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.     

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.     

Immunological responses and protective immunity in BCG vaccinated badgers following endobronchial infection with Mycobacterium bovis

European badgers (Meles meles) are a reservoir host of Mycobacterium bovis and are implicated in the transmission of tuberculosis to cattle in Ireland and Great Britain. The development of a vaccine for use in badgers is considered a key element of any campaign to eradicate the disease in livestock in both countries. In this study we have vaccinated groups of badgers with ∼5 × 10⁵ cfu of the BCG vaccine delivered via two alternative routes, subcutaneous and mucosal (intranasal/conjunctival). Following experimental endobronchial infection with ∼10⁴ cfu of M. bovis, all badgers were euthanised at 12 weeks post-infection. At post-mortem examination both vaccinated groups had significantly reduced severity of disease compared with the non-vaccinated controls. The analysis of immune responses throughout the study showed that vaccination with BCG did not generate any detectable immunological responses as measured by IFN-γ production in antigen-stimulated peripheral blood mononuclear cells (PBMC) and IgG serological responses. However, the levels of the responses increased following M. bovis infection, and the kinetic profiles corresponded to the severity of lesions recorded post-mortem. Significant differences were observed in the timing of development of the immune responses between vaccinates and controls. The results suggest that the immunological responses are associated with the levels of protective immunity and could be used as markers to monitor control of disease in badgers following vaccination.     

First data on Eurasian wild boar response to oral immunization with BCG and challenge with a Mycobacterium bovis field strain

The Eurasian wild boar (Sus scrofa) is considered a reservoir for bovine tuberculosis (bTB) caused by Mycobacterium bovis and closely related members of the Mycobacterium tuberculosis complex in south-central Spain. The vaccination of wildlife with BCG offers an alternative to culling and to movement restriction for the control of bTB among wildlife reservoirs. In this study, we hypothesized that oral BCG immunization of wild boar would affect the expression of immunoregulatory genes and confer protection against M. bovis. Three groups were used to describe the infection, pathological findings and gene expression profiles in wild boar: BCG-vaccinated and M. bovis-challenged (vaccinated challenged group; N = 6), non-vaccinated and M. bovis-challenged (non-vaccinated challenged group; N = 4), and non-vaccinated and mock-infected (control group; N = 2) animals. M. bovis was isolated from 50% (3/6) and 75% (3/4) of vaccinated challenged and non-vaccinated challenged animals, respectively. All four wild boar from the non-vaccinated challenged group developed bTB-compatible lesions 114 days after challenge. In contrast, only 50% of vaccinated challenged wild boar developed lesions. The PBMC mRNA levels of IL4, RANTES, C3, IFN-gamma and methylmalonyl-CoA mutase (MUT) were analyzed at several days post-vaccination (dpi). When vaccinated challenged animals were compared to controls, all five genes were significantly upregulated at the time of M. bovis infection at 186 dpi but IFN-gamma levels were also upregulated at 11 and 46 dpi. The C3 and MUT mRNA levels were higher at 46 dpi, and 11 and 186 dpi, respectively, in vaccinated protected wild boar when compared to non-vaccinated challenged animals. At the end of the experiment (300 dpi), the mRNA levels of selected genes were lower in non-vaccinated challenged animals when compared to control wild boar. Exposing wild boar to a dose of 10⁴ cfu of M. bovis by the oropharyngeal route is an adequate protocol to produce an infection model in this species. Our results suggested that oral BCG immunization of wild boar results in the upregulation of immunoregulatory genes that may be associated with protective response to M. bovis infection in this species. More studies on vaccine efficacy, delivery, and safety will be needed to confirm if oral vaccination with BCG could be used in bTB control programs for reducing M. bovis infection and clinical disease in wild boar.     

