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Background: Clostridioides difficile infection (CDI) causes substantial mortality and healthcare burden. We assessed the detoxified toxin-A/B PF-06425090 vaccine for primary CDI prevention., Methods: This phase 3 observer-blinded study randomized (1:1) ≥50-year-olds at increased CDI risk (N = 17 535) to receive 3 PF-06425090 or placebo doses (0, 1, and 6 months). Primary end points were first CDI episode (≥3 unformed stools within 24 hours; central laboratory-confirmed toxin A/B positive) ≥14 days post-dose 3 (PD3; first primary) and post-dose 2 (PD2; second primary). CDI duration, need for CDI-related medical attention (secondary end points), and antibiotic use (post hoc analysis) PD3 were evaluated. Tolerability and safety were assessed., Results: The primary end point was not met (17 PF-06425090 and 25 placebo recipients had first CDI episode ≥14 days PD3 [vaccine efficacy (VE) = 31.0% (96.4% confidence interval [CI], -38.7% to 66.6%)]; 24 PF-06425090 and 34 placebo recipients had first CDI episode ≥14 days PD2 [VE = 28.6% (96.4% CI, -28.4% to 61.0%)]. Median CDI duration was lower with PF-06425090 (1 day) versus placebo (4 days; 2-sided nominal P = .02). Of participants with first CDI episode, 0 PF-06425090 and 11 placebo recipients sought CDI-related medical attention (post hoc analysis estimated VE = 100%; 95% CI, 59.6% to 100.0%) and 0 PF-06425090 and 10 placebo recipients required antibiotic treatment (VE = 100%; 95% CI, 54.8% to 100.0%). Local reactions were more frequent in PF-06425090 recipients, and systemic events were generally similar between groups; most were mild to moderate. Adverse event rates were similar between groups., Conclusions: Three PF-06425090 doses were safe and well tolerated. Although the primary end point was not met, PF-06425090 reduced symptom duration, CDI that required medical attention, and CDI-directed antibiotic treatment, highlighting its potential to reduce CDI-associated healthcare burden., Clinical Trials Registration: NCT03090191., Competing Interests: Potential conflicts of interest. C. J. D. receives research support from Pfizer, Clorox, and Ecolab. E. R. D. receives research support from Theriva Biologics, Ferring, and Pfizer and is a consultant for Merck, Pfizer, Seres, Ferring, AstraZeneca, Abbott, Summit, and GSK. N. P. K. receives research support from Pfizer, Merck, Sanofi Pasteur, and GSK. E. G. L. receives research support from Pfizer. K. S. reports no conflicts of interest. M. H. W. has received consulting fees from Ferring, GSK, Nestlé, Paion, Pfizer, Phico Therapeutics, Qpex Biopharma, Seres, Summit, Tillotts, and Vedanta; lecture fees from GSK, Pfizer, Seres, and Tillotts; and grant support from GSK, Pfizer, Seres, Summit, the European Tissue Symposium, and Tillotts. J. L., S. B., H. Z., K. K., R. B., H. M. S., S. L., E. L., W. V. K., M. W. P. C. W., A. S. A., K. U. J., W. C. G., and N. K. are current or former employees of Pfizer and may hold stock or stock options. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: There is no vaccine against the major global pathogen Chlamydia trachomatis; its different serovars cause trachoma in the eye or chlamydia in the genital tract. We did a clinical trial administering CTH522, a recombinant version of the C trachomatis major outer membrane molecule, in different dose concentrations with and without adjuvant, to establish its safety and immunogenicity when administered intramuscularly, intradermally, and topically into the eye, in prime-boost regimens., Methods: CHLM-02 was a phase 1, double-blind, randomised, placebo-controlled trial at the National Institute for Health Research Imperial Clinical Research Facility, London, UK. Participants were healthy men and non-pregnant women aged 18-45 years, without pre-existing C trachomatis genital infection. Participants were assigned into six groups by the electronic database in a pre-prepared randomisation list (A-F). Participants were randomly assigned (1:1:1:1:1) to each of the groups A-E (12 participants each) and 6 were randomly assigned to group F. Investigators were masked to treatment allocation. Groups A-E received investigational medicinal product and group F received placebo only. Two liposomal adjuvants were compared, CAF01 and CAF09b. The groups were intramuscular 85 