Evidence of an effect of BCG revaccination on incidence of tuberculosis in school-aged children in Brazil: second report of the BCG-REVAC cluster-randomised trial

BCG revaccination is still used in some tuberculosis endemic countries. Until now, the little evidence available suggested that BCG revaccination confers very limited additional protection, although there was no information on whether protection depends on the setting and age of revaccination, or if protection increases with time since vaccination. Here we report on an extended follow up of the BCG-REVAC trial, a cluster randomised trial conducted in the Brazilian cities Salvador and Manaus including over 200,000 children aged 7-14 years aimed to evaluate the efficacy of BCG revaccination in children who had received neonatal BCG vaccination. With the extended follow-up (9 years) and the additional cases accrued we now have enough power to report vaccine efficacy separately for the two cities (with different distances from Equator and presumably different prevalence of non-tuberculosis mycobacteria), and by age at vaccination and clinical form. The overall vaccine efficacy was 12% (−2 to 24%) as compared to 9% (−16 to 29%) for the 5-year follow up. Vaccine efficacy was higher in Salvador (19%, 3 to 33%) than in Manaus (1%, −27 to 27%) with the highest vaccine efficacy in children from Salvador aged <11 years at revaccination (33%, 3 to 54%). The findings are in line with the hypothesis that BCG vaccination offers higher efficacy in low NTMb prevalence, and show that revaccination with BCG can offer weak protection in selected subgroups.     

Risk of lymphoma and leukaemia after bacille Calmette-Guérin and smallpox vaccination: A Danish case-cohort study

Vaccines may have non-specific effects as suggested mainly in mortality studies from low-income countries. The objective was to examine the effects of BCG and smallpox vaccinations on subsequent risk of lymphoma and leukaemia in a Danish population experiencing rapid out-phasing of these vaccines. In a background cohort (N = 47,622) from the Copenhagen School Health Records Register, cases of leukaemia (N = 20) and lymphoma (N = 51) were identified through the Danish Cancer Registry. The vaccination status of the cases was compared with the vaccination status of a 5% random sample (N = 2073) of the background cohort and analysed in a case-cohort design. BCG vaccination reduced the risk of lymphomas (HR = 0.49 (95% CI: 0.26–0.93)), whereas smallpox vaccination did not (HR = 1.32 (0.56–3.08)). With the small number of leukaemia cases, the analysis of leukaemia had limited power (BCG vaccination HR = 0.81 (0.31–2.16); smallpox vaccination HR=1.32 (0.49–3.53)). The present study with very reliable vaccine history information indicates a beneficial effect of BCG vaccination on the risk of lymphomas.     

The immunological effect of revaccination with Bacille Calmette-Guérin vaccine at 19 months of age

Background

Bacille Calmette-Guérin (BCG) vaccination has important non-specific immune effects. In a randomized trial in Guinea-Bissau, BCG revaccination was associated with significantly increased survival in children who received diphtheria-tetanus-pertussis (DTP)-booster vaccine before enrolment and in children who did not receive micronutrient supplementation (MN). Within the trial we assessed the immunological effects of BCG revaccination.

Methods

Children were randomized to BCG or nothing. Blood was sampled 6–11 weeks after randomization (early sample group) or 5–9 months later (late sample group). In vitro cytokine responses (interferon (IFN)-γ, interleukin (IL)-13, tumor-necrosis-factor (TNF)-α, and IL-10) were assessed in whole blood cultures stimulated with lipopolysaccharide (LPS), purified protein derivative (PPD) or phytohaemagglutinin (PHA). Effect-modification by sex, DTP-booster vaccination and MN was studied.

Results

Cytokines were measured in 345 infants. BCG was associated with significantly increased IFN-γ (geometric mean ratio (GMR) = 4.54 (95% confidence interval: 3.13–6.58)) and IL-13 (GMR = 1.43 (1.00–2.05)) PPD responses, the effect being strongest in the early sample group. Across all three conditions BCG tended to increase IL-10 (LPS, PHA, PPD: GMR = 1.20, 1.12, 1.20), most pronounced in the late sample group. BCG reduced the TNF-α/IL-10 ratio in boys with DTP-booster at bleeding and increased it in those without (interaction test: p = 0.03). In children without MN, BCG was associated with reduced TNF-α response in the early sample group (p = 0.006), and increased IL-10 in the late sample group (p = 0.03).

