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Here, we report on a first-in-man trial where the tuberculosis (TB) vaccine Ag85B-ESAT-6 (H1) was adjuvanted with escalating doses of a novel liposome adjuvant CAF01. On their own, protein antigens cannot sufficiently induce immune responses in humans, and require the addition of an adjuvant system to ensure appropriate delivery and concomitant immune activation. To date no approved adjuvants are available for induction of cellular immunity, which seems essential for a number of vaccines, including vaccines against TB. We vaccinated four groups of human volunteers: a non-adjuvanted H1 group, followed by three groups with escalating doses of CAF01-adjuvanted H1 vaccine. All subjects were vaccinated at 0 and 8 weeks and followed up for 150 weeks. Vaccination did not cause local or systemic adverse effects besides transient soreness at the injection site. Two vaccinations elicited strong antigen-specific T-cell responses which persisted after 150 weeks follow-up, indicating the induction of a long-lasting memory response in the vaccine recipients. These results show that CAF01 is a safe and tolerable, Th1-inducing adjuvant for human TB vaccination trials and for vaccination studies in general where cellular immunity is required., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A woman developed Marburg haemorrhagic fever in the Netherlands, most likely as a consequence of being exposed to virus-infected bats in the python cave in Maramagambo Forest during a visit to Uganda. The clinical syndrome was dominated by acute liver failure with secondary coagulopathy, followed by a severe systemic inflammatory response, multiorgan failure, and fatal cerebral oedema. A high blood viral load persisted during the course of the disease. The initial systemic inflammatory response coincided with peaks in interferon-γ and tumour necrosis factor-α concentrations in the blood. A terminal rise in interleukin-6, placental growth factor (PlGF), and soluble vascular endothelial growth factor receptor-1 (sVEGF-R1) seemed to suggest an advanced pathophysiological stage of Marburg haemorrhagic fever associated with vascular endothelial dysfunction and fatal cerebral oedema. The excess of circulating sVEGF-R1 and the high sVEGF-R1:PlGF ratio shortly before death resemble pathophysiological changes thought to play a causative part in pre-eclampsia. Aggressive critical-care treatment with renal replacement therapy and use of the molecular absorbent recirculation system appeared able to stabilise--at least temporarily--the patient's condition., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

New TB vaccines are urgently needed because of the apparent lack of effect of the BCG vaccine on rates of adult contagious pulmonary tuberculosis and the risk of disseminated BCG disease in immunocompromised individuals. Since BCG appears to protect children, the primary target for vaccine development is a booster vaccine for adults but such vaccines ideally need to be able to efficiently prime mycobacterially naïve individuals as well as boost individuals previously vaccinated with BCG and those latently infected with TB. Protective immunity against Mycobacterium tuberculosis depends mainly on the generation of a Th1-type cellular immune response characterized by interferon-gamma (IFN-γ) production. In the present study, we monitored safety and IFN-γ responses in healthy BCG-vaccinated and prior or latently TB-infected individuals receiving a novel vaccine composed of the fusion protein Ag85B-ESAT-6 combined with the adjuvant IC31(®), administered at 0 and 2 months. Vaccination caused few local or systemic adverse effects besides transient soreness at the injection site, but it elicited strong antigen-specific T cell responses against Ag85B-ESAT-6 and both the Ag85B and ESAT-6 components, that could be augmented by second vaccination. The strong responses persisted through 32 weeks of follow-up, indicating the induction of a persistent memory response in the vaccine recipients., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Five to ten percent of immunocompetent persons fail to develop a protective immune response to hepatitis B vaccination, and are defined non-responders (NR). We investigated the immune response to intradermal hepatitis B vaccination after pre-treatment of the skin with the TLR7 agonist imiquimod., Methods: Twenty-one non-responders (anti-HBs <10 IU/l after at least 6 intramuscular hepatitis B vaccinations) were randomly assigned to the control group (N=11) or the experimental group (N=10). Participants in both groups received 3 intradermal (ID) vaccinations with 5 microg HBsAg (0.125 mL) at 0, 1 and 6 months. In the experimental group, the dermal site of injection was pre-treated with 250 mg imiquimod ointment. Anti-HBs antibodies were determined at 0, 1, 2, 6 and 7 months., Results: In both study groups, 70% of the participants developed a protective immune response (anti-HBs >or=10 IU/l), after the 3rd intradermal vaccination., Conclusion: The application of imiquimod on the skin prior to intradermal vaccination did not enhance the humoral response to hepatitis B vaccine. However, irrespective of imiquimod application, 70% of the NR who had not responded to 6 previous intramuscular vaccinations, developed a protective immune response with high affinity antibodies after 3 ID hepatitis B vaccinations with 5 microg HBsAg., ((c) 2010 Elsevier Ltd. All rights reserved.)