μg CTH522-CAF01, or placebo on day 0 and two boosters or placebo at day 28 and 112, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (A); intramuscular 85 μg CTH522-CAF01, two boosters at day 28 and 112 with additional topical ocular administration of CTH522, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (B); intramuscular 85 μg CTH522-CAF01, two boosters at day 28 and 112 with additional intradermal administration of CTH522, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (C); intramuscular 15 μg CTH522-CAF01, two boosters at day 28 and 112, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (D); intramuscular 85 μg CTH522-CAF09b, two boosters at day 28 and 112, and a mucosal recall with either placebo or CTH522 topical ocularly at day 140 (E); intramuscular placebo (F). The primary outcome was safety; the secondary outcome (humoral immunogenicity) was the percentage of trial participants achieving anti-CTH522 IgG seroconversion, defined as four-fold and ten-fold increase over baseline concentrations. Analyses were done as intention to treat and as per protocol. The trial is registered with ClinicalTrials.gov, NCT03926728, and is complete., Findings: Between Feb 17, 2020 and Feb 22, 2022, of 154 participants screened, 65 were randomly assigned, and 60 completed the trial (34 [52%] of 65 women, 46 [71%] of 65 White, mean age 26·8 years). No serious adverse events occurred but one participant in group A2 discontinued dosing after having self-limiting adverse events after both placebo and investigational medicinal product doses. Study procedures were otherwise well tolerated; the majority of adverse events were mild to moderate, with only seven (1%) of 865 reported as grade 3 (severe). There was 100% four-fold seroconversion rate by day 42 in the active groups (A-E) and no seroconversion in the placebo group. Serum IgG anti-CTH522 titres were higher after 85 μg CTH522-CAF01 than 15 μg, although not significantly (intention-to-treat median IgG titre ratio groups A-C:D=5·6; p=0·062), with no difference after three injections of 85 μg CTH522-CAF01 compared with CTH522-CAF09b (group E). Intradermal CTH522 (group C) induced high titres of serum IgG anti-CTH522 neutralising antibodies against serovars B (trachoma) and D (urogenital). Topical ocular CTH522 (group B) at day 28 and 112 induced higher total ocular IgA compared with baseline (p<0·001). Participants in all active vaccine groups, particularly groups B and E, developed cell mediated immune responses against CTH522., Interpretation: CTH522, adjuvanted with CAF01 or CAF09b, is safe and immunogenic, with 85 μg CTH522-CAF01 inducing robust serum IgG binding titres. Intradermal vaccination conferred systemic IgG neutralisation breadth, and topical ocular administration increased ocular IgA formation. These findings indicate CTH522 vaccine regimens against ocular trachoma and urogenital chlamydia for testing in phase 2, clinical trials., Funding: The EU Horizon Program TRACVAC., Competing Interests: Declaration of interests KMP had membership of the data safety monitoring board for NCT05249829 and has membership for NCT05575492, has received a fee for speaking from Seqirus and Sanofi Pasteur, and has research funding from the Chan Zuckerberg Initiative, the Medical Research Council–UK Research and Innovation, the Vaccine Task Force, and National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC) outside the submitted work. PLA, FF, IR, and AWO are co-inventors on a patent for vaccines against chlamydia [US10925954, EP2976355]. All rights have been assigned to Statens Serum Institut, a Danish not-for-profit institute under the Ministry of Health. The authors have no other relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the participant matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Introduction: A subset of interstitial cystitis/bladder pain syndrome (IC/BPS) patients experience recurrent urinary tract infection (rUTI) associated with symptom flares. Recurrent UTI subjects with associated IC/BPS were enrolled in the first North American early clinical experience trial evaluating a new sublingual UTI preventative vaccine, MV140. It has been shown that women with rUTI develop an imbalance in the T helper 1 and 2 (Th2 over-expression) in the bladder mucosa. Our hypothesis-generating secondary analysis