Conclusion

BCG revaccination resulted in a strong IFN-γ response to PPD, which waned slightly over time. BCG also affected the pro-/anti-inflammatory balance, with reduced TNF-α and increased IL-10 responses to LPS, PHA and PPD. This effect depended on sex, DTP-booster vaccination and micronutrient supplementation, being most pronounced in children who had received DTP-booster before enrolment and children who had not received MN, i.e. the group of children which also had lower mortality after BCG revaccination.     

Waning immunity to measles in young adults and booster effects of revaccination in secondary school students

The increasing proportions of adult cases were observed in the recent measles outbreaks in Zhejiang Province, China. In order to identify the high-risk age groups of measles for targeted intervention, a seroprevalence survey of measles antibody was conducted among 1961 participants aged 0–60 years randomly selected by age-stratified purpose sampling, and the effect of revaccination program in secondary school was evaluated in Zhejiang Province. The adjusted overall seropositivity rate of measles was 88% (95% confidence interval [CI]: 86–89%) with geometric mean titers (GMT), 976 ± 86 mIU/ml. The seropositivity rate of measles was significantly lower in subjects aged 15–19 years than aged 5–9 years (90% vs 96%, χ² = 5.21, p = 0.022). Both seropositivity rate and GMT level of measles were higher in participants aged 10–14 years with ≥2 doses MCV than those with only 1 dose (95% vs 81%, 1276 mIU/ml vs 666 mIU/ml). The seropositivity rate increased from 91% to 100% after revaccination with MCV among 184 secondary school students. The proportions of measles cases aged ≥15 years were reduced gradually (χ² = 55.47, p = 0.000) from 2009 to 2011 after implementing the revaccination campaign on secondary school students since 2008. Our findings strongly suggested that a revaccination opportunity with MCV for adolescents helps to improve the population immunity, and it can be conducted effectively and practically in secondary school students.     

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).     

Lymph node targeting of BCG vaccines amplifies CD4 and CD8 T-cell responses and protection against Mycobacterium tuberculosis

Vaccination with Mycobacterium bovis BCG provides limited protection against pulmonary tuberculosis and a risk of dissemination in immune-compromised vaccinees. For the development of new TB vaccines that stimulate strong T-cell responses a variety of strategies is being followed, especially recombinant BCG and attenuated M. tuberculosis. The objective of the current study was to test potential benefits of vaccination through direct lymph-node targeting of wildtype BCG; the recommended route of vaccination with BCG is intradermal. C57BL/6 mice were immunised with BCG by intradermal, subcutaneous or intralymphatic injections. Cellular immune responses and protection against M. tuberculosis were determined. Intralymphatic vaccination was 100–1000 times more effective in stimulating BCG-specific immune responses than intradermal or subcutaneous immunisation. Intralymphatic administration stimulated high frequencies of mycobacterium-specific lymphocytes with strong proliferating capacity and production of TNF-α, IL-2, IL-17 and, especially, IFN-γ secretion by. CD4 and CD8 T cells. Most importantly, intralymphatic vaccination with 2 × 10³ CFU BCG induced sustained protection against M. tuberculosis in intratracheally challenged C57BL/6 mice, whereas subcutaneous vaccination with 2 × 10⁵ CFU BCG conferred only a transient protection. Hence, direct administration of M. bovis BCG to lymph nodes demonstrates that efficient targeting to lymph nodes may help to overcome the efficacy problems of vaccination with BCG.     

The incidence of pediatric invasive Haemophilus influenzae and pneumococcal disease in Chiba prefecture,Japan before and after the introduction of conjugate vaccines

The Haemophilus influenzae type b (Hib) vaccine and the heptavalent pneumococcal conjugate vaccine (PCV7) were introduced in Japan in 2008 and 2010, respectively. In 2011, immunization with these two vaccines was encouraged throughout Japan through a governmental program. Children treated in Chiba prefecture for culture-proven invasive H. influenzae disease (IHiD) and invasive Streptococcus pneumoniae disease (IPD) were identified in a prefectural surveillance study from 2008 to 2013. The incidence rate ratio (IRR) and its confidence interval (CI) were calculated to compare the 3 years before and after governmental financial support for vaccination. The average number of IHiD and IPD cases among children <5 years of age in 2011–2013 decreased 84% (IRR: 0.16, 95% CI: 0.09–0.26, p < 0.0001) and 51% (IRR: 0.49, 95% CI: 0.37–0.63, p < 0.0001) compared with those occurring in 2008–2010. The most common non-PCV7 serotype encountered in 2011 and 2013 was 19A. After governmental subsidization of Hib and PCV7 vaccination, IHiD and IPD decreased in Chiba prefecture, Japan. Continuous surveillance is necessary to determine the effectiveness of these two vaccines and for detection of emerging invasive serotypes.     

