BACKGROUND:Although BCG provides protection against severe forms of tuberculosis in children, its efficacy against pulmonary tuberculosis in adolescents and adults is highly variable, and it offers limited and inconsistent protection against infection and transmission. VPM1002 is a recombinant BCG vaccine that showed manageable toxicity and immunogenicity in phase 1 trials in adults and in phase 2 trials in South African newborns. We compared VPM1002 with BCG for the prevention of Mycobacterium tuberculosis infection in infants. METHODS:This double-blind, randomised, active-controlled, phase 3 trial was conducted at ten main sites and four satellite sites in sub-Saharan Africa, ranging from rural to urban settings, with experience in tuberculosis trials. Healthy newborn infants, aged 0-14 days and with a birthweight of at least 2·3 kg, were randomly assigned (1:1) to receive single 0·05 mL doses of either VPM1002 or BCG, administered intradermally. Follow-up was extended from 36 months up to 48 months (due to the lower than expected event rate) or until 632 cases of M tuberculosis had accrued. The randomisation was done centrally through an interactive web response system and allocation was stratified by maternal HIV status at a 1:10 ratio, using a permuted block design with variable block sizes. Only the site personnel involved in preparation and administration of the vaccines were not masked to the trial. Mothers were aged 18 years or older, free from active tuberculosis, and without household contact with an individual with tuberculosis within the 3 months before enrolment. Neonates were excluded for any fever, acute or chronic illness, congenital malformation, substantial skin lesion or infection at the site of injection, or previous receipt of routine BCG vaccination. The primary endpoint was non-inferiority of VPM1002 versus BCG for prevention of M tuberculosis infection, defined by incident QuantiFERON-TB Gold Plus (QFT; an interferon-γ release assay [IGRA]) conversion, assessed every 6 months from month 6 until the final visit and more frequently in suspected cases of tuberculosis. In the time-to-event efficacy analysis, participants with missing event occurrence data were censored at the last timepoint for which there was no clear evidence of the event occurrence. The primary efficacy analysis was in the per-protocol population (randomly assigned, vaccinated participants with at least one post-vaccination result and no major efficacy-relevant protocol deviations) with a supportive intention-to-treat analysis of all randomly assigned participants; both were analysed as assigned. As estimates were concordant, intention-to-treat results are presented. Safety was analysed as treated in all vaccinated participants. Non-inferiority required the upper bound of the 95% CI for the hazard ratio (HR) to be less than 1·25. The trial was registered on ClinicalTrials.gov (NCT04351685) and PACTR (PACTR202007868402718) and is complete. FINDINGS:Between Nov 9, 2020, and June 21, 2022, we enrolled 6950 infants. The trial was terminated early in October, 2024, due to a lower than expected QFT conversion rate. After the withdrawal of ten infants, 6940 were randomly assigned to treatment, including 720 infants born to mothers living with HIV and 6220 HIV-unexposed infants. Overall, 3449 male and 3491 female infants were included in the intention-to-treat population. 6897 infants received vaccination (3452 received VPM1002 and 3445 received BCG). Median follow-up was 35 months (IQR 30-38). QFT conversion occurred in 184 (5·3%) of 3471 infants in the VPM1002 group and 150 (4·3%) of 3469 infants in the BCG group. Cox proportional hazards regression analysis (VPM1002 vs BCG) revealed VPM1002 was not non-inferior to BCG, with an HR of 1·23 (95% CI 0·99-1·53). Adverse event profiles, including serious adverse events and deaths, were similar between groups; no vaccine-related serious adverse events were reported. INTERPRETATION:VPM1002 did not show non-inferiority to BCG on the primary endpoint of QFT conversion. Because fewer infections occurred than expected (334 of 632 planned events, despite extending the duration to 48 months), the trial did not have sufficient statistical certainty to definitively compare the two vaccines. Moreover, discordance between the QFT surrogate and confirmed tuberculosis endpoints, approximately 33·0% higher household tuberculosis exposure in the VPM1002 group, and violation of the proportional hazards assumption when tuberculosis exposure was included as a covariate (that is, the effect of tuberculosis exposure on QFT conversion was not constant over time, precluding reliable HR estimation without penalised modelling) collectively add to this uncertainty. Both vaccines showed similar adverse event profiles. These findings highlight challenges in using IGRA-defined infection endpoints in infant vaccine trials. FUNDING:European and Developing Countries Clinical Trials Partnership 2 (EDCTP2) programme (RIA2016V-1645-priMe), supported by the European Union and co-funded by Deutsches Zentrum für Luft- und Raumfahrt (DLR) and the European Investment Bank (EIB).

