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1.  Testing the hypothesis that diphtheria–tetanus–pertussis vaccine has negative non-specific and sex-differential effects on child survival in high-mortality countries 
BMJ Open  2012;2(3):e000707.
Measles vaccines (MV) have sex-differential effects on mortality not explained by protection against measles infection.
The authors examined whether whole-cell diphtheria–tetanus–pertussis (DTP) vaccine has sex-differential and non-specific effects.
Data sources and eligibility
Following previous reviews and a new search, the effect of DTP on mortality up to the next vaccination was assessed in all studies where DTP was given after BCG or DTP was given after MV and there was prospective follow-up after ascertainment of vaccination status.
High-mortality countries in Africa and Asia.
The initial observation of negative effect of DTP generated six hypotheses, which were examined in all available studies and two randomised trials reducing the time of exposure to DTP.
Main outcome
Consistency between studies.
In the first study, DTP had negative effects on survival in contrast to the beneficial effects of BCG and MV. This pattern was repeated in the six other studies available. Second, the two ‘natural experiments’ found significantly higher mortality for DTP-vaccinated compared with DTP-unvaccinated children. Third, the female–male mortality ratio was increased after DTP in all nine studies; in contrast, the ratio was decreased after BCG and MV in all studies. Fourth, the increased female mortality associated with high-titre measles vaccine was found only among children who had received DTP after high-titre measles vaccine. Fifth, in six randomised trials of early MV, female but not male mortality was increased if DTP was likely to be given after MV. Sixth, the mortality rate declined markedly for girls but not for boys when DTP-vaccinated children received MV. The authors reduced exposure to DTP as most recent vaccination by administering a live vaccine (MV and BCG) shortly after DTP. Both trials reduced child mortality.
These observations are incompatible with DTP merely protecting against the targeted diseases. With herd immunity to whooping cough, DTP is associated with higher mortality for girls. Randomised studies of DTP are warranted to measure the true impact on survival.
Article summary
Article focus
MV has sex-differential non-specific effects for child survival. We examined whether DTP vaccine has negative effects for survival, particularly for girls.
We tested six hypotheses suggesting that DTP may have negative health consequences if found to be true.
Furthermore, we conducted two randomised trials reducing the time of exposure to DTP as most recent vaccination by providing a live vaccine shortly after DTP.
Key messages
All available studies suggest that the effect of DTP on child survival is opposite of the effects of BCG and MV. In the two natural experiments, DTP-vaccinated children had significantly higher mortality than DTP-unvaccinated children.
Among DTP-vaccinated children, girls have higher mortality than boys in all studies, whereas the tendency is the opposite for BCG- and measles-vaccinated children. DTP administered after MV in randomised trials of MV is associated with increased female but not male mortality.
Reducing time of exposure to DTP as the most recent vaccination with BCG or MV reduce child mortality.
Strengths and limitations of this study
Since the healthiest children are vaccinated first, one would expect DTP to be associated with a benefit. However, all the data suggest consistently that DTP is associated with a negative effect for girls.
A randomised trial of the effect of DTP on overall survival could not be conducted. There is a need to conduct such studies now.
PMCID: PMC3364456  PMID: 22619263
2.  The Effect of 50 000 IU Vitamin A with BCG Vaccine at Birth on Growth in the First Year of Life 
Journal of Tropical Medicine  2011;2011:570170.
Vitamin A supplements may interact with diphtheria-tetanus-pertussis (DTP) vaccine causing increased female mortality. In a randomised trial of neonatal vitamin A supplementation (VAS), we examined growth during the first year of life in 808 children, pursuing the hypothesis that a negative interaction between VAS and DTP in girls would be reflected in growth. Length and weight were measured at 6 weekly visits and WHO-growth-reference z-scores derived. Neonatal VAS had no effect on anthropometric measures at 12 months, but may interact sex differentially with routine vaccines. While BCG was the most recent vaccine, neonatal VAS benefitted growth (difference in weight-for-length z-score (dWFL: 0.31(95% CI: 0.03–0.59)). While DTP was the most recent vaccine, VAS tended to affect growth adversely in girls (dWFL = −0.21 (−0.48–0.06)). After measles vaccine (MV) there was no overall effect of neonatal VAS. The VAS effect differed significantly between the BCG and DTP windows (P = 0.03), and the difference was borderline significant between the DTP and MV windows for girls (P = 0.09).
PMCID: PMC3170791  PMID: 21912559
3.  Does the effect of vitamin A supplements depend on vaccination status? An observational study from Guinea-Bissau 
BMJ Open  2012;2(1):e000448.
Vitamin A supplementation (VAS) is estimated to reduce all-cause mortality by 24%. Previous studies indicate that the effect of VAS may vary with vaccination status. The authors evaluated the effect of VAS provided in campaigns on child survival overall and by sex and vaccination status at the time of supplementation.
Observational cohort study.
Setting and participants
The study was conducted in the urban study area of the Bandim Health Project in Guinea-Bissau. The authors documented participation or non-participation in two national vitamin A campaigns in December 2007 and July 2008 for children between 6 and 35 months of age. Vaccination status was ascertained by inspection of vaccination cards. All children were followed prospectively.
Outcome measures
Mortality rates for supplemented and non-supplemented children were compared in Cox models providing mortality rate ratios (MRRs).
