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.     

A recombinant adenovirus expressing immunodominant TB antigens can significantly enhance BCG-induced human immunity

Background

Despite the availability of Bacille Calmette Guérin (BCG) vaccines, Mycobacterium tuberculosis currently infects billions of people and millions die annually from tuberculosis (TB) disease. New TB vaccines are urgently needed.

Methods

We studied the ability of AERAS-402, a recombinant, replication-deficient adenovirus type 35 expressing the protective M. tuberculosis antigens Ag85A, Ag85B, and TB10.4, to boost BCG immunity in an area of low TB endemicity.

Results

In volunteers primed with BCG 3 or 6 months prior to AERAS-402 boosting, significant CD4⁺ and CD8⁺ T cell responses were induced. Ag85-specific responses were more strongly boosted than TB10.4-specific responses. Frequencies of TB-specific CD8⁺ T cells reached > 50 fold higher than pre-AERAS boosting levels, remarkably higher than reported in any previous human TB vaccine trial. Multiparameter flow cytometric assays demonstrated that AERAS-402-boosted CD4⁺ and CD8⁺ T cells were multifunctional, producing multiple cytokines and other immune effector molecules. Furthermore, boosted T cells displayed lymphoproliferative capacity, and tetramer analyses confirmed that antigen-specific CD8⁺ T cells were induced. BCG and AERAS-402 vaccinations given 3 and 6 months apart appeared equivalent.

Conclusions

Our results indicate that AERAS-402 is a promising TB vaccine candidate that can significantly enhance both CD4⁺ and CD8⁺ TB-specific T cell responses after BCG priming.ClinicalTrials.gov Identifier: NCT01378312.     

The recombinant tuberculosis vaccine rBCG ΔureC::hly induces apoptotic vesicles for improved priming of CD4 and CD8 T cells

Background

The recombinant BCG ΔureC::hly⁺ (rBCG) vaccine candidate is more efficient than parental BCG (pBCG) against tuberculosis (TB) in preclinical models. Evidence exists for superior CD4 and CD8 T cell stimulation. Although the responsible immune mechanisms are incompletely understood, crosspriming of CD8 T cells has been proposed as a major mechanism underlying better protection of rBCG over pBCG. The present study investigates the role of apoptotic vesicles from pBCG- and rBCG-infected macrophages in crosspriming.

Methods

Apoptotic vesicles were isolated from pBCG- and rBCG-infected mouse macrophages. The priming potential of the isolated vesicles was evaluated in terms of dendritic cell activation and specific T cell stimulation.

Results

Apoptotic vesicles from both pBCG- and rBCG-infected macrophages activated dendritic cells but to a different degree. Overall, rBCG-infected apoptotic vesicles induced more profound CD4 and CD8 T cell responses as compared to pBCG.

Conclusions

These data support the notion that the improved vaccine efficacy of rBCG rests on enhanced crosspriming as a consequence of stronger apoptosis.     

Characterization and immune effect of the hepatitis B–BCG combined vaccine for using a needle innoculation

Objective

To prepare the hepatitis B–Mycobacterium bovis Bacillus Calmette-Guérin combined vaccine (HB–BCG combined vaccine) and resolve a needle problem of the two kinds of hepatitis B vaccine (HB vaccine) and M. bovis Bacillus Calmette-Guérin (BCG) for the innoculation.

Methods

The hepatitis B surface antigen (HBsAg) was prepared by the genetic engineering technique, BCG was produced using routine biological technique, and then the finished products of the HB–BCG combined vaccine were processed on the above foundation. The content of HBsAg was measured by Enzyme linked immunosorbent assay (ELISA), the immune effect of BCG was detected by purified protein derivative (PPD) test. Cellular immune response, safety, partial poison and allergy were tested. The stability of HB–BCG combined vaccine was detected by ELISA and viable count method.