Goats are natural hosts of Mycobacterium (M.) bovis, and affected herds can be the cause of significant economic losses. Similarites in disease course and lesions of M. bovis infections in goats and M. tuberculosis in humans make goats good models for human tuberculosis. The aim of this investigation was to characterize M. bovis challenge models in goats. For this, goats were endobronchially inoculated with three doses of M. bovis or culture medium. Clinical signs, shedding, and immune responses were monitored until 146 days post inoculation (dpi). At necropsy, lesions were examined by computed tomography, histology, and bacteriological culture. Infected goats did not develop clinical signs. M. bovis was cultured from feces, but never from nasal swabs. IGRAs were positive from 28 dpi onwards, antibodies at 140 dpi, and SICCT at 146 dpi. The increase in CD25+, IFN-γ+, and IFN-γ-releasing T-cell subpopulations was time-related, but not dose-dependent. All infected goats developed paucibacillary granulomas in the lungs and regional lymph nodes. M. bovis was regularly cultured. Dose-dependent effects included the size of pulmonary lesions, caverns, intestinal lesions, and early generalization in the high-dose group. In summary, reproducible challenge models with dose-dependent differences in lesions were established, which may serve for testing vaccines for veterinary or medical use.

Background: This study assessed the safety and immunogenicity of a new booster vaccine against tetanus, diphtheria, and pertussis manufactured by Serum Institute of India Pvt. Ltd (SIIPL Tdap). Methods: The Phase II/III trial was randomized (2:1), observer blinded and active controlled. Healthy subjects aged 4-65 years received a single dose of either SIIPL Tdap or comparator Tdap vaccine (Boostrix (R), GlaxoSmithKline, Belgium), and were followed-up for 30 days. Blood samples for safety and immunogenicity assessments were collected pre-vaccination and on day 30 post-vaccination. The study assessed safety and reactogenicity of SIIPL Tdap compared to the comparator Tdap as well as the co-primary immunogenicity out-comes: (i) seroprotection rates against diphtheria toxoid (DT) and tetanus toxoid (TT) and (ii) the booster response rates against pertussis toxoid (PT), filamentous hemagglutinin (FHA) and pertactin (PRN) 30 days post-vaccination in all study subjects. A margin of-10 % was used for non-inferiority testing. Secondary outcomes included the booster response rates against DT and TT, seropositivity rates against pertussis antigens, and antibody geometric mean concentrations (GMCs) for all vaccine components.Results: At Day 30 post-vaccination, SIIPL Tdap was assessed as non-inferior to the comparator Tdap in terms of: i) seroprotection rates against DT (94.4 % vs. 94.9 %) and TT (99.9 % vs. 100 %) and ii) pertussis booster response rates (93.8 % vs. 88.4 % anti-PT, 89.7 % vs. 90.9 % anti-FHA and 86.3 % vs. 84.4 % anti-PRN), for SIIPL Tdap versus comparator Tdap, respectively. GMCs for anti-PT and anti-PRN were higher in subjects vaccinated with SIIPL Tdap compared to comparator Tdap. All other secondary outcomes were comparable. The overall frequency of local and systemic solicited AEs was comparable; no treatment related SAEs were reported.Conclusions: Booster vaccination with SIIPL Tdap was non-inferior to comparator Tdap with respect to the immunogenicity of the vaccine components and was equally well tolerated. EudraCT number: 2019-002706-46.