The authors obtained information from 93% of 5567 children in 2007 and 90% of 5799 children in 2008. The VAS coverage was 58% in 2007 and 68% in 2008. Mortality in the supplemented group was 1.5% (44 deaths/2873 person-years) and 1.6% (20 deaths/1260 person-years) in the non-supplemented group (adjusted MRR=0.78 (0.46; 1.34)). The effect was similar in boys and girls. Vaccination cards were seen for 86% in 2007 and 84% in 2008. The effect of VAS in children who had measles vaccine as their last vaccine (2814 children, adjusted MRR=0.34 (0.14; 0.85)) differed from the effect in children who had diphtheria–tetanus–pertussis vaccine as their last vaccine (3680 children, adjusted MRR=1.29 (0.52; 3.22), p=0.04 for interaction).
The effect of VAS differed by most recent vaccination, being beneficial after measles vaccine but not after diphtheria–tetanus–pertussis vaccine.
Article summary
Article focus
Vitamin A supplementation (VAS) is estimated to reduce all-cause mortality by 24%.
The effect of VAS may vary with vaccination status, being beneficial with or after measles vaccine (MV) but not after diphtheria–tetanus–pertussis (DTP) vaccine.
Key messages
The effect of VAS is heterogeneous.
The effect of VAS varied with vaccination status: supplemented children had lower mortality than non-supplemented children when MV was the most recent vaccine but not when DTP was the most recent vaccine.
The effect of VAS tended to differ by season of supplementation.
Strengths and limitations of this study
Information was collected on the individual level, and the children were followed prospectively.
Due to the observational nature of the study, the comparison of supplemented and non-supplemented children should be interpreted with caution.
However, a selection bias is unlikely to have worked in different directions for children who had DTP and MV as the most recent vaccine.
PMCID: PMC3278485  PMID: 22240648
4.  Vaccination coverage and out-of-sequence vaccinations in rural Guinea-Bissau: an observational cohort study 
BMJ Open  2012;2(6):e001509.
The WHO aims for 90% coverage of the Expanded Program on Immunization (EPI), which in Guinea-Bissau included BCG vaccine at birth, three doses of diphtheria−tetanus−pertussis vaccine (DTP) and oral polio vaccine (OPV) at 6, 10 and 14 weeks and measles vaccine (MV) at 9 months when this study was conducted. The WHO assesses coverage by 12 months of age. The sequence of vaccines may have an effect on child mortality, but is not considered in official statistics or assessments of programme performance. We assessed vaccination coverage and frequency of out-of-sequence vaccinations by 12 and 24 months of age.
Observational cohort study.
Setting and participants
The Bandim Health Project's (BHP) rural Health and Demographic Surveillance site covers 258 randomly selected villages in all regions of Guinea-Bissau. Villages are visited biannually and vaccination cards inspected to ascertain vaccination status. Between 2003 and 2009 vaccination status by 12 months of age was assessed for 5806 children aged 12–23 months; vaccination status by 24 months of age was assessed for 3792 children aged 24–35 months.
Outcome measures
Coverage of EPI vaccinations and frequency of out-of-sequence vaccinations.
Half of 12-month-old children and 65% of 24-month-old children had completed all EPI vaccinations. Many children received vaccines out of sequence: by 12 months of age 54% of BCG-vaccinated children had received DTP with or before BCG and 28% of measles-vaccinated children had received DTP with or after MV. By 24 months of age the proportion of out-of-sequence vaccinations was 58% and 35%, respectively, for BCG and MV.
In rural Guinea-Bissau vaccination coverage by 12 months of age was low, but continued to increase beyond 12 months of age. More than half of all children received vaccinations out of sequence. This highlights the need to improve vaccination services.
PMCID: PMC3532986  PMID: 23166127
5.  Determinants of third dose of diphtheria–tetanus–pertussis (DTP) completion among children who received DTP1 at rural immunization centres in Pakistan: a cohort study 
In Pakistan, a high proportion of children fail to complete third dose of diphtheria-tetanus-pertussis (DTP3) after having received the first dose (DTP1). A cohort study was conducted to identify the factors predicting three doses of diphtheria–tetanus–pertussis (DTP3) completion among children who have received DTP1 at six centres of Expanded Programme on Immunization (EPI) in rural Pakistan.
We analyzed a cohort of mother–child pairs enrolled at DTP1 between November 2005 and May 2006 in the standard care group of a larger randomized controlled trial. Data were collected from mothers on a structured questionnaire at enrolment, and each child was followed up at clinic visits for 90 days to record dates of DTP2 and DTP3. Multivariable log-binomial regression analysis was performed to identify the independent predictors of DTP3 completion.
Only 39% (149/378) of enrolled children completed DTP3 during the follow-up period. After adjusting for the centre of enrolment in multivariable analysis, DTP3 completion was higher among children who were ≤60 days old at enrolment [adjusted risk ratio (Adj. RR) 1.39, 95% confidence interval (CI): 1.06–1.82], who were living in a household with monthly household income >Rs. 3000 (US$ 50) (Adj. RR 1.76, 95% CI: 1.16–2.65), and who were living ≤10 min away from EPI centre (Adj. RR 1.31, 95% CI: 1.04–1.66).
Interventions targeting childhood immunization dropouts should focus on bringing more children to EPI centres on-time for initial immunization. Relocation of existing EPI centres and creation of new EPI centres at appropriate locations may decrease the travel time to the EPI centres and result in fewer immunization dropouts.
