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.     

Early loss of measles antibodies after MMR vaccine among HIV-infected adults receiving HAART

Objective

: The objective of the study was to evaluate the immune response to measles vaccine of HIV-infected adults in comparison to HIV non-infected adults.

Design

We conducted a cross-sectional study to identify adults lacking measles antibodies. 26 HIV-infected patients and 22 controls found to be measles seronegative in the cross-sectional study, received the MMR vaccine. We prospectively followed patients and measured measles antibodies, and cellular proliferative responses against measles antigens. We registered all adverse events at baseline, 3 and 12 months after vaccination.

Methods

We determined measles antibodies by ELISA and cellular proliferative response in PBMC's at baseline, and repeated measurements at 3 and 12 months after vaccination.

Results

The humoral immune response to the vaccine between HIV-infected adults and the HIV-uninfected group was not statistically different at 3 months (81% vs. 86% respectively). One year after vaccination, a higher proportion of HIV-infected adults had lost measles antibodies in contrast to controls. The cellular response was not statistically different between the groups at baseline, 3 and 12 months after immunization despite the waning of antibodies at 12 months. No severe adverse events were observed. Most patients were receiving HAART and had a mean CD4+ cell count of 496 cells/mL.

Conclusions

The initial humoral immune response to measles vaccine was not different between HIV-infected adults and HIV-uninfected adults. However, HIV-infected adults have a rapid decline of measles antibodies despite their high CD4+ cell count and sustained cellular proliferative response.     

Serum IgG titres,but not avidity,correlates with neutralizing antibody response after H5N1 vaccination

Background

Influenza H5N1 virus constitutes a pandemic threat and development of effective H5N1 vaccines is a global priority. Anti-influenza antibodies directed towards the haemagglutinin (HA) define a correlate of protection. Both antibody concentration and avidity may be important for virus neutralization and resolving influenza disease.

Methods

We conducted a phase I clinical trial of a virosomal H5N1 vaccine adjuvanted with the immunostimulating complex Matrix M™. Sixty adults were intramuscularly immunized with two vaccine doses (21 days apart) of 30 μg HA alone or 1.5, 7.5 or 30 μg HA adjuvanted with Matrix M™. Serum H5 HA1-specific antibodies and virus neutralization were determined at days 0, 21, 42, 180 and 360 and long-term memory B cells at day 360 post-vaccination. The binding of the HA specific antibodies was measured by avidity NaSCN-elution ELISA and surface plasmon resonance (SPR).

Results

The H5 HA1-specific IgG response peaked after the second dose (day 42), was dominated by IgG1 and IgG3 and was highest in the adjuvanted vaccine groups. IgG titres correlated significantly with virus neutralization at all time points (Spearman r ≥ 0.66, p < 0.0001). By elution ELISA, serum antibody avidity was highest at days 180 and 360 post vaccination and did not correlate with virus neutralization. Long-lasting H5 HA1-specific memory B cells produced high IgG antibody avidity similar to serum IgG.

Conclusions

Maturation of serum antibody avidity continued up to day 360 after influenza H5N1 vaccination. Virus neutralization correlated with serum H5 HA1-specific IgG antibody concentrations and not antibody avidity.     

Comparing the safety and immunogenicity of a candidate TB vaccine MVA85A administered by intramuscular and intradermal delivery

Background

New vaccines to prevent tuberculosis are urgently needed. MVA85A is a novel viral vector TB vaccine candidate designed to boost BCG-induced immunity when delivered intradermally. To date, intramuscular delivery has not been evaluated. Skin and muscle have distinct anatomical and immunological properties which could impact upon vaccine-mediated cellular immunity.

Methods

We conducted a randomised phase I trial comparing the safety and immunogenicity of 1 × 10⁸ pfu MVA85A delivered intramuscularly or intradermally to 24 healthy BCG-vaccinated adults.