A more effective vaccine against tuberculosis than Bacille Calmette-Guérin (BCG) is urgently needed. BCG derived recombinant VPM1002 has been found to be more efficacious and safer than the parental strain in mice models. Newer candidates, such as VPM1002 Δpdx1 (PDX) and VPM1002 ΔnuoG (NUOG), were generated to further improve the safety profile or efficacy of the vaccine. Herein, we assessed the safety and immunogenicity of VPM1002 and its derivatives, PDX and NUOG, in juvenile goats. Vaccination did not affect the goats' health in regards to clinical/hematological features. However, all three tested vaccine candidates and BCG induced granulomas at the site of injection, with some of the nodules developing ulcerations approximately one month post-vaccination. Viable vaccine strains were cultured from the injection site wounds in a few NUOG- and PDX- vaccinated animals. At necropsy (127 days post-vaccination), BCG, VPM1002, and NUOG, but not PDX, still persisted at the injection granulomas. All strains, apart from NUOG, induced granuloma formation only in the lymph nodes draining the injection site. In one animal, the administered BCG strain was recovered from the mediastinal lymph nodes. Interferon gamma (IFN-γ) release assay showed that VPM1002 and NUOG induced a strong antigen-specific response comparable to that elicited by BCG, while the response to PDX was delayed. Flow cytometry analysis of IFN-γ production by CD4+, CD8+, and γδ T cells showed that CD4+ T cells of VPM1002- and NUOG-vaccinated goats produced more IFN-γ compared to BCG-vaccinated and mock-treated animals. In summary, the subcutaneous application of VPM1002 and NUOG induced anti-tuberculous immunity, while exhibiting a comparable safety profile to BCG in goats.

Bovine tuberculosis (bTB) not only poses a zoonotic threat to humans but also has a significant economic impact on livestock production in many areas of the world. Effective vaccines for humans, livestock, and wildlife are highly desirable to control tuberculosis. Suitable large animal models are indispensable for meaningful assessment of vaccine candidates. Here, we describe the refinement of an animal model for bTB in goats. Intrabronchial inoculation procedure via video-guided endoscopy in anesthetized animals, collection of lungs after intratracheal fixation in situ, and imaging of lungs by computed tomography (CT) were established in three goats using barium sulfate as surrogate inoculum. For subsequent infection experiments, four goats were infected with 4.7 × 102 colony-forming units of M. bovis by intrabronchial inoculation using video-guided endoscopy with spray catheters. Defined amounts of inoculum were deposited at five sites per lung. Four age-matched goats were mock-inoculated. None of the goats developed clinical signs until they were euthanized 5 months post infection, but simultaneous skin testing confirmed bTB infection in all goats inoculated with M. bovis. In tissues collected at necropsy, M. bovis was consistently re-isolated from granulomas in lymph nodes, draining the lungs of all the goats infected with M. bovis. Further dissemination was observed in one goat only. Pulmonary lesions were quantified by CT and digital 2D radiography (DR). CT revealed mineralized lesions in all the infected goats ranging from <5 mm to >10 mm in diameter. Small lesions <5 mm predominated. The DR failed to detect small lesions and to determine the exact location of lesions because of overlapping of pulmonary lobes. Relative volume of pulmonary lesions was low in three but high in one goat that also had extensive cavitation. CT lesions could be correlated to gross pathologic findings and histologic granuloma types in representative pulmonary lobes. In conclusion, video-guided intrabronchial inoculation with spray catheters, mimicking the natural way of infection, resulted in pulmonary infection of goats with M. bovis. CT, but not DR, presented as a highly sensitive method to quantify the extent of pulmonary lesions. This goat model of TB may serve as a model for testing TB vaccine efficacy.

