval upper limit (350 × 109cells/l), while over half, 54.85% and 56.98% had mean corpuscular volume (MCV) and mean corpuscular haemoglobin (MCH) values below the lower limits of 77.0–105.0 fl and 26.0–34.0 pg, respectively. A small proportion were outside the reference limits for haematocrit, namely 15.71% below and 7.14% above the normal limits of 0.31–0.38 l/l. For male and female infants, 33.65% and 18.04% of alkaline phosphatase (ALP) values and 7.01% and 14.56% of alanine transaminase (ALT) values were above the upper limits, respectively. For male infants, 10.83% of gamma‐glutamyl transferase (GGT) values, and for female infants, 31.11% of GGT values were below the lower limits of 12 U/l for males and 15 U/l for females. We observed no significant deviations (>10% out of bound) from NHLS reference intervals in the remaining haematology and biochemistry parameters measured.
Conclusions
Haematology and biochemistry parameters in apparently healthy South African infants deviate frequently from national laboratory reference intervals, including abnormalities consistent with subclinical hypochromic microcytic anaemia. It is important that clinical laboratory reference intervals for children are derived locally, rather than being adopted from Caucasian norms in developed countries, because clinical trials of vaccines, drugs and diagnostics are increasingly conducted in sub‐Saharan Africa.
Objectif
Les intervalles de référence des laboratoires pédiatriques utilisés en Afrique et en Asie seraient dérivés d'intervalles historiques de nourrissons à prédominance caucasienne en Europe ou en Amérique du Nord. Ces intervalles pourraient donc ne pas être compatibles avec l’étendue de la normalité pour les populations des pays en développement. Nous avons cherché à comparer les paramètres hématologiques et biochimiques chez des nourrissons sains sud‐africains avec les intervalles de référence des laboratoires locaux.
Méthodes
Nous avons comparé les résultats hématologiques et biochimiques de 634 nourrissons non exposés au VIH, âgés de 3 à 6 mois, vivant dans une zone rurale de la province du Wertern Cap en Afrique du Sud aux intervalles de référence fournis par les Services Nationaux de Laboratoire de Santé (NHLS) d'Afrique du Sud. Nous avons calculé le pourcentage des valeurs hors limites observées (en termes de limites inférieures et supérieures) par rapport aux intervalles de référence de laboratoire.
Résultats
Sur les 634 nourrissons sains examinés, 316 (49,84%) étaient masculins et 318 (50,16%) féminins. Une majorité (91,05%) avait des numérations plaquettaires au‐dessus de la limite supérieure de l'intervalle de référence de laboratoire (350 x 109 cellules/L), tandis que plus de la moitié, 54,85% et 56,98% avaient des valeurs moyennes de volume corpusculaire et d'hémoglobine corpusculaire en dessous des limites inférieures de 77.0‐105.0 fl et 26.0‐34.0 pg, respectivement. Une petite proportion était en dehors des limites de référence pour l'hématocrite, à savoir 15,71% en dessous et 7,14% au‐dessus des limites normales de 0,31 l/L ‐ 0,38 l/L. Chez les nourrissons masculins et féminins, 33,65% et 18,04% des valeurs de la phosphatase alcaline (ALP) et 7,01% et 14,56% des valeurs de l'alanine transaminase (ALT) étaient respectivement au‐dessus des limites supérieures. Chez les nourrissons masculins, 10,83% des valeurs du gamma glutamyl transférase (GGT) et chez les nourrissons féminins, 31,11% des GGT étaient en dessous des limites inférieures de 12 U/L pour les garçonnets et de 15 U/L pour les fillettes. Nous n'avons pas observé d’écart significatif (> 10% hors limite) par rapport aux intervalles de référence des NHLS pour les autres paramètres hématologiques et biochimiques mesurés.
Conclusions
Les paramètres hématologiques et biochimiques des nourrissons sud‐africains sains s’écartent fréquemment des intervalles de référence nationaux de laboratoire, y compris des anomalies cohérentes avec l'anémie microcytaire hypochrome sub‐clinique. Il est important que les intervalles de référence des laboratoires cliniques pour les enfants soient dérivés localement plutôt qu'adoptés à partir des normes caucasiennes dans les pays développés, car les essais cliniques de vaccins, médicaments et diagnostics sont de plus en plus menés en Afrique subsaharienne
South Africa.
To evaluate the long-term effectiveness of infant modified vaccinia Ankara virus-expressing antigen 85A (MVA85A) vaccination against tuberculosis (TB).
We analysed data from a ...double-blind randomised placebo-controlled Phase 2b MVA85A infant TB vaccine trial (2009-2012), with extended post-trial follow-up (2012-2014). Isoniazid preventive therapy (IPT) was provided by public health services according to national guidelines. The primary outcome was curative treatment for TB disease. Survival analysis and Poisson regression were used for study analysis.
Total follow-up was 10 351 person-years of observation (pyo). Median follow-up age was 4.8 years (interquartile range 4.4-5.2). There were 328 (12%) TB cases. TB disease incidence was 3.2/100 pyo (95%CI 2.8-3.5) overall, and respectively 3.3 (95%CI 2.9-3.9) and 3.0 (95%CI 2.6-3.5)/100 pyo in the MVA85A vaccine and placebo arms. A total of 304 children (11%) received IPT, with respectively 880 and 9471 pyo among IPT and non-IPT recipients. There were 23 (7.6%) TB cases among 304 IPT recipients vs. 305 (12.9%) among 2374 non-IPT recipients (P = 0.008). IPT effectiveness was 85% (95%CI 76-91).
Extended follow-up confirms no long-term effectiveness of infant MVA85A vaccination, but a six-fold reduction in TB risk can be attributed to IPT. National TB programmes in high TB burden countries should ensure optimal implementation of IPT for eligible children.
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