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1.  Effect of single-dose anthelmintic treatment during pregnancy on an infant's response to immunisation and on susceptibility to infectious diseases in infancy: a randomised, double-blind, placebo-controlled trial 
Lancet  2011;377(9759):52-62.
Summary
Background
Helminth infections affect the human immune response. We investigated whether prenatal exposure to and treatment of maternal helminth infections affects development of an infant's immune response to immunisations and unrelated infections.
Methods
In this randomised, double-blind, placebo-controlled trial, we enrolled 2507 women in the second or third trimester of pregnancy who were planning to deliver in Entebbe General Hospital, Entebbe, Uganda. With a computer-generated random number sequence in blocks of 100, we assigned patients to 440 mg albendazole and 40 mg/kg praziquantel (n=628), 440 mg albendazole and a praziquantel-matching placebo (n=625), 40 mg/kg praziquantel and an albendazole-matching placebo (n=626), or an albendazole-matching placebo and praziquantel-matching placebo (n=628). All participants and hospital staff were masked to allocation. Primary outcomes were immune response at age 1 year to BCG, tetanus, and measles immunisation; incidence of infectious diseases during infancy; and vertical HIV transmission. Analysis was by intention-to-treat. This trial is registered, number ISRCTN32849447.
Findings
Data were available at delivery for 2356 women, with 2345 livebirths; 2115 (90%) of liveborn infants remained in follow-up at 1 year of age. Neither albendazole nor praziquantel treatments affected infant response to BCG, tetanus, or measles immunisation. However, in infants of mothers with hookworm infection, albendazole treatment reduced interleukin-5 (geometric mean ratio 0·50, 95% CI 0·30–0·81, interaction p=0·02) and interleukin-13 (0·52, 0·34–0·82, 0·0005) response to tetanus toxoid. The rate per 100 person-years of malaria was 40·9 (95% CI 38·3–43·7), of diarrhoea was 134·1 (129·2–139·2), and of pneumonia was 22·3 (20·4–24·4). We noted no effect on infectious disease incidence for albendazole treatment (malaria [hazard ratio 0·95, 95% CI 0·79–1.14], diarrhoea [1·06, 0·96–1·16], pneumonia [1·11, 0·90–1·38]) or praziquantel treatment (malaria [1·00, 0·84–1·20], diarrhoea [1·07, 0·98–1·18], pneumonia [1·00, 0·80–1·24]). In HIV-exposed infants, 39 (18%) were infected at 6 weeks; vertical transmission was not associated with albendazole (odds ratio 0·70, 95% CI 0·35–1·42) or praziquantel (0·60, 0·29–1·23) treatment.
Interpretation
These results do not accord with the recently advocated policy of routine antenatal anthelmintic treatment, and the value of such a policy may need to be reviewed.
Funding
Wellcome Trust.
doi:10.1016/S0140-6736(10)61457-2
PMCID: PMC3018567  PMID: 21176950
2.  Factors affecting the infant antibody response to measles immunisation in Entebbe-Uganda 
BMC Public Health  2013;13:619.
Background
Vaccine failure is an important concern in the tropics with many contributing elements. Among them, it has been suggested that exposure to natural infections might contribute to vaccine failure and recurrent disease outbreaks. We tested this hypothesis by examining the influence of co-infections on maternal and infant measles-specific IgG levels.
Methods
We conducted an observational analysis using samples and data that had been collected during a larger randomised controlled trial, the Entebbe Mother and Baby Study (ISRCTN32849447). For the present study, 711 pregnant women and their offspring were considered. Helminth infections including hookworm, Schistosoma mansoni and Mansonella perstans, along with HIV, malaria, and other potential confounding factors were determined in mothers during pregnancy and in their infants at age one year. Infants received their measles immunisation at age nine months. Levels of total IgG against measles were measured in mothers during pregnancy and at delivery, as well as in cord blood and from infants at age one year.
Results
Among the 711 pregnant women studied, 66% had at least one helminth infection at enrolment, 41% had hookworm, 20% M. perstans and 19% S. mansoni. Asymptomatic malaria and HIV prevalence was 8% and 10% respectively. At enrolment, 96% of the women had measles-specific IgG levels considered protective (median 4274 mIU/ml (IQR 1784, 7767)). IgG levels in cord blood were positively correlated to maternal measles-specific IgG levels at delivery (r = 0.81, p < 0.0001). Among the infants at one year of age, median measles-specific IgG levels were markedly lower than in maternal and cord blood (median 370 mIU/ml (IQR 198, 656) p < 0.0001). In addition, only 75% of the infants had measles-specific IgG levels considered to be protective. In a multivariate regression analysis, factors associated with reduced measles-specific antibody levels in infancy were maternal malaria infection, infant malaria parasitaemia, infant HIV and infant wasting. There was no association with maternal helminth infection.
Conclusion
Malaria and HIV infection in mothers during pregnancy, and in their infants, along with infant malnutrition, may result in reduction of the antibody response to measles immunisation in infancy. This re-emphasises the importance of malaria and HIV control, and support for infant nutrition, as these interventions may have benefits for vaccine efficacy in tropical settings.
doi:10.1186/1471-2458-13-619
PMCID: PMC3733798  PMID: 23816281
Infections; Co-infections; Measles; Helminth; Malaria; HIV; Maternal; Infants; Pregnancy; Immunisation
3.  The influence of BCG vaccine strain on mycobacteria-specific and non-specific immune responses in a prospective cohort of infants in Uganda 
Vaccine  2012;30(12):2083-2089.
Highlights
► Largest study comparing BCG strains and first to assess strain effects on non-specific responses. ► Cytokine responses to both mycobacterial and non-mycobacterial stimuli are strain-dependent. ► BCG-Denmark causes higher cytokine levels and more scars and adverse events than two other strains. ► Sex may interact with the effect of strain; non-specific responses are not associated with scars. ► BCG strain choice may be important and should be evaluated in novel vaccine strategies using BCG.
Background
Globally, BCG vaccination varies in efficacy and has some non-specific protective effects. Previous studies comparing BCG strains have been small-scale, with few or no immunological outcomes and have compared TB-specific responses only. We aimed to evaluate both specific and non-specific immune responses to different strains of BCG within a large infant cohort and to evaluate further the relationship between BCG strain, scarring and cytokine responses.
Methods
Infants from the Entebbe Mother and Baby Study (ISRCTN32849447) who received BCG-Russia, BCG-Bulgaria or BCG-Denmark at birth, were analysed by BCG strain group. At one year, interferon-gamma (IFN-γ), interleukin (IL)-5, IL-13 and IL-10 responses to mycobacteria-specific antigens (crude culture filtrate proteins and antigen 85) and non-mycobacterial stimuli (tetanus toxoid and phytohaemagglutinin) were measured using ELISA. Cytokine responses, scar frequency, BCG associated adverse event frequency and mortality rates were compared across groups, with adjustments for potential confounders.
Results
Both specific and non-specific IFN-γ, IL-13 and IL-10 responses in 1341 infants differed between BCG strain groups including in response to stimulation with tetanus toxoid. BCG-Denmark immunised infants showed the highest cytokine responses. The proportion of infants who scarred differed significantly, with BCG scars occurring in 52.2%, 64.1% and 92.6% of infants immunised with BCG Russia, BCG-Bulgaria and BCG-Denmark, respectively (p < 0.001). Scarred infants had higher IFN-γ and IL-13 responses to mycobacterial antigens only than infants without a scar. The BCG-Denmark group had the highest frequency of adverse events (p = 0.025). Mortality differences were not significant.