Results

Intramuscular and intradermal MVA85A were well tolerated. Intradermally-vaccinated subjects experienced significantly more local adverse events than intramuscularly-vaccinated subjects, with no difference in systemic adverse events. Both routes generated strong and sustained Ag85A-specific IFNγ T cell responses and induced multifunctional CD4+ T cells. The frequencies of CD4+ T cells expressing chemokine receptors CCR4, CCR6, CCR7 and CXCR3 induced by vaccination was similar between routes.

Conclusions

In this phase I trial the intramuscular delivery of MVA85A was well tolerated and induced strong, durable cellular immune responses in healthy BCG vaccinated adults, comparable to intradermal delivery. These findings are important for TB vaccine development and are of relevance to HIV, malaria, influenza and other intracellular pathogens for which T cell-inducing MVA-based vaccine platforms are being evaluated.     

Associations between race,sex and immune response variations to rubella vaccination in two independent cohorts

Introduction

Immune response variations after vaccination are influenced by host genetic factors and demographic variables, such as race, ethnicity and sex. The latter have not been systematically studied in regard to live rubella vaccine, but are of interest for developing next generation vaccines for diverse populations, for predicting immune responses after vaccination, and for better understanding the variables that impact immune response.

Methods

We assessed associations between demographic variables, including race, ethnicity and sex, and rubella-specific neutralizing antibody levels and secreted cytokines (IFNγ, IL-6) in two independent cohorts (1994 subjects), using linear and linear mixed models approaches, and genetically defined racial and ethnic categorizations.

Results

Our replicated findings in two independent, large, racially diverse cohorts indicate that individuals of African descent have significantly higher rubella-specific neutralizing antibody levels compared to individuals of European descent and/or Hispanic ethnicity (p < 0.001).

Conclusion

Our study provides consistent evidence for racial/ethnic differences in humoral immune response following rubella vaccination.     

Knowledge,attitudes and vaccination coverage of healthcare workers regarding occupational vaccinations

Objectives

Immunization of healthcare workers (HCWs) is a major issue for infection control in healthcare facilities. The aim of this study was to evaluate knowledge regarding occupational vaccinations, HBV, varicella and influenza vaccination rates and attitudes towards influenza vaccine among HCWs.

Design and setting

A cross-sectional survey was conducted in two wards (Medicine and Paediatrics) of a 1182-bed teaching hospital in Paris, France.

Methods

A standardized, anonymous, self-administered questionnaire was used.

Results

Of 580 HCWs, 395 (68%) completed the questionnaire. Knowledge about the occupational vaccinations of HCWs was low. HBV (69%), tuberculosis (54%) and influenza (52%) were the most cited vaccinations. Paediatric staff was more aware of influenza and pertussis immunizations (p < .05). HBV vaccination rate was 93%, among whom 65% were aware of their immune status. Influenza vaccination rate for 2006–2007 was 30% overall, ranging from 50% among physicians to 20% among paramedical staff (p < .05). Physicians based their refusal on doubts about vaccine efficacy, although paramedics feared side effects. Influenza vaccination was associated with knowledge of vaccine recommendations [OR = 1.75, 95% CI: 1.13–2.57] and contact with patients [OR = 3.05, 95% CI: 1.50–5.91].

Conclusions

Knowledge of recommended occupational vaccinations is insufficient in HCWs, except for HBV and influenza. Although the HBV vaccine coverage of HCWs is satisfactory, a large proportion of them is unaware of immune status. Influenza vaccine coverage remains low, especially among paramedical staff because of fear of side effects. As vaccine coverage is associated with knowledge, educational campaigns should be strengthened to increase the adhesion of HCWs to vaccinations.     

Antibody response to an eight-site intradermal rabies vaccination in patients infected with Human Immunodeficiency Virus

Objective

To investigate the rabies virus neutralizing antibody response in HIV-1-infected patients with CD4+ cell count ≤200 cells/μL or >200 cells/μL after post-exposure prophylaxis using an eight-site intradermal rabies vaccination regimen.