BACKGROUND:Tuberculosis is a major public health problem worldwide. Immunisation with Mycobacterium bovis BCG vaccine is partially effective in infants, reducing the incidence of miliary and tuberculosis meningitis, but is less effective against pulmonary tuberculosis. We aimed to compare safety and immunogenicity of VPM1002-a recombinant BCG vaccine developed to address this gap-with BCG in HIV exposed and HIV unexposed newborn babies. METHODS:This double-blind, randomised, active controlled phase 2 study was conducted at four health centres in South Africa. Eligible neonates were aged 12 days or younger with a birthweight of 2·5-4·2 kg, and could be HIV exposed (seropositive mothers) or unexposed (seronegative mothers). Newborn babies were excluded if they had acute or chronic illness, fever, hypothermia, sepsis, cancer, or congenital malformation, or if they received blood products or immunosuppressive therapy. Participants were excluded if their mothers (aged ≥18 years) had active tuberculosis disease, diabetes, a history of immunodeficiency except for HIV, hepatitis B or syphilis seropositivity, received blood products in the preceding 6 months, any acute infectious disease, or any suspected substance abuse. Participants were randomly assigned to VPM1002 or BCG vaccination in a 3:1 ratio, stratified by HIV status using the random number generator function in SAS, using a block size of eight paticipants. The primary outcome was non-inferiority (margin 15%) of VPM1002 to BCG vaccine in terms of incidence of grade 3-4 adverse drug reactions or ipsilateral or generalised lymphadenopathy of 10 mm or greater in diameter by 12 months. The primary outcome was assessed in all vaccinated participants (safety population) at regular follow-up visits until 12 months after vaccination. Secondary immunogenicity outcomes were interferon-γ levels and percentages of multifunctional CD4+ and CD8+ T cells among all lymphocytes across the 12 month study period. The study was registered with ClinicalTrials.gov, NCT02391415. FINDINGS:Between June 4, 2015 and Oct 16, 2017, 416 eligible newborn babies were randomly assigned and received study vaccine. Seven (2%) of 312 participants in the VPM1002 group had a grade 3-4 vaccine-related adverse reaction or lymphadenopathy of 10 mm or greater in diameter compared with 34 (33%) of 104 participants in the BCG group (risk difference -30·45% [95% CI -39·61% to -21·28%]; pnon-inferiority<0·0001); VPM1002 was thus non-inferior to BCG for the primary outcome. Incidence of severe injection site reactions was lower with VPM1002 than BCG: scarring occurred in 65 (21%) participants in the VPM1002 group versus 77 (74%) participants in the BCG group (p<0·0001); ulceration occurred in one (<1%) versus 15 (14%; p<0·0001); and abscess formation occurred in five (2%) versus 23 (22%; p<0·0001). Restimulated IFNγ concentrations were lower in the VPM1002 group than the BCG group at week 6, week 12, month 6, and month 12. The percentage of multifunctional CD4+ T cells was higher in the VPM1002 group than the BCG group at day 14 but lower at week 6, week 12, month 6, and month 12. The percentage of multifunctional CD8+ T cells was lower in the VPM1002 group than the BCG group at week 6, week 12, and month 6, but did not differ at other timepoints. INTERPRETATION:VPM1002 was less reactogenic than BCG and was not associated with any serious safety concern. Both vaccines were immunogenic, although responses were higher with the BCG vaccine. VPM1002 is currently being studied for efficacy and safety in a multicentric phase 3 clinical trial in babies in sub-Saharan Africa. FUNDING:Serum Institute of India.

Background. Bacille Calmette-Guerin (BCG) vaccination can potentially reduce the rate of respiratory infections in vulnerable populations. This study evaluates the safety and efficacy of VPM1002 (a genetically modified BCG) as prophylaxis against severe respiratory tract infections including coronavirus disease 2019 (COVID-19) in an elderly population. Methods. In this phase 3, randomized, double-blind, placebo-controlled, multicenter clinical trial, healthy elderly volunteers (N = 2064) were enrolled, randomized (1:1) to receive either VPM1002 or placebo, and followed up remotely for 240 days. The primary outcome was the mean number of days with severe respiratory infections at hospital and/or at home. Secondary endpoints included the incidence of self-reported fever, number of hospital and intensive care unit (ICU) admissions, and number of adverse events. Results. A total of 31 participants in the VPM1002 group reported at least 1 day with severe respiratory disease and a mean number of days with severe respiratory disease of 9.39 +/- 9.28 while in the placebo group; 38 participants reported a mean of 14.29 +/- 16.25 days with severe respiratory disease. The incidence of self-reported fever was lower in the VPM1002 group (odds ratio, 0.46 [95% confidence interval, .28-.74]; P =.001), and consistent trends to fewer hospitalization and ICU admissions due to COVID-19 were observed after VPM1002 vaccination. Local reactions typical for BCG were observed in the VPM1002-vaccinated group, which were mostly of mild intensity. Conclusions. Vaccination with VPM1002 is well tolerated and seems to have a prophylactic effect against severe respiratory disease in the elderly.