Conclusions
Both specific and non-specific immune responses to the BCG vaccine differ by strain. Scarring after BCG vaccination is also strain-dependent and is associated with higher IFN-γ and IL-13 responses to mycobacterial antigens. The choice of BCG strain may be an important factor and should be evaluated when testing novel vaccine strategies that employ BCG in prime–boost sequences, or as a vector for other vaccine antigens.
doi:10.1016/j.vaccine.2012.01.053
PMCID: PMC3314967  PMID: 22300718
BCG; Strain; Immune response; Non-specific effects; BCG scar
4.  Factors associated with tuberculosis infection, and with anti-mycobacterial immune responses, among five year olds BCG-immunised at birth in Entebbe, Uganda 
Vaccine  2015;33(6):796-804.
Highlights
•Urban residence and history of TB contact/disease were associated with increased risk of latent TB infection at age five years.•BCG vaccine strain, LTBI, HIV and malaria infections, and anthropometry predict anti-mycobacterial immune responses.•Helminth infections do not influence response to BCG vaccination.•Cytokine responses at one year were not associated with LTBI at age five years.
Background
BCG is used widely as the sole licensed vaccine against tuberculosis, but it has variable efficacy and the reasons for this are still unclear. No reliable biomarkers to predict future protection against, or acquisition of, TB infection following immunisation have been identified. Lessons from BCG could be valuable in the development of effective tuberculosis vaccines.
Objectives
Within the Entebbe Mother and Baby Study birth cohort in Uganda, infants received BCG at birth. We investigated factors associated with latent tuberculosis infection (LTBI) and with cytokine response to mycobacterial antigen at age five years. We also investigated whether cytokine responses at one year were associated with LTBI at five years of age.
Methods
Blood samples from age one and five years were stimulated using crude culture filtrates of Mycobacterium tuberculosis in a six-day whole blood assay. IFN-γ, IL-5, IL-13 and IL-10 production was measured. LTBI at five years was determined using T-SPOT.TB® assay. Associations with LTBI at five years were assessed using multivariable logistic regression. Multiple linear regression with bootstrapping was used to determine factors associated with cytokine responses at age five years.
Results
LTBI prevalence was 9% at age five years. Only urban residence and history of TB contact/disease were positively associated with LTBI. BCG vaccine strain, LTBI, HIV infection, asymptomatic malaria, growth z-scores, childhood anthelminthic treatment and maternal BCG scar were associated with cytokine responses at age five. Cytokine responses at one year were not associated with acquisition of LTBI by five years of age.
Conclusion
Although multiple factors influenced anti-myocbacterial immune responses at age five, factors likely to be associated with exposure to infectious cases (history of household contact, and urban residence) dominated the risk of LTBI.
doi:10.1016/j.vaccine.2014.12.015
PMCID: PMC4317190  PMID: 25529292
Tuberculosis; HIV; Helminth; Pregnancy; Bacille Calmette–Guerin; Crude culture filtrate protein
5.  A randomised controlled trial of the effects of albendazole in pregnancy on maternal responses to mycobacterial antigens and infant responses to bacille Calmette-Guérin (BCG) immunisation [ISRCTN32849447] 
Background
Maternal schistosomiasis and filariasis have been shown to influence infant responses to neonatal bacille Calmette-Guérin (BCG) immunisation but the effects of maternal hookworm, and of de-worming in pregnancy, are unknown.
Methods
In Entebbe, Uganda, we conducted a randomised, double-blind, placebo-controlled trial of a single dose of 400 mg of albendazole in the second trimester of pregnancy. Neonates received BCG. Interferon-gamma (IFN-γ) and interleukin (IL)-5 responses to a mycobacterial antigen (crude culture filtrate proteins (CFP) of Mycobacterium tuberculosis) were measured in a whole blood assay. We analysed results for binary variables using χ2 tests and logistic regression. We analysed continuous variables using Wilcoxon's tests.
Results
Maternal hookworm was associated with reduced maternal IFN-γ responses to CFP (adjusted odds ratio for IFN-γ > median response: 0.14 (95% confidence interval 0.02–0.83, p = 0.021). Conversely, maternal hookworm was associated with subsequent increased IFN-γ responses in their one-year-old infants (adjusted OR 17.65 (1.20–258.66; p = 0.013)). Maternal albendazole tended to reduce these effects.
Conclusion
Untreated hookworm infection in pregnancy was associated with reduced maternal IFN-γ responses to mycobacterial antigens, but increased responses in their infants one year after BCG immunisation. The mechanisms of these effects, and their implications for protective immunity remain, to be determined.
doi:10.1186/1471-2334-5-115
PMCID: PMC1352364  PMID: 16371154
6.  Maternal immunisation with trivalent inactivated influenza vaccine for prevention of influenza in infants in Mali: a prospective, active-controlled, observer-blind, randomised phase 4 trial 
The Lancet. Infectious Diseases  2016;16(9):1026-1035.
Summary
Background
Despite the heightened risk of serious influenza during infancy, vaccination is not recommended in infants younger than 6 months. We aimed to assess the safety, immunogenicity, and efficacy of maternal immunisation with trivalent inactivated influenza vaccine for protection of infants against a first episode of laboratory-confirmed influenza.
Methods
We did this prospective, active-controlled, observer-blind, randomised phase 4 trial at six referral centres and community health centres in Bamako, Mali. Third-trimester pregnant women (≥28 weeks' gestation) were randomly assigned (1:1), via a computer-generated, centre-specific list with alternate block sizes of six or 12, to receive either trivalent inactivated influenza vaccine or quadrivalent meningococcal vaccine. Study personnel administering vaccines were not masked to treatment allocation, but allocation was concealed from clinicians, laboratory personnel, and participants. Infants were visited weekly until age 6 months to detect influenza-like illness; laboratory-confirmed influenza diagnosed with RT-PCR. We assessed two coprimary objectives: vaccine efficacy against laboratory-confirmed influenza in infants born to women immunised any time prepartum (intention-to-treat population), and vaccine efficacy in infants born to women immunised at least 14 days prepartum (per-protocol population). The primary outcome was the occurrence of a first case of laboratory-confirmed influenza by age 6 months. This trial is registered with ClinicalTrials.gov, number NCT01430689.
Findings
We did this trial from Sept 12, 2011, to Jan 28, 2014. Between Sept 12, 2011, and April 18, 2013, we randomly assigned 4193 women to receive trivalent inactivated influenza vaccine (n=2108) or quadrivalent meningococcal vaccine (n=2085). There were 4105 livebirths; 1797 (87%) of 2064 infants in the trivalent inactivated influenza vaccine group and 1793 (88%) of 2041 infants in the quadrivalent meningococcal vaccine group were followed up until age 6 months. We recorded 5279 influenza-like illness episodes in 2789 (68%) infants, of which 131 (2%) episodes were laboratory-confirmed influenza. 129 (98%) cases of laboratory-confirmed influenza were first episodes (n=77 in the quadrivalent meningococcal vaccine group vs n=52 in the trivalent inactivated influenza vaccine group). In the intention-to-treat population, overall infant vaccine efficacy was 33·1% (95% CI 3·7–53·9); in the per-protocol population, vaccine efficacy was 37·3% (7·6–57·8). Vaccine efficacy remained robust during the first 4 months of follow-up (67·9% [95% CI 35·1–85·3] by intention to treat and 70·2% [35·7–87·6] by per protocol), before diminishing during the fifth month (57·3% [30·6–74·4] and 60·7 [33·8–77·5], respectively). Adverse event rates in women and infants were similar among groups. Pain at the injection site was more common in women given quadrivalent meningococcal vaccine than in those given trivalent inactivated influenza vaccine (n=253 vs n=132; p<0·0001), although 354 [92%] reactions were mild. Obstetrical and non-obstetrical serious adverse events were reported in 60 (3%) women in the quadrivalent meningococcal vaccine group and 61 (3%) women in the trivalent inactivated influenza vaccine group. Presumed neonatal infection was more common in infants in the trivalent inactivated influenza vaccine group than in those in the quadrivalent meningococcal vaccine group (n=60 vs n=37; p=0·02). No serious adverse events were related to vaccination.
