Ontogeny of Toll-Like and NOD-Like Receptor-Mediated Innate Immune Responses in Papua New Guinean Infants

Studies addressing the ontogeny of the innate immune system in early life have reported mainly on Toll-like receptor (TLR) responses in infants living in high-income countries, with little or even no information on other pattern recognition receptors or on early life innate immune responses in children living under very different environmental conditions in less-developed parts of the world. In this study, we describe whole blood innate immune responses to both Toll-like and nucleotide-binding oligomerization domain (NOD)-like receptor agonists including the widely used vaccine adjuvant ‘alum’ in a group of Papua New Guinean infants aged 1–3 (n = 18), 4–6 (n = 18), 7–12 (n = 21) and 13–18 (n = 10) months old. Depending on the ligands and cytokines studied, different age-related patterns were found: alum-induced IL-1β and CXCL8 responses were found to significantly decline with increasing age; inflammatory (IL-6, IL-1β, IFN-γ) responses to TLR2 and TLR3 agonists increased; and IL-10 responses remained constant or increased during infancy, while TNF-α responses either declined or remained the same. We report for the first time that whole blood innate immune responses to the vaccine adjuvant alum decrease with age in infancy; a finding that may imply that the adjuvant effect of alum in pediatric vaccines could be age-related. Our findings further suggest that patterns of innate immune development may vary between geographically diverse populations, which in line with the ‘hygiene hypothesis’ particularly involves persistence of innate IL-10 responses in populations experiencing higher infectious pressure

Safety and Immunogenicity of Neonatal Pneumococcal Conjugate Vaccination in Papua New Guinean Children: A Randomised Controlled Trial

Background: Approximately 826,000 children, mostly young infants, die annually from invasive pneumococcal disease. A 6-10-14-week schedule of pneumococcal conjugate vaccine (PCV) is efficacious but neonatal PCV may provide earlier protection and better coverage. We conducted an open randomized controlled trial in Papua New Guinea to compare safety, immunogenicity and priming for memory of 7-valent PCV (PCV7) given in a 0-1-2-month (neonatal) schedule with that of the routine 1-2-3-month (infant) schedule. Methods: We randomized 318 infants at birth to receive PCV7 in the neonatal or infant schedule or no PCV7. All infants received 23-valent pneumococcal polysaccharide vaccine (PPV) at age 9 months. Serotype-specific serum IgG for PCV7 (VT) serotypes and non-VT serotypes 2, 5 and 7F were measured at birth and 2, 3, 4, 9, 10 and 18 months of age. Primary outcomes were geometric mean concentrations (GMCs) and proportions with concentration ≥0.35 µg/ml of VT serotype-specific pneumococcal IgG at age 2 months and one month post-PPV.Results: We enrolled 101, 105 and 106 infants, respectively, into neonatal, infant and control groups. Despite high background levels of maternally derived antibody, both PCV7 groups had higher GMCs than controls at age 2 months for serotypes 4 (p<0.001) and 9V (p<0.05) and at age 3 months for all VTs except 6B. GMCs for serotypes 4, 9V, 18C and 19F were significantly higher (p<0.001) at age 2 months in the neonatal (one month post-dose2 PCV7) than in the infant group (one month post-dose1 PCV7). PPV induced significantly higher VT antibody responses in PCV7-primed than unprimed infants, with neonatal and infant groups equivalent. High VT and non-VT antibody concentrations generally persisted to age 18 months. Conclusions: PCV7 is well-tolerated and immunogenic in PNG neonates and young infants and induces immunologic memory to PPV booster at age 9 months with antibody levels maintained to age 18 months

Preparing for Life: Plasma Proteome Changes and Immune System Development During the First Week of Human Life.

Neonates have heightened susceptibility to infections. The biological mechanisms are incompletely understood but thought to be related to age-specific adaptations in immunity due to resource constraints during immune system development and growth. We present here an extended analysis of our proteomics study of peripheral blood-plasma from a study of healthy full-term newborns delivered vaginally, collected at the day of birth and on day of life (DOL) 1, 3, or 7, to cover the first week of life. The plasma proteome was characterized by LC-MS using our established 96-well plate format plasma proteomics platform. We found increasing acute phase proteins and a reduction of respective inhibitors on DOL1. Focusing on the complement system, we found increased plasma concentrations of all major components of the classical complement pathway and the membrane attack complex (MAC) from birth onward, except C7 which seems to have near adult levels at birth. In contrast, components of the lectin and alternative complement pathways mainly decreased. A comparison to whole blood messenger RNA (mRNA) levels enabled characterization of mRNA and protein levels in parallel, and for 23 of the 30 monitored complement proteins, the whole blood transcript information by itself was not reflective of the plasma protein levels or dynamics during the first week of life. Analysis of immunoglobulin (Ig) mRNA and protein levels revealed that IgM levels and synthesis increased, while the plasma concentrations of maternally transferred IgG1-4 decreased in accordance with their in vivo half-lives. The neonatal plasma ratio of IgG1 to IgG2-4 was increased compared to adult values, demonstrating a highly efficient IgG1 transplacental transfer process. Partial compensation for maternal IgG degradation was achieved by endogenous synthesis of the IgG1 subtype which increased with DOL. The findings were validated in a geographically distinct cohort, demonstrating a consistent developmental trajectory of the newborn's immune system over the first week of human life across continents. Our findings indicate that the classical complement pathway is central for newborn immunity and our approach to characterize the plasma proteome in parallel with the transcriptome will provide crucial insight in immune ontogeny and inform new approaches to prevent and treat diseases