BACKGROUND Bacille Calmette-Guérin (BCG) vaccination can potentially reduce the rate of respiratory infections in vulnerable populations. This study evaluates the safety and efficacy of VPM1002 (a genetically modified BCG) as prophylaxis against severe respiratory tract infections including COVID-19 in an elderly population. METHODS In this phase III, randomized, double-blind, placebo-controlled, multicenter clinical trial, healthy elderly volunteers (n = 2064) were enrolled, randomized (1:1) to receive either VPM1002 or placebo, and followed up remotely for 240 days. The primary outcome was the mean number of days with severe respiratory infections at hospital and/or at home. Secondary endpoints included the incidence of self-reported fever, number of hospital and ICU admissions, and number of adverse events. RESULTS A total of 31 participants in the VPM1002 group reported at least 1 day with severe respiratory disease and a mean number of days with severe respiratory disease of 9.39 ± 9.28 days while in the placebo group, 38 participants reported a mean of 14.29 ± 16.25 days with severe respiratory disease. The incidence of self-reported fever was lower in the VPM1002 group (odds ratio: 0.46; 95% CI: 0.28 to 0.74; p-value: 0.001) and consistent trends to less hospitalization and ICU admissions due to COVID-19 were observed after VPM1002-vaccination. Local reactions typical for BCG were observed in the VPM1002-vaccinated group, which were mostly of mild intensity. CONCLUSIONS Vaccination with VPM1002 is well tolerated and seems to have a prophylactic effect against severe respiratory diseases in the elderly. (ClinicalTrials.gov: NCT04435379).

Tuberculous granulomas are highly dynamic structures reflecting the complex host–mycobacterium interactions. The objective of this study was to compare granuloma development at the site of vaccination with BCG and its recombinant derivatives in goats. To characterize the host response, epithelioid cells, multinucleated giant cells (MNGC), T cell subsets, B cells, plasma cells, dendritic cells and mycobacterial antigen were labelled by immunohistochemistry, and lipids and acid-fast bacteria (AFB) were labelled by specific staining. Granulomas with central caseous necrosis developed at the injection site of most goats though lesion size and extent of necrosis differed between vaccine strains. CD4+ T and B cells were more scarce and CD8+ cells were more numerous in granulomas induced by recombinant derivatives compared to their parental BCG strain. Further, the numbers of MNGCs and cells with lipid bodies were markedly lower in groups administered with recombinant BCG strains. Microscopic detection of AFB and mycobacterial antigen was rather frequent in the area of central necrosis, however, the isolation of bacteria in culture was rarely successful. In summary, BCG and its recombinant derivatives induced reproducibly subcutaneous caseous granulomas in goats that can be easily monitored and surgically removed for further studies. The granulomas reflected the genetic modifications of the recombinant BCG-derivatives and are therefore suitable models to compare reactions to different mycobacteria or TB vaccines.

ABSTRACT Background: VPM1002BC is a modified mycobacterium Bacillus Calmette Guérin (BCG) for the treatment of non-muscle invasive bladder cancer (NMIBC). The genetic modifications are expected to result in better immunogenicity and less side effects. We report on patient safety and immunology of the first intravesical application of VPM1002BC in human. Methods: Six patients with BCG failure received a treatment of 6 weekly instillations with VPM1002BC. Patients were monitored for adverse events (AE), excretion of VPM1002BC and cytokines, respectively. Results: No DLT (dose limiting toxicity) occurred during the DLT-period. No grade ≥3 AEs occurred. Excretion of VPM1002BC in the urine was limited to less than 24 hours. Plasma levels of TNFα significantly increased after treatment and blood-derived CD4+ T cells stimulated with PPD demonstrated significantly increased intracellular GM-CSF and IFN expression. Conclusion: The intravesical application of VPM1002BC is safe and well tolerated by patients and results in a potential Th1 weighted immune response.

Infections with the human cytomegalovirus (HCMV) are associated with severe clinical manifestations in children following prenatal transmission and after viral reactivation in immunosuppressed individuals. The development of an HCMV vaccine has long been requested but there is still no licensed product available. Subviral dense bodies (DB) are immunogenic in pre-clinical models and are thus a promising HCMV vaccine candidate. Recently, we established a virus based on the laboratory strain Towne that synthesizes large numbers of DB containing the pentameric protein complex gH/gL/UL128-131 (Towne-UL130repΔGFP). The work presented here focuses on providing strategies for the production of a safe vaccine based on that strain. A GMP-compliant protocol for DB production was established. Furthermore, the DB producer strain Towne-UL130rep was attenuated by deleting the UL25 open reading frame. Additional genetic modifications aim to abrogate its capacity to replicate in vivo by conditionally expressing pUL51 using the Shield-1/FKBP destabilization system. We further show that the terminase inhibitor letermovir can be used to reduce infectious virus contamination of a DB vaccine by more than two orders of magnitude. Taken together, strategies are provided here that allow for the production of a safe and immunogenic DB vaccine for clinical testing.