Inhibition of IFN-γ promotes anti-asthma effect of Mycobacterium bovis Bacillus Calmette-Guerin neonatal vaccination: A murine asthma model

Objective

The Mycobacterium bovis Bacillus Calmette-Guerin (BCG) neonatal vaccination inhibits allergy-induced pathologic changes. However, the mechanisms underlying this process are unclear. This study aimed to investigate the role of interferon (IFN)-γ and interleukin (IL)-17 in the protective effects of the BCG neonatal vaccination on allergic pulmonary inflammation and airway hyperresponsiveness (AHR).

Methods

Wild type (WT)-neonate and IL-17 knock out (KO) neonate mice were vaccinated with BCG. A murine asthma model was developed by sensitization and then challenging with ovalbumin (OVA). Recombinant IL-17 or recombinant IFN-γ was delivered to the airway to overexpress IL-17 or IFN-γ. An anti-IFN-γ neutralizing antibody was used to block the effects of IFN-γ.

Results

We found exogenous IL-17 delivered to the airway reversed the anti-asthma effects of the neonatal BCG vaccination. BCG neonatal vaccination further reduced OVA-induced inflammation and AHR in IL-17 KO mice. Inhibition of IFN-γ in BCG neonatal vaccinated OVA-induced asthma model mice led to a further reduction in airway inflammation and AHR. In addition, airway inflammation and AHR were robust following treatment with exogenous IFN-γ. Neutralizing IL-17 was not sufficient to block OVA-induced airway inflammation and AHR. In IL-17 KO mice, airway inflammation and AHR did not occur following treatment with an anti-IFN-γ neutralizing antibody.

Conclusions

In an OVA-induced murine asthma model, inhibition of IFN-γ enhanced the anti-asthma effects of BCG neonatal vaccination.     

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.     

Humoral responses to independent vaccinations are correlated in healthy boosted adults

Background

Roughly half of U.S. adults do not receive recommended booster vaccinations, but protective antibody levels are rarely measured in adults. Demographic factors, vaccination history, and responses to other vaccinations could help identify at-risk individuals. We sought to characterize rates of seroconversion and determine associations of humoral responses to multiple vaccinations in healthy adults.

Methods

Humoral responses toward measles, mumps, tetanus toxoid, pertussis, hepatitis B surface antigen, and anthrax protective antigen were measured by ELISA in post-immunization samples from 1465 healthy U.S. military members. We examined the effects of demographic and clinical factors on immunization responses, as well as assessed correlations between vaccination responses.

Results

Subsets of boosted adults did not have seroprotective levels of antibodies toward measles (10.4%), mumps (9.4%), pertussis (4.7%), hepatitis B (8.6%) or protective antigen (14.4%) detected. Half-lives of antibody responses were generally long (>30 years). Measles and mumps antibody levels were correlated (r = 0.31, p < 0.001), but not associated with select demographic features or vaccination history. Measles and mumps antibody levels also correlated with tetanus antibody response (r = 0.11, p < 0.001).

Conclusions

Vaccination responses are predominantly robust and vaccine specific. However, a small but significant portion of the vaccinated adult population may not have quantitative seroprotective antibody to common vaccine-preventable infections.     

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.     

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.     

Oral vaccination of badgers (Meles meles) with BCG and protective immunity against endobronchial challenge with Mycobacterium bovis

Eurasian badgers (Meles meles) are a reservoir host of Mycobacterium bovis and are implicated in the transmission of tuberculosis to cattle in Ireland and Great Britain. The development of a vaccine for use in badgers is considered a key element of any long-term sustainable campaign to eradicate the disease from livestock in both countries. The aim of this study was to investigate the protective response of badgers vaccinated orally with Bacille Calmette–Guérin (BCG) encapsulated in a lipid formulation, followed by experimental challenge with M. bovis. A group of badgers was vaccinated by inoculating the BCG–lipid mixture containing approximately 10⁸ colony forming units (cfu) of BCG into the oesophagus. The control group was sham inoculated with the lipid formulation only. Thirteen weeks after vaccination all the badgers were challenged with approximately 10⁴ cfu of M. bovis delivered by endobronchial inoculation. Blood samples were taken throughout the study and the cell mediated immune (CMI) responses in peripheral blood were monitored by the IFN-γ ELISA and ELISPOT assay. At 17 weeks after infection all the badgers were examined post-mortem to assess the pathological and bacteriological responses to challenge. All badgers in both groups were found to be infected. However, a significant protective effect of BCG vaccination was measured as a decrease in the number and severity of gross lesions, lower bacterial load in the lungs, and fewer sites of infection. The analysis of immune responses showed that vaccination with BCG did not generate any detectable CMI immunological responses, however the levels of the responses increased in both groups following M. bovis infection. The results of the study showed that vaccination with oral BCG in the lipid formulation generated a protective effect in the badgers.     

