The immunological effects of oral polio vaccine provided with BCG vaccine at birth: A randomised trial

Background

Vaccines may have non-specific effects. An observational study from Guinea-Bissau suggested that oral polio vaccine at birth (OPV0) provided with Bacillus Calmette–Guérin (BCG) vaccine was associated with down-regulation of the immune response to BCG vaccine 6 weeks later. Based on the previous finding, we wanted to test our a priori hypothesis that OPV would dampen the immune response to BCG, and secondarily to test immune responses to other antigens.

Methods

The study was conducted at the Bandim Health Project in Guinea-Bissau in 2009–2010. Infants were randomised to OPV0 + BCG versus BCG alone at birth, and subsequently randomised to have a blood sample taken at 2, 4 or 6 weeks post-randomisation. Excreted levels of cytokines (IL-2, IL-5, IL-10, TNF-α and IFN-γ) were measured from whole blood in vitro stimulations with a panel of recall vaccine antigens (BCG, PPD, OPV), mitogen (PHA) or innate agonists (LPS, Pam3cys, PolyI:C). Additionally, we measured the local reaction to BCG, white blood cell distribution, C-reactive protein (CRP) and retinol-binding protein (RBP). Cytokine production was analysed as the prevalence ratios of responders above the median.

Results

Blood samples from 430 infants (209 OPV0 + BCG; 221 BCG alone) were analysed. There were no strong differences in effects 2, 4 and 6 weeks post-randomisation and subsequent analyses were performed on the pooled data. As hypothesised, receiving OPV0 + BCG versus BCG alone was associated with significantly lower prevalence of IFN-γ responses to PPD (prevalence ratio (PR): 0.84 (0.72–0.98)) and reduced IL-5 to PPD (PR: 0.78 (0.64–0.96)). No effects were observed for CPR, RBP, white blood cell distribution, or BCG scar prevalence.

Conclusion

The results corroborate that OPV attenuates the immune response to co-administered BCG at birth.     

Delaying BCG vaccination from birth to 10 weeks of age may result in an enhanced memory CD4 T cell response

Background

In most tuberculosis (TB) endemic countries, bacillus Calmette–Guérin (BCG) is usually given around birth to prevent severe TB in infants. The neonatal immune system is immature. Our hypothesis was that delaying BCG vaccination from birth to 10 weeks of age would enhance the vaccine-induced immune response.

Methods

In a randomized clinical trial, BCG was administered intradermally either at birth (n = 25) or at 10 weeks of age (n = 21). Ten weeks after vaccination, and at 1 year of age, vaccine-specific CD4 and CD8 T cell responses were measured with a whole blood intracellular cytokine assay.

Results

Infants who received delayed BCG vaccination demonstrated higher frequencies of BCG-specific CD4 T cells, particularly polyfunctional T cells co-expressing IFN-γ, TNF-α and IL-2, and most strikingly at 1 year of age.

Conclusions

Delaying BCG vaccination from birth to 10 weeks of age enhances the quantitative and qualitative BCG-specific T cell response, when measured at 1 year of age.     

Safety and reactogenicity of BCG revaccination with isoniazid pretreatment in TST positive adults

Rationale

Global tuberculosis (TB) control may require mass vaccination with a new TB vaccine, such as a recombinant bacille Calmette Guerin (BCG) or attenuated Mycobacterium tuberculosis (MTB). The safety profile of live mycobacterial vaccines in latently infected adults with prior infant BCG vaccination is unknown.

Objectives

Evaluate safety and reactogenicity of BCG revaccination, with or without isoniazid (INH) pretreatment, in adults with latent MTB infection (LTBI).

Methods

Eighty-two healthy, HIV uninfected, South African adults, with a BCG scar and tuberculin skin test (TST) diameter ≥15 mm, were randomized to receive 6 months of INH, starting either before, or 6 months after, intradermal revaccination with BCG Vaccine SSI (Statens Serum Institut, Copenhagen). Safety and reactogenicity data are reported through 3 months post BCG revaccination.

Results

Baseline characteristics were similar between treatment arms. Mean baseline TST diameter was 20 ± 4 mm. Seventy-two subjects received BCG revaccination. Injection site erythema (68%) and induration (86%) peaked 1 week after revaccination. Ulceration (76%) peaked at 2 weeks, and resolved by 3 months in all but 3 subjects. Diameter of ulceration was >10 mm in only 8%, but a residual scar was common (85%). No regional lymphadenitis or serious morbidity related to BCG was seen. Reactogenicity was not affected by INH pretreatment.