PMCID: PMC2858790  PMID: 19930140
childhood immunization; Expanded Programme on Immunization; dropouts; determinants; cohort study; Pakistan
6.  The effect of vitamin A supplementation administered with missing vaccines during national immunization days in Guinea-Bissau 
Background WHO recommends high-dose Vitamin A supplementation (VAS) at vaccination contacts after 6 months of age. It has not been studied whether the effect of VAS on mortality depends on the type of vaccine. We have hypothesized that VAS administered with measles vaccine (MV) is more beneficial than VAS with diphtheria–tetanus–pertussis (DTP) vaccine. We assessed the effect of VAS administered with different vaccines during national immunization days (NIDs).
Methods In 2003, VAS was distributed during NIDs in Guinea-Bissau. Children 6 months or older were given VAS, and if they were missing vaccines, these were often given as well. We compared survival between children who had received VAS alone, VAS with DTP or DTP + MV, or VAS with MV. We also compared the survival between participants and non-participants. We followed 6- to 17-month old children until 18 months of age and analysed survival in Cox models.
Results Twenty of 982 VAS-recipients died during follow-up. The mortality rate ratio (MRR) for VAS with DTP + MV or VAS with DTP was 3.43 (1.36–8.61) compared with VAS only. There were no deaths among those who received VAS with MV alone (P = 0.0005 for homogeneity of VAS effects). Children who received VAS with DTP had higher mortality than non-participants who did not receive VAS [MRR = 3.04 (1.31–7.07)].
Conclusion The study design does not allow for definite conclusions. However, the results are compatible with our a priori hypothesis that VAS is more beneficial when given with MV and potentially harmful when given with DTP. Randomized trials testing the impact on mortality of the current WHO policy seem warranted.
PMCID: PMC2639368  PMID: 18796481
Vitamin A; diphtheria–tetanus–pertussis vaccine; measles vaccine; child mortality; low income populations
7.  Short-term and long-term antibody response by mice after immunization against Neisseria meningitidis B or diphtheria toxoid 
Serogroup B Neisseria meningitidis (MenB) is a major cause of invasive disease in early childhood worldwide. The only MenB vaccine available in Brazil was produced in Cuba and has shown unsatisfactory efficacy when used to immunize millions of children in Brazil. In the present study, we compared the specific functional antibody responses evoked by the Cuban MenB vaccine with a standard vaccine against diphtheria (DTP: diphtheria, tetanus, pertussis) after primary immunization and boosting of mice. The peak of bactericidal and opsonic antibody titers to MenB and of neutralizing antibodies to diphtheria toxoid (DT) was reached after triple immunization with the MenB vaccine or DTP vaccine, respectively. However, 4 months after immunization, protective DT antibody levels were present in all DTP-vaccinated mice but in only 20% of the mice immunized against MenB. After 6 months of primary immunization, about 70% of animals still had protective neutralizing DT antibodies, but none had significant bactericidal antibodies to MenB. The booster doses of DTP or MenB vaccines produced a significant antibody recall response, suggesting that both vaccines were able to generate and maintain memory B cells during the period studied (6 months post-triple immunization). Therefore, due to the short duration of serological memory induced by the MenB vaccine (VA-MENGOC-BC® vaccine), its use should be restricted to outbreaks of meningococcal disease.
PMCID: PMC3854364  PMID: 23369971
Serological memory; Antibody recall response; Booster immunization
8.  The impact of different doses of vitamin A supplementation on male and female mortality. A randomised trial from Guinea-Bissau 
BMC Pediatrics  2011;11:77.
Vitamin A supplementation (VAS) given to children between 6 months and 5 years of age is known to reduce mortality in low-income countries. We have previously observed that girls benefit more from a lower dose of VAS than the one recommended by WHO, the effect being strongest if diphtheria-tetanus-pertussis vaccine (DTP) was the most recent vaccination. We aimed to test these observations.
During national immunisations days in Guinea-Bissau, West Africa, combining oral polio vaccination and VAS, we randomised 8626 children between 6 months and 5 years of age to receive the dose of VAS recommended by WHO or half this dose. Mortality rate ratios (MRRs) were assessed after 6 and 12 month.
The overall mortality rate among participants was lower than expected. There was no significant difference in mortality at 6 months and 12 months of follow up between the low dose VAS group and the recommended dose VAS group. The MRRs were 1.23 (0.60-2.54) after 6 months and 1.17 (0.73-1.87) after 12 months. This tendency was similar in boys and girls. The low dose was not associated with lower mortality in girls if the most recent vaccine was DTP (MRR = 0.60 (0.14-2.50) after 6 months).
Our sample size does not permit firm conclusions since mortality was lower than expected. We could not confirm a beneficial effect of a lower dose of VAS on mortality in girls.
Trial registration
The study was registered under, number NCT00168636
PMCID: PMC3175170  PMID: 21884606
9.  Simultaneous administration of diphtheria-tetanus-pertussis-polio and hepatitis B vaccines in a simplified immunization program: immune response to diphtheria toxoid, tetanus toxoid, pertussis, and hepatitis B surface antigen. 
Infection and Immunity  1986;51(3):784-787.