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.     

Tuberculin reactivity in a population of schoolchildren with high BCG vaccination coverage.

OBJECTIVE: To investigate the influence of BCG vaccination or revaccination on tuberculin skin test reactivity, in order to guide the correct interpretation of this test in a setting of high neonatal BCG vaccination coverage and an increasing BCG revaccination coverage at school age. METHODS: We conducted tuberculin skin testing and BCG scar reading in 1 148 children aged 7-14 years old in the city of Salvador, Bahia, Brazil. We measured the positive effect of the presence of one or two BCG scars on the proportion of tuberculin skin test results above different cut-off levels (induration sizes of > or = 5 mm, > or = 10 mm, and > or = 15 mm) and also using several ranges of induration size (0, 1-4, 5-9, 10-14, and > or = 15 mm). We also measured the effects that age, gender, and the school where the child was enrolled had on these proportions. RESULTS: The proportion of tuberculin results > or = 10 mm was 14.2% (95% confidence interval (CI) = 8.0%-20.3%) for children with no BCG scar, 21.3% (95% CI = 18.5%-24.1%) for children with one BCG scar, and 45.0% (95% CI = 32.0%-58.0%) for children with two BCG scars. There was evidence for an increasing positive effect of the presence of one and two BCG scars on the proportion of results > or = 5 mm and > or = 10 mm. Similarly, there was evidence for an increasing positive effect of the presence of one and two scars on the proportion of tuberculin skin test results in the ranges of 5-9 mm and of 10-14 mm. The BCG scar effect on the proportion of results > or = 5 mm and > or = 10 mm did not vary with age. There was no evidence for BCG effect on the results > or = 15 mm. CONCLUSIONS: In Brazilian schoolchildren, BCG-induced tuberculin reactivity is indistinguishable, for results under 15 mm, from reactivity induced by Mycobacterium tuberculosis infection. BCG revaccination at school age increases the degree of BCG-induced tuberculin reactivity found among schoolchildren. This information should be taken into account in tuberculin skin test surveys intended to estimate M. tuberculosis prevalence or to assess transmission patterns as well as in tuberculin skin testing of individuals used as an auxiliary tool in diagnosing tuberculosis. Taking this information into consideration is especially important when there is increasing BCG revaccination coverage.     

Prevalence of immunity to hepatitis viruses A and B in a large cohort of HIV/HCV-coinfected patients, and factors associated with HAV and HBV vaccination

Hepatitis A (HAV) and B (HBV) vaccination is strongly recommended for HIV-infected patients, especially those with hepatitis C coinfection. The aim of this study was to determine the prevalence of antibodies directed against HAV and HBV in a large cohort of HIV/HCV-coinfected patients, and to identify factors associated with HAV and HBV vaccination.

Patients and methods

We studied 1175 HIV/HCV-coinfected patients enrolled in the ANRS CO13 HEPAVIH cohort, whose HAV and HBV serostatus was known.

Results

1056 patients (89.9%) have been tested for anti-HBc IgG, anti-HBs, and HbsAg. Only 10.9% of patients had received HBV vaccination and 70% of the patients with no HBV immunity (231/265) had never received HBV vaccination. In multivariate analysis, male sex (OR 2.0. 95% CI 1.1-3.8; p = 0.02), a higher level of school education (OR 2.5, 95% CI 1.3-4.5; p = 0.003), a higher CD4 cell nadir (OR 1.05, 95% CI 1.009-1.103; p = 0.018) and no cirrhosis (OR 2.7, 95% CI 1.2-6.4; p = 0.02) were associated with HBV vaccination.Only 368 patients (31.3%) were tested for immunity to HAV. Despite a frequent lack of HAV immunity (48.3%), a low rate of HAV vaccination (6%) was observed. In multivariate analysis, a higher level of school education (OR 3.6, 95% CI 1.03-12.4; p = 0.045) was the only factor associated with HAV vaccination.HAV screening rates and HAV and HBV vaccination rates were low in this population of HIV/HCV-coinfected patients. The benefits of routine HAV and HBV screening, vaccination and post-vaccination testing should be emphasized.     