Methods

In a prospective cohort study, 27 HIV-1 infected patients were recruited, none of which had a history of rabies vaccination. All patients provided informed consent and were separated into two groups according to their CD4+ cell count (patients with CD4+ counts of ≤200 cells/μL and patients with CD4+ counts of >200 cells/μL). All patients received Purified Chick Embryo Cell rabies Vaccine (PCECV) using a modified eight-site regimen in which 0.1 mL of vaccine was injected intradermally on each of days 0, 3, 7, 14, and 30 (8–8–8–8–8). CD4+ cell counts, HIV-1 viral load and rabies virus neutralizing antibody (RVNAb) concentrations as determined by the Rapid Fluorescent Focus Inhibition Test (RFFIT) were evaluated on blood samples taken on days 0, 3, 7, 14, 30, 90, 180 and 365 after vaccination.

Results

Of the 27 patients included in the study, 18 patients (67%) had CD4+ cell counts of >200 cells/μL and 9 patients (33%) had CD4+ counts of ≤200 cells/μL. No patients had detectable RVNAb concentrations on day 0. By day 14, all patients had adequate RVNAb concentrations (≥0.5 IU/mL). There was no statistically significant difference in RVNAb concentrations between the two groups on days 3, 7, 14, 30, 90, 180 and 365 after vaccination.

Conclusion

PCECV is immunogenic in HIV-1-infected patients with CD4+ cell counts below 200 cells/μL when administered in a modified eight-site intradermal PEP regimen.     

Nanoparticle size influences the magnitude and quality of mucosal immune responses after intranasal immunization

Background

The development of nanoparticulate antigen-delivery systems is an important emerging area of vaccinology, being sought to amplify immune responses to recombinant antigens that are poorly immunogenic. Nanoparticle size may play an important role in influencing the activity of such particulate-based adjuvants.

Methods

To explore how the size of nanoparticles that are in the range of many common viruses can modulate the magnitude and quality of mucosal immune responses, the model antigen ovalbumin (OVA) was conjugated to 30 nm or 200 nm polypropylene sulfide nanoparticles (NPs) and administered intranasally to C57BL/6 mice.

Results

We show that by increasing the size of the NPs from 30 to 200 nm, OVA was more effectively delivered into both MHC class I and MHC class II-presentation pathways. Intranasal immunization with the 200 nm NPs increased the magnitude of CD4⁺ T cell responses in the lungs, as well as systemic and mucosal humoral responses. Most importantly, 200 nm NPs increased the proportion of antigen-specific polyfunctional CD4⁺ T cells as compared to 30 nm NPs.

Conclusions

The 200 nm NPs are a very interesting antigen nanocarrier for prophylactic vaccines against mucosal pathogens that require multifunctional CD4⁺ T cells for protection. These results contribute to our understanding of how the size of an antigen-conjugated nanoparticle modulates mucosal immune responses to a protein antigen and may be useful to engineer subunit vaccines able to elicit appropriate mucosal immune responses that correlate with protection.     

Intradermal influenza vaccination in immunocompromized patients is immunogenic and feasible

Background

Many strategies, including intradermal vaccination, have been tested to augment antibody responses upon vaccination. This strategy has not been evaluated in different groups of immunocompromized patients. We conducted a prospective, randomized study to compare the humoral response upon standard intramuscular influenza vaccination with the response upon reduced-dose intradermal vaccination in patients treated with anti-tumor necrosis factor (TNF)-alpha, human immunodeficiency virus (HIV)-infected patients, hematologic stem cell transplantation (HSCT) patients, and healthy controls.

Methods

In total 156 immunocompromized patients and 41 healthy controls were randomized to receive either 0.5 mL of the 2005/2006 trivalent influenza vaccine intramuscular or 0.1 mL intradermal. Humoral responses, determined by hemagglutination inhibition assay, were measured before and 28 days postvaccination. Geometric mean titers (GMTs) and protection rates (PRs) are reported as primary outcomes, adverse events as a secondary outcome.