We studied the interactions of hepatitis B vaccine with other vaccines used in the World Health Organization expanded programs of immunization. Three groups of Senegalese children were vaccinated with hepatitis B vaccine (HB) alone, diphtheria-tetanus-pertussis (DTP)-polio vaccine alone, or a combination of hepatitis B vaccine and DTP-polio vaccines simultaneously. The immune responses to HBsAg, tetanus toxoid, diphtheria toxoid, and pertussis were measured after one and two vaccinations at 6-month intervals. The immune responses to the combination of HB vaccine and DTP-polio vaccines were similar to the immune responses observed after administration of each vaccine alone. In addition, no adverse reactions were noted. These experimental trials also demonstrated that with a DTP-polio vaccine containing 30Lf of tetanus and diphtheria toxoids, two doses given at 6-month intervals are sufficient to provide a satisfactory immune response. In the case of pertussis and HB vaccines; however, a third dose is necessary.
PMCID: PMC260966  PMID: 2936684
10.  Malaria chemoprophylaxis and the serologic response to measles and diphtheria-tetanus-whole-cell pertussis vaccines 
Malaria Journal  2005;4:53.
Acute malaria has been associated with a decreased antibody response to tetanus and diphtheria toxoids, meningococcal, salmonella, and Hib vaccines. Interest in giving malaria drug therapy and prevention at the time of childhood immunizations has increased greatly following recent trials of intermittent preventive therapy during infancy (IPTi), stimulating this re-analysis of unpublished data. The effect of malaria chemoprophylaxis on vaccine response was studied following administration of measles vaccines and diphtheria-tetanus-whole cell pertussis (DTP) vaccines.
In 1975, six villages divided into two groups of children ≤74 months of age from Burkina Faso, were assigned to receive amodiaquine hydrochloride chemoprophylaxis (CH+) every two weeks for seven months or no chemoprophylaxis (CH-). After five months, children in each group received either one dose of measles or two doses of DTP vaccines.
For recipients of the measles vaccine, the seroconversion rates in CH+ and CH- children, respectively, were 93% and 96% (P > 0.05). The seroresponse rates in CH+ and CH- children respectively, were 73% and 86% for diphtheria (P > 0.05) and 77% and 91% for tetanus toxoid (P > 0.05). In a subset analysis, in which only children who strictly adhered to chemoprophylaxis criteria were included, there were, likewise, no significant differences in seroconversion or seroresponse for measles, diphtheria, or tetanus vaccines (P > 0.05). While analysis for pertussis showed a 43% (CH+) and 67% (CH-) response (P < 0.05), analyses using logistic regression to control for sex, age, chemoprophylaxis, weight-for-height Z-score, and pre-vaccination geometric mean titer (GMT), demonstrated that chemoprophylaxis was not associated with a significantly different conversion rate following DTP and measles vaccines. Seven months of chemoprophylaxis decreased significantly the malaria IFA and ELISA GMTs in the CH+ group.
Malaria chemoprophylaxis prior to vaccination in malaria endemic settings did not improve or impair immunogenicity of DTP and measles vaccines. This is the first human study to look at the association between malaria chemoprophylaxis and the serologic response to whole-cell pertussis vaccine.
PMCID: PMC1308854  PMID: 16271153
11.  The effect of neonatal vitamin A supplementation on growth in the first year of life among low-birth-weight infants in Guinea-Bissau: two by two factorial randomised controlled trial 
BMC Pediatrics  2013;13:87.
Vitamin A supplementation (VAS) may amplify the effect of vaccines. We therefore investigated if neonatal VAS given with and without Bacille Calmette-Guérin (BCG) vaccine to low-birth-weight (LBW) neonates had an effect on growth in the first year of life. We hypothesised that VAS would be particularly beneficial when provided with BCG.
We conducted a randomised two-by-two factorial trial in Guinea-Bissau; 1,717 LBW neonates were randomly allocated to VAS or placebo at birth as well as early or the usual postponed BCG vaccination. Anthropometric measurements were obtained at 2, 6, and 12 months after inclusion.
Overall there was no effect of neonatal VAS on growth in the first year of life. By 2 months, VAS tended to have a beneficial effect on weight and head circumference when given with BCG but not when given without BCG (interaction: weight-for-age p = 0.07 and head circumference-for-age: p = 0.06). By 6 months, there was a beneficial effect of VAS on head circumference and weight among children who had not received DTP vaccine 2 months after inclusion (weight: 0.18 (0.00; 0.36) and head circumference 0.27 (0.06; 0.48)), but no beneficial effect among those who had received DTP.
The results support other trials indicating that neonatal VAS does not have consistent effects on childhood growth and if anything the effects seem to be temporary. They also show that the effect may differ by vaccination status, being beneficial when given with BCG at birth and when DTP is delayed.
Trial registration (NCT00168610) (nct00168610)
PMCID: PMC3680237  PMID: 23702185
Neonatal vitamin A supplementation; Low-birth-weight; Growth; Non-specific effects; DTP; BCG
12.  Do Beliefs of Inner-City Parents About Disease and Vaccine Risks Affect Immunization? 
The objective of this study was to understand how low income, inner-city parents of preschool children think about childhood diseases and prevention and the impact that this has on late receipt of vaccines.
Parents of all children born between 1/1/91 and 5/31/95, whose child received medical assistance and their health care at one of four inner-city, primary care clinics in Pittsburgh, PA., completed a telephone interview and gave consent for a vaccine record review. The main outcome measures were lateness for first and third diphtheria and tetanus toxoids and pertussis vaccines (DTP) and not receiving at least 4 DTP, 3 polio virus containing and 1 measles, mumps and rubella (MMR) doses by 19 months.
483 parents participated. Fifteen percent of children were late for the first DTP, 52% for the third DTP and, 40% had not received at least 4 DTP, 3 polio and 1 MMR by 19 months of age. Statistically significant factors associated with lateness at 19 months included: having three or more children, having two children, beliefs regarding the severity of immunization side effects and, being African American.