Interpretation
Vaccination of pregnant women with trivalent inactivated influenza vaccine in Mali—a poorly resourced country with high infant mortality—was technically and logistically feasible and protected infants from laboratory-confirmed influenza for 4 months. With adequate financing to procure the vaccine, implementation will parallel the access to antenatal care and immunisation coverage of pregnant women with tetanus toxoid.
Funding
Bill & Melinda Gates Foundation.
doi:10.1016/S1473-3099(16)30054-8
PMCID: PMC4985566  PMID: 27261067
7.  Maternal Infection with Trypanosoma cruzi and Congenital Chagas Disease Induce a Trend to a Type 1 Polarization of Infant Immune Responses to Vaccines 
Background
We previously showed that newborns congenitally infected with Trypanosoma cruzi (M+B+) display a strong type 1 parasite-specific T cell immune response, whereas uninfected newborns from T. cruzi-infected mothers (M+B−) are prone to produce higher levels of proinflammatory cytokines than control neonates (M−B−). The purpose of the present study was to determine if such fetal/neonatal immunological environments could alter the response to standard vaccines administered in early life.
Methodology
Infants (6–7 months old) living in Bolivia, an area highly endemic for T. cruzi infection, and having received Bacillus Calmette Guerin (BCG), hepatitis B virus (HBV), diphtheria and tetanus vaccines, were enrolled into the M+B+, M+B−, M−B− groups mentioned above. The production of IFN-γ and IL-13, as markers of Th1 and Th2 responses respectively, by peripherical blood mononuclear cells stimulated with tuberculin purified protein derivative of Mycobacterium tuberculosis (PPD) or the vaccinal antigens HBs, diphtheria toxoid (DT) or tetanus toxoid (TT), as well as circulating levels of IgG antibodies against HBsAg, DT and TT were analyzed in infants. Cellular responses to the superantigen SEB were also monitored in M+B+, M+B−, M−B−infants and newborns.
Principal Findings
M+B+ infants developed a stronger IFN-γ response to hepatitis B, diphtheria and tetanus vaccines than did M+B− and M−B− groups. They also displayed an enhanced antibody production to HBsAg. This was associated with a type 1-biased immune environment at birth, since cells of M+B+ newborns produced higher IFN-γ levels in response to SEB. M+B− infants produced more IFN-γ in response to PPD than the other groups. IL-13 production remained low and similar in all the three groups, whatever the subject's ages or vaccine status.
Conclusion
These results show that: i) both maternal infection with T. cruzi and congenital Chagas disease do not interfere with responses to BCG, hepatitis B, diphtheria and tetanus vaccines in the neonatal period, and ii) the overcoming of immunological immaturity by T. cruzi infection in early life is not limited to the development of parasite-specific immune responses, but also tends to favour type 1 immune responses to vaccinal antigens.
Author Summary
Vaccines are of crucial importance to prevent morbidity and mortality due to infectious diseases in childhood. A modulation of the fetal/neonatal immune system (considered immature) toward Th1 or Th2 dominance could modify responses to vaccines administered in early life. T. cruzi is the agent of Chagas' disease, in Latin America currently infecting about 2 million women at fertile ages who are susceptible to transmitting the parasite to their fetus. In previous studies we showed that T. cruzi-infected mothers can induce a pro-inflammatory environment in their uninfected neonates (M+B−), whereas congenitally infected newborns (M+B+) are able to develop a pro-Th1 parasite-specific T cell response. In the present study, we analysed the cellular and/or antibody responses to Bacillus Calmette Guerin (BCG), hepatitis B birus (HBV), diphtheria and tetanus vaccines in 6- to 7-month-old infants living in Bolivia. M+B− infants produced more IFN-γ in response to BCG, whereas M+B+ infants developed a stronger IFN-γ response to hepatitis B, diphtheria and tetanus vaccines and enhanced antibody production to HBs antigen. These results show that both maternal infection with T. cruzi and congenital Chagas disease do not interfere with responses to BCG, hepatitis B, diphtheria and tetanus vaccines in the neonatal period and that T. cruzi infection in early life tends to favour type 1 immune responses to vaccinal antigens.
doi:10.1371/journal.pntd.0000571
PMCID: PMC2796860  PMID: 20041029
8.  Impact of Anthelminthic Treatment in Pregnancy and Childhood on Immunisations, Infections and Eczema in Childhood: A Randomised Controlled Trial 
PLoS ONE  2012;7(12):e50325.
Background
Helminth infections may modulate immune responses to unrelated pathogens and allergens; these effects may commence prenatally. We addressed the hypothesis that anthelminthic treatment in pregnancy and early childhood would improve responses to immunisation and modulate disease incidence in early childhood with both beneficial and detrimental effects.
Methods and Findings
A randomised, double-blind, placebo-controlled trial was conducted in Entebbe, Uganda [ISRCTN32849447]. In three independent randomisations, 2507 pregnant women were allocated to receive single-dose albendazole or placebo, and praziquantel or placebo; 2016 of their offspring were randomised to receive quarterly single-dose albendazole or placebo from age 15 months to 5 years. Primary outcomes were post-immunisation recall responses to BCG and tetanus antigens, and incidence of malaria, diarrhoea, and pneumonia; incidence of eczema was an important secondary outcome. Analysis was by intention-to-treat. Of 2345 live births, 1622 (69%) children remained in follow-up at age 5 years. 68% of mothers at enrolment, and 11% of five-year-olds, had helminth infections. Maternal hookworm and Schistosoma mansoni were effectively treated by albendazole and praziquantel, respectively; and childhood hookworm and Ascaris by quarterly albendazole. Incidence rates of malaria, diarrhoea, pneumonia, and eczema were 34, 65, 10 and 5 per 100 py, respectively. Albendazole during pregnancy caused an increased rate of eczema in the children (HR 1.58 (95% CI 1.15–2.17), p = 0.005). Quarterly albendazole during childhood was associated with reduced incidence of clinical malaria (HR 0.85 (95% CI 0.73–0.98), p = 0.03). There were no consistent effects of the interventions on any other outcome.
Conclusions
Routine use of albendazole in pregnancy may not always be beneficial, even in tropical developing countries. By contrast, regular albendazole treatment in preschool children may have an additional benefit for malaria control where helminths and malaria are co-endemic. Given the low helminth prevalence in our children, the effect of albendazole on malaria is likely to be direct.
Trial registration
Current Controlled Trials ISRCTN32849447
doi:10.1371/journal.pone.0050325
PMCID: PMC3517620  PMID: 23236367
9.  Neonatal Tetanus Immunity in Nigeria: The Effect of HIV Infection on Serum Levels and Transplacental Transfer of Antibodies 
Journal of Tropical Medicine  2016;2016:7439605.
Background. Tetanus toxoid immunisation of pregnant mother has remained the most effective strategy in eliminating neonatal tetanus. Impaired production and/or transplacental transfer of antibodies may affect the effectiveness of this strategy. We studied the effect of maternal HIV infection on serum levels and transplacental transfer of anti-tetanus antibodies. Methods. A total of 162 mother-baby paired serum samples were taken and analysed for anti-tetanus antibody levels using ELISA. Maternal HIV status was also determined by double ELISA technique. Maternal TT vaccination status was also documented. Results. Thirty-eight (23.5%) mothers and 41 (25.3%) babies were seronegative, out of whom 8 mothers were HIV positive and 9 babies were HIV exposed. HIV infected mothers and HIV exposed infants were, respectively, 16.27 times (OR = 16.27, 95% CI = 3.28 to 80.61) and 33.75 times (OR = 33.75, 95% CI = 4.12 to 276.40) more likely to be seronegative for anti-tetanus antibody. Similarly, HIV positive mother-newborn pairs were 7.46 times more likely to have a poor transplacental transfer of tetanus antibodies (OR = 7.46, 95% CI = 1.96 to 28.41). Conclusions. Maternal HIV infection is associated with impaired maternofoetal transfer of anti-tetanus antibodies and seronegativity among mothers and their newborns. Hence, this may hinder efforts to eliminate neonatal tetanus.
doi:10.1155/2016/7439605
PMCID: PMC4745869  PMID: 26904135
10.  Non-specific immunological effects of selected routine childhood immunisations: systematic review 
The BMJ  2016;355:i5225.
