Anne Balloch

Hyporesponsiveness to re-challenge dose following pneumococcal polysaccharide vaccine at 12 months of age, a randomized controlled trial.

BACKGROUND To evaluate the immunological impact of the 23-valent pneumococcal polysaccharide vaccine (23vPPS) at 12 months, for children who have received zero to three infant doses of seven-valent pneumococcal conjugate vaccine (PCV), on responses to a subsequent exposure to a small dose of 23vPPS (mPPS). METHODS Five hundred and fifty-two Fijian infants were stratified by ethnicity and randomized into eight groups to receive zero, one, two, or three PCV doses at 14 weeks, six and 14 weeks, or six, ten, and 14 weeks. Within each group, half received 23vPPS at 12 months and all received mPPS at 17 months. Sera were taken prior and one month post-mPPS. FINDINGS By 17 months, geometric mean antibody concentrations (GMC) to all 23 serotypes in 23vPPS were significantly higher in children who had received 23vPPS at 12 months compared to those who had not. Post-mPPS, children who had not received the 12 month 23vPPS had a significantly higher GMC for all PCV serotypes compared with those who had (each p<0.02). For the non-PCV serotypes, children who had not received the 12 month 23vPPS had significantly higher GMC for six of 16 non-PCV serotypes (7F, 9N, 12F, 19A, 22F, 33F) than those who did (each p<0.02). After adjusting for the pre-mPPS level, exposure to 23vPPS was associated with a lower response to mPPS for all serotypes (each p<0.001). INTERPRETATION Despite higher antibody concentrations at 17 months in children who had received 23vPPS at 12 months, the response to a re-challenge was poor for all 23 serotypes compared to children who had not received the 12 month 23vPPS.

The clinical syndrome of specific antibody deficiency in children

Specific antibody deficiency (SAD) is an immune deficiency which has been reported in adults and children with recurrent respiratory tract infections; however, the clinical features of SAD are not well described. This study evaluated formally the clinical syndrome of SAD, by comparing the clinical features of children with SAD and those of children with recurrent infection but normal immune function tests. SAD was defined as an adequate IgG antibody response to less than 50% of 12 pneumococcal serotypes tested following 23‐valent unconjugated pneumococcal immunization. An adequate IgG antibody response was defined as a post‐immunization titre of ≥ 1·3 µg/ml or ≥ four times the preimmunization value. Seventy‐four children with recurrent infection were evaluated where immune deficiencies other than SAD had been excluded. Eleven (14·9%) of these children had SAD. Clinical features differed between the group with SAD and the group with normal antibody responses. A history of otitis media, particularly in association with chronic otorrhoea was associated with SAD [relative risk (RR) of SAD in those with chronic otorrhoea 4·64 (P = 0·02)]. SAD was associated with allergic disease, particularly allergic rhinitis [RR of SAD in those with allergic rhinitis 3·77 (P = 0·04)]. These two clinical associations of SAD were independent in this study [RR of chronic otorrhoea in those with allergic rhinitis 0·85 (P = 0·28)]. SAD was not an age‐related phenomenon in this population. SAD has a distinct clinical phenotype, presenting as recurrent infection associated with chronic otorrhoea and/or allergic disease, and the condition should be sought in children with these features.

Immunogenicity following one, two, or three doses of the 7-valent pneumococcal conjugate vaccine.

The aim was to identify an appropriate infant pneumococcal vaccination strategy for resource poor countries. Fijian infants received zero, one, two, or three doses of 7-valent pneumococcal conjugate vaccine (PCV) in early infancy. Following three PCV doses, geometric mean concentration (GMC) to all seven serotypes were > or = 1.0 microg/mL, and >85% of children achieved antibody levels > or = 0.35 microg/mL at 18 weeks. Following two doses, GMC were lower for 6B, 14, and 23F, but higher for 19F compared with three doses. Following a single dose, significant responses were seen for all serotypes post-primary series compared with the unvaccinated. By 12 months, differences between two and three doses persisted for serotype 14 only. Although GMC following three doses are higher than after two doses, the differences were small. A single dose may offer some protection for most serotypes.