The results of this study indicate that a combination of life circumstances as well as cognitive factors were associated with late immunization.
PMCID: PMC2568314
Immunization behavior; parental beliefs; health communication; health behavior; health disparities
13.  Do beliefs of inner-city parents about disease and vaccine risks affect immunization? 
OBJECTIVE: The objective of this study was to understand how low income, inner-city parents of preschool children think about childhood diseases and prevention and the impact that this has on late receipt of vaccines. METHODS: Parents of all children born between January 1, 1991, and May 31, 1995, whose child received medical assistance and health care at one of four inner-city, primary care clinics in Pittsburgh, PA, completed a telephone interview and gave consent for a vaccine record review. The main outcome measures were lateness for first and third diphtheria and tetanus toxoids and pertussis vaccines (DTP) and not receiving at least four DTP, three polio virus containing and one measles, mumps and rubella (MMR) doses by 19 months. RESULTS: A total of 483 parents participated. Fifteen percent of children were late for the first DTP, 52% for the third DTP, and 40% had not received at least four DTP, three polio and one MMR by 19 months of age. Statistically significant factors associated with lateness at 19 months included: having three or more children, having two children, beliefs regarding the severity of immunization side effects, and being African American. CONCLUSIONS: The results of this study indicate that a combination of life circumstances, as well as cognitive factors were associated with late immunization.
PMCID: PMC2594140  PMID: 12392046
14.  Fast, Antigen-Saving Multiplex Immunoassay To Determine Levels and Avidity of Mouse Serum Antibodies to Pertussis, Diphtheria, and Tetanus Antigens ▿ † 
To enhance preclinical evaluation of serological immune responses to the individual diphtheria, tetanus, and pertussis (DTP) components of DTP combination vaccines, a fast hexavalent bead-based method was developed. This multiplex immunoassay (MIA) can simultaneously determine levels of specific mouse serum IgG antibodies to P antigens P.69 pertactin (P.69 Prn), filamentous hemagglutinin (FHA), pertussis toxin (Ptx), and combined fimbria type 2 and 3 antigens (Fim2/3) and to diphtheria toxin (Dtx) and tetanus toxin (TT) in a single well. The mouse DTP MIA was shown to be specific and sensitive and to correlate with the six single in-house enzyme-linked immunosorbent assays (ELISAs) for all antigens. Moreover, the MIA was expanded to include avidity measurements of DTP antigens in a multivalent manner. The sensitivities of the mouse DTP avidity MIA per antigen were comparable to those of the six individual in-house avidity ELISAs, and good correlations between IgG concentrations obtained by both methods for all antigens tested were shown. The regular and avidity mouse DTP MIAs were reproducible, with good intra- and interassay coefficients of variability (CV) for all antigens. Finally, the usefulness of the assay was demonstrated in a longitudinal study of the development and avidity maturation of specific IgG antibodies in mice having received different DTP vaccines. We conclude that the hexaplex mouse DTP MIA is a specific, sensitive, and high-throughput alternative for ELISA to investigate the quantity and quality of serological responses to DTP antigens in preclinical vaccine studies.
PMCID: PMC3122557  PMID: 21325488
15.  Randomized controlled trial to improve childhood immunization adherence in rural Pakistan: redesigned immunization card and maternal education 
A substantial dropout from the first dose of diphtheria-tetanus-pertussis (DTP1) to the 3rd dose of DTP (DTP3) immunization has been recorded in Pakistan. We conducted a randomized controlled trial to assess the effects of providing substantially redesigned immunization card, center-based education, or both interventions together on DTP3 completion at six rural Expanded Programme on Immunization (EPI) centers in Pakistan.
Mother-child units were enrolled at DTP1 and randomized to four study groups: redesigned card, center-based education, combined intervention, and standard care. Each child was followed-up for 90 days to record the dates of DTP2 and DTP3 visits. The study outcome was DTP3 completion by the end of follow-up period in each study group.
We enrolled 378 mother-child units in redesigned card group, 376 in center-based education group, 374 in combined intervention group, and 378 in standard care group. By the end of follow-up, 39% of children in standard care group completed DTP3. Compared to this, a significantly higher proportion of children completed DTP3 in redesigned card group (66%) (crude Risk Ratio [RR] = 1.7; 95% CI = 1.5, 2.0), center-based education group (61%) (RR = 1.5; 95% CI = 1.3, 1.8), and combined intervention group (67%) (RR = 1.7; 95% CI = 1.4, 2.0).
Improved immunization card alone, education to mothers alone, or both together were all effective in increasing follow-up immunization visits. The study underscores the potential of study interventions’ public health impact and necessitates their evaluation for complete EPI schedule at a large scale in the EPI system.
PMCID: PMC3763701  PMID: 21159080
16.  Role of endotoxin in alterations of hepatic drug metabolism by diphtheria and tetanus toxoids and pertussis vaccine adsorbed. 
Infection and Immunity  1992;60(9):3790-3798.