Though widely used, the BCG vaccine has had little apparent effect on rates of adult pulmonary tuberculosis. Moreover, the risk of disseminated BCG disease in immunocompromised individuals means that improved TB vaccines ideally need to be able to efficiently prime mycobacterially-naïve individuals as well as boost individuals previously vaccinated with BCG. Protective immunity against Mycobacterium tuberculosis is thought to depend on the generation of a Th1-type cellular immune response characterized by interferon-gamma (IFN-gamma) production. In the present study, we monitored safety and IFN-gamma responses in healthy TB-naïve humans receiving an entirely novel vaccine, composed of the fusion protein Ag85B-ESAT-6, administered at 0 and 2 months either as recombinant protein alone or combined with two concentrations of the novel adjuvant IC31. Vaccination did not cause local or systemic adverse effects besides transient soreness at the injection site, but it elicited strong antigen-specific T cell responses against H1 and both the Ag85B and the ESAT-6 components. These strong responses persisted through 2.5 years of follow-up, indicating the induction of a substantial memory response in the vaccine recipients., ((c) 2010 Elsevier Ltd. All rights reserved.)

The type-1 cytokine (interleukin 12, interleukin 23, interferon gamma, interleukin 17) signalling pathway is triggered during infection by activation of phagocyte-expressed pattern-recognition receptors that recognise specific pathogen-associated molecular patterns. Triggering of this pathway results, among other things, in activation of microbicidal mechanisms in phagocytic cells. Individuals with a deficiency in one of the proteins in the pathway are unusually susceptible to otherwise poorly pathogenic, mostly environmental, mycobacteria and salmonellae. Individuals with deficiencies in other innate immune signalling proteins show unusual susceptibility to pathogens other than mycobacteria or salmonellae. We discuss recent insights into key molecules involved in type-1 cytokine signalling pathways and provide an update on the molecular genetic defects underlying mendelian susceptibility to mycobacterial disease. We also discuss deficiencies in the innate immune signalling proteins that lead to susceptibility to other pathogens. Knowledge of innate immune signalling has allowed the identification of defects in such patients. However, some patients have enhanced susceptibility to pathogens even though no mutations have been found in the candidate genes identified thus far. Whereas a few patients might have autoantibodies against type-1 cytokines, others might harbour mutations in new genes and pathways that still need to be identified.

The neutralising antibody response after the yellow fever vaccine (YF-17D) skin test was measured in 7 egg allergic persons in whom further vaccination was abandoned because of a strong local urticarial reaction to the YF-17D vaccine test dose. We found that this test dose of 0.1mL of YF-17D vaccine was sufficient to induce a protective antibody response in all 7 subjects. Intradermal injection of 1/5th dose of the yellow fever vaccine appears to be sufficient, in non-allergic as well as allergic persons, and non-inferior to the subcutaneous full dose.

Pre-exposure vaccination of persons at risk with intradermally administered reduced dose cell culture rabies vaccines remains controversial in low-enzootic countries. In a prospective clinical trial of adult volunteers (N=25), we studied the immune response to purified chick embryo cell vaccine (PCECV) administered intradermally at a reduced dose (0.1 mL) in a three-dose schedule (0, 7 and 21 days). In 10 subjects, immunogenicity of intradermally administered one-dose booster vaccination with 0.1 mL PCECV was investigated. All participants were seroconverted 3 weeks after primary and 1 week after booster vaccination (antibody titre > or = 0.5 EU/mL, measured by enzyme linked immunosorbent assay). Local adverse events such as erythema and swelling were moderate and transitory. The intradermal vaccination route offers an efficacious and cost-reducing strategy to increase the accessibility of cell culture rabies vaccines.