will suggest that this infection subcategory of IC/BPS patients develop a similar imbalance of Th1-Th2 response type to bacteria present in their urinary microbiome, leading to a bladder hypersensitivity that responds to mucosal immune modulation., Methods: Female participants with ≥3 documented UTI/year underwent a 3-month vaccination treatment period with a 9-month efficacy period after completion of vaccine treatment (total 12 months). There were no exclusion criteria for subjects in relation to baseline urinary symptoms and/or discomfort/pain. Primary outcome was no UTI following vaccination. Secondary outcomes included change in UTI incidence, overall patient-reported subjective global assessment (SGA responder defined as moderately or markedly improved on 7-point scale), and safety., Results: Sixteen subjects with IC/BPS-related symptoms and rUTI (mean age 47; range 23-74 years; mean number of UTI episodes in previous year 6.1 +/- 4.2) were eligible to be included in the Health Canada-approved MV140 vaccine study for prevention of rUTI. All subjects completed the 3-month vaccination period. One subject was lost to follow-up after their 6-month visit. Six subjects were UTI-free, while all 16 subjects had a reduction in UTI episodes compared to the year pre-vaccination. The total post-vaccination reduction in UTI episodes compared to pre-vaccination was 80% (0.1 UTI/subject/month from 0.5 UTI/subject/month, respectively). At 12 months, 13 subjects (81%) were SGA responders (moderately or markedly improved), and the responders reported a reduction in IC/BPS symptoms, with 8 subjects reporting significant or almost complete resolution of their specific long-term bladder discomfort/pain and bothersome urinary frequency or urgency. Four subjects reported mild and self-limited adverse events during vaccination period, but none were related to MV140 vaccine., Conclusion: Sublingual MV140 vaccine in IC/BPS patients with rUTI not only achieved UTI-free or reduced UTI incidence status but also, after approximately 9 months post vaccination, resolution of patients' long-term treatment-refractory IC/BPS symptoms. This suggests some cases of IC/BPS may be etiologically based on Th2-driven hypersensitivity to bacteria within or entering the urinary microbiome that responds to a vaccine whose mechanism of action is to normalize or balance the bladder Th1/Th2 mucosal immune system.

Bovine respiratory disease (BRD) is one of the most common diseases in the cattle industry worldwide; it is caused by multiple bacterial or viral coinfections, of which Mycoplasma bovis ( M. bovis ) and bovine herpesvirus type 1 (BoHV-1) are the most notable pathogens. Although live vaccines have demonstrated better efficacy against BRD induced by both pathogens, there are no combined live and marker vaccines. Therefore, we developed an attenuated and marker M. bovis -BoHV-1 combined vaccine based on the M. bovis HB150 and BoHV-1 gG-/tk- strain previously constructed in our lab and evaluated in rabbits. This study aimed to further evaluate its safety and protective efficacy in cattle using different antigen ratios. After immunization, all vaccinated cattle had a normal rectal temperature and mental status without respiratory symptoms. CD4 + , CD8 + , and CD19 + cells significantly increased in immunized cattle and induced higher humoral and cellular immune responses, and the expression of key cytokines such as IL-4, IL-12, TNF-α, and IFN-γ can be promoted after vaccination. The 1.0 × 10 8 CFU of M. bovis HB150 and 1.0 × 10 6 TCID 50 BoHV-1 gG-/tk- combined strain elicited the most antibodies while significantly increasing IgG and cellular immunity after challenge. In conclusion, the M. bovis HB150 and BoHV-1 gG-/tk- combined strain was clinically safe and protective in calves; the mix of 1.0 × 10 8 CFU of M. bovis HB150 and 1.0 × 10 6 TCID 50 BoHV-1 gG-/tk- strain was most promising due to its low amount of shedding and highest humoral and cellular immune responses compared with others. This study introduces an M. bovis -BoHV-1 combined vaccine for application in the cattle industry., Competing Interests: Author LY is employed by the company Wuhan Keqian Biology Co., Ltd., Wuhan, China. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhang, Liu, Zhang, Wang, Xu, Zhao, Xiang, Wu, Yang, Chen, Guo and Chen.)