Results

The two kinds of antigens (HBsAg and BCG) had good compatibility. The comparison on immune effects of HB–BCG combined vaccine and BCG showed no significant difference. The comparison on immune effects of HB–BCG combined vaccine group (first dose for HB–BCG Combined vaccine, second and third dose for HB vaccine) and HB vaccine group (three dose all for HB vaccine) demonstrated that anti-HBs levels of the HB–BCG combined vaccine group were higher than that of HB vaccine group. No statistical significance was observed between the combined vaccine group and HB vaccine group after three doses immunization schedules. The results of safety in HB–BCG combined vaccine group accorded with that of BCG group, it had been not found the pathological changes of the tuberculosis. The characteristic and process in pathological changes of HB–BCG combined vaccine group and BCG group were similar in the partial poison test. HBsAg did not strengthen the inflammation reaction caused by BCG. Systemic allergy had not been found. The HB–BCG combined vaccine was stable in 2 years.

Conclusion

The immune effects of the HB–BCG combined vaccine were not lower than the two kinds of single dose vaccine, it had good safety.     

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).     

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

Background

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

Methods

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

Results

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

Conclusion

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

Low-dose BCG vaccination protects free-ranging cattle against naturally-acquired bovine tuberculosis

Vaccination of cattle with Mycobacterium bovis BCG has been shown to protect against infection with virulent strains of M. bovis, and against resultant bovine tuberculosis (TB). Here we report on a large-scale trial in New Zealand where free-ranging cattle were vaccinated with 3 x 10⁵ BCG via injection, a lower dose than any previously trialed in cattle against exposure to a natural force of M. bovis infection. In a multi-year enrolment study involving >800 animals, three cohorts of 1–2 year old cattle were randomised to receive vaccine or to serve as non-vaccinated controls. Cattle were slaughtered and subject to standard abattoir post mortem examination for M. bovis culture-positive TB lesions after up to 3.7 years of in-field exposure; additionally, lymph node samples from approximately half of the cattle were examined further to identify infection in the absence of lesions. Overall TB prevalence, as identified by gross lesions detected at slaughter, was low among farmed cattle at the study site (<4% annually). There were two lesioned cases among 520 vaccinated trial cattle (0.38%) compared to eight among 297 non-vaccinated trial cattle (2.69%). Trial vaccine efficacy was 85.7% against abattoir-detectable TB (statistically significant protection), and 86.7% when adjusted for duration of exposure. BCG vaccination did not significantly affect the response rates of cattle to ante mortem skin- or blood-tests in diagnostic tests conducted >7 months post-vaccination. Use of a reduced, yet effective, dose of BCG would increase the cost effectiveness of using this vaccine in a bovine TB control programme.     

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.     

Safety and immunogenicity of an investigational vaccine containing two common pneumococcal proteins in toddlers: A phase II randomized clinical trial

Background

To provide broader protection against pneumococcal disease, new vaccines containing conserved Streptococcus pneumoniae proteins are being developed. This study assessed the safety, reactogenicity and immunogenicity of four formulations containing pneumococcal proteins pneumolysin toxoid (dPly) and histidine triad protein (PhtD) in toddlers.

Methods

In this phase II, multicenter, observer-blind study (www.clinicaltrials.gov: NCT00985751) conducted in the Czech Republic, toddlers (12–23 months) were randomized (1:1:1:1:1) to receive one of four investigational vaccine formulations (10 or 30 μg each of dPly and PhtD, alone or in combination with polysaccharide conjugates from the pneumococcal non-typeable Haemophilus influenzae protein-D conjugate vaccine [PHiD-CV]), or the licensed PHiD-CV, in a 2-dose primary series plus booster at study months 0, 2 and 6. Solicited local and general symptoms were recorded within seven days post-vaccination, unsolicited symptoms within 31 days post-vaccination, and serious adverse events (SAEs) during the entire study period. Antibody concentrations against the vaccine components were measured pre-vaccination, one month post-dose 2, pre- and one month post-booster.

Results

257 toddlers were enrolled and vaccinated. Percentages of solicited local and general symptoms following the different investigational formulations were generally within the same ranges as for PHiD-CV. After each dose, grade 3 fever (>40.0 °C, rectal measurement) was reported for maximum one toddler in each group with no differences between investigational formulations and PHiD-CV during primary vaccination. 23 SAEs were reported for 17 toddlers, with distribution balanced between all groups except the group receiving 30 μg dPly/PhtD with PHiD-CV-conjugates (no SAEs reported). None of the SAEs were considered to be vaccine-related.For all pneumococcal protein-containing formulations, anti-PhtD and anti-Ply antibody geometric mean concentrations increased from pre-vaccination to post-dose 2 and from pre- to post-booster vaccination.