Mycobacterium (M.) tuberculosis (Mtb) verursacht Millionen Todesfälle weltweit und ist zunehmend resistent gegen Antibiotika. Eine Impfung als Präventionsmaßnahme steht für Mtb nur eingeschränkt zur Verfügung. M. bovis und M. caprae, befallen Nutztiere mit hohen ökonomischen Verlusten und zoonotischer Gefährdung des Verbrauchers. Staatliche Maßnahmen können die Prävalenz der Infektion zwar senken, vermögen aber nicht die Infektionsketten innerhalb humaner und tierischer Populationen bzw. zwischen diesen gänzlich zu unterbrechen. Es bedarf daher der Verbesserung von Impfstoffen für die Human- und Tiermedizin. Ziel der Studie ist die Weiterentwicklung des Impfstoffes VPM1002, welcher sich in klinischer Prüfung befindet. Ein Parameter zur Wirksamkeitsprüfung, soll die Auswertung tuberkulosetypischer Lungenläsionen mittels bildgebender Techniken sein. Dafür wurden computertomografische und radiologische Aufnahmen infizierter Lungen angefertigt und ausgewertet.

The only licensed vaccine against tuberculosis (TB), bacille Calmette-Guérin (BCG), protects against severe extrapulmonary forms of TB but is virtually ineffective against the most prevalent form of the disease, pulmonary TB. BCG was genetically modified at the Max Planck Institute for Infection Biology to improve its immunogenicity by replacing the urease C encoding gene with the listeriolysin encoding gene from Listeria monocytogenes. Listeriolysin perturbates the phagosomal membrane at acidic pH. Urease C is involved in neutralization of the phagosome harboring BCG. Its depletion allows for rapid phagosome acidification and promotes phagolysosome fusion. As a result, BCGΔureC::hly (VPM1002) promotes apoptosis and autophagy and facilitates release of mycobacterial antigens into the cytosol. In preclinical studies, VPM1002 has been far more efficacious and safer than BCG. The vaccine was licensed to Vakzine Projekt Management and later sublicensed to the Serum Institute of India Pvt. Ltd., the largest vaccine producer in the world. The vaccine has passed phase I clinical trials in Germany and South Africa, demonstrating its safety and immunogenicity in young adults. It was also successfully tested in a phase IIa randomized clinical trial in healthy South African newborns and is currently undergoing a phase IIb study in HIV exposed and unexposed newborns. A phase II/III clinical trial will commence in India in 2017 to assess efficacy against recurrence of TB. The target indications for VPM1002 are newborn immunization to prevent TB as well as post-exposure immunization in adults to prevent TB recurrence. In addition, a Phase I trial in non-muscle invasive bladder cancer patients has been completed, and phase II trials are ongoing. This review describes the development of VPM1002 from the drawing board to its clinical assessment.

ABSTRACT Tuberculosis is a global threat to which infants are especially vulnerable. Effective vaccines are required to protect infants from this devastating disease. VPM1002, a novel recombinant Mycobacterium bovis bacillus Calmette-Guérin (BCG) vaccine previously shown to be safe and immunogenic in adults, was evaluated for safety in its intended target population, namely, newborn infants in a region with high prevalence of tuberculosis. A total of 48 newborns were vaccinated intradermally with VPM1002 ( n = 36) or BCG Danish strain ( n = 12) in a phase II open-labeled, randomized trial with a 6-month follow-up period. Clinical and laboratory measures of safety were evaluated during this time. In addition, vaccine-induced immune responses to mycobacteria were analyzed in whole-blood stimulation and proliferation assays. The safety parameters and immunogenicity were comparable in the two groups. Both vaccines induced interleukin-17 (IL-17) responses; however, VPM1002 vaccination led to an increase of CD8 + IL-17 + T cells at the week 16 and month 6 time points. The incidence of abscess formation was lower for VPM1002 than for BCG. We conclude that VPM1002 is a safe, well-tolerated, and immunogenic vaccine in newborn infants, confirming results from previous trials in adults. These results strongly support further evaluation of the safety and efficacy of this vaccination in larger studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01479972.)

Tuberculosis remains a major health threat and vaccines better than bacillus Calmette-Guérin (BCG) are urgently required. Here we describe our experience with a recombinant BCG expressing listeriolysin and deficient in urease. This potential replacement vaccine has demonstrated superior efficacy and safety over BCG in Mycobacterium tuberculosis aerosol-challenged mice and was safe in numerous animal models including immune-deficient mice, guinea pigs, rabbits and nonhuman primates. Phase I clinical trials in adults in Germany and South Africa have proven safety and a current Phase IIa trial is under way to assess immunogenicity and safety in its target population, newborns in a high tuberculosis incidence setting, with promising early results. Second-generation candidates are being developed to improve safety and efficacy.