Conclusion

BCG revaccination of MTB infected adults is safe, well tolerated, and reactogenicity is similar to that of primary BCG vaccination. Clinical trials of live recombinant BCG or attenuated MTB vaccines may be considered in latently infected adults, with or without INH pretreatment (ClinicalTrials.gov identifier: NCT01119521).     

No effect of oral polio vaccine administered at birth on mortality and immune response to BCG. A natural experiment

Background

WHO recommends oral polio vaccine at birth (OPV0) in polio endemic countries. During a period without OPV in Guinea-Bissau in 2004, we observed that not receiving OPV0 was associated with significantly decreased mortality in boys and better immune response to BCG vaccination. In 2007, whilst conducting a trial of BCG and vitamin A supplementation (VAS) at birth to low birthweight (LBW) children, OPV was again lacking for a short period. We used this natural experiment to test the previous observations.

Methods

In the trial LBW infants were randomised to early or delayed BCG and VAS or placebo at birth. We noted whether the children received OPV0 or not. We compared children who received No OPV0 with those who received OPV0 in the 2 months before and the 2 months after the period without OPV. Mortality was compared in Cox regression models providing adjusted hazard ratios (aHR); the immune response to BCG was assessed in Poisson models providing adjusted prevalence ratios (aPR).

Results

Ninety-nine children received No OPV0 and were compared with 243 children who received OPV0. No OPV0 was associated with insignificantly higher mortality during the first year of life, the aHR being 1.83 (95% CI: 0.93–3.61). The effect was similar in boys and girls. Overall, there was no significant association between No OPV0 and having a positive PPD response (aPR = 1.33 (0.64–2.78)) or a scar (aPR = 1.02 (0.93–1.11)) after BCG vaccination, though No OPV0 boys were more likely to develop a scar (aPR: 1.10 (1.01–1.20)).

Conclusions

The findings did not support our previous observation that not receiving OPV0 was associated with reduced mortality in boys. The findings weakly supported that OPV0 leads to a dampened response to simultaneously administered BCG vaccine in boys.     

Comparative performance of public and private sector delivery of BCG vaccination: Evidence from Sub-Saharan Africa

Background

The private sector is an important source of health care in the developing world. However, there is limited evidence on how private providers compare to public providers, particularly for preventive services such as immunizations. We used data from Sub-Saharan Africa (SSA) to assess public–private differences in Bacillus Calmette–Guérin (BCG) vaccine delivery.

Methods and findings

We used demographic and health surveys from 102,629 children aged 0–59 months from 29 countries across SSA to measure differences in BCG status for children born at private versus public health facilities (BCG is recommended at birth). We used a probit model to estimate public–private differences in BCG delivery, while controlling for key confounders. Next, we estimated how differences in BCG status evolved over time for children born at private versus public facilities. Finally, we estimated heterogeneity in public–private differences based on wealth and rural–urban residency. We found that children born at a private facility were 7.1 percentage points less likely to receive BCG vaccine in the same month as birth than children born at a public facility (95% CI 6.3–8.0; p < 0.001). Most of this difference was driven by for-profit private providers (as opposed to NGOs) where the BCG provision rate was 10.0 percentage points less than public providers (95% CI 9.0–11.2; p < 0.001) compared to only 2.4 percentage points for NGOs (95% CI 1.0–3. 8; p < 0.01). Moreover, children born at private for-profit facilities remained less likely to be vaccinated up to 59 months after birth. Finally, public–private differences were more pronounced for poorer children and children in rural areas.

Conclusions

The for-profit private sector performed substantially worse than the public sector in providing BCG vaccine to newborns, resulting in a longer duration of vulnerability to tuberculosis. This disparity was greater for poorer children and children in rural areas.     

Comparison of antibody and cell-mediated immune responses of foals and adult horses after vaccination with live Mycobacterium bovis BCG

Background

Equine neonates have reduced humoral and cell-mediated immune responses compared to adult horses after administration of killed vaccines. As a basis for this study, we hypothesized that newborn foals can mount strong immune responses after vaccination with live Mycobacterium bovis BCG.

