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Jones C.E.,Imperial College London | Jones C.E.,University of Cape Town | Naidoo S.,University of Cape Town | De Beer C.,University of Cape Town | And 7 more authors.
JAMA - Journal of the American Medical Association

Context: Altered immune responses might contribute to the high morbidity and mortality observed in human immunodeficiency virus (HIV)-exposed uninfected infants. Objective: To study the association of maternal HIV infection with maternal- and infant-specific antibody levels to Haemophilus influenzae type b (Hib), pneumococcus, Bordetella pertussis antigens, tetanus toxoid, and hepatitis B surface antigen. Design, Setting, and Participants: A community-based cohort study in Khayelitsha, Western Cape Province, South Africa, between March 3, 2009, and April 28, 2010, of 109 HIV-infected and uninfected women and their infants. Serum samples from 104 women and 100 infants were collected at birth and samples from 93 infants were collected at 16 weeks. Main Outcome Measure: Level of specific antibody in mother-infant pairs at delivery and in infants at 16 weeks, determined by enzyme-linked immunosorbent assays. Results: At birth, HIV-exposed uninfected infants (n=46) had lower levels of specific antibodies than unexposed infants (n=54) did to Hib (0.37 [interquartile range {IQR}, 0.22-0.67] mg/L vs 1.02 [IQR, 0.34-3.79] mg/L; P<.001), pertussis (16.07 [IQR, 8.87-30.43] Food and Drug Administration [FDA] U/mL vs 36.11 [IQR, 20.41-76.28] FDA U/mL; P<.001), pneumococcus (17.24 [IQR, 11.33-40.25] mg/L vs 31.97 [IQR, 18.58-61.80] mg/L; P=.02), and tetanus (0.08 [IQR, 0.03-0.39] IU/mL vs 0.24 [IQR, 0.08-0.92] IU/mL; P=.006). Compared with HIV-uninfected women (n=58), HIV-infected women (n=46) had lower specific antibody levels to Hib (0.67 [IQR, 0.16-1.54] mg/L vs 1.34 [IQR, 0.15-4.82] mg/L; P=.009) and pneumococcus (33.47 [IQR, 4.03-69.43] mg/L vs 50.84 [IQR, 7.40-118.00] mg/L; P=.03); however, no differences were observed for antipertussis or antitetanus antibodies. HIV-exposed uninfected infants (n=38) compared with HIV-unexposed infants (n=55) had robust antibody responses following vaccination, with higher antibody responses to pertussis (270.1 [IQR, 84.4-355.0] FDA U/mL vs 91.7 [IQR, 27.9-168.4] FDA U/mL; P=.006) and pneumoccocus (47.32 [IQR, 32.56-77.80] mg/L vs 14.77 [IQR, 11.06-41.08] mg/L; P=.001). Conclusion: Among South African infants, antenatal HIV exposure was associated with lower specific antibody responses in exposed uninfected infants compared with unexposed infants at birth, but with robust responses following routine vaccination. ©2011 American Medical Association. All rights reserved. Source

Flanagan K.L.,Medical Research Council UK The Gambia | Burl S.,Medical Research Council UK The Gambia | Lohman-Payne B.L.,University of Washington | Plebanski M.,Monash University
Expert Review of Vaccines

Newborns and infants are highly susceptible to infectious diseases, resulting in high mortality and morbidity, particularly in resource-poor settings. Many vaccines require several booster doses, resulting in an extensive vaccine schedule, and yet there is still inadequate protection from some of these diseases. This is partly due to the immaturity of the neonate and infant immune system. Little is known about the specific modifications to immunological assessment protocols in early life but increasing knowledge of infant immunology has helped provide better recommendations for assessing these responses. Since most new vaccines will eventually be deployed in low-income settings such as Africa, the logistics and resources of assessing immunity in such settings also need to be understood. In this article, we will review immunity to vaccines in early life, discuss the many challenges associated with assessing immunogenicity and provide practical tips. © 2010 Expert Reviews Ltd. Source

Kirby M.J.,London School of Hygiene and Tropical Medicine | Bah P.,Medical Research Council UK The Gambia | Jones C.O.H.,London School of Hygiene and Tropical Medicine | Kelly A.H.,London School of Hygiene and Tropical Medicine | And 2 more authors.
American Journal of Tropical Medicine and Hygiene