Results

Reduced-dose intradermal vaccination leads to similar GMTs and PRs, within all tested groups, compared to the standard intramuscular vaccination. Healthy controls yielded significantly better GMTs and PRs than immunocompromized patients. Local skin reactions after intradermal vaccination occurred less frequent and were milder in immunocompromized patients than in healthy subjects and were predictive for a positive vaccination outcome for individual subjects.

Conclusions

Intradermal influenza vaccination is a feasible alternative for standard intramuscular vaccination in several groups of immunocompromized patients, including those treated with anti-TNF, HIV-infected patients and HSCT patients. The occurrence of a local skin reaction after intradermal vaccination is predictive of a response to at least one of the vaccine antigens.     

Oral vaccination against HPV E7 for treatment of cervical intraepithelial neoplasia grade 3 (CIN3) elicits E7-specific mucosal immunity in the cervix of CIN3 patients

Background

Cervical intraepithelial neoplasia grade 3 (CIN3) is a mucosal precancerous lesion caused by high-risk human papillomavirus (HPV). Induction of immunological clearance of CIN3 by targeting HPV antigens is a promising strategy for CIN3 therapy. No successful HPV therapeutic vaccine has been developed.

Methods

We evaluated the safety and clinical efficacy of an attenuated Lactobacillus casei expressing modified full-length HPV16 E7 protein in patients with HPV16-associated CIN3. Ten patients were vaccinated orally during dose optimization studies (1, 2, 4, or 6 capsules/day) at weeks 1, 2, 4, and 8 (Step 1). Seven additional participants were only tested using the optimized vaccine formulation (Step 2), giving a total of 10 patients who received optimized vaccination. Cervical lymphocytes (CxLs) and peripheral blood mononuclear cells (PBMCs) were collected and E7 specific interferon-γ-producing cells were counted (E7 cell-mediated immune responses: E7-CMI) by ELISPOT assay. All patients were re-evaluated 9 weeks after initial vaccine exposure using cytology and biopsy to assess pathological efficacy.

Results

No patient experienced an adverse event. E7-CMI in both CxLs and PBMCs was negligible at baseline. All patients using 4–6 capsules/day showed increased E7-CMI in CxLs, whereas patients using 1–2 capsules/day did not. No patient demonstrated an increase in E7-CMI in their PBMCs. In comparison between patients of cohorts, E7-CMI at week 9 (9 wk) in patients on 4 capsules/day was significantly higher than those in patients on 1, 2, or 6 capsules/day. Most patients (70%) taking the optimized dose experienced a pathological down-grade to CIN2 at week 9 of treatment. E7-CMI in CxLs correlated directly with the pathological down-grade.

Conclusions

Oral administration of an E7-expressing Lactobacillus-based vaccine can elicit E7-specific mucosal immunity in the uterine cervical lesions. We are the first to report a correlation between mucosal E7-CMI in the cervix and clinical response after immunotherapy in human mucosal neoplasia.     

The effect of diabetes mellitus on immunological response to hepatitis B virus vaccine in individuals with chronic kidney disease: A meta-analysis of current literature

Background

Patients with chronic kidney disease (CKD) often fail to produce protective antibodies to hepatitis B virus (HBV) surface antigen after vaccination. Diabetes mellitus (DM) is the most common cause of CKD; however it is not clear whether it affects immunological response to HBV vaccine in these patients.

Aims

We aimed to evaluate the immunological response to HBV vaccine in diabetic patients with CKD by conducting a meta-analysis of the current literature.

Methods

Only studies that evaluated the seroprotection rate for diabetic against non-diabetic CKD patients or the immunological response of these groups to HBV vaccine were included. We applied the random effects model of DerSimonian and Laird, with heterogeneity (Q statistic), publication bias (Egger and Begg test) and sensitivity analyses. The rate of patients showing seroprotective anti-HBsAg titers (>10 IU/mL) at completion of HBV vaccination schedule in the diabetic versus the non-diabetic CKD patients was set as our end-point of interest.