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.     

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.     

How do anticipated worry and regret predict seasonal influenza vaccination uptake among Chinese adults?

Objectives

To test two hypothesized models of how anticipated affect, cognitive risk estimate and vaccination intention might influence vaccination uptake against seasonal influenza.

Methods

The study collected baseline and follow-up data during the main influenza seasons (January–March) of 2009 and 2010, respectively, among 507 university students and staff of a university in Hong Kong. Following logistic regression to determine eligible variables, two mediation models of cognitive risk estimate, anticipated affect, vaccination intention and vaccination uptake against seasonal influenza were tested using structural equation modeling.

Results

Mediation analyses found that anticipated worry if not vaccinated influenced seasonal influenza vaccination uptake through its effects on either perceived probability of influenza infection (β = 0.45) or intention (β = 0.45) while anticipated regret if not vaccinated influenced vaccination uptake through its effect on intention (β = 0.45) only; anticipated regret if vaccinated impeded vaccination uptake indirectly through its effect on vaccination intention (β = −0.26) or directly (β = −0.20); perceived probability of influenza infection influenced vaccination uptake through its effect on intention (β = 0.20) or directly (β = 0.22); and finally, intention influenced vaccination uptake directly (β = 0.58).

Conclusion

The results suggest that anticipated affect seems to drive risk estimates related to seasonal influenza vaccination rather than vice versa and intention remains an important mediator of the associations of anticipated affect and cognitive risk estimate with vaccination uptake against seasonal influenza.     

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).     

Pandemic influenza A(H1N1)pdm09 improves vaccination routine in subsequent years: A cohort study from 2009 to 2011

Background

In 2009 the pandemic influenza virus A(H1N1)pdm09 emerged with guidance that people at risk should be vaccinated. It is unclear how this event affected the underlying seasonal vaccination rate in subsequent years.

Purpose

To investigate the association of pandemic influenza A(H1N1)pdm09 and seasonal flu vaccination status in 2009 with vaccination rates in 2010 and 2011.

Methods

Data were collected in 40 Dutch family practices on patients at risk for influenza during 2009–2011; data analysis was conducted in 2012.

Results

A multilevel logistic regression model (n = 41,843 patients) adjusted for practice and patient characteristics (age and gender, as well as those patient groups at risk), showed that people who were vaccinated against A(H1N1)pdm09 in 2009 were more likely to have been vaccinated in 2010 (OR 6.02; 95%CI 5.62–6.45, p < .0001). This likelihood was even more for people who were vaccinated against seasonal flu in 2009 (OR 13.83; 95%CI 12.93–14.78, p < .0001). A second analysis on the uptake rate in 2011 (n = 39,468 patients) showed that the influence of the vaccination state in 2009 declined after two years, but the diminishing effect was smaller for people vaccinated against A(H1N1)pdm09 than for seasonal flu (OR 5.50; 95%CI 5.13–5.90, p < .0001; OR 10.98; 95%CI 10.26–11.75, p < .0001, respectively).

Conclusion

Being vaccinated against A(H1N1)pdm09 and seasonal influenza in the pandemic year 2009 enhanced the probability of vaccination in the next year and this was still effective in 2011. This suggests that peoples’ vaccination routines were not changed by the rumor around the outbreak of A(H1N1)pdm09, but rather confirmed underlying behavior.     