Methods

Healthy 4-day-old foals (n = 7), 4-month-old foals (n = 7) and adult horses (n = 6) were vaccinated once with live M. bovis BCG. Age-matched animals (n = 5 per group) were used as unvaccinated controls. Relative vaccine-specific immunoglobulin concentrations and whole blood mRNA expression of IFN-γ, IL-4, and IL-10 were measured prior to and 2, 4, 6, and 8 weeks after vaccination. Eight weeks after vaccination, delayed type hypersensitivity (DTH) responses were assessed by measuring the increase in double skin thickness after intradermal injection of purified protein derivative.

Results

Both groups of foals and adult horses responded with a significant increase in vaccine-specific total IgG, IgGa, IgGc, IgG(T), and IgM concentrations. In contrast, only adult horses mounted significant IgGb responses. Vaccine-specific concentrations of total IgG and IgGa were significantly higher in adult horses than in 4-day-old foals whereas IgGc responses were significantly higher in 4-day-old foals than in the other two age groups. Adult horses had significantly higher basal IFN-γ and IL-4 mRNA expression than both groups of foals but vaccination with M. bovis BCG did not significantly increase expression of these cytokines, regardless of age group. Immunized horses had significantly higher DTH responses than age-matched unvaccinated controls. DTH responses were significantly greater in both groups of vaccinated foals than in vaccinated adult horses.

Conclusion

Despite a naïve immune system, newborn foals have the ability to mount robust antibody and cell-mediated immune responses to M. bovis BCG.     

Socio-demographic determinants of timely adherence to BCG,Penta3, measles,and complete vaccination schedule in Burkina Faso

Objective

To identify the determinants of timely vaccination among young children in the North-West of Burkina Faso.

Methods

This study included 1665 children between 12 and 23 months of age from the Nouna Health and Demographic Surveillance System, born between September 2006 and December 2008. The effect of socio-demographic variables on timely adherence to the complete vaccination schedule was studied in multivariable ordinal logistic regression with 3 distinct endpoints: (i) complete timely adherence, (ii) failure, and (iii) missing vaccination. Three secondary endpoints were timely vaccination with BCG, Penta3, and measles, which were studied with standard multivariable logistic regression.

Results

Mothers’ education, socio-economic status, season of birth, and area of residence were significantly associated with failure of timely adherence to the complete vaccination schedule. Year of birth, ethnicity, and the number of siblings was significantly related to timely vaccination with Penta3 but not with BCG or measles vaccination. Children living in rural areas were more likely to fail timely vaccination with BCG than urban children (OR = 1.79, 95%CI = 1.24–2.58 (proximity to health facility), OR = 3.02, 95%CI = 2.18–4.19 (long distance to health facility)). In contrast, when looking at Penta3 and measles vaccination, children living in rural areas were far less likely to have failed timely vaccinations than urban children. Mother's education positively influenced timely adherence to the vaccination schedule (OR = 1.42, 95%CI 1.06–1.89). There was no effect of household size or the age of the mother.

Conclusions

Additional health facilities and encouragement of women to give birth in these facilities could improve timely vaccination with BCG. Rural children had an advantage over the urban children in timely vaccination, which is probably attributable to outreach vaccination teams amongst other factors. As urban children rely on their mothers’ own initiative to get vaccinated, urban mothers should be encouraged more strongly to get their children vaccinated in time.     

Non-specific and sex-differential effects of vaccinations on child survival in rural western India

Background

Studies from Africa have suggested marked non-specific effects (NSEs) of routine vaccinations with effects on child survival. There have been few studies from Asia. We re-analyzed a study from Maharashtra, India, which had collected information on vaccinations during infancy and survival until 5 years of age.

Design

4138 children born between 1987 and 1989 were visited at home every three months to collect information on nutritional status and vaccinations. Since nutritional status was a determinant of time to vaccinations, we adjusted for nutritional status in the analyzes of the association between vaccinations and mortality.

Setting

45 contiguous villages in Shirur Administrative Block in Pune District.

Main outcome measures

Mortality rate ratios (MRR) for different vaccination status groups.