Non-specific effect of Bacille Calmette-Guérin vaccine on the immune response to routine immunisations

Bacille Calmette-Guérin (BCG) is one of the most commonly administered vaccines worldwide. In addition to protection against tuberculosis (TB), evidence suggests that BCG immunisation has a number of additional beneficial non-specific immunological effects. These include a reduction in overall infant and child mortality attributable to causes other than TB in high-mortality regions. The antibody response to immunisations provides an opportunity to investigate the influence of BCG on the immune response to unrelated antigens. This study compared the antibody response to routine immunisations in BCG-immunised and non-BCG-immunised infants. BCG-immunised infants were recruited from a related study in which BCG was given at birth and non-BCG-immunised infants were recruited from immunisation clinics. All infants received their routine immunisations according to the Australian National Immunisation Program. Concentrations of antibodies against pneumococcal (anti-Pn Ps), Haemophilus influenzae type B (anti-Hib), tetanus toxoid (anti-TT) and hepatitis B surface (anti-HBs) antigen were measured four weeks after the last (six month) set of infant immunisations. A total of 127 parents agreed for their infants to take part in the study of which 108 were included in the final analysis (56 BCG-immunised and 52 non-BCG-immunised). The geometric mean concentration (GMC) of anti-Pn Ps IgG for all serotypes, anti-Hib IgG and anti-TT IgG were higher in the BCG-immunised group than the non-BCG-immunised group. This difference reached statistical significance for serotype 9V (p<0.01) and 18C (p=0.04). The GMC of anti-HBs IgG was lower in the BCG-immunised group than the non-BCG-immunised group (p=0.03). The majority of participants in both groups had antibody levels above the protective threshold. BCG immunisation at birth influences the antibody response to routine immunisations administered later in infancy. This has important implications for the introduction of both pneumococcal conjugate and novel TB vaccines in resource-limited countries.

Infants aged 12 months can mount adequate serotype-specific IgG responses to pneumococcal polysaccharide vaccine

1 0.17 (0.13-0.22) 2.04 (1.49-2.80) <.0001 2 0.28 (0.23-0.35) 12.48 (9.66-16.12) <.0001 3 0.37 (0.26-0.53) 13.74 (10.55-17.91) <.0001 4 0.08 (0.06-0.10) 2.37 (1.76-3.20) <.0001 5 0.26 (0.20-0.34) 2.77 (2.15-3.57) <.0001 6B 0.14 (0.12-0.17) 0.31 (0.23-0.42) <.05 7F 0.10 (0.08-0.14) 2.58 (1.98-3.37) <.0001 8 0.26 (0.20-0.32) 13.59 (10.72-17.23) <.0001 9N 0.12 (0.09-0.15) 3.06 (2.18-4.30) <.0001 9V 0.09 (0.07-0.12) 1.21 (0.90-1.62) <.0001 10A 0.20 (0.16-0.24) 0.87 (0.65-1.17) <.0001 11A 0.10 (0.08-0.13) 2.21 (1.58-3.08) <.0001 12F 0.06 (0.05-0.08) 0.39 (0.28-0.54) <.0001 14 0.20 (0.16-0.25) 0.41 (0.29-0.59) NS 15B 0.17 (0.14-0.22) 0.79 (0.59-1.05) <.0001 17F 0.11 (0.09-0.13) 1.39 (0.98-1.97) <.0001 18C 0.07 (0.05-0.08) 1.23 (0.88-1.72) <.0001 19A 0.29 (0.24-0.36) 0.79 (0.55-1.12) <.05 19F 0.47 (0.36-0.62) 1.15 (0.81-1.62) NS 20 0.10 (0.08-0.12) 0.90 (0.61-1.34) <.0001 22F 0.36 (0.29-0.46) 5.23 (3.47-7.88) <.0001 23F 0.19 (0.15-0.25) 0.42 (0.30-0.57) NS 33F 0.14 (0.11-0.17) 2.01 (1.44-2.80) <.0001

Safety and immunogenicity of the 23-valent pneumococcal polysaccharide vaccine at 12 months of age, following one, two, or three doses of the 7-valent pneumococcal conjugate vaccine in infancy.

Fijian infants aged 6 weeks were stratified by ethnicity and randomized to receive 0, 1, 2, or 3 PCV-7 doses with or without the 23-valent pneumococcal polysaccharide vaccine (PPV-23) at 12 months. Strong booster effects for all 7 PCV-7 serotypes were elicited, and for 4/7 serotypes these responses were highest in the single PCV-7 group. There were fourfold rises in GMC for all non-PCV-7 serotypes. By 17 months the PPV-23 group still had significantly higher GMC (each p<0.001) for all serotypes. The PPV-23 was well tolerated and induced excellent responses for all serotypes which were greatest in the single PCV-7 group.