Results

We identified seven studies that fulfilled our inclusion criteria involving 15,073 unique patients with CKD. Aggregation of study results showed a significant decrease in response rates among the diabetic versus the non-diabetic patients [pooled odds ratio = 0.58 (95% CI 0.37–0.89), Q(6) = 11.3, I² = 50%]. The P-value was 0.07 for our test of heterogeneity.

Conclusions

Our meta-analysis determined that HBV vaccination's seroprotection rate in diabetic CKD patients is significantly lower than that in non-diabetic CKD patients. Therefore, using vaccine adjuvants such as oral levamisole, granulocyte macrophage-colony stimulating factor or intradermal injection might be advisable in these patients.     

Comparable humoral response after two doses of adjuvanted influenza A/H1N1pdm2009 vaccine or natural infection in allogeneic stem cell transplant recipients

Background

The present study evaluated immunogenicity and tolerance of two-dose influenza A/H1N1pdm09 vaccination in allogeneic hematopoietic stem cell transplantation (HSCT) recipients, and compared the vaccine-induced humoral response to that triggered by natural infection in another group of HSCT patients.

Methods

Adult allogeneic HSCT recipients vaccinated with two doses of influenza A/H1N1pdm09 vaccine, separated by 3 weeks, and patients with proven influenza A/H1N1pdm09 infection were included. Antibody responses were measured by hemagglutination-inhibition assay 1) on days 0, 21, 42 and 6 months after the first vaccine injection in vaccinated patients and 2) before pandemic and after influenza A/H1N1pdm09 infection, in patients presented natural infection.

Results

At baseline, 3% of 59 recipients of adjuvanted vaccine and 0% of 20 infected patients were seroprotected (antibody titer ≥ 1/40). Seroprotection rate observed 42 days after vaccination was not different from that observed after natural infection (66% and 60% respectively, p = 0.78). In vaccinated patients, seroprotection rate increased significantly from 54% to 66% between day 21 and 42 (p = 0.015). Moreover, after 6 months, seroprotection rate in 21 vaccinated patients was similar to that observed in 10 infected patients evaluated at least 76 days after infection (D76–217) (60% and 81% respectively, p = 0.2). In multivariate analysis, no immunosuppressive treatment or chronic graft-versus-host disease (GVHD) and longer time between transplantation and vaccination/infection were associated with a stronger humoral response. The adjuvanted vaccine was safe with low rate of GVHD worsening.

Conclusion

In HSCT recipients, two doses of influenza A/H1N1pdm09 adjuvanted vaccine were safe and induced a humoral response comparable to that triggered by natural infection in these patients.     

Impact of anti-orthopoxvirus neutralizing antibodies induced by a heterologous prime-boost HIV-1 vaccine on insert-specific immune responses

Background

The impact of anti-vector immunity on the elicitation of insert-specific immune responses is important to understand in vaccine development. HVTN 055 was a 150 person phase I randomized, controlled HIV vaccine trial of recombinant modified vaccinia Ankara (rMVA) and fowlpox (rFPV) with matched HIV-1 inserts which demonstrated increased CD8+ T-cell immune responses in the heterologous vaccine group. The controls used in this study were the empty vectors (MVA and FPV).

Methods

Anti-MVA and anti-vaccinia neutralizing antibodies (NAbs) were measured and compared with cellular and humoral HIV-1-specific immune responses.

Results

Elicitation of anti-vector responses increased with increasing dose of MVA and up to 2 administrations. Further inoculations of MVA (up to 5) did not increase the magnitude of the anti-MVA response but did delay the anti-vector NAb titre decay. There was no evidence that the insert impaired the anti-vector response, nor that anti-vector immunity attenuated the insert-specific responses.