Administration of diphtheria and tetanus toxoids and pertussis vaccine adsorbed (DTP vaccine) or endotoxin (LPS) resulted in marked alterations in hepatic drug-metabolizing enzymes in endotoxin-responsive (R) and non-endotoxin-responsive (NR) mice. A single human dose (0.5 ml) of DTP vaccine increased hexobarbital-induced sleep times to 1.6- to 1.8-fold above those of controls in both strains of mice. This effect persisted for 7 days. In contrast, Bordetella pertussis LPS-treated mice showed an increase at 1 day (3.0-fold for R mice and 1.5-fold for NR mice), which returned to control levels by day 7. Furthermore, cytochrome P-450 levels were decreased 30 to 40% 24 h after DTP vaccine administration in both R and NR mice, while after LPS administration they were decreased 30% in R mice and less than 10% in NR mice. Both spleen and liver weights of R and NR mice were increased 7 to 14 days following DTP vaccine administration. However, LPS treatment had no apparent effect on liver weights, and spleen weights of R mice were elevated from days 3 to 7. Histopathologic tissue examination showed random, multifocal inflammation with hepatocyte necrosis after DTP vaccine administration to both R and NR mice and an absence of lesions in LPS-treated mice. Premixing LPS with polymyxin eliminated the increased sleep times, but premixing DTP vaccine with polymyxin did not affect the increased sleep times. Levels of tumor necrosis factor and interleukin-6 in plasma of R mice were markedly increased after DTP and LPS treatment, while NR mice had reduced increases. These results suggest that LPS contributes to the alterations in R and NR mice seen within the first 24 h of vaccine administration but that it is not likely to contribute to the effects observed at later time points.
PMCID: PMC257391  PMID: 1500188
17.  A mid-term assessment of progress towards the immunization coverage goal of the Global Immunization Vision and Strategy (GIVS) 
BMC Public Health  2011;11:806.
The Global Immunization Vision and Strategy (GIVS) (2006-2015) aims to reach and sustain high levels of vaccine coverage, provide immunization services to age groups beyond infancy and to those currently not reached, and to ensure that immunization activities are linked with other health interventions and contribute to the overall development of the health sector.
To examine mid-term progress (through 2010) of the immunization coverage goal of the GIVS for 194 countries or territories with special attention to data from 68 countries which account for more than 95% of all maternal and child deaths.
We present national immunization coverage estimates for the third dose of diphtheria and tetanus toxoid with pertussis (DTP3) vaccine and the first dose of measles containing vaccine (MCV) during 2000, 2005 and 2010 and report the average annual relative percent change during 2000-2005 and 2005-2010. Data are taken from the WHO and UNICEF estimates of national immunization coverage, which refer to immunizations given during routine immunization services to children less than 12 months of age where immunization services are recorded.
Globally DTP3 coverage increased from 74% during 2000 to 85% during 2010, and MCV coverage increased from 72% during 2000 to 85% during 2010. A total of 149 countries attained or were on track to achieve the 90% coverage goal for DTP3 (147 countries for MCV coverage). DTP3 coverage ≥ 90% was sustained between 2005 and 2010 by 99 countries (98 countries for MCV). Among 68 priority countries, 28 countries were identified as having made either insufficient or no progress towards reaching the GIVS goal of 90% coverage by 2015 for DTP3 or MCV. DTP3 and MCV coverage remained < 70% during 2010 for 16 and 21 priority countries, respectively.
Progress towards GIVS goals highlights improvements in routine immunization coverage, yet it is troubling to observe priority countries with little or no progress during the past five years. These results highlight that further efforts are needed to achieve and maintain the global immunization coverage goals.
PMCID: PMC3210114  PMID: 21999521
immunization coverage; statistics; immunization; monitoring; Global Immunization Vision and Strategy (GIVS)
18.  Timing of routine immunisations and subsequent hay fever risk 
Archives of Disease in Childhood  2005;90(6):567-573.
Background: Suggestions that immunisation influences allergic disease risk, either positively (pertussis) or negatively (BCG) are of concern for vaccination policy.
Aims: To determine whether DTP, MMR, and BCG vaccination in infancy influenced hay fever risk.
Methods: Case-control study of 7098 hay fever cases and controls, within two primary care databases. One control per case was matched for practice, age, and sex. Odds ratios (OR) were derived using conditional logistic regression.
Results: Compared to those completing in month 5 (base group) (39.3%), DTP unvaccinated children (4.3%) had a similar risk of hay fever (OR = 0.94, 95% CI 0.73 to 1.23). However, those completing after 12 months (4.2%) had a reduced risk (OR = 0.60, 95% CI 0.45 to 0.76) compared to the base group. Compared to those vaccinated in month 14 (base group) (29.5%), MMR unvaccinated children (2.3%) had an OR of 0.79 (95% CI 0.58 to 1.08). Completion of MMR after two years was associated with reduced hay fever risk (OR = 0.62, 95% CI 0.48 to 0.80) compared to the base group. The effects of late immunisation with DTP and MMR were independent. Those vaccinated with BCG by age 2 (2.4%) had an odds ratio of 1.28 (95% CI 0.96 to 1.70). Adjustment for consulting behaviour, social factors, or sibship size did not alter these associations.
Conclusions: Immunisation against DTP or MMR does not increase the risk of hay fever. The lower confidence limit for BCG vaccination contradicts the hypothesised protective effect. The reduced risk of hay fever among children immunised late may be explained by a third factor causing both postponement and reduced risk such as intercurrent febrile illnesses.
PMCID: PMC1720414  PMID: 15908618
19.  Childhood vaccination in informal urban settlements in Nairobi, Kenya: Who gets vaccinated? 
BMC Public Health  2011;11:6.