The social acceptability and durability of two house screening interventions were addressed using focus group discussions, questionnaires, indoor climate measurements, and durability surveys. Participants recognized that screening stopped mosquitoes (79-96%) and other insects (86-98%) entering their houses. These and other benefits were appreciated by significantly more recipients of full screening than users of screened ceilings. Full screened houses were 0.26°C hotter at night (P = 0.05) than houses with screened ceilings and 0.51°C (P < 0.001) hotter than houses with no screening (28.43°C), though only 9% of full screened house users and 17% of screened ceiling users complained about the heat. Although 71% of screened doors and 85% of ceilings had suffered some damage after 12 months, the average number of holes of any size was < 5 for doors and < 7 for ceilings. In conclusion, house screening is a well-appreciated and durable vector control tool. Copyright © 2010 by The American Society of Tropical Medicine and Hygiene. Source

Burl S.,Medical Research Council UK The Gambia | Adetifa U.J.,Medical Research Council UK The Gambia | Cox M.,Medical Research Council UK The Gambia | Touray E.,Medical Research Council UK The Gambia | And 4 more authors.

The tuberculin skin test (TST) is widely used in TB clinics to aid Mycobacterium tuberculosis (M.tb) diagnosis, but the definition and the significance of a positive test in very young children is still unclear. This study compared the TST in Gambian children at 4 1/2 months of age who either received BCG vaccination at birth (Group 1) or were BCG naïve (Group 2) in order to examine the role of BCG vaccination and/or exposure to environmental mycobacteria in TST reactivity at this age. Nearly half of the BCG vaccinated children had a positive TST (≥5 mm) whereas all the BCG naïve children were nonreactive, confirming that recent BCG vaccination affects TST reactivity. The BCG naïve children demonstrated in vitro PPD responses in peripheral blood in the absence of TST reactivity, supporting exposure to and priming by environmental mycobacterial antigens. Group 2 were then vaccinated at 4 1/2 months of age and a repeat TST was performed at 20-28 months of age. Positive reactivity (≥5 mm) was evident in 11.1% and 12.5% infants from Group 1 and Group 2 respectively suggesting that the timing of BCG vaccination had little effect by this age. We further assessed for immune correlates in peripheral blood at 4 1/2 months of age. Mycobacterial specific IFNγ responses were greater in TST responders than in nonresponders, although the size of induration did not correlate with IFNγ. However the IFNγ: IL-10 ratio positively correlated with TST induration suggesting that the relationship between PPD induced IFNγ and IL-10 in the peripheral blood may be important in controlling TST reactivity. Collectively these data provide further insights into how the TST is regulated in early life, and how a positive response might be interpreted. © 2010 Burl et al. Source

Burl S.,Medical Research Council UK The Gambia | Burl S.,Imperial College London | Townend J.,Medical Research Council UK The Gambia | Njie-Jobe J.,Medical Research Council UK The Gambia | And 11 more authors.

The global burden of neonatal and infant mortality due to infection is staggering, particularly in resource-poor settings. Early childhood vaccination is one of the major interventions that can reduce this burden, but there are specific limitations to inducing effective immunity in early life, including impaired neonatal leukocyte production of Th1-polarizing cytokines to many stimuli. Characterizing the ontogeny of Toll-like receptor (TLR)-mediated innate immune responses in infants may shed light on susceptibility to infection in this vulnerable age group, and provide insights into TLR agonists as candidate adjuvants for improved neonatal vaccines. As little is known about the leukocyte responses of infants in resource-poor settings, we characterized production of Th1-, Th2-, and anti-inflammatory- cytokines in response to agonists of TLRs 1-9 in whole blood from 120 Gambian infants ranging from newborns (cord blood) to 12 months of age. Most of the TLR agonists induced TNFα, IL-1β, IL-6, and IL-10 in cord blood. The greatest TNFα responses were observed for TLR4, -5, and -8 agonists, the highest being the thiazoloquinoline CLO75 (TLR7/8) that also uniquely induced cord blood IFNγ production. For most agonists, TLR-mediated TNFα and IFNγ responses increased from birth to 1 month of age. TLR8 agonists also induced the greatest production of the Th1-polarizing cytokines TNFα and IFNγ throughout the first year of life, although the relative responses to the single TLR8 agonist and the combined TLR7/8 agonist changed with age. In contrast, IL-1β, IL-6, and IL-10 responses to most agonists were robust at birth and remained stable through 12 months of age. These observations provide fresh insights into the ontogeny of innate immunity in African children, and may inform development of age-specific adjuvanted vaccine formulations important for global health. © 2011 Burl et al. Source

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