Conclusion

Two doses of MVA may be ideal for the elicitation of orthopoxvirus immune responses with further doses maintaining increased titres against the vector. We found no evidence that eliciting HIV insert- or MVA vector-specific immune responses interfered with elicitation of immune responses to the other.     

Are immunosuppressive medications associated with decreased responses to routine immunizations? A systematic review

Background

Long-term immunosuppressive medications are being used more commonly for a variety of medical conditions, including immune-mediated diseases and organ transplantation. While these medications are often necessary, they are associated with an increased risk of serious infections. Vaccination may be a way to prevent a variety of infections but vaccine responses among patients receiving immunosuppressive therapies have been variable.

Purpose

To systematically review the literature describing immune responses among patients on immunosuppressive therapies to vaccinations including influenza, pneumococcal, meningococcal, hepatitis A and B, tetanus toxoid, pertussis, varicella, and zoster.

Data sources

English language citations in the MEDLINE and EMBASE databases from 1985 to 2010.

Study selection

Two reviewers independently screened titles and abstracts to identify prospective, controlled studies reporting pre- and post-vaccination titers of recommended vaccines in patients receiving long-term immunosuppressive therapies for full-text review.

Data extraction

Three reviewers independently assessed study characteristics including treatment regimens and pre- and post-vaccination titers.

Data synthesis

Of the 972 identified titles, fifteen met inclusion criteria. Ten studies assessed the effects of immunosuppressive medications on responses to influenza vaccine, four studies investigated responses following pneumococcal vaccination, and one study assessed both influenza and pneumococcal vaccination. Five of the studies that evaluated influenza vaccination showed partially diminished responses among individuals receiving immunosuppressive therapies, while one of the pneumococcal vaccine studies showed significantly decreased responses following vaccination. Patients treated with more than one immunosuppressive medication were the least likely to respond to vaccination.

Limitations

The heterogeneity of reported outcomes limits generalizeability.

Conclusions

Immunosuppressive therapy, particularly combination regimens, may blunt response to influenza and pneumococcal vaccinations. To ensure the best chance of response, immunizations should be administered prior to initiation of immunosuppressive medications whenever possible.     

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.     

Heterologous priming–boosting with DNA and vaccinia virus expressing kinetoplastid membrane protein-11 induces potent cellular immune response and confers protection against infection with antimony resistant and sensitive strains of Leishmania (Leishmania) donovani

Background

Emergence of resistance against commonly available drugs poses a major threat in the treatment of visceral leishmaniasis (VL), particularly in the Indian subcontinent. Absence of any licensed vaccine against VL emphasizes the urgent need to develop an effective alternative vaccination strategy.

Methodology

We developed a novel heterologous prime boost immunization strategy using kinetoplastid membrane protein-11 (KMP-11) DNA priming followed by boosting with recombinant vaccinia virus (rVV) expressing the same antigen. The efficacy of this vaccination regimen in a murine and hamster model of visceral leishmaniasis caused by both antimony resistant (Sb-R) and sensitive (Sb-S) Leishmania (L.) donovani is examined.

Result

Heterologous prime-boost (KMP-11 DNA/rVV) vaccination was able to protect mice and hamsters from experimental VL induced by both Sb-S and Sb-R-L. (L.) donovani isolates. Parasite burden is kept significantly low in the vaccinated groups even after 60 days post-infection in hamsters, which are extremely susceptible to VL. Protection in mice is correlated with strong cellular and humoral immune responses. Generation of polyfunctional CD8⁺ T cell was observed in vaccinated groups, which is one of the most important prerequisite for successful vaccination against VL. Protection was accompanied with generation of antigen specific CD4⁺ and CD8⁺ cells that produced effector cytokines such as IFN-γ, IL-2 and TNF-α. KMP-11-DNA/rVV vaccination also developed strong cytotoxic response and reversed T-cell impairment to induce antigen specific T cell proliferation.