Objective To identify and characterise non-specific immunological effects after routine childhood vaccines against BCG, measles, diphtheria, pertussis, and tetanus.
Design Systematic review of randomised controlled trials, cohort studies, and case-control studies.
Data sources Embase, PubMed, Cochrane library, and Trip searched between 1947 and January 2014. Publications submitted by a panel of experts in the specialty were also included.
Eligibility criteria for selecting studies All human studies reporting non-specific immunological effects after vaccination with standard childhood immunisations. Studies using recombinant vaccines, no vaccine at all, or reporting only vaccine specific outcomes were excluded. The primary aim was to systematically identify, assemble, and review all available studies and data on the possible non-specific or heterologous immunological effects of BCG; measles; mumps, measles, and rubella (MMR); diphtheria; tetanus; and pertussis vaccines.
Results The initial search yielded 11 168 references; 77 manuscripts met the inclusion criteria for data analysis. In most included studies (48%) BCG was the vaccine intervention. The final time point of outcome measurement was primarily performed (70%) between one and 12 months after vaccination. There was a high risk of bias in the included studies, with no single study rated low risk across all assessment criteria. A total of 143 different immunological variables were reported, which, in conjunction with differences in measurement units and summary statistics, created a high number of combinations thus precluding any meta-analysis. Studies that compared BCG vaccinated with unvaccinated groups showed a trend towards increased IFN-γ production in vitro in the vaccinated groups. Increases were also observed for IFN-γ measured after BCG vaccination in response to in vitro stimulation with microbial antigens from Candida albicans, tetanus toxoid, Staphylococcus aureas, lipopolysaccharide, and hepatitis B. Cohort studies of measles vaccination showed an increase in lymphoproliferation to microbial antigens from tetanus toxoid and C albicans. Increases in immunogenicity to heterologous antigens were noted after diphtheria-tetanus (herpes simplex virus and polio antibody titres) and diphtheria-tetanus-pertussis (pneumococcus serotype 14 and polio neutralising responses) vaccination.
Conclusions The papers reporting non-specific immunological effects had heterogeneous study designs and could not be conventionally meta-analysed, providing a low level of evidence quality. Some studies, such as BCG vaccine studies examining in vitro IFN-γ responses and measles vaccine studies examining lymphoproliferation to microbial antigen stimulation, showed a consistent direction of effect suggestive of non-specific immunological effects. The quality of the evidence, however, does not provide confidence in the nature, magnitude, or timing of non-specific immunological effects after vaccination with BCG, diphtheria, pertussis, tetanus, or measles containing vaccines nor the clinical importance of the findings.
doi:10.1136/bmj.i5225
PMCID: PMC5063033  PMID: 27737830
11.  Effect of Antenatal Parasitic Infections on Anti-vaccine IgG Levels in Children: A Prospective Birth Cohort Study in Kenya 
PLoS Neglected Tropical Diseases  2015;9(1):e0003466.
Background
Parasitic infections are prevalent among pregnant women in sub-Saharan Africa. We investigated whether prenatal exposure to malaria and/or helminths affects the pattern of infant immune responses to standard vaccinations against Haemophilus influenzae (Hib), diphtheria (DT), hepatitis B (Hep B) and tetanus toxoid (TT).
Methods and Findings
450 Kenyan women were tested for malaria, schistosomiasis, lymphatic filariasis (LF), and intestinal helminths during pregnancy. After three standard vaccinations at 6, 10 and 14 weeks, their newborns were followed biannually to age 36 months and tested for absolute levels of IgG against Hib, DT, Hep B, and TT at each time point. Newborns’ cord blood (CB) lymphocyte responses to malaria blood-stage antigens, soluble Schistosoma haematobium worm antigen (SWAP), and filaria antigen (BMA) were also assessed. Three immunophenotype categories were compared: i) tolerant (those having Plasmodium-, Schistosoma-, or Wuchereria-infected mothers but lacking respective Th1/Th2-type recall responses at birth to malaria antigens, SWAP, or BMA); ii) sensitized (those with infected/uninfected mothers and detectable Th1/Th2-type CB recall response to respective parasite antigen); or iii) unexposed (no evidence of maternal infection or CB recall response).
Overall, 78.9% of mothers were infected with LF (44.7%), schistosomiasis (32.4%), malaria (27.6%) or hookworm (33.8%). Antenatal maternal malaria, LF, and hookworm were independently associated with significantly lower Hib-specific IgG. Presence of multiple maternal infections was associated with lower infant IgG levels against Hib and DT antigens post-vaccination. Post-vaccination IgG levels were also significantly associated with immunophenotype: malaria-tolerized infants had reduced response to DT, whereas filaria-tolerized infants showed reduced response to Hib.
Conclusions
There is an impaired ability to develop IgG antibody responses to key protective antigens of Hib and diphtheria in infants of mothers infected with malaria and/or helminths during pregnancy. These findings highlight the importance of control and prevention of parasitic infections among pregnant women.
Author Summary
Parasitic infections are prevalent among pregnant women in sub-Saharan Africa. Prenatal exposure to parasitic infections can generate several potential effects on fetal immune responses and affect functional antibody generation during subsequent vaccination. There is a paucity of data on the detrimental effects of chronic parasitic infections during pregnancy on the response to vaccine from birth to childhood. This paper highlights the overwhelming presence of helminth infection and malaria in pregnant women in rural Kenya. The study shows that the presence of single and multiple antenatal parasitic infections is associated with impaired infant IgG levels against Haemophilus influenzae (Hib) and diphtheria (DT) antigens post-vaccination from birth to 30 months of age. This study found that the response to DT was reduced in malaria-tolerized infants, and the response to Hib was impaired in filarial-tolerized infants; by contrast, the Schistosoma-tolerized group showed no effect. Deworming campaigns must be directed towards pregnant mothers, infants, and young children to improve response to vaccination.
doi:10.1371/journal.pntd.0003466
PMCID: PMC4295886  PMID: 25590337
12.  Interventions for improving coverage of childhood immunisation in low- and middle-income countries 
Background
Immunisation is a powerful public health strategy for improving child survival, not only by directly combating key diseases that kill children but also by providing a platform for other health services. However, each year millions of children worldwide, mostly from low- and middle-income countries (LMICs), do not receive the full series of vaccines on their national routine immunisation schedule. This is an update of the Cochrane review published in 2011 and focuses on interventions for improving childhood immunisation coverage in LMICs.
Objectives
To evaluate the effectiveness of intervention strategies to boost and sustain high childhood immunisation coverage in LMICs.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) 2016, Issue 4, part of The Cochrane Library. www.cochranelibrary.com, including the Cochrane Effective Practice and Organisation of Care (EPOC) Group Specialised Register (searched 12 May 2016); MEDLINE In-Process and Other Non-Indexed Citations, MEDLINE Daily and MEDLINE 1946 to Present, OvidSP (searched 12 May 2016); CINAHL 1981 to present, EbscoHost (searched 12 May 2016); Embase 1980 to 2014 Week 34, OvidSP (searched 2 September 2014); LILACS, VHL (searched 2 September 2014); Sociological Abstracts 1952 - current, ProQuest (searched 2 September 2014). We did a citation search for all included studies in Science Citation Index and Social Sciences Citation Index, 1975 to present; Emerging Sources Citation Index 2015 to present, ISI Web of Science (searched 2 July 2016). We also searched the two Trials Registries: ICTRP and ClinicalTrials.gov (searched 5 July 2016)
Selection criteria
Eligible studies were randomised controlled trials (RCT), non-RCTs, controlled before-after studies, and interrupted time series conducted in LMICs involving children aged from birth to four years, caregivers, and healthcare providers.