Recent trends in global vaccination coverage have shown increases with most countries reaching 90% DTP3 coverage in 2008, although pockets of undervaccination continue to persist in parts of sub-Saharan Africa particularly in the urban slums. The objectives of this study were to determine the vaccination status of children aged between 12-23 months living in two slums of Nairobi and to identify the risk factors associated with incomplete vaccination.
The study was carried out as part of a longitudinal Maternal and Child Health study undertaken in Korogocho and Viwandani slums of Nairobi. These slums host the Nairobi Urban Health and Demographic Surveillance System (NUHDSS) run by the African Population and Health Research Centre (APHRC). All women from the NUHDSS area who gave birth since September 2006 were enrolled in the project and administered a questionnaire which asked about the vaccination history of their children. For the purpose of this study, we used data from 1848 children aged 12-23 months who were expected to have received all the WHO-recommended vaccinations. The vaccination details were collected during the first visit about four months after birth with follow-up visits repeated thereafter at four month intervals. Full vaccination was defined as receiving all the basic childhood vaccinations by the end of 24 months of life, whereas up-to-date (UTD) vaccination referred to receipt of BCG, OPV 1-3, DTP 1-3, and measles vaccinations within the first 12 months of life. All vaccination data were obtained from vaccination cards which were sighted during the household visit as well as by recall from mothers. Multivariate models were used to identify the risk factors associated with incomplete vaccination.
Measles coverage was substantially lower than that for the other vaccines when determined using only vaccination cards or in addition to maternal recall. Up-to-date (UTD) coverage with all vaccinations at 12 months was 41.3% and 51.8% with and without the birth dose of OPV, respectively. Full vaccination coverage (57.5%) was higher than up-to-date coverage (51.8%) at 12 months overall, and in both slum settlements, using data from cards. Multivariate analysis showed that household assets and expenditure, ethnicity, place of delivery, mother's level of education, age and parity were all predictors of full vaccination among children living in the slums.
The findings show the extent to which children resident in slums are underserved with vaccination and indicate that service delivery of immunization services in the urban slums needs to be reassessed to ensure that all children are reached.
PMCID: PMC3024932  PMID: 21205306
20.  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
21.  Maiden immunization coverage survey in the republic of South Sudan: a cross-sectional study providing baselines for future performance measurement 
Since the comprehensive peace agreement was signed in 2005, institutionalization of immunization services in South Sudan remained a priority. Routine administrative reporting systems were established and showed that national coverage rates for DTP-3 rose from 20% in 2002 to 80% in 2011. This survey was conducted as part of an overall review of progress in implementation of the first EPI Multi-Year Plan for South Sudan 2007-2011. This report provides maiden community coverage estimates for immunization.
A cross sectional community survey was conducted between January and May 2012. Ten cluster surveys were conducted to generate state-specific coverage estimates. The WHO 30x7 cluster sampling method was employed. Data was collected using pre-tested, interviewer guided, structured questionnaires through house to house visits.
The fully immunized children were 7.3%. Coverage for specific antigens were; BCG (28.3%), DTP-1(25.9%), DTP-3 (22.0%), Measles (16.8%). The drop-out rate between the first and third doses of DTP was 21.3%. Immunization coverage estimates based on card and history were higher, at 45.7% for DTP-3, 45.8% for MCV and 32.2% for full immunization. Majority of immunizations (80.8%) were received at health facilities compared to community service points (19.2%). The major reason for missed immunizations was inadequate information (41.1%).
The proportion of card-verified, fully vaccinated among children aged 12-23 months is very low at 7.3%. Future efforts to improve vaccination quality and coverage should prioritize training of vaccinators and program communication to levels equivalent or higher than investments in EPI cold chain systems since 2007.
PMCID: PMC4033584  PMID: 24876899
Immunization Coverage Survey; South Sudan
22.  Frequency of apnea, bradycardia, and desaturations following first diphtheria-tetanus-pertussis-inactivated polio-Haemophilus influenzae type B immunization in hospitalized preterm infants 
BMC Pediatrics  2006;6:20.
Adverse cardiorespiratory events including apnea, bradycardia, and desaturations have been described following administration of the first diphtheria-tetanus-pertussis-inactivated polio-Haemophilus influenzae type B (DTP-IPV-Hib) immunization to preterm infants. The effect of the recent substitution of acellular pertussis vaccine for whole cell pertussis vaccine on the frequency of these events requires further study.
Infants with gestational age of ≤ 32 weeks who received their first DTP-IPV-Hib immunization prior to discharge from two Edmonton Neonatal Intensive Care Units January 1, 1996 to November 30, 2000 were eligible for the study. Each immunized infant was matched by gestational age to one control infant. The number of episodes of apnea, bradycardia, and/or desaturations (ABD) and the treatment required for these episodes in the 72 hours prior to and 72 hours post-immunization (for the immunized cohort) or at the same post-natal age (for controls) was recorded.
Thirty-four infants who received DTP-IPV-Hib with whole cell pertussis vaccine, 90 infants who received DTP-IPV-Hib with acellular pertussis vaccine, and 124 control infants were entered in the study. Fifty-six immunized infants (45.1%) and 36 control infants (29.0%) had a resurgence of or increased ABD in the 72 hours post-immunization in the immunized infants and at the same post-natal age in the controls with an adjusted odds ratio for immunized infants of 2.41 (95% CI 1.29,4.51) as compared to control infants. The incidence of an increase in adverse cardiorespiratory events post-immunization was the same in infants receiving whole cell or acellular pertussis vaccine (44.1% versus 45.6%). Eighteen immunized infants (14.5%) and 51 control infants (41.1%) had a reduction in ABD in the 72 hours post- immunization or at the equivalent postnatal age in controls for an odds ratio of 0.175 (95%CI 0.08, 0.39). The need for therapy of ABD in the immunized infants was not statistically different from the control infants. Lower weight at the time of immunization was a risk factor for a resurgence of or increased ABD post-immunization. Birth weight, gestational age, postnatal age or sex were not risk factors.