Conclusion

KMP-11 is a unique antigen with high epitope density. Heterologous prime boost vaccination activates CD4⁺ and CD8⁺ T-cell mediated immunity to confer resistance to VL. This immunization method also produces high quality T-cells secreting multiple effector cytokines thus enhancing durability of the immune response. Thus the vaccination regime as described in the present study could provide a potent strategy for future anti-leishmanial vaccine development.     

Protein-energy malnutrition alters IgA responses to rotavirus vaccination and infection but does not impair vaccine efficacy in mice

Background

Conflicting evidence links malnutrition to the reduced efficacy of rotavirus vaccines in developing countries, where diarrhea and undernutrition remain leading causes of child deaths. Here, we adapted mouse models of rotavirus vaccination (rhesus rotavirus, RRV), rotavirus infection (EDIM), and protein-energy malnutrition (PEM) to test the hypothesis that undernutrition reduces rotavirus vaccine immunogenicity and efficacy.

Methods

We randomized wild type Balb/C dams with 3-day-old pups to a control diet (CD) or an isocaloric, multideficient regional basic diet (RBD) that produces PEM. At 3 weeks of age, we weaned CD and RBD pups to their dams’ diet and subrandomized weanlings to receive a single dose of either live oral rotavirus vaccine (RRV) or PBS. At 6 weeks of age, we orally challenged all groups with murine rotavirus (EDIM). Serum and stool specimens were collected before and after RRV and EDIM administration to measure viral shedding and antibody responses by ELISA.

Results

RBD pups and weanlings exhibited significant failure to thrive compared to age-matched CD mice (P < .0001). RRV vaccination induced higher levels of serum anti-RV IgA responses in RBD vs. CD mice (P < .0001). Vaccination protected CD and RBD mice equally against EDIM infection, as measured by viral shedding. In unvaccinated RBD mice, EDIM shedding peaked 1 day earlier (P < .05), however we detected no effects of undernutrition on viral clearance nor of infection on bodyweight. EDIM infection provoked higher anti-RV serum IgA levels in RBD vs. CD mice, regardless of vaccination (P < .0001). Last, RRV vaccination mitigated stool IgA responses to EDIM more in CD vs. RBD mice (P < .0001).

Conclusions

Despite modulated IgA responses to vaccination and infection, undernutrition does not impair rotavirus vaccine efficacy nor exacerbate infection in this mouse model of protein-energy malnutrition. Alternative models are needed to elucidate host-pathogen factors undermining rotavirus vaccine effectiveness in high-risk global settings.     

Factors associated with the immune response to hepatitis A vaccination in HIV-infected patients in the era of highly active antiretroviral therapy

Introduction

HIV seropositivity is considered a risk factor for complications in hepatitis A virus (HAV) infection. HAV vaccination schedules are widely implemented in HIV-infected patients, but the immune response remains impaired.

Methods

We analysed the response to vaccination (antiHAV titres ≥20 IU/l) in 282 HIV-infected patients included in a standard (1440 Elisa Units (EU) at 0, 6 months) or rapidly accelerated schedule (720 EU at 0, 7, 21 days and 6 months) between 1997 and 2009. Factors associated with the response to vaccination were analysed using logistic regression.

Results

The overall response rate was 73.4%. Male sex (OR: 0.16, 95% CI 0.05–0.51) and hepatitis C virus co-infection (OR: 0.30, 95% CI 0.14–0.74) were associated with a lower probability of response. Protective antibody response was associated with a higher CD4/CD8 ratio (OR: 3.69, 95% CI 1.3–10.5) and having received two doses of standard schedule (compared with patients receiving only one dose of the same schedule) (OR: 2.51, 95% CI 1.22–5.15). Three doses of the rapidly accelerated schedule were not more effective than a single dose of 1440 EU (OR: 1.32, 95% CI 0.48–3.63).