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.     

Prevalence of protective level of hepatitis B antibody 3 years after revaccination in HIV-infected children on antiretroviral therapy

After responding to highly active antiretroviral therapy (HAART), HIV-infected children had a good response to hepatitis B immunization. However, there are limited data on the durability of antibody to hepatitis B surface antigen (anti-HBs) in these children. The primary objective of this study is to determine the prevalence of protective anti-HBs level 3 years after a 3-dose HBV revaccination among HIV-infected children with immune recovery (CD4 cell ≥15%) while on HAART. The secondary objective is to assess immunologic memory among children who had waning of anti-HBs. An anti-HBs level of ≥10 mIU/mL was defined as a protective antibody level. Sixty-nine HIV-infected children who had history of a 3-dose HBV revaccination while receiving HAART were enrolled. The mean (SD) of CD4 cell and duration of HAART at time of revaccination was 27.2% (6.7) and 5.9 years (0.4), respectively. The proportion of children with protective anti-HBs level 3 years after the revaccination was 71.0% [95% CI, 58.8-81.3]. The geometric mean titer was 114(SD 5) IU/mL. By multivariate logistic analysis, the predictors for protective anti-HBs level 3 years after revaccination were CD4 cell count ≥500 cells/mm³ at the time of vaccination (p = 0.04) and anti-HBs level ≥ 100 IU/mL at 1 month after completion of the 3-dose vaccination (p < 0.001). Anamnestic response after one booster dose was demonstrated among 14 of 17 children who had waning protective anti-HBs level (82.4% [95% CI, 62.2-102.6]). Our findings support the recommendation of giving a 3-dose HBV vaccination to HIV-infected children with immune recovery while receiving HAART.     

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.     

Immune interference in the setting of same-day administration of two similar inactivated alphavirus vaccines: Eastern equine and western equine encephalitis

We compared the effect on primary vaccination plaque-reduction neutralization 80% titers (PRNT80) responses of same-day administration (at different injection sites) of two similar investigational inactivated alphavirus vaccines, eastern equine encephalitis (EEE) vaccine (TSI-GSD 104) and western equine encephalitis (WEE) vaccine (TSI-GSD 210) to separate administration. Overall, primary response rate for EEE vaccine was 524/796 (66%) and overall primary response rate for WEE vaccine was 291/695 (42%). EEE vaccine same-day administration yielded a 59% response rate and a responder geometric mean titer (GMT) = 89 while separate administration yielded a response rate of 69% and a responder GMT = 119. WEE vaccine same-day administration yielded a 30% response rate and a responder GMT = 53 while separate administration yielded a response rate of 54% and a responder GMT = 79. EEE response rates for same-day administration (group A) vs. non-same-day administration (group B) were significantly affected by gender. A logistic regression model predicting response to EEE comparing group B to group A for females yielded an OR = 4.10 (95% CL 1.97–8.55; p = .0002) and for males yielded an OR = 1.25 (95% CL 0.76–2.07; p = .3768). WEE response rates for same-day administration vs. non-same-day administration were independent of gender. A logistic regression model predicting response to WEE comparing group B to group A yielded an OR = 2.14 (95% CL 1.22–3.73; p = .0077). We report immune interference occurring with same-day administration of two completely separate formalin inactivated viral vaccines in humans. These findings combined with the findings of others regarding immune interference would argue for a renewed emphasis on studying the immunological mechanisms of induction of inactivated viral vaccine protection.     

Pertussis vaccination coverage among adults in the Lyon area

Background

The compliance with recommendations for Pertussis vaccination was assessed in the Lyon population through vaccination coverage (VC).

Methods

A cross-sectional study was conducted in collaboration with 10 private biological analysis laboratories between October 2010 and March 2012, on 1930 adults (>19 years of age) from the Lyon area. Proof of vaccination (PV) was requested to prove the current vaccination status.

Results

A percentage of 30.3% (585/1930) of surveyed individuals provided a PV. A positive vaccination status was confirmed in 10.76% [CI 95% 8.45–13.48] (63/585) and didn’t vary in relation to gender (P = 0.57), age (P = 0.06), or level of schooling (P = 0.41). Coverage vaccination was not updated in parents with childbearing project (84.2% (64/76) [CI 95% 74.7–91.2]) or people in contact with children less than 6 years of age (83.6% (87/104) [CI 95% 75.6–89.8]). Pertussis vaccination wasn’t confirmed in 80.0% (124/155) of those who thought being vaccine up to date.