Data collection and analysis
We independently screened the search output, reviewed full texts of potentially eligible articles, assessed risk of bias, and extracted data in duplicate; resolving discrepancies by consensus. We then conducted random-effects meta-analyses and used GRADE to assess the certainty of evidence.
Main results
Fourteen studies (10 cluster RCTs and four individual RCTs) met our inclusion criteria. These were conducted in Georgia (one study), Ghana (one study), Honduras (one study), India (two studies), Mali (one study), Mexico (one study), Nicaragua (one study), Nepal (one study), Pakistan (four studies), and Zimbabwe (one study). One study had an unclear risk of bias, and 13 had high risk of bias. The interventions evaluated in the studies included community-based health education (three studies), facility-based health education (three studies), household incentives (three studies), regular immunisation outreach sessions (one study), home visits (one study), supportive supervision (one study), information campaigns (one study), and integration of immunisation services with intermittent preventive treatment of malaria (one study).
We found moderate-certainty evidence that health education at village meetings or at home probably improves coverage with three doses of diphtheria-tetanus-pertussis vaccines (DTP3: risk ratio (RR) 1.68, 95% confidence interval (CI) 1.09 to 2.59). We also found low-certainty evidence that facility-based health education plus redesigned vaccination reminder cards may improve DTP3 coverage (RR 1.50, 95% CI 1.21 to 1.87). Household monetary incentives may have little or no effect on full immunisation coverage (RR 1.05, 95% CI 0.90 to 1.23, low-certainty evidence). Regular immunisation outreach may improve full immunisation coverage (RR 3.09, 95% CI 1.69 to 5.67, low-certainty evidence) which may substantially improve if combined with household incentives (RR 6.66, 95% CI 3.93 to 11.28, low-certainty evidence). Home visits to identify non-vaccinated children and refer them to health clinics may improve uptake of three doses of oral polio vaccine (RR 1.22, 95% CI 1.07 to 1.39, low-certainty evidence). There was low-certainty evidence that integration of immunisation with other services may improve DTP3 coverage (RR 1.92, 95% CI 1.42 to 2.59).
Authors' conclusions
Providing parents and other community members with information on immunisation, health education at facilities in combination with redesigned immunisation reminder cards, regular immunisation outreach with and without household incentives, home visits, and integration of immunisation with other services may improve childhood immunisation coverage in LMIC. Most of the evidence was of low certainty, which implies a high likelihood that the true effect of the interventions will be substantially different. There is thus a need for further well-conducted RCTs to assess the effects of interventions for improving childhood immunisation coverage in LMICs.
Interventions that will increase and sustain the uptake of vaccines in low- and middle-income countries
What is the aim of this review?
The aim of this Cochrane review was to evaluate the effect of different strategies to increase the number of children in low-and-middle-income countries who are vaccinated to prevent infection by a disease. Researchers in Cochrane collected and analysed all relevant studies to answer this question and found 14 relevant studies.
Do strategies to improve childhood vaccination work?
Giving information about vaccination to parents and community members, handing out specially designed vaccination reminder cards, offering vaccines through regular immunisation outreach with and without household incentives (rewards), identifying unvaccinated children through home visits and referring them to health clinics, and integrating vaccination services with other services may lead to more children getting vaccinated. However, offering parents money to vaccinate their children may not improve vaccination uptake. Most of these findings were of low-certainty, and we need more well-conducted research in this area.
What was studied in the review?
Millions of children in low-and-middle-income countries still die from diseases that could have been prevented with vaccines. There are a number of reasons for this. Governments and others have tried different strategies to increase the number of children vaccinated.
What are the main results of the review?
The review authors found 14 relevant studies from Georgia, Ghana, Honduras, India, Mali, Mexico, Nicaragua, Nepal, Pakistan, and Zimbabwe. The studies compared people receiving these strategies to people who only received the usual healthcare services. The studies showed the following:
Giving information and discussing vaccination with parents and other community members at village meetings or at home probably leads to more children receiving three doses of diphtheria-tetanus-pertussis vaccine (moderate-certainty evidence).
Giving information to parents about the importance of vaccinations during visits to health clinics combined with a specially designed participant reminder card and integration of vaccination services with other health services may improve the uptake of three doses of diphtheria-tetanus-pertussis vaccine (low-certainty evidence).
Offering money to parents on the condition that they vaccinate their children may make little or no difference to the number of children that are fully vaccinated (low-certainty evidence).
Using vaccination outreach teams to offer vaccination to villages on fixed times monthly may improve coverage for full vaccination (low-certainty evidence).
How up-to-date is this review?
The review authors searched for studies that were published up to May 2016.
doi:10.1002/14651858.CD008145.pub3
PMCID: PMC4981642  PMID: 27394698
13.  Impact of conflict on infant immunisation coverage in Afghanistan: a countrywide study 2000–2003 
Background
Infant immunisation is an effective public health intervention to reduce the morbidity and mortality of vaccine preventable diseases. However, some developing countries fail to achieve desirable vaccination coverage; Afghanistan is one such country. The present study was performed to evaluate the progress and variation in infant immunisation coverage by district and region in Afghanistan and to assess the impact of conflict and resource availability on immunisation coverage.
Results
This study analysed reports of infant immunisation from 331 districts across 7 regions of Afghanistan between 2000 and 2003. Geographic information system (GIS) analysis was used to visualise the distribution of immunisation coverage in districts and to identify geographic inequalities in the process of improvement of infant immunisation coverage. The number of districts reporting immunisation coverage increased substantially during the four years of the study. Progress in Bacillus Calmette-Guerin (BCG) immunisation coverage was observed in all 7 regions, although satisfactory coverage of 80% remained unequally distributed. Progress in the third dose of Diphtheria-Pertussis-Tetanus (DPT3) immunisation differed among regions, in addition to the unequal distribution of immunisation coverage in 2000. The results of multivariate logistic regression analysis indicated a significant negative association between lack of security in the region and achievement of 80% coverage of immunisation regardless of available resources for immunisation, while resource availability showed no relation to immunisation coverage.
Conclusion
Although progress was observed in all 7 regions, geographic inequalities in these improvements remain a cause for concern. The results of the present study indicated that security within a country is an important factor for affecting the delivery of immunisation services.
doi:10.1186/1476-072X-6-23
PMCID: PMC1899486  PMID: 17555557
14.  Delayed BCG Vaccination Results in Minimal Alterations in T cell Immunogenicity of Acellular Pertussis and Tetanus Immunizations in HIV-Exposed Infants 
Vaccine  2015;33(38):4782-4789.
Background
Bacille Calmette-Guerin (BCG) is effective in preventing disseminated tuberculosis (TB) in children but may also have non-specific benefits, and is thought to improve immunity to unrelated antigens through trained innate immunity. In HIV-infected infants, there is a risk of BCG-associated adverse events. We aimed to explore whether delaying BCG vaccination by 8 weeks, when in utero HIV is excluded, affected T-cell responses to B. pertussis (BP) and tetanus toxoid (TT), in HIV-exposed, uninfected infants.
Methods
Infants were randomized to receive BCG vaccination at birth or 8 weeks of age. At 8 and 14 weeks, T cell proliferation and intracellular cytokine (IL-2, IL-13, IL-17, and IFN-γ) expression was analyzed in response to BP, TT and Staphylococcal enterotoxin B (SEB) antigens.