Pneumococcal polysaccharide vaccine at 12 months of age produces functional immune responses

BACKGROUND Infections with Streptococcus pneumoniae (pneumococcus) are a cause of significant child mortality. Pneumococcal glycoconjugate vaccines are expensive and provide limited serotype coverage. The 23-valent pneumococcal polysaccharide vaccine (Pneumovax) might provide wider serotype coverage but is reported to be weakly immunogenic in children less than 2 years of age. We have previously reported that Pneumovax administered to healthy 12-month-old Fijian infants elicits significant serotype-specific IgG responses. However, the functional capacity of these responses in 12-month-old infants is not known. OBJECTIVE We sought to assess the functional, serotype-specific immune response of 12-month-old infants after immunization with Pneumovax. METHODS Functional responses of 12-month-old infants were assessed by using the opsonophagocytic and antibody avidity assay against 8 serotypes and 23 serotypes, respectively. RESULTS Seventy-one percent of infants produced strong opsonophagocytic activity against 4 of 8 serotypes, and 30% produced high-avidity serotype-specific IgG antibodies to 10 of 23 serotypes at 2 weeks after Pneumovax. Responses were protective for most serotypes that cause disease in Western countries, whereas responses to most of the epidemiologically relevant serotypes for developing countries were low. CONCLUSION This is the first comprehensive study evaluating the functional antibody response to Pneumovax in 12-month-old infants. Pneumovax induced functional antibody responses to several serotypes causing disease in Western countries but induced poorer responses to serotypes that are responsible for the majority of disease in developing countries. Pneumovax might be of benefit in some populations, but further studies are required before this can be recommended in developing countries.

Opsonophagocytic activity following a reduced dose 7-valent pneumococcal conjugate vaccine infant primary series and 23-valent pneumococcal polysaccharide vaccine at 12 months of age

Opsonophagocytic activity (OPA) was measured following reduced infant doses of 7-valent pneumococcal conjugate vaccine (PCV-7) with or without 23-valent pneumococcal polysaccharide vaccine (PPV-23) at 12 months, and subsequent re-exposure to a small dose of pneumococcal polysaccharide antigens (mPPS) at 17 months. Fijian infants were randomized to receive 0, 1, 2, or 3 PCV-7 doses. Half received PPV-23 at 12 months and all received mPPS at 17 months. OPA was performed on up to 14 serotypes. Three and 2 PCV-7 doses resulted in similar OPA for most PCV-7 serotypes up to 9 months and for half of the serotypes at 12 months. A single dose improved OPA compared with the unvaccinated group. PPV-23 significantly improved OPA for all serotypes tested but in general, was associated with diminished responses following re-challenge.

Results from an inter-laboratory comparison of pneumococcal serotype-specific IgG measurement and critical parameters that affect assay performance

Quantitation of specific IgG to polysaccharides (serotypes) of Streptococcus pneumoniae provides the basis for evaluating vaccine efficacy. Different enzyme-linked immunosorbent assay (ELISA) methods are used internationally, making comparisons between laboratories difficult. We undertook an inter-laboratory comparison between two international laboratories performing serotype-specific IgG ELISAs using a panel of well-characterized serum samples: the Murdoch Childrens Research Institute Pneumococcal Laboratory (Melbourne, Australia) and the Vaccine Immunology Laboratory, National Public Health Institute (Helsinki, Finland). While good agreement was found for the inter-laboratory comparison for most serotypes, differences in ELISA methodology influenced specific IgG measurement. Therefore, use of the World Health Organization (WHO)-based ELISA methods for measurement of serotype-specific IgG is reliable, accurate and provides consistent results between international laboratories.

Anti-Inflammatory Effects of Vitamin D on Human Immune Cells in the Context of Bacterial Infection

Vitamin D induces a diverse range of biological effects, including important functions in bone health, calcium homeostasis and, more recently, on immune function. The role of vitamin D during infection is of particular interest given data from epidemiological studies suggesting that vitamin D deficiency is associated with an increased risk of infection. Vitamin D has diverse immunomodulatory functions, although its role during bacterial infection remains unclear. In this study, we examined the effects of 1,25(OH)2D3, the active metabolite of vitamin D, on peripheral blood mononuclear cells (PBMCs) and purified immune cell subsets isolated from healthy adults following stimulation with the bacterial ligands heat-killed pneumococcal serotype 19F (HK19F) and lipopolysaccharide (LPS). We found that 1,25(OH)2D3 significantly reduced pro-inflammatory cytokines TNF-α, IFN-γ, and IL-1β as well as the chemokine IL-8 for both ligands (three- to 53-fold), while anti-inflammatory IL-10 was increased (two-fold, p = 0.016) in HK19F-stimulated monocytes. Levels of HK19F-specific IFN-γ were significantly higher (11.7-fold, p = 0.038) in vitamin D-insufficient adults (<50 nmol/L) compared to sufficient adults (>50 nmol/L). Vitamin D also shifted the pro-inflammatory/anti-inflammatory balance towards an anti-inflammatory phenotype and increased the CD14 expression on monocytes (p = 0.008) in response to LPS but not HK19F stimulation. These results suggest that 1,25(OH)2D3 may be an important regulator of the inflammatory response and supports further in vivo and clinical studies to confirm the potential benefits of vitamin D in this context.