Conclusions

The Lyon population poorly complied with the cocooning strategy implemented in 2004. The pertussis vaccine coverage confirmed by a PV proved the inadequate rate of vaccination compared to objectives. It is mandatory to strengthen the vaccinal policy for this vaccine booster.     

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.     

Effectiveness of rotavirus vaccines in preventing cases and hospitalizations due to rotavirus gastroenteritis in Navarre, Spain

Two rotavirus vaccines have been available since 2006. This study evaluates the effectiveness of these vaccines using a test-negative case-control design in Navarre, Spain. We included children 3-59 months of age who sought medical care for gastroenteritis and for whom stool samples were taken between January 2008 and June 2011. About 9% had received the pentavalent vaccine (RotaTeq) and another 8% received the monovalent vaccine (Rotarix). Cases were the 756 children with confirmed rotavirus and controls were the 6036 children who tested negative for rotavirus. Thirty-five percent of cases and 9% of controls had required hospitalization (p < 0.0001). The adjusted effectiveness of complete vaccination was 78% (95% CI: 68-85%) in preventing rotavirus gastroenteritis and 83% (95% CI: 65-93%) in preventing hospitalization for rotavirus gastroenteritis. No differences between the two vaccines were detected (p = 0.4523). Both vaccines were highly effective in preventing cases and hospital admissions in children due to rotavirus gastroenteritis.     

Immune interference after sequential alphavirus vaccine vaccinations

We compared the effect of order of administration of investigational alphavirus vaccines on neutralizing antibody response. Volunteers who received the inactivated eastern and western equine encephalitis (EEE and WEE) vaccines before live attenuated Venezuelan (VEE) vaccine had significantly lower rates of antibody response than those receiving VEE vaccine before EEE and WEE vaccines (66.7% vs. 80.6%; p = 0.026). The odds of having a VEE antibody non-response among those initially receiving EEE and WEE vaccines, adjusted for gender, were significant (odds ratio [OR] = 2.20; 95% CI = 1.2–4.1 [p = 0.0145]) as were the odds of non-response among females adjusted for group (OR = 1.81; 95% CI = 1.2–2.7 [p = 0.0037]). Antibody interference and gender effect have major implications for vaccine strategy among those receiving multiple alphavirus vaccines and those developing next generation vaccines for these threats.     

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.     

HPV vaccination: Are we initiating too late?

Background

Human papillomavirus (HPV) vaccination is recommended in early adolescence. While limited data suggest that patients frequently delay initiation of the three-dose series, age-based variability in initiation of HPV vaccination and its clinical relevance are not well described. Thus, this study aims to characterize HPV vaccination delay among adolescent and young adult females.

Methods

This retrospective cohort study examined age at HPV vaccination initiation and missed opportunities for receipt of the first vaccine dose (HPV1) among 11–26 year-old females (n = 22,900) receiving care at 16 urban academically-affiliated ambulatory care clinics between 2007 and 2011. Predictors of timely vaccination and post-licensure trends in age at HPV1 receipt were assessed using multivariable logistic regression and a generalized linear mixed model, respectively. Chlamydia trachomatis and Papanicolaou screening before HPV vaccination initiation, as markers of prior sexual experience and associated morbidity, were examined in a subcohort of subjects (n = 15,049).

Results

The proportion of 11–12 year-olds who initiated HPV vaccination increased over time (44.4% [2007] vs. 74.5% [2011], p < 0.01). Initiation rates also improved among 13–26 year-olds. Thus, the mean age at HPV1 receipt remained unchanged between 2007 and 2011 (16.0 ± 2.7 vs. 15.9 ± 4.0 years, p = 0.45). Spanish language was a positive predictor (AOR 1.62, 95% CI 1.05–2.48) of HPV vaccination initiation among 11–12 year-olds in 2011. The majority (70.8–76.4%) of unvaccinated subjects experienced missed vaccination opportunities. Of the subcohort, 36.9% underwent Chlamydia screening before HPV1 receipt (19.1% with ≥1 positive result). Of those with prior Papanicolaou screening (16.6%), 32.1% had ≥1 abnormal result.

Conclusions

These low-income, minority females frequently delayed initiation of HPV vaccination. Many had evidence of prior sexual experience and associated morbidity, placing them at risk of HPV-related complications. Promoting timely HPV vaccination and reducing missed vaccination opportunities are crucial.