Background: Mycobacterium welchii (Mycobacterium w) vaccine was one of the many strategies used to both treat and prevent coronavirus disease 2019 (COVID-19) infection. We report the results of a retrospective analysis of 15 cases with vaccine-site granulomas after administration of prophylactic Mycobacterium w vaccine as part of a trial for COVID-19 and our experience in managing those cases., Methods: This was a retrospective analysis of 15 patients with vaccine-site granulomas who were given the vaccine as a prophylactic measure as part of a trial with informed consent., Results: The mean average age of cases was 37 and the male-to-female ratio was 1:0.87. All of the patients developed erythematous tender nodules over the injection sites within a month of receiving the inoculations. Mycobacterial cultures and cartridge-based nucleic acid amplification tests yielded negative results. Skin biopsy revealed granulomatous dermatitis with acid-fast bacilli positivity. A diagnosis of noninfective granulomatous dermatitis was made. Treatment started with analgesics and anti-inflammatory agents. Systemic antibiotics were required in 9/15 patients. Patients are being followed up with no reported recurrence till date., Conclusion: The possibility of injection-site granuloma should be taken into the risk-benefit analysis for the administration of Mycobacterium w vaccine and the patients should be counseled as such. Patients with persistent ulceration respond to combinations of doxycycline, ofloxacin, and clarithromycin., (Copyright © 2024 Copyright: © 2024 International Journal of Mycobacteriology.)

Clostridioides difficile infection (CDI) is a serious healthcare-associated disease, causing symptoms such as diarrhea and pseudomembranous colitis. The major virulence factors responsible for the disease symptoms are two secreted cytotoxic proteins, TcdA and TcdB. A parenteral vaccine based on formaldehyde-inactivated TcdA and TcdB supplemented with alum adjuvant, has previously been investigated in humans but resulted in an insufficient immune response. In search for an improved response, we investigated a novel toxin inactivation method and a novel, potent adjuvant. Inactivation of toxins by metal-catalyzed oxidation (MCO) was previously shown to preserve neutralizing epitopes and to annihilate reversion to toxicity. The immunogenicity and safety of TcdA and TcdB inactivated by MCO and combined with a novel carbohydrate fatty acid monosulphate ester-based (CMS) adjuvant were investigated in rabbits. Two or three intramuscular immunizations generated high serum IgG and neutralizing antibody titers against both toxins. The CMS adjuvant increased antibody responses to both toxins while an alum adjuvant control was effective only against TcdA. Systemic safety was evaluated by monitoring body weight, body temperature, and analysis of red and white blood cell counts shortly after immunization. Local safety was assessed by histopathologic examination of the injection site at the end of the study. Body weight gain was constant in all groups. Body temperature increased up to 1 ˚C one day after the first immunization but less after the second or third immunization. White blood cell counts, and percentage of neutrophils increased one day after immunization with CMS-adjuvanted vaccines, but not with alum. Histopathology of the injection sites 42 days after the last injection did not reveal any abnormal tissue reactions. From this study, we conclude that TcdA and TcdB inactivated by MCO and combined with CMS adjuvant demonstrated promising immunogenicity and safety in rabbits and could be a candidate for a vaccine against CDI., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Rene Jørgensen reports financial support was provided by European Vaccine Initiative. Rene Jørgensen reports a relationship with Eurostars that includes: funding grants., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Lyme borreliosis, potentially associated with serious long-term complications, is caused by the species complex Borrelia burgdorferi sensu lato. We investigated a novel Lyme borreliosis vaccine candidate (VLA15) targeting the six most common outer surface protein A (OspA) serotypes 1-6 to prevent infection with pathogenic Borrelia spp prevalent in Europe and North America., Methods: This was a partially randomised, observer-masked, phase 1 study in healthy adults older than 18 years to younger than 40 years (n=179) done in trial sites in Belgium and the USA. Following a non-randomised run-in phase, a sealed envelope randomisation method was applied with a 1:1:1:1:1:1 ratio; three dose concentrations of VLA15 (12 μg, 48 μg, and 90 μg) were administered by intramuscular injection on days 1, 29, and 57. The primary outcome was safety (frequency of adverse events up to day 85) assessed in participants who received at least one vaccination. Immunogenicity was a secondary outcome. The trial is registered with ClinicalTrials.gov, NCT03010228, and is complete., Findings: Between Jan 23, 2017 and Jan 16, 2019, of 254 participants screened for eligibility, 179 were randomly assigned into six groups: alum-adjuvanted 12 μg (n=29), 48 μg (n=31), or 90 μg (n=31) and non-adjuvanted 12 μg (n=29 participants), 48 μg (n=29), or 90 μg (n=30). VLA15 was safe and well tolerated and the majority of adverse events