Results

The study area has male preferential treatment, but the female–male mortality ratio varied between age groups with different pre-dominant vaccines; it was high in the age group in which diphtheria–tetanus–pertussis (DTP) vaccine predominates and low in the age group in which measles vaccine (MV) is given. Children who followed the WHO recommended schedule of first BCG and then DTP vaccination were vaccinated earlier than other children (p < 0.01). Two-thirds of the children had received BCG and DTP out-of-sequence, i.e. BCG and DTP simultaneously or BCG after DTP. Children who received BCG and DTP simultaneously or BCG as most recent vaccination had significantly lower mortality than children having DTP as the most recent vaccination, the mortality rate ratio being 0.15 (0.03–0.70).

Conclusions

BCG out-of-sequence may be associated with lower mortality than DTP as the most recent vaccination. Given the public health implications, this possibility should be tested in randomized trials. Excess female mortality may also be related to vaccination policy.     

Cluster randomized trial of a toolkit and early vaccine delivery to improve childhood influenza vaccination rates in primary care

Purpose

To increase childhood influenza vaccination rates using a toolkit and early vaccine delivery in a randomized cluster trial.

Methods

Twenty primary care practices treating children (range for n = 536–8183) were randomly assigned to Intervention and Control arms to test the effectiveness of an evidence-based practice improvement toolkit (4 Pillars Toolkit) and early vaccine supplies for use among disadvantaged children on influenza vaccination rates among children 6 months–18 years. Follow-up staff meetings and surveys were used to assess use and acceptability of the intervention strategies in the Intervention arm. Rates for the 2010–2011 and 2011–2012 influenza seasons were compared. Two-level generalized linear mixed modeling was used to evaluate outcomes.

Results

Overall increases in influenza vaccination rates were significantly greater in the Intervention arm (7.9 percentage points) compared with the Control arm (4.4 percentage points; P < 0.034). These rate changes represent 4522 additional doses in the Intervention arm vs. 1390 additional doses in the Control arm. This effect of the intervention was observed despite the fact that rates increased significantly in both arms – 8/10 Intervention (all P < 0.001) and 7/10 Control sites (P-values = 0.04 to <0.001). Rates in two Intervention sites with pre-intervention vaccination rates >58% did not significantly increase. In regression analyses, a child's likelihood of being vaccinated was significantly higher with: younger age, white race (Odds ratio [OR] = 1.29; 95% confidence interval [CI] = 1.23–1.34), having commercial insurance (OR = 1.30; 95%CI = 1.25–1.35), higher pre-intervention practice vaccination rate (OR = 1.25; 95%CI = 1.16–1.34), and being in the Intervention arm (OR = 1.23; 95%CI = 1.01–1.50). Early delivery of influenza vaccine was rated by Intervention practices as an effective strategy for raising rates.

Conclusions

Implementation of a multi-strategy toolkit and early vaccine supplies can significantly improve influenza vaccination rates among children in primary care practices but the effect may be less pronounced in practices with moderate to high existing vaccination rates.Clinical trial registry name/number: From Innovation to Solutions: Childhood Influenza/NCT01664793.     

Does oral polio vaccine at birth affect the size of the thymus? Observations within a randomized trial

Background

There is increasing evidence that vaccines have an effect on general mortality which goes beyond specific disease protection. Oral polio vaccine (OPV) is widely used in low-income countries, but in observational studies in Guinea-Bissau we observed that not receiving OPV at birth was associated with reduced overall male infant mortality and enhanced immune response to BCG vaccine. We therefore initiated a randomized trial to test the overall effect of OPV at birth (OPV0).

Objective

A small thymic gland is a predictor of mortality in high-mortality settings. Within the trial we aimed to test whether no-OPV0 was associated with increased thymic size.

Methods

In 511 normal birth weight infants who were randomized to receive or not receive OPV0, thymic index and thymus/weight index were measured before randomization and after 2 weeks (N = 49), 4 weeks (N = 308) or 6 weeks (N = 27). The association between OPV0 and the log transformed thymic size indicators were analyzed in ANCOVA models with thymic size at follow-up as the outcome and adjusting for thymic size at enrollment and age at follow-up. Estimates were reported as geometric mean ratios (GMR) with 95% confidence intervals, comparing no-OPV0 to OPV0.

