Tessa Goetghebuer

Neonatal bacillus Calmette-Guérin vaccination induces adult-like IFN-gamma production by CD4+ T lymphocytes

The immaturity of the neonatal immune system in mice is associated with defective IFN‐γ production and Th2‐biased immune responses. In this study, infants vaccinated at birth with BCG produced similar concentrations of IFN‐γ in response to PPD and showed similar frequencies of IFN‐γ‐producing lymphocytes as compared to immune adults. Infants and adults produced only low concentrations of IL‐4 and IL‐5. CD4+ T lymphocytes were the main source of IFN‐γ. Similar proportions of Th1 and Th0 PPD‐specific T cell clones were observed in infants and adults. This study demonstrates that the human neonatal immune response to BCG is not biased towards Th2 and is characterized by the predominant production of IFN‐γ by CD4+ T lymphocytes.

Genetic regulation of immune responses to vaccines in early life

Infant immunization is the most cost-effective strategy to prevent infectious diseases in childhood, but is limited by immaturity of the immune system. To define strategies to improve vaccine immunogenicity in early life, the role of genetic and environmental factors in the control of vaccine responses in infant twins was studied. Immune responses to BCG, polio, hepatitis B, diphtheria, pertussis and tetanus vaccines were measured at 5 months of age in 207 Gambian twin pairs recruited at birth. Intrapair correlations for monozygous and dizygous pairs were compared to estimate the environmental and genetic components of variation in responses. High heritability was observed for antibody (Ab) responses to hepatitis B (77%), oral polio (60%), tetanus (44%) and diphtheria (49%) vaccines. Significant heritability was also observed for interferon-γ and interleukin-13 responses to tetanus, pertussis and some BCG vaccine antigens (39–65%). Non-HLA genes played a dominant role in responses to Ab-inducing vaccines, whereas responses to BCG were predominantly controlled by genes within the HLA class II locus. Genetic factors, particularly non-HLA genes, significantly modulate immune responses to infant vaccination. The identification of the specific genes involved will provide new targets for the development of vaccines and adjuvants for young infants that work independently of HLA.

Outcome of meningitis caused by Streptococcus pneumoniae and Haemophilus influenzae type b in children in The Gambia

Summary In developing countries, endemic childhood meningitis is a severe disease caused most commonly by Streptococcus pneumoniae or Haemophilus influenzae type b (Hib). Although many studies have shown that fatality rates associated with meningitis caused by these organisms are high in developing countries, little is known about the long‐term outcome of survivors. The purpose of this study was to assess the importance of disabilities following pneumococcal and Hib meningitis in The Gambia. 257 children aged 0–12 years hospitalized between 1990 and 1995 with culture‐proven S. pneumoniae (n = 134) or Hib (n = 123) meningitis were included retrospectively in the study. 48% of children with pneumococcal meningitis and 27% of children with Hib meningitis died whilst in hospital. Of the 160 survivors, 89 (55%) were followed up between September 1996 and October 1997. Of the children with pneumococcal meningitis that were traced, 58% had clinical sequelae; half of them had major disabilities preventing normal adaptation to social life. 38% of survivors of Hib meningitis had clinical sequelae, a quarter of whom had major disabilities. Major handicaps found were hearing loss, mental retardation, motor abnormalities and seizures. These data show that despite treatment with effective antibiotics, pneumococcal and Hib meningitis kill many Gambian children and leave many survivors with severe sequelae. Hib vaccination is now given routinely in The Gambia; an effective pneumococcal vaccine is needed.

Predominant influence of environmental determinants on the persistence and avidity maturation of antibody responses to vaccines in infants.

BACKGROUND Immune responses are complex traits influenced by genetic and environmental factors. We previously reported that genetic factors control early antibody responses to vaccines in Gambian infants. For the present study, we evaluated the determinants of the memory phase of immunoglobulin G (IgG) responses. METHODS Antibody responses to tetanus toxoid (TT), measles vaccines, and environmental antigens (total IgG levels) were measured in 210 Gambian twin pairs recruited at birth. Intrapair correlations for monozygous and dizygous pairs were compared to estimate the environmental and genetic components of variations in response. RESULTS In contrast to antibody responses measured in infants at age 5 months, 1 month after immunization, no significant contribution of genetic factors to anti-TT antibody and total IgG levels was detected at age 12 months. Genetic factors controlled measles antibody responses in 12-month-old infants, which indicates that the increasing influence of environmental determinants on anti-TT responses was not related to the older age of the children but, rather, to the time elapsed since immunization. Environmental factors also predominantly controlled affinity maturation and the production of high-avidity antibodies to TT. CONCLUSIONS Genetic determinants control the early phase of the vaccine antibody response in Gambian infants, whereas environmental determinants predominantly influence antibody persistence and avidity maturation.

Delay in motor development of twins in Africa: a prospective cohort study.