Conclusion

The low responses observed in patients receiving a single dose suggest the need to emphasize adhesion to vaccination protocols to avoid failure. The CD4/CD8 ratio may be considered as an immune status marker which could help to better choose the moment of vaccination. Our findings underscore the importance of identifying strategies that optimize the timing and effectiveness of hepatitis A vaccination in HIV-infected patients and of the need for further studies on individual factors such as sex and hepatitis C co-infection that may affect the response to vaccination. Likewise, the sub-optimal effectiveness of three doses of 720 EU in the rapidly accelerated schedule, if confirmed in future studies, might lead to a revision of the current schedule recommended for HIV-infected travellers.     

Influenza vaccination and risk of hospitalization among adults with laboratory confirmed influenza illness

Background

Influenza vaccine is moderately effective for preventing influenza illness. It is not known if vaccination reduces the risk of subsequent hospital admission among patients with vaccine failure and laboratory confirmed influenza illness.

Methods

Patients in a community cohort presenting with acute respiratory illness were prospectively enrolled and tested for influenza during 8 seasons to estimate seasonal vaccine effectiveness. Hospital admissions within 14 days after illness onset were identified for all participants aged ≥20 years with laboratory confirmed influenza. The association between vaccination and hospital admission was examined in a propensity score adjusted logistic regression model. The model was validated by examining the association between vaccination and hospital admission in participants without influenza.

Results

Influenza was identified in 1393 (28%) of 4996 participants. Sixty-two (6%) of 1020 with influenza A and 17 (5%) of 369 with influenza B were hospitalized. Vaccination was not associated with a reduced risk of hospital admission among all participants with influenza [adjusted odds ratio (aOR) = 1.08; 95% CI: 0.62, 1.88]; or among those with influenza A (aOR = 1.35; 95% CI: 0.71, 2.57) or influenza B (aOR = 0.67; 95% CI: 0.21, 2.15). Influenza vaccination was not associated with hospitalization after non-influenza respiratory illness (aOR = 1.14; 95% CI: 0.84, 1.54).

Conclusions

Influenza vaccination did not reduce the risk of subsequent hospital admission among patients with vaccine failure. These findings do not support the hypothesis that vaccination mitigates influenza illness severity.     

The novel tuberculosis vaccine,AERAS-402, is safe in healthy infants previously vaccinated with BCG,and induces dose-dependent CD4 and CD8T cell responses

Background

Efforts to reduce risk of tuberculosis disease in children include development of effective vaccines. Our aim was to test safety and immunogenicity of the new adenovirus 35-vectored tuberculosis vaccine candidate AERAS-402 in infants, administered as a boost following a prime with the Bacille Calmette-Guerin vaccine.

Methods

In a phase 1 randomised, double-blind, placebo-controlled, dose-escalation trial, BCG-vaccinated infants aged 6–9 months were sequentially assigned to four study groups, then randomized to receive an increasing dose-strength of AERAS-402, or placebo. The highest dose group received a second dose of vaccine or placebo 56 days after the first. The primary study outcome was safety. Whole blood intracellular cytokine staining assessed immunogenicity.

Results

Forty-two infants received AERAS-402 and 15 infants received placebo. During follow-up of 182 days, an acceptable safety profile was shown with no serious adverse events or discontinuations related to the vaccine. AERAS-402 induced a specific T cell response. A single dose of AERAS-402 induced CD4T cells predominantly expressing single IFN-γ whereas two doses induced CD4T cells predominantly expressing IFN-γ, TNF-α and IL-2 together. CD8T cells were induced and were more likely to be present after 2 doses of AERAS-402.

Conclusions

AERAS-402 was safe and immunogenic in healthy infants previously vaccinated with BCG at birth. Administration of the highest dose twice may be the most optimal vaccination strategy, based on the induced immunity. Multiple differences in T cell responses when infants are compared with adults vaccinated with AERAS-402, in the same setting and using the same whole blood intracellular cytokine assay, suggest specific strategies may be important for vaccination for each population.