Epidemiology of Concomitant Infection Due to Loa loa and Mansonella perstans in Gabon

Loa loa and Mansonella perstans are blood filarial parasites, endemic in the central and western African forest block, and transmitted by chrysops and culicoides flies, respectively. Loa loa is pathogenic and represents a major obstacle to the control of co-endemic filariae. Treatment of individuals with >8000 Loa loa microfilariae/ml can result in severe adverse reactions. M. perstans is prevalent in the tropics, with undefined clinical symptoms. We screened 4392 individuals for these infections in 212 Gabonese villages. The overall prevalence rates were 22.4% for Loa loa microfilariae, 10.2% for M. perstans, and 3.2% for mixed infection. These rates varied across the different ecosystems: forest, savannah, Lakeland, river (Ogouée), and equator. A correlation was found between the prevalence and intensity of microfilariae, while a negative relationship was found between clinical symptoms (pruritis, Calabar swelling) and the prevalence of Loa loa microfilaremia. This study confirms the spatial uniformity of the relationship between parasitological indices, and provides a map and baseline data for implementation of mass chemotherapy for these infections

Selection for Genetic Variation Inducing Pro-Inflammatory Responses under Adverse Environmental Conditions in a Ghanaian Population

BACKGROUND:Chronic inflammation is involved in the pathogenesis of chronic age-associated, degenerative diseases. Pro-inflammatory host responses that are deleterious later in life may originate from evolutionary selection for genetic variation mediating resistance to infectious diseases under adverse environmental conditions. METHODOLOGY/PRINCIPAL FINDINGS:In the Upper-East region of Ghana where infection has remained the leading cause of death, we studied the effect on survival of genetic variations at the IL10 gene locus that have been associated with chronic diseases. Here we show that an IL10 haplotype that associated with a pro-inflammatory innate immune response, characterised by low IL-10 (p = 0.028) and high TNF-alpha levels (p = 1.39 x 10(-3)), was enriched among Ghanaian elders (p = 2.46 x 10(-6)). Furthermore, in an environment where the source of drinking water (wells/rivers vs. boreholes) influences mortality risks (HR 1.28, 95% CI [1.09-1.50]), we observed that carriers of the pro-inflammatory haplotype have a survival advantage when drinking from wells/rivers but a disadvantage when drinking from boreholes (p(interaction) = 0.013). Resequencing the IL10 gene region did not uncover any additional common variants in the pro-inflammatory haplotype to those SNPs that were initially genotyped. CONCLUSIONS/SIGNIFICANCE:Altogether, these data lend strong arguments for the selection of pro-inflammatory host responses to overcome fatal infection and promote survival in adverse environments

Host Determinants of Reinfection with Schistosomes in Humans: A Systematic Review and Meta-analysis

Background: Schistosomiasis is still a major public health burden in the tropics and subtropics. Although there is an effective chemotherapy (Praziquantel) for this disease, reinfection occurs rapidly after mass drug administration (MDA). Because the entire population do not get reinfected at the same rate, it is possible that host factors may play a dominant role in determining resistance or susceptibility to reinfection with schistosomes. Here, we systematically reviewed and meta-analyzed studies that reported associations between reinfection with the principal human-infecting species (S. mansoni, S. japonicum and S. haematobium) and host socio-demographic, epidemiological, immunological and genetic factors.Methodology/Principal Findings: PubMed, Scopus, Google Scholar, Cochrane Review Library and African Journals Online public databases were searched in October 2013 to retrieve studies assessing association of host factors with reinfection with schistosomes. Meta-analysis was performed to generate pooled odds ratios and standardized mean differences as overall effect estimates for dichotomous and continuous variables, respectively. Quality assessment of included studies, heterogeneity between studies and publication bias were also assessed. Out of the initial 2739 records, 109 studies were included in the analyses, of which only 32 studies with 37 data sets were eligible for quantitative data synthesis. Among several host factors identified, strong positive association was found with age and pre-treatment intensity, and only slightly for gender. These factors are major determinants of exposure and disease transmission. Significant positive association was found with anti-SWA IgG4 level, and a negative overall effect for association with IgE levels. This reconfirmed the concept that IgE/IgG4 balance is a major determinant of protective immunity against schistosomiasis. Other identified determinants were reported by a small number of studies to enable interpretation.Conclusions: Our data contribute to the understanding of host-parasite interaction as it affects reinfection, and is a potential tool to guide planning and tailoring of community interventions to target high-risk groups