Results
Delaying BCG vaccination did not alter T-cell proliferation to BP or TT antigens. Infants immunized with BCG at birth had higher CD4+ T cell proliferation to SEB at 14 weeks of age (p=0.018). Birth-vaccinated infants had increased CD8+ IL-2 expression in response to BP, but not TT or SEB, at 8 weeks. Infants vaccinated with BCG at 8 weeks had significantly lower IL-13 expression by BP-specific CD4+ and CD8+ T cells at 14 weeks (p=0.032 and p=0.0035 respectively). There were no observed differences in multifunctional cytokine response to TT, BP or SEB between infants vaccinated with BCG at birth versus 8 weeks of age.
Conclusion
Delaying BCG vaccination until 8 weeks of age results in robust T-cellular responses to BP and TT in HIV-exposed infants.
Clinical Trial Registry
NCT02062580
doi:10.1016/j.vaccine.2015.07.096
PMCID: PMC4562895  PMID: 26259542
BCG vaccine; T cell; Tetanus; Pertussis; Infants; HIV
15.  Combined diphtheria, tetanus, pertussis, and Haemophilus influenzae type b vaccines for primary immunisation. 
Archives of Disease in Childhood  1996;75(4):298-303.
A total of 146 infants were immunised at ages 2, 3, and 4 months with a combined diphtheria, tetanus, pertussis (DTP)--Haemophilus influenzae type b (Hib) tetanus toxoid conjugate (PRP-T) vaccine (Pasteur Merieux) to assess the antibody response and adverse events associated with immunisation. Adverse events, including fever, were recorded by parents in a diary for three days following each injection. Blood was taken before the first immunisation and four weeks after the third immunisation to assess antibody response. Data were compared with those from historical controls who had received DTP and PRP-T vaccines by separate injection. The combined vaccine was well tolerated. Rates of local and general reactions were similar to those reported for infants immunised by separate injection. All infants achieved protective antibody titres (> 0.01 IU/ml) for diphtheria and tetanus; 98% acquired Hib (PRP) antibody > 0.15 microgram/ml and 82.5% > 1.0 microgram/ml. Pertussis antibody titres (pertussis toxin, filamentous haemagglutinin, total agglutinins, and agglutinins 2 and 3) showed appreciable rise following immunisation. DTP and PRP-T vaccines provide similar antibody responses and adverse effects whether mixed in the same syringe or administered by separate injection. The vaccines could be combined for use in the United Kingdom primary immunisation schedule.
PMCID: PMC1511738  PMID: 8984914
16.  Acellular pertussis vaccine given by accelerated schedule: response of preterm infants 
Objective: To describe the immune response of preterm infants to a diphtheria/tetanus/three component acellular pertussis (DTaP) vaccine, under an accelerated schedule, and the effects of steroids on this response. To compare responses with those of term infants.
Design: Prospective observational study.
Setting: Five Wessex neonatal units; Hertfordshire immunisation clinics.
Patients: Infants born at < 32 weeks; term controls.
Interventions: DTaP-Haemophilus influenzae type b vaccine given at 2, 3, and 4 months. Blood taken to assess antibody responses to vaccines.
Main outcome measures: IgG geometric mean concentrations (GMC) to vaccines.
Results: A total of 130 preterm (mean gestational age 29.1 weeks) and 54 term infants were recruited. After the third immunisation, preterm infants had similar GMCs to controls to diphtheria, tetanus, filamentous haemagglutinin (FHA), and pertactin (PRN), but a significantly lower GMC to pertussis toxin (PT). Responses to tetanus and PRN increased with age at the third immunisation, and those to tetanus, FHA, PRN, and PT increased with gestational age at birth. Response to tetanus correlated negatively with the number of doses of antenatal steroids received. There was no association between responses and postnatal steroids.
Conclusion: When immunised with a combined acellular pertussis- H influenzae type b vaccine under an accelerated schedule, IgG GMC of preterm infants to PT was reduced. GMCs to tetanus, FHA, PRN, and PT increased with gestational age at birth, and GMCs to tetanus and PRN increased with age at the third immunisation. There is, however, no benefit in delaying immunisation. Anti-tetanus IgG decreased with increasing number of doses of antenatal steroids. There was no effect for postnatal steroids.
doi:10.1136/fn.89.1.F57
PMCID: PMC1721649  PMID: 14711858
17.  The impact of HIV exposure and maternal Mycobacterium tuberculosis infection on infant immune responses to bacille Calmette-Guérin vaccination 
AIDS (London, England)  2015;29(2):155-165.
Objective:
The objective of this study is to assess the effect of maternal HIV and Mycobacterium tuberculosis (Mtb) infection on cellular responses to bacille Calmette-Guérin (BCG) immunization.
Design:
A mother–infant cohort study.
Methods:
Samples were collected from mother–infant pairs at delivery. Infants were BCG-vaccinated at 6 weeks of age and a repeat blood sample was collected from infants at 16 weeks of age. BCG-specific T-cell proliferation and intracellular cytokine expression were measured by flow cytometry. Secreted cytokines and chemokines in cell culture supernatants were analysed using a Multiplex assay.
Results:
One hundred and nine (47 HIV-exposed and 62 HIV-unexposed) mother–infants pairs were recruited after delivery and followed longitudinally. At birth, proportions of mycobacteria-specific proliferating T cells were not associated with either in-utero HIV exposure or maternal Mtb sensitization. However, in-utero HIV exposure affected infant-specific T-cell subsets [tumour necrosis factor-alpha (TNF-α) single positive proliferating CD4+ T cells and interferon-gamma (IFN-γ), TNF-α dual-positive CD4+ T cells]. Levels of TNF-α protein in cell culture supernatants were also significantly higher in HIV-exposed infants born to Mtb-sensitized mothers. In the presence of maternal Mtb sensitization, frequencies of maternal and newborn BCG-specific proliferating CD4+ T cells were positively correlated. Following BCG vaccination, there was no demonstrable effect of HIV exposure or maternal Mtb infection on infant BCG-specific T-cell proliferative responses or concentrations of secreted cytokines and chemokines.
Conclusion:
Effects of maternal HIV and Mtb infection on infant immune profiles at birth are transient only, and HIV-exposed, noninfected infants have the same potential to respond to and be protected by BCG vaccination as HIV-unexposed infants.
doi:10.1097/QAD.0000000000000536
PMCID: PMC4284011  PMID: 25535752
bacille Calmette-Guérin; HIV infection; HIV-exposed; immunogenicity; Mycobacterium tuberculosis infection; uninfected infants; vaccination
18.  The Effect of Maternal Helminth Infection on Maternal and Neonatal Immune Function and Immunity to Tuberculosis 
PLoS ONE  2014;9(4):e93429.
Background
M. tuberculosis and helminth infection each affects one third of the world population. Helminth infections down regulate cell mediated immune responses and this may contribute to lower efficacy of BCG vaccination and higher prevalence of tuberculosis.
Objective
To determine the effect of maternal helminth infection on maternal and neonatal immune function and immunity to TB.
Methods
In this cross sectional study, eighty five pregnant women were screened for parasitic and latent TB infections using Kato-Katz and QFT-GIT tests, respectively. IFN-γ and IL-4 ELISpot on Cord blood Mononuclear Cells, and total IgE and TB specific IgG ELISA on cord blood plasma was performed to investigate the possible effect of maternal helminth and/or latent TB co-infection on maternal and neonatal immune function and immunity to TB.