Twins are prone to developmental delay due to prematurity and low birthweight. However it is unknown if twinning is an independent risk factor for developmental delay. The objective of this study was to compare the attainment of a set of gross motor milestones in a cohort of twins and singletons in The Gambia. Eighty-four pairs of twins and 72 singletons were enrolled at birth and followed up until 18 months of age. The mean age at achieving milestones was higher in twins for each development outcome and the difference between twins and singletons was significant after adjustment for confounders for maintaining head, sitting without support and walking. In twins, we found a highly significant correlation within pairs for most milestones. When monozygotic and dizygotic twins were compared, a significant heritability was observed for crawling, sitting, standing and walking, with over 90% of population variance observed due to genetic factors rather than environmental factors. There was little evidence for a genetic contribution towards very early milestones. In conclusion, our data suggest that twinning is an independent risk factor for developmental delay in early life in The Gambia, and that genetic factors contribute strongly to certain motor development outcomes.

Hunting for immune response regulatory genes: vaccination studies in infant twins

The contribution of twin studies towards unraveling the complex mechanisms of multifactorial diseases is increasingly recognized. Recent twin studies using infant vaccination as a model for infectious diseases have confirmed the importance of host genetic factors as major regulators of the immune response. A combination of twin-based family studies and population-based association studies should lead to the identification of the specific genes involved. These genes and their products have the potential to be developed as targets for novel therapeutic and prophylactic agents against infectious diseases.

Calendar Time Trends in the Incidence and Prevalence of Triple-Class Virologic Failure in Antiretroviral Drug-Experienced People With HIV in Europe

Background: Despite the increasing success of antiretroviral therapy (ART), virologic failure of the 3 original classes [triple-class virologic failure, (TCVF)] still develops in a small minority of patients who started therapy in the triple combination ART era. Trends in the incidence and prevalence of TCVF over calendar time have not been fully characterised in recent years. Methods: Calendar time trends in the incidence and prevalence of TCVF from 2000 to 2009 were assessed in patients who started ART from January 1, 1998, and were followed within the Collaboration of Observational HIV Epidemiological Research Europe (COHERE). Results: Of 91,764 patients followed for a median (interquartile range) of 4.1 (2.0–7.1) years, 2722 (3.0%) developed TCVF. The incidence of TCVF increased from 3.9 per 1000 person-years of follow-up [95% confidence interval (CI): 3.7 to 4.1] in 2000 to 8.8 per 1000 person-years of follow-up (95% CI: 8.5 to 9.0) in 2005, but then declined to 5.8 per 1000 person-years of follow-up (95% CI: 5.6 to 6.1) by 2009. The prevalence of TCVF was 0.3% (95% CI: 0.27% to 0.42%) at December 31, 2000, and then increased to 2.4% (95% CI: 2.24% to 2.50%) by the end of 2005. However, since 2005, TCVF prevalence seems to have stabilized and has remained below 3%. Conclusions: The prevalence of TCVF in people who started ART after 1998 has stabilized since around 2005, which most likely results from the decline in incidence of TCVF from this date. The introduction of improved regimens and better overall HIV care is likely to have contributed to these trends. Despite this progress, calendar trends should continue to be monitored in the long term.

Predictors of CD4+ T-Cell Counts of HIV Type 1–Infected Persons After Virologic Failure of All 3 Original Antiretroviral Drug Classes

BACKGROUND Low CD4(+) T-cell counts are the main factor leading to clinical progression in human immunodeficiency virus type 1 (HIV-1) infection. We aimed to investigate factors affecting CD4(+) T-cell counts after triple-class virological failure. METHODS We included individuals from the COHERE database who started antiretroviral therapy from 1998 onward and who experienced triple-class virological failure. CD4(+) T-cell counts obtained after triple-class virologic failure were analyzed using generalized estimating equations. RESULTS The analyses included 2424 individuals with a total of 23 922 CD4(+) T-cell count measurements. In adjusted models (excluding current viral load and year), CD4(+) T-cell counts were higher with regimens that included boosted protease inhibitors (increase, 22 cells/µL [95% confidence interval {CI}, 3.9-41]; P = .017) or drugs from the new classes (increase, 39 cells/µL [95% CI, 15-62]; P = .001), compared with nonnucleoside reverse-transcriptase inhibitor-based regimens. These associations disappeared when current viral load and/or calendar year were included. Compared with viral levels of <2.5 log(10) copies/mL, levels of 2.5-3.5, 3.5-4.5, 4.5-5.5, and >5.5 log(10) copies/mL were associated with CD4(+) T-cell count decreases of 51, 84, 137, and 186 cells/µL, respectively (P < .001). CONCLUSIONS The approximately linear inverse relationship between log(10) viral load and CD4(+) T-cell count indicates that there are likely immunologic benefits from lowering viral load even by modest amounts that do not lead to undetectable viral loads. This is important for patients with low CD4(+) T-cell counts and few drug options.