A genomics-based approach to assessment of vaccine safety and immunogenicity in children

Immune responses to vaccines in infants and young children are typically Th2-biased, giving rise to concerns regarding potential atopy-like side effects, and antagonism of Th1-associated sterilising immunity. Conventional immunological methodology has limited capacity to effectively address these problems because of the inherent complexity of the immune responses involved. In the present study, we sought to develop an unbiased systems biology approach to elucidate superficially similar Th2-associated responses to paediatric vaccines and allergens, and to differentiate between them via gene coexpression network analysis. We demonstrate below that in immune responses to the diptheria/acellular pertussis/tetanus and pneumococcal polysaccharide conjugate vaccines, potentially antagonistic Th1-/IFN-associated and Th2-associated gene networks coexist in an apparent state of dynamic equilibrium, whereas in Th2-dominant allergen-specific responses of atopics the Th1 and IFN networks are respectively disrupted and downregulated. Capacity to detect and interpret these covert differences between responses to vaccines and allergens relies on the use of sophisticated algorithms that underpin coexpression network analysis, which identify genes that function co-ordinately in complex pathways. This methodology has significant potential to identify covert interactions between inflammatory pathways triggered by vaccination, and as such may be a useful tool in prediction of vaccinesafety/efficacy

An unopposed proinflammatory response is beneficial for survival in the oldest old. Results of the Leiden 85-plus study

The capacity to generate an efficient innate immune response is pivotal for survival. The objective of this study was to investigate innate immune function in relation to long-term survival in the oldest old. We measured ex vivo lipopolysaccharide-induced proinflammatory and antiinflammatory cytokine responses in 562 participants aged 85 years of the general population who were followed for mortality during 10 years. Compared with participants with a high proinflammatory and antiinflammatory response profile, 85 year olds with an overall low proinflammatory and antiinflammatory response had a significant higher mortality risk (hazard ratio: 1.79, 95% confidence interval: 1.29-2.50), whereas participants with a high proinflammatory and low antiinflammatory response had a survival benefit (hazard ratio: 0.74, 95% confidence interval: 0.57-0.97). This benefit was even more pronounced in survivors past 90 years of age (hazard ratio: 0.50, 95% confidence interval: 0.26-0.96). In old age, the capacity to generate an unopposed proinflammatory innate immune response is predictive of long-term survival

Maternal Antibodies to Pneumolysin but Not to Pneumococcal Surface Protein A Delay Early Pneumococcal Carriage in High-Risk Papua New Guinean Infants▿

Immunization of pregnant women can be an efficient strategy to induce early protection in infants in developing countries. Pneumococcal protein-based vaccines may have the capacity to induce pneumococcal serotype-independent protection. To understand the potential of maternal pneumococcal protein-specific antibodies in infants in high-risk areas, we studied the placental transfer of naturally acquired antibodies to pneumolysin (Ply) and pneumococcal surface protein A family 1 and 2 (PspA1 and PspA2) in relation to onset of pneumococcal nasopharyngeal carriage in infants in Papua New Guinea (PNG). In this study, 76% of the infants carried Streptococcus pneumoniae in the upper respiratory tract within the first month of life, at a median age of 19 days. Maternal and cord blood antibody titers to Ply (ρ = 0.824, P < 0.001), PspA1 (ρ = 0.746, P < 0.001), and PspA2 (ρ = 0.631, P < 0.001) were strongly correlated. Maternal pneumococcal carriage (hazard ratio [HR], 2.60; 95% confidence interval [CI], 1.25 to 5.39) and younger maternal age (HR, 0.74; 95% CI, 0.54 to 1.00) were independent risk factors for early carriage, while higher cord Ply-specific antibody titers predicted a significantly delayed onset (HR, 0.71; 95% CI, 0.52 to 1.00) and cord PspA1-specific antibodies a significantly younger onset of carriage in PNG infants (HR, 1.57; 95% CI, 1.03 to 2.40). Maternal vaccination with a pneumococcal protein-based vaccine should be considered as a strategy to protect high-risk infants against pneumococcal disease by reducing carriage risks in both mothers and infants

Alum-induced chemokine production with increasing age in infancy.

<p>Whole blood samples from PNG infants aged 1–3 months (n = 10, <i>white bars</i>), 4–6 months (n = 9, <i>light grey bars</i>), 7–12 months (n = 10, <i>dark grey bars</i>) or 13–18 months (n = 9, <i>black bars</i>) were stimulated with Alum. Presented are the geometric means and 95% confidence intervals (pg/mL) for each age group for background-adjusted chemokine responses. Significance level is indicated where p<0.10.</p