Result
The prevalence of helminth infections in pregnant women was 27% (n = 23), with Schistosoma mansoni the most common helminth species observed (20% of women were infected). Among the total of 85 study participants 25.8% were QFT-GIT positive and 17% had an indeterminate result. The mean total IgE value of cord blood was significantly higher in helminth positive than negative women (0.76 vs 0.47, p = 0.042). Cross placental transfer of TB specific IgG was significantly higher in helminth positive (21.9±7.9) than negative (12.3±5.1), p = 0.002) Latent TB Infection positive participants. The IFN-γ response of CBMCs to ESAT-6/CFP-10 cocktail (50 vs 116, p = 0.018) and PPD (58 vs 123, p = 0.02) was significantly lower in helminth positive than negative participants. There was no significant difference in IL-4 response of CBMCs between helminth negative and positive participants.
Conclusions
Maternal helminth infection had a significant association with the IFN-γ response of CBMCs, total IgE and cross placental transfer of TB specific IgG. Therefore, further studies should be conducted to determine the effect of these factors on neonatal immune response to BCG vaccination.
doi:10.1371/journal.pone.0093429
PMCID: PMC3977838  PMID: 24710174
19.  Safety and Immunogenicity of Tetanus Diphtheria and Acellular Pertussis (Tdap) Immunization During Pregnancy in Mothers and Infants: A Randomized Clinical Trial 
JAMA  2014;311(17):1760-1769.
Importance
Maternal immunization with tetanus toxoid and reduced diphtheria toxoid acellular pertussis (Tdap) vaccine could prevent infant pertussis. The effect of vaccine-induced maternal antibodies on infant responses to diphtheria and tetanus toxoids acellular pertussis (DTaP) immunization is unknown.
Objective
To evaluate the safety and immunogenicity of Tdap immunization during pregnancy and its effect on infant responses to DTaP.
Design, Setting and Participants
Phase I, randomized, double-masked, placebo-controlled clinical trial conducted in private (Houston) and academic (Durham, Seattle) obstetric practices from 2008 to 2012. Forty eight healthy 18–45 year-old pregnant women received Tdap (n=33) or placebo (n=15) at 30–32 weeks’ gestation with cross-over Tdap immunization postpartum.
Interventions
Tdap vaccination at 30–32 weeks’ gestation or post-partum.
Outcome Measures
Primary: Maternal and infant adverse events, pertussis illness and infant growth and development (Bayley-III screening test) until 13 months of age. Secondary: Antibody concentrations in pregnant women before and 4 weeks after Tdap immunization or placebo, at delivery and 2 months postpartum, and in infants at birth, 2 months, and after the third (7 months) and fourth (13 months) doses of DTaP.
Results
All participants delivered healthy newborns. No Tdap-associated serious adverse events occurred in women or infants. Injection site reactions after Tdap immunization were reported in 78.8% (95% CI: 61.1%, 91.0%) and 80% (CI: 51.9%, 95.7%) pregnant and postpartum women, respectively. Injection site pain was the predominant symptom. Systemic symptoms were reported in 36.4% (CI: 20.4%, 54.9%) and 73.3% (CI: 44.9%, 92.2%) pregnant and postpartum women, respectively. Malaise and myalgia were most common. Growth and development were similar in both infant groups. No cases of pertussis occurred. Significantly higher concentrations of pertussis antibodies were measured at delivery in women who received Tdap during pregnancy and in their infants at birth and at age 2 months when compared to infants of women immunized postpartum. Antibody responses in infants of Tdap recipients during pregnancy were modestly lower after 3 DTaP doses, but not different following the fourth dose.
Conclusions and Relevance
This preliminary safety assessment did not find an increased risk of adverse events among women who received Tdap vaccine at 30–32 weeks’ gestation or their infants. Maternal immunization with Tdap resulted in high concentrations of pertussis antibodies in infants during the first 2 months of life and did not substantially alter infant responses to DTaP. Further research is needed to provide definitive evidence of the safety and efficacy of Tdap vaccination during pregnancy.
Trial Registration
ClinicalTrials.gov, study identifier: NCT00707148. URL: http://www.clinicaltrials.gov
doi:10.1001/jama.2014.3633
PMCID: PMC4333147  PMID: 24794369
Maternal immunization; Pertussis; infants; maternal antibodies; response to active immunization
20.  Effect of a fourth Haemophilus influenzae type b immunisation in preterm infants who received dexamethasone for chronic lung disease 
Aim: To assess whether a fourth Hib polysaccharide-tetanus protein conjugate vaccine (PRP-T) would improve antibody response in preterm infants previously treated with dexamethasone for chronic lung disease.
Methods: In a pilot study 12 infants born at less than 30 weeks gestation who had received corticosteroids were given a supplementary Hib dose six weeks after completion of the primary immunisation course. Serum samples obtained before and at eight weeks following the fourth Hib dose were analysed for total level and avidity of anti-PRP antibody.
Results: There was no significant increase in the geometric mean titre (GMT) of anti-PRP antibody resulting from the fourth Hib immunisation (GMT: pre 2.35 µg/ml, post 2.24 µg/ml, p = 0.79). A subgroup of six infants had subprotective antibody levels (<1.0 µg/ml) after the primary immunisation course, which remained subprotective following the extra Hib immunisation. Despite the poor response in total antibody level, the study group showed a significant rise in PRP specific IgG avidity following the fourth immunisation (GMAI: pre 0.076, post 0.138, p = 0.043).
Conclusion: An additional Hib immunisation given to recently steroid treated preterm infants six weeks after completion of the primary schedule did not augment primary immunogenicity. However, increasing avidity may imply successful priming and long term immunity to Hib.
doi:10.1136/fn.88.1.F58
PMCID: PMC1755995  PMID: 12496229
21.  Integration of hepatitis B vaccination into rural African primary health care programmes. 
BMJ : British Medical Journal  1991;302(6772):313-316.
OBJECTIVE--To determine the efficacy of hepatitis B vaccine when added to the routine expanded programme on immunisation under field conditions in rural Africa. DESIGN--Infants were immunised according to two schedules--an early schedule at birth, 3 months, and 6 months and a later schedule to correspond with routine vaccination in the expanded programme on immunisation at 3 months, 4 1/2 months, and 6 months. SETTING--Venda, northern Transvaal, South Africa, a self governing region of 7460 square kilometers varying from rural villages to small towns. SUBJECTS--The 1989 birth cohort of Venda. MAIN OUTCOME MEASURES--Coverage for hepatitis B vaccine at first, second, and third doses; serological assessment of vaccine efficacy by prevalence of antibodies to hepatitis B surface antigen in infants who had completed the three dose course of immunisation; antibodies to hepatitis B core antigen to determine if natural infection occurred. RESULTS--Vaccine coverage for hepatitis B dropped sharply from 99% to 53% to 39% for the first, second, and third dose respectively. In contrast, vaccine coverage was maintained at 97-99% for the three doses of poliomyelitis vaccine. Serological evaluation of vaccine efficacy showed that only 3.5% of recipients of all three doses failed to develop antibodies to hepatitis B surface antigen. Only 6.6% of vaccine recipients were vaccinated according to either the early or later schedules whereas 93.4% received their doses of vaccine at intervals beyond the limits of either of the planned schedules. There was, however, no significant difference in seroconversion to the surface antigen between the "unscheduled" or scheduled groups of those who were vaccinated according to the early or late schedules. The pattern of prevalence of antibodies to hepatitis B core antigen, which showed a sharp fall in children aged over 7 months, suggested that the antibodies were acquired passively rather than by active infection. CONCLUSIONS--Supplementation of the present expanded programme on immunisation with hepatitis B vaccine in rural Africa is fraught with difficulties. However, the vaccine was effective within a fairly wide spacing of dosage. Adding hepatitis B vaccine to diphtheria, tetanus, and pertussis as a tetravalent vaccine is proposed as a means of effectively integrating it into the expanded programme on immunisation in Third World settings.
PMCID: PMC1668978  PMID: 1825799
22.  Evaluation of TLR Agonists as Potential Mucosal Adjuvants for HIV gp140 and Tetanus Toxoid in Mice 
PLoS ONE  2012;7(12):e50529.