Results

No-OPV0 was not associated with thymic index after 2 weeks (GMR: 1.14 (0.99–1.30)), after 4 weeks (GMR: 0.98 (0.93–1.05)) or after 6 weeks (GMR: 1.00 (0.81–1.23)). However, no-OPV0 was associated with increased thymus/weight index after 2 weeks (GMR: 1.22 (1.06–1.40)), but the effect was not seen after 4 weeks (GMR: 0.97 (0.92–1.03)) and 6 weeks (GMR: 0.99 (0.82–1.19)). There were no strong sex-differences.

Discussion

Overall there was no effect on thymic size of OPV0 when administered with BCG. The results could indicate that if an effect occurs, it is only within the first weeks after vaccination.     

Group M consensus Gag and Nef peptides are as efficient at detecting clade A1 and D cross-subtype T-cell functions as subtype-specific consensus peptides

Objective

Evaluating HIV-1 specific T-cell response in African populations is sometimes compromised by extensive virus diversity and paucity of non-clade B reagents. We evaluated whether consensus group M (ConM) peptides could serve as comparable substitutes for detecting immune responses in clade A and clade D HIV-1 infection.

Methods

Frequencies, breadths and polyfunctionality (≥3 functions: IFN-γ, IL-2, TNF-α and Perforin) of HIV-specific responses utilizing ConM, ConA and ConD Gag and Nef peptides was compared.

Results

Median genetic distances of infecting gag sequences from consensus group M were (8.9%, IQR 8.2–9.7 and 9%, IQR 3.3–10) for consensus A and D, respectively. Of 24 subjects infected with A and D clade virus, Gag responses were detected in comparable proportions of subjects when using ConM peptides 22/24, ConA peptides 17/24, and ConD peptides 21/24; p = 0.12. Nef responses were also detected at similar proportions of subjects when using ConM peptides 15/23, ConA peptides 19/23, and ConD peptides 16/23, p = 0.39. Virus-specific CD4+ and CD8+ T-cell polyfunctionality were also detected in similar proportions of infected individuals when using different peptide sets.

Conclusions

These data support the use of consensus group M overlapping peptide sets as reagents for detecting HIV-specific responses in a clade A and D infected population, but underscore the limitations of utilizing these reagents when evaluating the breadth of virus-specific responses.     

Well-woman visit of mothers and human papillomavirus vaccine intent and uptake among their 9–17 year old children

Objective

To examine the association between attending a well-woman clinic in the prior 2 years and obtaining the human papillomavirus (HPV) vaccine for their 9–17-year-old child.

Methods

Women (n = 1256) who attended reproductive health clinics during September 2011 to February 2013 and had ≥1 children 9–17 years of age were asked to complete a self-administered questionnaire containing questions on demographic characteristics, prior well-woman visits, HPV awareness, and HPV vaccine intent and uptake among their adolescent children.

Results

Nearly 78% of women reported having undergone a well-woman visit during the past 2 years. Bivariate analysis showed that the HPV vaccine initiation (23.9% vs. 14.0%, P = .004) and completion (13.6% vs. 6.7%, P = .011) among 9–17 daughters differed between mothers who did or did not have a well-woman visit during the past 2 years. However, intent to vaccinate them (47.2% vs. 53.3%, P = .173) did not differ between these two groups. With regard to 9–17 year old sons, vaccine initiation (10.1% vs. 9.6%, P = .871), completion (4.6% vs. 2.4%, P = .273) and intent to vaccinate (47.3% vs. 52.1%, P = .311) did not differ between these two groups. Multivariable logistic regression analyses confirmed the findings of these bivariate analyses after adjusting for confounder variables.

Conclusion

The well-woman visit may be a missed opportunity for physicians to educate their patients about the benefits of HPV vaccination for their adolescent children in general and sons in particular. Intervention studies are warranted to assess the benefits of using this setting to improve HPV vaccine uptake in the US.     

Parental and community acceptance of the benefits and risks associated with meningococcal B vaccines

Objective

A new meningococcal serogroup B (Men B) vaccine has been licensed in the European Union (EU) and Australia. This study aimed to assess community and parental attitudes to introduction of new Men B vaccines and identify facilitators and barriers to vaccine implementation.

Methods

Cross-sectional survey including face-to-face interviews with adolescents, parents and adults from randomly selected households in South Australia in 2012. Survey data were weighted to the age, gender and geographical area profile of the population.