You have accessJournal of UrologyBladder Cancer: Basic Research IV1 Apr 2014MP39-08 A LISTERIOLYSIN EXPRESSING BCG WITH FAVOURABLE IMMUNOGENICITY AND PRECLINICAL TOXICITY AS A NOVEL TREATMENT FOR NON-MUSCLE INVASIVE BLADDER CANCER Cyrill Rentsch, Christian Wetterauer, Joel Gsponer, Heike Püschel, Alexander Bachmann, Leander Grode, Ankitha Minhas, Bernd Eisele, Doris Beherens, Willem de Blok, Nicole van der Wel, and Bas van Rhijn Cyrill RentschCyrill Rentsch More articles by this author , Christian WetterauerChristian Wetterauer More articles by this author , Joel GsponerJoel Gsponer More articles by this author , Heike PüschelHeike Püschel More articles by this author , Alexander BachmannAlexander Bachmann More articles by this author , Leander GrodeLeander Grode More articles by this author , Ankitha MinhasAnkitha Minhas More articles by this author , Bernd EiseleBernd Eisele More articles by this author , Doris BeherensDoris Beherens More articles by this author , Willem de BlokWillem de Blok More articles by this author , Nicole van der WelNicole van der Wel More articles by this author , and Bas van RhijnBas van Rhijn More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.1323AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES VPM1002 is a genetically modified BCG vaccine in which all antibiotic resistance cassettes have been removed. The main genetic modification consists of the incorporation of the pore-forming toxin listeriolysin of Listeria monocytogenes. Listerolysin activity leads to the disruption of both, lysosomal and cell membranes and induces apoptosis. Consequently, this leads to optimised exposure of extracellular antigens to MHC class I receptors and to potential induction of cancer specific cytotoxic T cells. VPM1002 has been tested with favourable toxicity and immunogenicity profiles (Th1, Th17) in phase I and II trials as a vaccine for tuberculosis. Here we report preclinical data and a planned safety program for its use in non-muscle invasive bladder cancer (NMIBC). METHODS Systemic spread of mycobacteria after intrabladder (i.b.) instillation or intravenous (i.v.) bolus injection was assessed using VPM1002 or BCG-medac in female BL/6 mice to receive: 10e5 CFU of VPM1002 or 10e5 CFU of BCG-medac by 6 i.b. administrations/week and 10e5 CFU of VPM1002 or BCG-medac administered i.v. Mortality, symptoms, and microbial organ culture were assessed at week 1, 3, 5, 6. Toxicology studies in SCID mice and comparative single dose toxicity studies using the single i.b. administration are ongoing. Furthermore, a repeat dose toxicity study in mouse including three dose levels of BCG and VPM1002 will be performed and reported. RESULTS No local intolerance reactions in the mice treated with 10e5 CFU VPM1002 or BCG medac/animal i.b./iv. were observed. No test item-related deaths were noted at any tested dosing. The body weights of all animals were in the normal range throughout the course of the study. Repeated i.v. treatment with 10e5 CFU VPM1002 or BCG-medac/animal caused slightly to severely enlarged spleens and enlarged livers. Considerable CFU counts were noted in liver, lungs and spleen of the animals treated with 10e5 CFU BCG-medac/animal i.v. In contrast, no relevant CFU counts were noted in the examined organs of the animals treated with VPM1002 i.v. After 220 days all SCID mice receiving BCG-medac have died and all of the VPM1002 treated animals are still alive. CONCLUSIONS VPM1002 is the potentially first recombinant BCG suitable for future use as a new therapeutic in patients affected by NMIBC. The preclinical and clinical toxicity profiles from vaccination studies are encouraging. A phase I/II clinical trial in patients with BCG induction failure is currently being developed. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e428 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Cyrill Rentsch More articles by this author Christian Wetterauer More articles by this author Joel Gsponer More articles by this author Heike Püschel More articles by this author Alexander Bachmann More articles by this author Leander Grode More articles by this author Ankitha Minhas More articles by this author Bernd Eisele More articles by this author Doris Beherens More articles by this author Willem de Blok More articles by this author Nicole van der Wel More articles by this author Bas van Rhijn More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...