Improvement in attitudes toward influenza vaccination in medical students following an integrated curricular intervention

Introduction

Vaccination of health care workers (HCW) reduces transmission of influenza among patients, yet uptake of vaccination remains low. If vaccination education is integrated into the early medical school curriculum, will student attitudes toward the vaccine change? The objectives of the study were to: (1) Determine influenza vaccination rates among entering medical students; (2) Assess the attitudes toward influenza vaccination; (3) Evaluate the effects of a multifaceted educational intervention on attitudes to vaccination.

Methods

Entering medical students were surveyed before and after an intervention at the beginning of the influenza season. This intervention provided by an inter-professional team, included education about influenza, importance of vaccination for HCWs, followed by vaccination administration practice, and ended with students vaccinating consenting classmates.

Results

The pre-intervention surveys and intervention were completed by 124 of 125 (99%) students. Pre-intervention survey revealed 60 (48%) of students had been previously vaccinated. Of the vaccinated students 91% had been recommended vaccination by their healthcare provider compared to 43% of non-vaccinated students. More positive attitudes were noted in the vaccinated students compared to non-vaccinated students: importance of vaccination (p < 0.01); HCWs should be vaccinated (p < 0.01); recommendation of vaccine to family and friends (p < 0.01). 97 (78%) students completed post-intervention surveys. Significant improvement in these attitudes was noted post-intervention compared to pre-intervention: importance of vaccination 93% versus 71% (p < 0.01); HCWs should be vaccinated 95% versus 83% (p < 0.01); recommendation to family and friends 93% versus 73% (p < 0.01); comfort with vaccine counseling 92% versus 41%; comfort with vaccine administration 84% versus 22% (p < 0.01).

Conclusion

Educating medical students and promoting the importance of vaccination early in a medical student's career using such an intervention is relatively simple and easily integrated into the curriculum. This intervention was successful in vaccinating all students, and demonstrated a marked positive shift in attitudes toward influenza vaccination.     

DNA vaccination protects against an influenza challenge in a double-blind randomised placebo-controlled phase 1b clinical trial

Background

We have developed a Trivalent DNA vaccine for influenza consisting of three plasmids expressing haemagglutinin from different seasonal influenza virus strains delivered using PMED™ (particle mediated epidermal delivery). We set out to determine whether this vaccine (with and without a molecular adjuvant DNA Encoded Immunostimulator-Labile Toxin (DEI-LT)) could protect subjects from a controlled influenza virus challenge.

Methods

Healthy adult subjects were screened for susceptibility to infection with influenza A/H3 Panama/2007/99 then vaccinated with 4 μg Trivalent influenza DNA vaccine, 2 μg Trivalent influenza DNA vaccine plus DEI-LT or placebo. Safety and serological responses to vaccination were assessed and on Day 56 subjects were challenged with A/H3 Panama/2007/99 virus.

Results

Vaccination with 4 μg Trivalent or 2 μg Trivalent/DEI-LT was well tolerated and induced antibody responses to two of the three influenza virus vaccine strains. Post challenge, subjects in the 4 μg Trivalent group (N = 27) showed reductions in disease symptoms and viral shedding compared to placebo (N = 27), with an overall vaccine efficacy of 41% (95% confidence interval (CI) = −1.5, 67.7) for ‘Any illness with or without fever’ and 53% for ‘Upper respiratory tract infection’ (95% CI = 8.0, 77.7).

Conclusion

It was concluded that PMED vaccination with 4 μg Trivalent influenza DNA vaccine was safe and elicited immunological responses that protected human subjects from influenza; this is the first report of protection of human subjects from disease by DNA vaccination.     

Défaut de couverture vaccinale pneumococcique chez l’adulte à risque

Objective

This study had for aim to assess pneumococcal vaccination rates in hospitalized patients.

Design

A prospective study was carried out in two medical wards of the Nice University Hospital, France. Patients were included from December 31, 2007 to February 12, 2008.