Results

3055 interviews were conducted with individuals aged 15–97 years, including 966 parents. Participation rate was 66.4%. 82.5% (95% CI 79.7–85.4) of parents (797/966) wanted their child to receive the Men B vaccine, with 12.2% (9.7–14.7) (118/966) unsure. Main parental concerns included potential side effects (41.3% (26.7–46.0)) and adequate vaccine testing (11.7% (9.4–14.1)). Potential for an extra injection at an immunisation visit resulted in 15.7% (12.8–18.5) of parents (n = 152/966) less likely to have their child immunised. Potential redness/swelling at the injection site or mild/moderate fever resulted in only 8.5% (6.3–10.7) and 10.8% (8.5–13.2) of parents, respectively, less likely to have their child immunised. Children being up to date with vaccinations and recommendation from family physician were the strongest independent predictors of parents agreeing their children should be immunised with Men B vaccine (OR = 6.58; p = 0.006 and OR = 4.15; p < 0.001, respectively). Only 16.4% (14.9–17.9) of adults (501/3055) stated that they would not want to receive a Men B vaccine, with family physician recommendation the strongest independent predictor of acceptance (OR = 3.81; p < 0.001).

Conclusions

There is strong community support for introduction of Men B vaccines, with parental willingness to have children immunised, impacted more by number of injections than potential for adverse events such as local reactions or fever.     

Safety and immunogenicity of the recombinant BCG vaccine VPM1002 in a phase 1 open-label randomized clinical trial

Background

Current vaccination using Mycobacterium bovis bacillus Calmette-Guérin (BCG), fails to prevent pulmonary tuberculosis (TB). New vaccination strategies are essential for reducing the global incidence of TB. We assessed the safety and immunogenicity of VPM1002, a recombinant BCG vaccine candidate. EudraCT (2007-002789-37) and ClinicalTrials.gov (NCT00749034).

Methods

Healthy volunteers were enrolled in a phase 1 open-label, dose escalation randomized clinical trial, and received one intradermal dose of VPM1002 (Mycobacterium bovis BCG ΔureC::hly Hm^R) or BCG. Immunogenicity was assessed by interferon-gamma (IFN-γ) production, cellular immune response markers by flow cytometry and serum antibodies against mycobacterial antigens.

Results

Eighty volunteers were randomized into two groups according to previous BCG vaccination and mycobacterial exposure (BCG-naïve, n = 40 and BCG-immune, n = 40). In each group, 30 individuals were vaccinated with VPM1002 (randomized to three escalating doses) and 10 with BCG. VPM1002 was safe and stimulated IFN-γ-producing and multifunctional T cells, as well as antibody-producing B cells in BCG-naïve and BCG-immune individuals.

Conclusions

VPM1002 was safe and immunogenic for B-cell and T-cell responses and hence will be brought forward through the clinical trial pipeline.     

Duration of protection against hepatitis A for the current two-dose vaccine compared to a three-dose vaccine schedule in children

Background

Hepatitis A is mostly a self-limiting disease but causes substantial economic burden. Consequently, United States Advisory Committee for Immunization Practices recommends inactivated hepatitis A vaccination for all children beginning at age 1 year and for high risk adults. The hepatitis A vaccine is highly effective but the duration of protection is unknown.

Methods

We examined the proportion of children with protective hepatitis A antibody levels (anti-HAV ≥20 mIU/mL) as well as the geometric mean concentration (GMC) of anti-HAV in a cross sectional convenience sample of individuals aged 12–24 years, who had been vaccinated with a two-dose schedule in childhood, with the initial dose at least 5 years ago. We compared a subset of data from persons vaccinated with two-doses (720 EL.U.) at age 3–6 years with a demographically similar prospective cohort that received a three-dose (360 EL.U.) schedule and have been followed for 17 years.

Results

No significant differences were observed when comparing GMC between the two cohorts at 10 (P = 0.467), 12 (P = 0.496), and 14 (P = 0.175) years post-immunization. For the three-dose cohort, protective antibody levels remain for 17 years and have leveled-off over the past 7 years.

Conclusion

The two- and three-dose schedules provide similar protection >14 years after vaccination, indicating a booster dose is not needed at this time. Plateauing anti-HAV GMC levels suggest protective antibody levels may persist long-term.     

Comparative varicella vaccine effectiveness during outbreaks in day-care centres

Background

Routine varicella vaccination for children >11 months was introduced in Germany in 2004 with three different vaccine brands available. In 2008 and 2009, we investigated seven varicella outbreaks in day-care centres (DCC).