Conclusion

All investigational vaccine formulations were well-tolerated and immunogenic when administered to toddlers as a 2-dose primary vaccination followed by a booster dose.     

Evaluation of Mycobacterium tuberculosis Early Secreted Antigenic Target 6 Recombinant Protein as a Diagnostic Marker in Skin Test

Objectives

Tuberculosis (TB) is the leading infectious disease in the developing world. Delayed-type hypersensitivity skin test diagnoses TB using tuberculin purified protein derivative (PPD), but this test is incapable of distinguishing Mycobacterium tuberculosis (MTB) infection from bacillus Calmette–Guérin (BCG) vaccination or an infection caused by nontuberculous mycobacteria (NTM). This study was performed to evaluate the use of recombinant early secretory antigenic target 6 (rESAT-6), a secretory protein found only in MTB, Mycobacterium bovis, and few other mycobacterial species, as a skin marker for MTB in guinea pigs.

Methods

We prepared recombinant MTB ESAT-6 and evaluated its use as a specific antigen for MTB in guinea pigs.

Results

Our results show that the purified MTB rESAT-6 antigen is capable of inducing a positive reaction only in guinea pigs sensitized to MTB. No such reaction was observed in the animals sensitized to M. bovis, BCG vaccination, or NTM (Mycobacterium avium).

Conclusion

Our study results confirm that the ESAT-6 antigen is more specific to MTB infection than PPD and could be used in more specific skin tests for detection of MTB in large animals and in humans.     

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.     

Heat shock protein complex vaccination induces protection against Helicobacter pylori without exogenous adjuvant

Background

The development of a vaccine against the human gastric pathogen Helicobacter pylori, the main causative agent of gastric adenocarcinoma, has been hampered by a number of issues, including the lack of a mucosal adjuvant for use in humans. Heat shock proteins (Hsp), highly conserved molecules expressed by both bacteria and mammalian species, possess a range of functions, including acting as chaperones for cellular proteins and the ability to activate innate immune receptors. Hsp complex (HspC) vaccines, containing Hsp derived from pathogenic bacteria, are immunostimulatory without addition of an exogenous adjuvant and can induce immunity against their chaperoned proteins. In this study we explored in mice the potential utility of a H. pylori HspC vaccine.

Results

Vaccination with H. pylori HspC, by either the subcutaneous or respiratory mucosal route, induced a strong antibody response, elevated gastric cytokine levels and significant protection against subsequent live challenge with this pathogen. The level of protection induced by non-adjuvanted HspC vaccine was equivalent to that which resulted from vaccination with adjuvanted vaccines. While protection induced by immunisation with adjuvanted vaccines was associated with the development of a moderate to severe atrophic gastritis, that induced by H. pylori HspC only resulted in a mild inflammatory response, despite an increase in pro-inflammatory gastric cytokines. This reduced gastritis correlated with an increase in IL-10 and IL-13 levels in the gastric tissues of HspC vaccinated, H. pylori challenged mice.

Conclusions

H. pylori HspC vaccines have the potential to overcome some of the issues preventing the development of a human vaccine against this pathogen: HspC induced protective immunity against H. pylori without addition of an adjuvant and without the induction of a severe inflammatory response. However, complete protection was not obtained so further optimisation of this technology is needed if a human vaccine is to become a reality.     