Results

Hundred and thirty-seven patients, aged 62 ± 20 years, were included. Pneumococcal vaccination was indicated for 62 patients (45 %). Among these 62 patients, 53 (85 %) had not been vaccinated in the previous 5 years, for the following reasons: no medical advice on vaccination (36 cases), no medical consultation in the past years (nine cases), patient opposed to vaccination (two cases), physician opposed to vaccination (one case), miscellaneous (five cases). Among the 53 patients, seven were vaccinated during their hospital stay and 13 were advised to be vaccinated by their general practitioner.

Conclusions

This study highlights a low rate of pneumococcal vaccination in hospitalized patients, mainly due to insufficient counseling from physicians, both in community or in hospital practice.     

Sustained protection against tuberculosis conferred to a wildlife host by single dose oral vaccination

Background

Vaccination of wildlife against bovine tuberculosis (TB) is being considered by several countries to reduce the transmission of Mycobacterium bovis infection to livestock. In New Zealand, where introduced brushtail possums (Trichosurus vulpecula) are the major wildlife hosts, we have previously shown that repeat applications of a lipid-encapsulated oral bacille Calmette-Guerin (BCG) vaccine reduce the incidence of naturally acquired TB in wild possums. Here we extend this conceptual demonstration to an operational level, assessing long-term protection against TB conferred to free-living possums by a single oral immunisation.

Methods

Possums in a non-TB area were randomly allocated to receive lipid-formulated BCG vaccine or remained unvaccinated. After initial trials to assess vaccine immunogenicity and establishment of protection within the first year post-vaccination, 13 individuals of each treatment group were relocated to a biosecurity facility and challenged (at 28 months post-vaccination) by subcutaneous injection of virulent M. bovis.

Results

Vaccine immunogenicity and short-term protection were confirmed at 2 months and 12 months post-vaccination, respectively. In the long-term assessment, vaccinated possums had significantly reduced bacterial counts in peripheral lymph nodes compared to controls, with 0.6–2.3 log₁₀-fold reductions in M. bovis burdens.

Discussion

The magnitude of protective response by possums to experimental challenge at 28 months post-vaccination is known to equate to a high degree of protection against natural infection in this species. With techniques for oral bait delivery well advanced, the longevity of protection demonstrated here shows that an operable wildlife vaccine against TB is feasible.     

Comparaison coût/bénéfice de la campagne vaccinale et de la réduction de l’absentéisme,après vaccination contre la grippe du personnel du CHU de Clermont-Ferrand

Objective

The aim of this study was to compare the cost of vaccination for the Clermont-Ferrand University hospital (CHU) personnel and the cost of sick leave among vaccinated and non-vaccinated employees in 2003, 2004, and 2005.

Design

The study included 7256 CHU staff (medical and non-medical personnel). The cost of sick leave was calculated on the basis of short-term disease (four to nine days) over the three months of the epidemic season in 2004, 2005, and 2006.

Results

In 2005, the overall cost of vaccination was 4.02 € per vaccinated employee. Over the three years, the total sick leave reached 804 days for employees vaccinated against 5670 for non-vaccinated employees. In 2003, 2004, and 2005, the vaccinal coverage was 13, 20.5, and 30.1%, the mean duration of sick leave was 0.16, 0.17, and 0.18 day among vaccinated staff, and 0.26, 0.39, and 0.34 day among non-vaccinated staff corresponding to a benefit per vaccinated employee of 5, 26, and 20 €, respectively for each year. The total benefit for the institution was 86,458 € (4630 + 38,168 + 43,660). If the vaccinated rate of 75% recommended by the Haute Autorité de santé (HAS) had been reached, the additional benefit would have been 250,193 € (33,157 + 152,256 + 65,180).

Conclusions

The number of sick leave days and the related cost were approximately twice less important for vaccinated employees, economically justifying this vaccination including a period of weak epidemic, as checked over three consecutive years.