Methods

Varicella disease and vaccination status of 1084 children was reviewed to evaluate vaccination coverage (VC), brand-specific varicella vaccine effectiveness (VE), and risk factors of breakthrough varicella (BV, >42 days after vaccination). A case was defined as a child with acute onset of varicella attending one of the respective DCC at the time of outbreak. Children with a previous history of varicella, age < 11 months, vaccinated at age < 11 months or <42 days before disease onset or during the outbreak were excluded from VE and BV risk factors analyses (adjusted for gender, age and DCC).

Findings

Of 631 children with available vaccination information, 392 (62%) were vaccinated at least once. Overall VE among 352 children eligible was 71% (95% confidence interval (CI) 57–81, p < 0.001) and differed significantly by disease severity and number of doses administered. Risk for BV was higher for 1 dose of Varilrix^® (RR = 2.8, 95%CI 1.0–7.8, p = 0.05) or Priorix-Tetra^® (RR = 2.4, 95%CI 0.7–8.3, p = 0.18) but lower for 2 doses of Priorix-Tetra^® (RR = 0.5, 95%CI 0.1–2.7, p = 0.41) than for 1 dose of Varivax^®.

Interpretation

Enhanced efforts to increase VC in Germany and 2 doses varicella vaccine might be successful to reduce the risk for BV. The evidence that VE and risk of BV are associated with vaccine brand needs further investigation.     

Causes of variation in BCG vaccine efficacy: Examining evidence from the BCG REVAC cluster randomized trial to explore the masking and the blocking hypotheses

BCG protection varies and in some places (nearest the equator) is low or absent. Understanding this variation can inform the efforts to develop new vaccines against tuberculosis. Two main hypotheses are used to explain this variation: under masking, new vaccines are unlikely to increase protection; under blocking new vaccines have a greater potential to be effective when BCG is not. We conducted a cluster randomized trial to explored the masking and blocking hypotheses by studying BCG vaccine efficacy of neonatal vaccination and when administered for the first or a second (revaccination) time at school age in two sites (Manaus close and Salvador further south from the equator). Seven hundred and sixty three state schools were matched on socio economic characteristics of the neighborhood and 239,934 children were randomized to vaccine (BCG vaccination at school age) or control group. Protection by first BCG vaccination at school age was high in Salvador (34%, 95% CI 7–53%, p = 0.017) but low in Manaus (8%, 95% CI t₀ 39–40%, p = 0.686). For revaccination at school age, protection was modest in Salvador (19%, 95% CI 3–33%, p = 0.022) and absent in Manaus (1%, 95% CI to 27–23%, p = 0.932). Vaccine efficacy for neonatal vaccination was similar in Salvador (40%, 95% CI 22–54%, p < 0.001) and Manaus (36%, 95% CI 11–53%, p = 0.008). Variation in BCG efficacy was marked when vaccine was given at school age but absent at birth, which points towards blocking as the dominant mechanism. New tuberculosis vaccines that overcome or by pass this blocking effect could confer protection in situations where BCG is not protective.     

Efficacy of different pneumococcal conjugate vaccine schedules against pneumonia,hospitalisation, and mortality: Re-analysis of a randomised trial in The Gambia

Background

Pneumococcal conjugate vaccines (PCV) reduce disease due to Streptococcus pneumoniae. We aimed to determine the efficacy of different PCV schedules in Gambian children.

Methods

We reanalysed data from a randomised placebo-controlled trial. Infants aged 6–51 weeks were allocated to three doses of nine-valent PCV (n = 8718) or placebo (n = 8719) and followed until age 30 months. We categorised participants to compare: (a) a first dose at age 6 or 10 weeks, (b) intervals of 1 or 2 months between doses, and (c) different intervals between second and third doses. The primary endpoint was first episode of radiologic pneumonia; other endpoints were hospitalisation and mortality. Using the placebo group as the reference population, Poisson regression models were used with follow-up after the first dose to estimate the efficacy of each schedule and from age 6 weeks to estimate the incidence rate difference between schedules.