Assessment of the safety of Bacillus Calmette-Guérin vaccine administered orally to badgers (Meles meles)

European badgers (Meles meles) are a wildlife reservoir for Mycobacterium bovis (M. bovis) in parts of England, Wales and Ireland, constituting a potential source of tuberculosis (TB) infection for cattle. Vaccination of badgers against TB is one of the tools available for helping reduce the prevalence of bovine TB in badgers, made possible by the licensing in 2010 of Bacillus Calmette-Guérin (BCG) vaccine for intramuscular administration to badgers (BadgerBCG). However, practical limitations associated with administering an injected vaccine to wild animals make an oral, bait-delivered form of the vaccine highly desirable. Evaluation of the safety of oral BCG to badgers and the environment is a mandatory step on the road to licensing an oral vaccine. This study had the following objectives: (a) to determine whether adverse effects followed the oral administration of BCG vaccine to badgers; (b) to measure the quantity and frequency of BCG excreted in the faeces of vaccinated badgers; and (c) to assess whether there was evidence of the vaccine spreading to unvaccinated, ‘sentinel’ badgers sharing the same environment as vaccinated animals. We report here that the oral administration per badger of ≥6.4 × 10⁹ cfu BCG, followed 14 days later by a single oral dose of ≥6.4 × 10⁷ cfu BCG caused no adverse physical effects and did not affect the social behaviour and feeding habits of the vaccinated animals. BCG was cultured from the faeces of two of nine vaccinated animals (372 cfu/g and 996 cfu/g, respectively) approximately 48 h after the higher dose of BCG was administered and by one of the nine vaccinated animal (80 cfu/g) approximately 24 h after receiving the lower dose of BCG. We found no evidence for the transmission of BCG to unvaccinated, sentinel, badgers housed with the vaccinated animals despite the occasional excretion of BCG in faeces.     

Circulating pneumococcal specific plasma and memory B cells in the elderly two years after pneumococcal conjugate versus polysaccharide vaccination

Background

Polysaccharide conjugate vaccines prime for lasting memory responses in children and young adults. The potential value of these vaccines in the elderly is unclear.

Methods

We compared the frequency of circulating pneumococcal capsular polysaccharide (PPS) specific IgG, IgA and IgM plasma and memory cells by cultured ELISpot and supernatant screening two years after vaccination with the 7-valent pneumococcal conjugate vaccine (7vCRM) and/or the 23-valent pneumococcal polysaccharide vaccine (PPV) in 252 adults aged 50–80 years. Some individuals received a six-month boost with 7vCRM or PPV. PPS specific IgG memory detected two years post-primary vaccination was correlated with published matched serum IgG concentration pre- and up to one year post-primary vaccination.

Results

There was no difference by vaccine schedule in the quantity of plasma or memory cells detected. The concentration of in vitro PPS IgG produced by memory B cells isolated two years post-vaccination correlated with pre-vaccination serum IgG concentration and not with D28 post-vaccination responses regardless of vaccination schedule.

Conclusions

This study shows that circulating memory B cells numbers two years following immunisation with 7vCRM or PPV are best predicted by pre-vaccination serotype specific serum antibody concentration and not early post-vaccination serum antibody responses.     

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

Background

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

Methods

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

Results

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

Conclusion

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

Immunogenicity,reactogenicity, and safety of inactivated quadrivalent influenza vaccine candidate versus inactivated trivalent influenza vaccine in healthy adults aged ≥18 years: A phase III,randomized trial

Background

Two influenza B lineages have been co-circulating since the 1980s, and because inactivated trivalent influenza vaccine (TIV) contains only one B strain, it provides little/no protection against the alternate B-lineage. We assessed a candidate inactivated quadrivalent influenza vaccine (QIV) containing both B lineages versus TIV in healthy adults.

Methods

Subjects received one dose of QIV (lot 1, 2, or 3) or one of two TIVs (B strain from Victoria or Yamagata lineage); randomization was 2:2:2:1:1. Hemagglutination-inhibition assays were performed 21-days post-vaccination; superiority of QIV versus TIV for the alternate B-lineage was demonstrated if the 95% confidence interval (CI) lower limit for the GMT ratio was ≥1.5, and non-inferiority against the shared strains was demonstrated if the 95% CI upper limit for the GMT ratio was ≤1.5. Reactogenicity and safety were assessed during the post-vaccination period. NCT01196975.

Results

Immunogenicity of QIV lots was consistent, QIV was superior to TIV for the alternate B-lineage strain, and QIV was non-inferior versus TIVs for shared strains (A/H1N1, A/H3N2, B-strain). Reactogenicity and safety profile of the QIV was consistent with seasonal influenza vaccines.