In the present study we investigate the impact of a range of TLR ligands and chitosan as potential adjuvants for different routes of mucosal immunisation (sublingual (SL), intranasal (IN), intravaginal (IVag) and a parenteral route (subcutaneous (SC)) in the murine model. We assess their ability to enhance antibody responses to HIV-1 CN54gp140 (gp140) and Tetanus toxoid (TT) in systemic and vaginal compartments. A number of trends were observed by route of administration. For non-adjuvanted antigen, SC>SL>IN immunisation with respect to systemic IgG responses, where endpoint titres were greater for TT than for gp140. In general, co-administration with adjuvants increased specific IgG responses where IN = SC>SL, while in the vaginal compartment IN>SL>SC for specific IgA. In contrast, for systemic and mucosal IgA responses to antigen alone SL>IN = SC. A number of adjuvants increased specific systemic IgA responses where in general IN>SL>SC immunisation, while for mucosal responses IN = SL>SC. In contrast, direct intravaginal immunisation failed to induce any detectable systemic or mucosal responses to gp140 even in the presence of adjuvant. However, significant systemic IgG responses to TT were induced by intravaginal immunisation with or without adjuvant, and detectable mucosal responses IgG and IgA were observed when TT was administered with FSL-1 or Poly I∶C. Interestingly some TLRs displayed differential activity dependent upon the route of administration. MPLA (TLR4) suppressed systemic responses to SL immunisation while enhancing responses to IN or SC immunisation. CpG B enhanced SL and IN responses, while having little or no impact on SC immunisation. These data demonstrate important route, antigen and adjuvant effects that need to be considered in the design of mucosal vaccine strategies.
doi:10.1371/journal.pone.0050529
PMCID: PMC3521731  PMID: 23272062
23.  The impact of helminths on the response to immunization and on the incidence of infection and disease in childhood in Uganda: design of a randomized, double-blind, placebo-controlled, factorial trial of deworming interventions delivered in pregnancy and early childhood [ISRCTN32849447] 
Background
Helminths have profound effects on the immune response, allowing long-term survival of parasites with minimal damage to the host. Some of these effects "spill-over", altering responses to non-helminth antigens or allergens. It is suggested that this may lead to impaired responses to immunizations and infections, while conferring benefits against inflammatory responses in allergic and autoimmune disease. These effects might develop in utero, through exposure to maternal helminth infections, or through direct exposure in later life.
Purpose
To determine the effects of helminths and their treatment in pregnancy and in young children on immunological and disease outcomes in childhood.
Methods
The trial has three randomized, double-blind, placebo-controlled interventions at two times, in two people: a pregnant woman and her child. Pregnant women are randomized to albendazole or placebo and praziquantel or placebo. At age 15 months their children are randomized to three-monthly albendazole or placebo, to continue to age five years. The proposed designation for this sequence of interventions is a 2 X 2(x2) factorial design.
Children are immunized with BCG and against polio, Diphtheria, tetanus, Pertussis, Haemophilus, hepatitis B and measles. Primary immunological outcomes are responses to BCG antigens and tetanus toxoid in whole blood cytokine assays and antibody assays at one, three and five years of age. Primary disease outcomes are incidence of malaria, pneumonia, diarrhoea, tuberculosis, measles, vertical HIV transmission, and atopic disease episodes, measured at clinic visits and twice-monthly home visits. Effects on anaemia, growth and intellectual development are also assessed.
Conclusion
This trial, with a novel design comprising related interventions in pregnant women and their offspring, is the first to examine effects of helminths and their treatment in pregnancy and early childhood on immunological, infectious disease and allergic disease outcomes. The results will enhance understanding of both detrimental and beneficial effects of helminth infection and inform policy. Clinical Trials 2007; 4: 42–57. http://ctj.sagepub.com
doi:10.1177/1740774506075248
PMCID: PMC2643383  PMID: 17327245
24.  Ethnic differences in selective neonatal BCG immunisation: white British children miss out 
Thorax  2005;61(3):247-249.
Background
Tuberculosis (TB) is a re‐emerging problem, especially in the larger cities of Western Europe. Selective neonatal BCG vaccination is recommended for infants at risk of TB in the UK. Neonatal BCG is safe and effective, with an overall protective value of 75%. This study aimed to assess BCG rates among at risk infants in Cardiff and the Vale of Glamorgan, South Wales in the year 2003.
Methods
A cohort of infants at risk for TB was identified from demographic data stored on a computerised maternity activity database. A manual search of immunisation records determined overall rates and the rates for infants belonging to various ethnic groups.
Results: Of 5308 infants born in 2003, 514 (9.6%) were at risk of TB; 423 (82.2%) of these infants were referred postnatally for BCG vaccination and 391 received it. Twenty six of the 41 at risk white British infants missed having a BCG vaccination compared with 47 of 288 Asian infants and seven of 39 black African babies. The rate of BCG vaccination among white British infants was 36.5% compared with 83.6% for Asian infants from the Indian subcontinent (χ2 = 7.25, p<0.01) and 82% for black African infants (χ2 = 4.48, p<0.05).
Conclusions: The overall BCG rate among at risk infants in Cardiff was 76% during the study period. The vaccination rate was poor among white British infants compared with other ethnic groups. Enhanced awareness of health professionals to recognise the need for vaccinating certain white children at risk of TB is essential to improve BCG coverage in an increasingly multiethnic population.
doi:10.1136/thx.2004.036269
PMCID: PMC2080732  PMID: 16384882
tuberculosis; infants; BCG vaccination; ethnicity
25.  Altered Memory T-Cell Responses to Bacillus Calmette-Guerin and Tetanus Toxoid Vaccination and Altered Cytokine Responses to Polyclonal Stimulation in HIV-Exposed Uninfected Kenyan Infants 
PLoS ONE  2015;10(11):e0143043.
Implementation of successful prevention of mother-to-child transmission of HIV strategies has resulted in an increased population of HIV-exposed uninfected (HEU) infants. HEU infants have higher rates of morbidity and mortality than HIV-unexposed (HU) infants. Numerous factors may contribute to poor health in HEU infants including immunological alterations. The present study assessed T-cell phenotype and function in HEU infants with a focus on memory Th1 responses to vaccination. We compared cross-sectionally selected parameters at 3 and 12 months of age in HIV-exposed (n = 42) and HU (n = 28) Kenyan infants. We measured ex vivo activated and bulk memory CD4 and CD8 T-cells and regulatory T-cells by flow cytometry. In addition, we measured the magnitude, quality and memory phenotype of antigen-specific T-cell responses to Bacillus Calmette-Guerin and Tetanus Toxoid vaccine antigens, and the magnitude and quality of the T cell response following polyclonal stimulation with staphylococcal enterotoxin B. Finally, the influence of maternal disease markers on the immunological parameters measured was assessed in HEU infants. Few perturbations were detected in ex vivo T-cell subsets, though amongst HEU infants maternal HIV viral load positively correlated with CD8 T cell immune activation at 12 months. Conversely, we observed age-dependent differences in the magnitude and polyfunctionality of IL-2 and TNF-α responses to vaccine antigens particularly in Th1 cells. These changes mirrored those seen following polyclonal stimulation, where at 3 months, cytokine responses were higher in HEU infants compared to HU infants, and at 12 months, HEU infant cytokine responses were consistently lower than those seen in HU infants. Finally, reduced effector memory Th1 responses to vaccine antigens were observed in HEU infants at 3 and 12 months and higher central memory Th1 responses to M. tuberculosis antigens were observed at 3 months only. Long-term monitoring of vaccine efficacy and T-cell immunity in this vulnerable population is warranted.
doi:10.1371/journal.pone.0143043
PMCID: PMC4646342  PMID: 26569505

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