There is an increase in adverse cardiorespiratory events following the first dose of DTP-IPV-Hib in preterm infants. Lower current weight was identified as a risk factor, with the risk being equivalent for whole cell versus acellular pertussis vaccine. Although most of these events are of limited clinical significance, cardiorespiratory monitoring of infants who are sufficiently preterm that they are receiving their first immunization prior to hospital discharge should be considered for 72 hours post-immunization.
PMCID: PMC1523189  PMID: 16784533
23.  Diphtheria-Tetanus-Pertussis Immunization by Intradermal Jet Injection 
British Medical Journal  1972;2(5807):197-199.
An intradermal jet injector was used to administer combined diphtheria, tetanus, and pertussis (D.T.P.) vaccines to infants aged 2 to 12 months. A second dose was given one month after the first and a third six months after the second. Each dose was considerably smaller than the standard intramuscular dose. Blood samples taken one month after the third dose showed a satisfactory diphtheria and tetanus antitoxin response in all but a few cases. The antibody response to the pertussis component was not examined. Reactions were insignificant. Intradermal jet injection is proposed as a cheap, extremely rapid, and effective technique for D.T.P. immunization, especially suitable for use in remote areas where trained staff and facilities are few and many children require immunization.
PMCID: PMC1787936  PMID: 5022729
24.  Association between sudden infant death syndrome and diphtheria-tetanus-pertussis immunisation: an ecological study 
BMC Pediatrics  2015;15(1):1.
Sudden infant death syndrome (SIDS) continues to be one of the main causes of infant mortality in the United States. The objective of this study was to analyse the association between diphtheria-tetanus-pertussis (DTP) immunisation and SIDS over time.
The Centers for Disease Control and Prevention provided the number of cases of SIDS and live births per year (1968–2009), allowing the calculation of SIDS mortality rates. Immunisation coverage was based on (1) the United States Immunization Survey (1968–1985), (2) the National Health Interview Survey (1991–1993), and (3) the National Immunization Survey (1994–2009). We used sleep position data from the National Infant Sleep Position Survey. To determine the time points at which significant changes occurred and to estimate the annual percentage change in mortality rates, we performed joinpoint regression analyses. We fitted a Poisson regression model to determine the association between SIDS mortality rates and DTP immunisation coverage (1975–2009).
SIDS mortality rates increased significantly from 1968 to 1971 (+27% annually), from 1971 to 1974 (+47%), and from 1974 to 1979 (+3%). They decreased from 1979 to 1991 (−1%) and from 1991 to 2001 (−8%). After 2001, mortality rates remained constant. DTP immunisation coverage was inversely associated with SIDS mortality rates. We observed an incidence rate ratio of 0.92 (95% confidence interval: 0.87 to 0.97) per 10% increase in DTP immunisation coverage after adjusting for infant sleep position.
Increased DTP immunisation coverage is associated with decreased SIDS mortality. Current recommendations on timely DTP immunisation should be emphasised to prevent not only specific infectious diseases but also potentially SIDS.
PMCID: PMC4326294  PMID: 25626628
Sudden infant death syndrome; Diphtheria-tetanus-pertussis immunisation; Time trends
25.  Vaccination Coverage Estimates for Selected Counties: Achievement of Healthy People 2010 Goals and Association with Indices of Access to Care, Economic Conditions, and Demographic Composition 
Public Health Reports  2008;123(2):155-172.
We provided vaccination coverage estimates for 181 counties; evaluated the extent to which Healthy People 2010 (HP 2010) vaccination coverage objectives were achieved; and examined how variations in those estimates depend on access to care and economic conditions.
We analyzed data for 24,031 children aged 19 to 35 months sampled from the 2004 and 2005 National Immunization Survey.
Children living in the 181 counties represented 49% of all the 19- to 35-month-old children living in the U.S. None of the 181 counties had coverage for the polio, measles-mumps-rubella, Haemophilus influenzae type B, and hepatitis B vaccines that was significantly lower than the HP 2010 objective of 90% coverage. However, as many as 30.4% of the counties did not achieve the HP 2010 objective for diphtheria, tetanus toxoids, and acellular pertussis or diphtheria and tetanus toxoids and pertussis (DtaP/DTP), and as many as 6.6% did not achieve the goal for varicella (VAR). If children who received three doses of DTaP/DTP had received a final fourth dose, and if all children had received one dose of VAR, all of the 181 counties would have achieved the HP 2010 vaccination coverage target of 80% for the entire 4:3:1:3:3:1 vaccination series. Factors found to be associated with low county-level vaccination coverage rates were correlates of poverty, and factors found to be associated with high county-level vaccination coverage rates were correlates of access to pediatric services.
HP 2010 vaccination coverage goals for all 181 counties can be achieved by improving vaccination coverage for only two vaccines. Those goals may be achieved most efficiently by targeting interventions in counties where indices of poverty are high or where access to pediatric services is low.
PMCID: PMC2239325  PMID: 18457068

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