Conclusion

QIV provided superior immunogenicity for the added B strain without affecting the antibody response to the TIV strains, and without compromising safety.     

Reduced antibody responses against Plasmodium falciparum vaccine candidate antigens in the presence of Trichuris trichiura

Background

Helminth infections are highly prevalent in the tropics and may have an effect on immune responses to vaccines due to their immunomodulatory effect. The prevalence of helminth infections in young children, the target group for malaria and most other vaccines, is high. Therefore we assessed the influence of helminth infection on vaccine-induced immune responses in a phase I clinical trial of the malaria vaccine candidate GMZ2.

Methods

Twenty Gabonese preschool-age children were vaccinated with GMZ2, a blood stage malaria vaccine candidate. Humoral immune response against the vaccine antigens and parasitological status were assessed. Vaccine-specific antibody concentrations and memory B-cell numbers were compared in worm infected and non-infected participants.

Results

Antibody response to GMZ2 was 3.4-fold (95% confidence interval: 1.6, 7.4) higher in Trichuris trichiura negative subjects compared to positive participants, whereas immunoglobulin subclass distribution was similar. Memory B-cell response was moderately increased in T. trichiura negative individuals, although the difference was not significant.

Conclusions

Future malaria vaccine development programs need to account for worm-mediated hyporesponsiveness of immune reactions.     

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.     

Microstructured liposome subunit vaccines reduce lung inflammation and bacterial load after Mycobacterium tuberculosis infection

Background

Tuberculosis is a disease affecting millions of people throughout the world. One of the main problems in controlling the disease is the low efficacy of the Bacillus Calmette–Guérin (BCG) vaccine in protecting young adults. The development of new vaccines that induce a long-lasting immune response or that stimulate the immunity induced by BCG may improve the control of tuberculosis.

Methods

The use of microstructured liposomes containing HspX, with or without MPL or CpG DNA adjuvants, as vaccines for tuberculosis was evaluated. The HspX-specific humoral and cellular immune responses to the different vaccine formulations were compared.

Results

All vaccines containing liposome microparticles and HspX were immunogenic. Vaccines formulated with CpG DNA and HspX induced the strongest humoral and cellular immune responses, mainly by inducing interferon-γ and tumor necrosis factor-α expression by both CD4⁺ and CD8⁺ T cells. HspX and MPL mainly induced CD8⁺ T-cell activation and specific humoral responses. When evaluated the protective efficacy of the formulations against Mycobacterium tuberculosis challenge, the microstructured liposome containing L-HspX and L-HspX-CPG DNA reduced both lung inflammatory lesions and the bacterial load.

Conclusion

We have thus demonstrated, for the first time, the use of microstructured liposomes as an adjuvant and delivery system for a vaccine formulation against tuberculosis.     

A novel adjuvant, mixture of alum and the beta-adrenergic receptor antagonist propranolol, elicits both humoral and cellular immune responses for heat-killed Salmonella typhimurium vaccine

Objective

To determine the efficacy of the mixture of propranolol (PRP), a beta-adrenergic receptor antagonist, and alum, as a new adjuvant, in the induction of humoral and cellular immunity in response to heat-killed Salmonella typhimurium (S. typhimurium) (HKST) as a model vaccine.

Methods

BALB/c mice were divided into five groups. Mice in the experimental groups received either the HKST vaccine alone or in combination with the adjuvant alum, PRP or the alum–PRP mixture. Mice in the negative control group received phosphate-buffered saline. All mice were immunized two times on days 0 and 14. Two weeks after the last immunization, immune responses to S. typhimurium were assessed.

Results

Administration of the alum–PRP mixture as an adjuvant increased the ability of the HKST vaccine to enhance lymphocyte proliferation, shifted the immune response towards a T-helper (Th) 1 pattern and increased S. typhimurium specific IgG, IgG2a and IgG1. This resulted in improved protective immunity against S. typhimurium.

Conclusion

Administration of the alum–PRP mixture as an adjuvant in combination with the HKST vaccine, can enhance both humoral and cellular immunity and shift the immune responses to a Th1 pattern.