were mild or moderate. Overall, adverse events were more frequent in the 48 μg and 90 μg groups (range 28-30 participants [94-97%]) when compared with the 12 μg group (25 [86%] participants, 95% CI 69·4-94·5) for adjuvanted and non-adjuvanted groups. Common local reactions were tenderness (151 [84%] participants; 356 events, 95% CI 78·3-89·4) and injection site pain (120 [67%]; 224 events, 59·9-73·5); most frequent systemic reactions were headache (80 [45%]; 112 events, 37·6-52·0), excessive fatigue (45 [25%]; 56 events, 19·4-32·0), and myalgia (45 [25%]; 57 events, 19·4-32·0). A similar safety and tolerability profile was observed between adjuvanted and non-adjuvanted formulations. The majority of solicited adverse events were mild or moderate. VLA15 was immunogenic for all OspA serotypes with higher immune responses induced in the adjuvanted higher dose groups (geometric mean titre range 90 μg with alum 61·3 U/mL-321·7 U/mL vs 23·8 U/mL-111·5 U/mL at 90 μg without alum)., Interpretation: This novel multivalent vaccine candidate against Lyme borreliosis was safe and immunogenic and paves the way to further clinical development., Funding: Valneva Austria., Competing Interests: Declaration of interests IL-R reports funding from Valneva to her institution for the conduct of this study. In addition, she received funding to her institution from several industry partners for the conduct of various vaccine trials, but none of them in the area of Lyme borreliosis. NB, RH, VK, NW, KD, SE-L, and WB are Valneva employees and own stock and share options in Valneva. AK, JL-S, and GL-R declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Fowl cholera (FC) caused by Pasteurella multocida is among the serious infectious diseases of poultry. Currently, formalin inactivated FC (FI-FC) vaccine is widely used in Ethiopia. However, reports of the disease complaint remain higher despite the use of the vaccine. The aim of this study was to develop and evaluate gamma-irradiated mucosal FC vaccines that can be used nationally. In a vaccination-challenge experiment, the performance of gamma-irradiated P. multocida (at 1 kGy) formulated with Montanide gel/01 PR adjuvant was evaluated at different dose rates (0.5 and 0.3 ml) and routes (intranasal, intraocular, and oral), in comparison with FI-FC vaccine in chicken. Chickens received three doses of the candidate vaccine at 3-week intervals. Sera, and trachea and crop lavage were collected to assess the antibody levels using indirect and sandwich ELISAs, respectively. Challenge exposure was conducted by inoculation at 3.5×10 9 CFU/ml of P. multocida biotype A intranasally 2 weeks after the last immunization. Repeated measures ANOVA test and Kaplan Meier curve analysis were used to examine for statistical significance of antibody titers and survival analysis, respectively. Sera IgG and secretory IgA titers were significantly raised after second immunization ( p =0.0001). Chicken survival analysis showed that intranasal and intraocular administration of the candidate vaccine at the dose of 0.3 ml resulted in 100% protection as compared to intramuscular injection of FI-FC vaccine, which conferred 85% protection ( p =0.002). In conclusion, the results of this study showed that gamma-irradiated FC mucosal vaccine is safe and protective, indicating its potential use for immunization of chicken against FC., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Dessalegn, Bitew, Asfaw, Khojaly, Ibrahim, Abayneh, Gelaye, Unger and Wijewardana.)

Q-VAX®, a whole cell, formalin-inactivated vaccine, is the only vaccine licensed for human use to protect against Coxiella burnetii , the cause of Q fever. Although this vaccine provides long-term protection, local and systemic reactogenic responses are common in previously sensitized individuals which prevents its use outside of Australia. Despite the importance of preventing these adverse reactions to develop widely accepted, novel vaccines against C. burnetii , little is understood about the underlying cellular mechanisms. This is mostly attributed to the use of a guinea pig reactogenicity model where complex cellular analysis is limited. To address this, we compared three different mouse strains develop a model of C. burnetii whole cell vaccine reactogenic responses. SKH1 and C57Bl/6, but not BALBc mice, develop local granulomatous reactions after either infection- or vaccine-induced sensitization. We evaluated local and systemic responses by measuring T cell populations from the vaccination site and spleen during elicitation using flow cytometry. Local reaction sites showed influx of IFNγ+ and IL17a+ CD4 T cells in sensitized mice compared with controls and a reduction in IL4+ CD4 T cells. Additionally, sensitized mice showed a systemic response to elicitation by an increase in IFNγ+ and IL17a+ CD4 T cells in the spleen. These results indicate that local and systemic C. burnetii reactogenic responses are consistent with a Th1 delayed-type hypersensitivity. Our experiments provide insights into the pathophysiology of C. burnetii whole cell vaccine reactogenicity and demonstrate that C57Bl/6 and SKH1 mice can provide a valuable model for evaluating the reactogenicity of novel C. burnetii vaccine candidates., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Fratzke, Gregory, van Schaik and Samuel.)