Results

Predicted efficacy in the groups aged 6 weeks (n = 2467, 154 events) or 10 weeks (n = 2420, 106 events) at first dose against radiologic pneumonia were 32% (95% CI 19–43%) and 33% (95% CI 21–44%), against hospitalisation 14% (95% CI 3–23%) and 17% (95% CI 7–26%), and against mortality 17% (95% CI −3 to 33%) and 16% (95% CI −3 to 32%) respectively. Predicted efficacy in the groups with intervals of 1 month (n = 2701, 133 events) or 2 months (n = 1351, 58 events) between doses against radiologic pneumonia were 33% (95% CI 20–44%) and 36% (95% CI 24–46%), against hospitalisation 15% (95% CI 5–24%) and 18% (95% CI 8–27%), and against mortality 17% (95% CI −2 to 33%) and 13% (95% CI −8 to 29%) respectively. Efficacy did not differ by interval between second and third doses, nor did the incidence rate difference between schedules.

Conclusions

We found no evidence that efficacy or effectiveness of PCV9 differed when doses were given with modest variability around the scheduled ages or intervals between doses.     

Vaccines safety; effect of supervision or SMS on reporting rates of adverse events following immunization (AEFI) with meningitis vaccine (MenAfriVac™): A randomized controlled trial

Background

To ensure vaccines safety, given the weaknesses of the national pharmacovigilance system in Cameroon, there is a need to identify effective interventions that can contribute to improving AEFI reporting.

Objective

To assess the effect of: (i) sending weekly SMS, or (ii) weekly supervisory visits on AEFI reporting rate during a meningitis immunization campaign conducted in Cameroon in 2012 using the meningitis A conjugate vaccine (MenAfriVac™).

Methods

Health facilities that met the inclusion criteria were randomly assigned to receive: (i) a weekly standardized SMS, (ii) a weekly standardized supervisory visits or (iii) no intervention. The primary outcome was the reported AEFI incidence rate from week 5 to 8 after the immunization campaign. Poisson regression model was used to estimate the effect of interventions after adjusting for health region, type of health facility, type and position of health workers as well as the cumulative number of AEFI reported from weeks 1 to 4.

Results

A total of 348 (77.2%) of 451 health facility were included, and 116 assigned to each of three groups. The incidence rate of reported AEFI per 100 health facility per week was 20.0 (15.9–24.1) in the SMS group, 40.2 (34.4–46.0) in supervision group and 13.6 (10.1–16.9) in the control group. Supervision led to a significant increase of AEFI reporting rate compared to SMS [adjusted RR = 2.1 (1.6–2.7); p < 0.001] and control [RR = 2.8(2.1–3.7); p < 0.001)] groups. The effect of SMS led to some increase in AEFI reporting rate compared to the control group, but the difference was not statistically significant [RR = 1.4(0.8–1.6); p = 0.07)].

Conclusion

Supervision was more effective than SMS or routine surveillance in improving AEFI reporting rate. It should be part of any AEFI surveillance system. SMS could be useful in improving AEFI reporting rates but strategies need to be found to improve its effectiveness, and thus maximize its benefits.     

BCG vaccination reduces risk of infection with Mycobacterium tuberculosis as detected by gamma interferon release assay

Aims

To investigate whether BCG vaccination, in addition to a reduction of active tuberculosis, leads to a reduction of Mycobacterium tuberculosis infection during an outbreak of tuberculosis.

Methods

Pupils (n = 199) of a Junior School exposed to a pupil with active pulmonary tuberculosis were screened using a gamma interferon release assay for detection of M. tuberculosis infection (ex vivo ELISPOT assay). Relative risk of M. tuberculosis infection and pulmonary tuberculosis associated with BCG vaccination were calculated and adjusted for exposure risk.

Results

Twenty-nine percent of children with previous BCG vaccination had a reactive gamma interferon release assay compared with 47% of unvaccinated children (unadjusted RR 0.61, 95%CI 0.39, 0.96). The protective effect of BCG vaccination persisted following adjustment for other risk factors for infection like ethnicity and proximity to the source case reflected in membership of class and activity groups (corrected relative risk 0.26, 95%CI 0.09, 0.69 and risk reduction of 74%, 95%CI 31%, 91%). A higher proportion of unvaccinated children (11%) were diagnosed with active pulmonary tuberculosis compared with 5% of vaccinated children (RR 0.51 95%CI 0.15, 1.70).

Conclusion

BCG vaccination was associated with a reduction of M. tuberculosis infection diagnosed by gamma interferon release assay testing in school children during a point source outbreak.