Bacille Calmette-Guérin (BCG) is the vaccine against tuberculosis (TB), but has varied efficacy in different geographical locations. Recombinant strategies to genetically modify the organism to... Show moreBacille Calmette-Guérin (BCG) is the vaccine against tuberculosis (TB), but has varied efficacy in different geographical locations. Recombinant strategies to genetically modify the organism to enhance the quality of the immune response have aimed at improving BCG efficacy. Here we describe such a strategy using rBCGΔureC∷hly expressing defined latency-associated antigens and test this construct for long-term protection against an isolate of the Mycobacterium tuberculosis (Mtb) Beijing/W lineage. Expression of the antigens Rv2659c, Rv3407 and Rv1733c by rBCGΔureC∷hly improved long-term efficacy in both lung and spleen at day 200 post-infection after intradermal vaccination of mice. Our data support expression of Mtb latency associated antigens by rBCG to improve protection against Mtb. Show less
Ample evidence suggests that infection with cytomegalovirus (CMV) leads to accelerated aging of the immune system and may contribute to poor responsiveness to influenza vaccination in older persons... Show moreAmple evidence suggests that infection with cytomegalovirus (CMV) leads to accelerated aging of the immune system and may contribute to poor responsiveness to influenza vaccination in older persons. The objective of this study was to investigate whether CMV infection, acquired earlier in life, affects the response to influenza vaccination in a randomized controlled trial among older persons in long-term care facilities. During the 1997-1998 influenza season, 731 residents (median age 83 [interquartile range 78-88], 75.4% female) in 14 long-term care facilities in the Netherlands were randomly assigned to receive 15 or 30 mu g of inactivated influenza vaccine, followed by a 15 mu g booster vaccine or a placebo vaccine at day 84. Blood samples were collected at day 0, day 25, day 84 and day 109. Seroresponses to influenza vaccination were measured by hemagglutination-inhibition tests to the A/H3N2 strain at all time points. Subsequently, baseline levels of IgG anti-CMV antibodies were measured using an automated chemiluminescent microparticle immunoassay. Participants with CMV antibody level >= 6 AU/mL were considered to harbor CMV infection. At baseline, no differences in pre-vaccination geometric mean antibody titers (GMT) were observed between participants with (n = 571, 78.1%) or without CMV infection (n = 160, 21.9%). During follow-up, participants with and without CMV infection had similar responses to influenza vaccination as measured with changes in GMT (linear mixed model, adjusted for gender, age, pre-vaccination GMT and vaccination strategy, p = 0.46). Analogously, no association was found between CMV infection and a more than 4-fold increase in antibody titer (Generalized Estimating Equations, adjusted OR 1.14 195%Cl 0.80;1.641) or an antibody titer >= 40 (adjusted OR 1.24 [95%Cl 0.86;1.80]). In conclusion, CmV infection did not explain poor responsiveness to influenza vaccination in residents of long-term care facilities. (C) 2011 Elsevier Ltd. All rights reserved. Show less
Carstens, M.G.; Camps, M.G.M.; Henriksen-Lacey, M.; Franken, K.; Ottenhoff, T.H.M.; Perrie, Y.; ... ; Jiskoot, W. 2011
The formulation of plasmid DNA (pDNA) in cationic liposomes is a promising strategy to improve the potency of DNA vaccines. In this respect, physicochemical parameters such as liposome size may be... Show moreThe formulation of plasmid DNA (pDNA) in cationic liposomes is a promising strategy to improve the potency of DNA vaccines. In this respect, physicochemical parameters such as liposome size may be important for their efficacy. The aim of the current study was to investigate the effect of vesicle size on the in vivo performance of liposomal pDNA vaccines after subcutaneous vaccination in mice. The tissue distribution of cationic liposomes of two sizes, 500 nm (PDI 0.6) and 140 nm (PDI 0.15), composed of egg PC, DOPE and DOTAP, with encapsulated OVA-encoding pDNA, was studied by using dual radiolabeled pDNA-liposomes. Their potency to elicit cellular and humoral immune responses was investigated upon application in a homologous and heterologous vaccination schedule with 3 week intervals. It was shown that encapsulation of pDNA into cationic lipsomes resulted in deposition at the site of injection, and strongest retention was observed at large vesicle size. The vaccination studies demonstrated a more robust induction of OVA-specific, functional CD8(+) T-cells and higher antibody levels upon vaccination with small monodisperse pDNA-liposomes, as compared to large heterodisperse liposomes or naked pDNA. The introduction of a PEG-coating on the small cationic liposomes resulted in enhanced lymphatic drainage, but immune responses were not improved when compared to non-PEGylated liposomes. In conclusion, it was shown that the physicochemical properties of the liposomes are of crucial importance for their performance as pDNA vaccine carrier, and cationic charge and small size are favorable properties for subcutaneous DNA vaccination. (C) 2011 Elsevier Ltd. All rights reserved. Show less
Carstens, M.G.; Camps, M.G.M.; Henriksen-Lacey, M.; Franken, K.; Ottenhoff, T.H.M.; Perrie, Y.; ... ; Jiskoot, W. 2011
The formulation of plasmid DNA (pDNA) in cationic liposomes is a promising strategy to improve the potency of DNA vaccines. In this respect, physicochemical parameters such as liposome size may be... Show moreThe formulation of plasmid DNA (pDNA) in cationic liposomes is a promising strategy to improve the potency of DNA vaccines. In this respect, physicochemical parameters such as liposome size may be important for their efficacy. The aim of the current study was to investigate the effect of vesicle size on the in vivo performance of liposomal pDNA vaccines after subcutaneous vaccination in mice. The tissue distribution of cationic liposomes of two sizes, 500 nm (PDI 0.6) and 140 nm (PDI 0.15), composed of egg PC, DOPE and DOTAP, with encapsulated OVA-encoding pDNA, was studied by using dual radiolabeled pDNA-liposomes. Their potency to elicit cellular and humoral immune responses was investigated upon application in a homologous and heterologous vaccination schedule with 3 week intervals. It was shown that encapsulation of pDNA into cationic lipsomes resulted in deposition at the site of injection, and strongest retention was observed at large vesicle size. The vaccination studies demonstrated a more robust induction of OVA-specific, functional CD8+ T-cells and higher antibody levels upon vaccination with small monodisperse pDNA-liposomes, as compared to large heterodisperse liposomes or naked pDNA. The introduction of a PEG-coating on the small cationic liposomes resulted in enhanced lymphatic drainage, but immune responses were not improved when compared to non-PEGylated liposomes. In conclusion, it was shown that the physicochemical properties of the liposomes are of crucial importance for their performance as pDNA vaccine carrier, and cationic charge and small size are favorable properties for subcutaneous DNA vaccination. Show less
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... Show moreNew 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 naive 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-gamma) production. In the present study, we monitored safety and IFN-gamma 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 (R), 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. (C) 2011 Elsevier Ltd. All rights reserved. Show less
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... Show moreNew 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. Show less