The antibody production by HIV-infected adults after two vaccinations with conjugated pneumococcal vaccine (CPV) and consecutive vaccination with polysaccharide pneumococcal vaccine (PPV) was studied. Thirty days after the second CPV, the geometric mean antibody concentrations (GMC) against pneumococcal polysaccharide serotypes (PPS) 6B, 14 and 19F were significantly lower in the group HIV-infected individuals with <200x10(6)/l CD4(+) T lymphocytes (group 1) than in the group with >/=200x10(6)/l CD4(+) T lymphocytes (group 2) and healthy controls. Thirty days after PPV vaccination the GMC against PPS 6B, 14, 19F and 23F in group 1, and against 6B and 19F in group 2, were significantly lower compared with healthy controls. Both in HIV-infected and in healthy individuals who received CPV and PPV the postvaccination GMC against PPS 14, 19F and 23F were higher compared with historical controls who were not previously immunized with CPV but only received PPV. We conclude that the antibody response to CPV is impaired in HIV-infected individuals. Higher antibody concentrations were achieved in HIV-infected and healthy individuals after sequential vaccination with CPV and PPV compared with PPV vaccination alone.

In a consecutive 3-year study the antibody response after immunization with influenza vaccine of a cohort of HIV-infected adults was studied. The haemagglutination-inhibiting (HAI) antibody titres after vaccination correlated with the number of CD4(+) T lymphocytes (p<0.001), the prevaccination antibody titres (p<0.001), and the proliferative response to anti-CD3 (p<0.001). Severely impaired antibody responses were observed in HIV-infected individuals with CD4(+) T-lymphocyte counts < or =100x10(6)/l. Significantly higher prevaccination antibody titres were observed in healthy controls in the 2nd or 3rd year of vaccination, but not in HIV-infected individuals. Annually repeated vaccination of HIV-infected individuals did not lead to higher postvaccination antibody titres. Annual vaccination of HIV-infected individuals with CD4(+) T-lymphocyte counts exceeding 100x10(6)/l seems to be worthwhile, although it may not be expected to render the same level of protection against influenza as in non-infected individuals.

We studied the production of IgG antibodies against eight pneumococcal polysaccharide serotypes (PPS) 1, 4, 6B, 9V, 14, 18C, 19F and 23F after vaccination of 50 HIV-infected adults with 23-valent Pneumovax((R))23 and the course of the antibodies against four PPS during the following years. Mean antibody concentrations against PPS 18C, 19F and 23F were sigificantly lower in the patients with CD4(+)-lymphocyte counts <200x10(6)/l than in healthy controls; mean antibody concentrations against PPS 1, 4, 9V, 6B and 14 were similar in HIV-infected individuals and controls. Although it has been assumed that polysaccharides induce a T-cell-independent immune response, our results indicate that some PPS are T-cell-independent type 2 antigens. The rates of decline of mean antibody concentrations in HIV-infected individuals and in healthy controls were similar during 5 y after vaccination. However, as a consequence of the low postvaccination antibody concentrations against several PPS, within 3 y after vaccination most HIV-infected individuals had antibody concentrations below the level which is assumed to be required for protection.

Infections with Salmonella species, including Salmonella typhi, are more frequently observed in HIV-infected individuals than in healthy individuals. HIV-infected individuals were vaccinated with polysaccharide vaccine against Salmonella typhi (Typhim-Vi) which is assumed to be a T-cell-independent antigen. We found that the antibody response in patients with < 200 x 10(6)/l CD4+ T lymphocytes was significantly lower compared with patients with > or = 200 x 10(6)/l CD4+ T lymphocytes and healthy controls. The antibody response after vaccination with the polysaccharide salmonella Vi-antigen was correlated with the number of CD4+ T lymphocytes and therefore Typhim-Vi can be considered to be a T-cell-independent type 2 antigen. The results of this study indicate that after vaccination the proportion of HIV-infected individuals with protective antibody concentrations against Salmonella typhi will be lower than in healthy controls.