Infectious complications are a major cause of morbidity and mortality in B-cell hematological malignancies (HM). Prophylaxis for recurrent infections in HM patients with antibody deficiency consists of first-line antibiotics and when unsuccessful, gammaglobulin replacement therapy (IgRT). Recent knowledge of trained immunity-based vaccines (TIbV), such as the sublingual polybacterial formulation MV130, has shown a promising strategy in the management of patients with recurrent infections. We sought to determine the clinical benefit of MV130 in a cohort of HM patients with recurrent respiratory tract infections (RRTIs) who underwent immunization with MV130 for 3 months. Clinical information included the frequency of infections, antibiotic use, number of visits to the GP and hospitalizations previous and after MV130 immunotherapy. Improvement on infection rate was classified as: clear (>60% reduction of infection), partial (26%-60%) and low (≤25%) improvement. Fifteen HM patients (aged 42 to 80 years; nine females) were included in the study. All patients reduced their infection rate. Analysis of paired data revealed that the median (range, min - max) of respiratory infectious rate significantly decreased from 4.0 (8.0-3.0) to 2.0 (4.0-0.0) ( p <0.001) at 12 months of MV130. A clear clinical improvement was observed in 53% (n = 8) of patients, partial improvement in 40% (n = 6) and low improvement in 7% (n = 1). These data correlated with a decrease on antibiotic consumption from 3.0 (8.0-1.0) to 1.0 (2.0-0.0) ( p = 0.002) during 12 months after initiation of treatment with MV130. The number of infectious-related GP or emergency room visits declined from 4.0 (8.0-2.0) to 2.0 (3.0-0.0) ( p <0.001), in parallel with a reduction in hospital admissions due to infections ( p = 0.032). Regarding safety, no adverse events were observed. On the other hand, immunological assessment of serum IgA and IgG levels demonstrated an increase in specific antibodies to MV130-contained bacteria following MV130 immunotherapy. In conclusion, MV130 may add clinical benefit reducing the rate of infections and enhancing humoral immune responses in these vulnerable patients., Competing Interests: LC and CD-R belong to the Immunotek R+D Department. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ochoa-Grullón, Benavente Cuesta, González Fernández, Cordero Torres, Pérez López, Peña Cortijo, Conejero Hall, Mateo Morales, Rodríguez de la Peña, Díez-Rivero, Rodríguez de Frías, Guevara-Hoyer, Fernández-Arquero and Sánchez-Ramón.)

Background: In the absence of a licensed vaccine, Clostridioides (formerly Clostridium) difficile infection represents a substantial health burden. The aim of this study was to evaluate the efficacy, immunogenicity, and safety of a toxoid vaccine candidate., Methods: We did a phase 3 multicentre, observer-blind, randomised, controlled trial at 326 hospitals, clinics, and clinical research centres in 27 countries in the USA, Canada, Latin America, Europe, and the Asia-Pacific region. We included adults aged 50 years or older who were considered to be at an increased risk of C difficile infection because they had previously had two hospital stays (each ≥24 h in duration) and had received systemic antibiotics in the previous 12 months (risk stratum 1), or because they were anticipating being admitted to hospital for 72 h or more for elective surgery within 60 days of enrolment (risk stratum 2). Eligible participants were stratified by geographical region and the two risk strata, and randomly assigned (2:1), with a fixed block size of three, to receive either a C difficile toxoid vaccine candidate, containing toxoids A and B (C difficile vaccine candidate group), or a placebo vaccine (placebo group). Participants, investigators, and personnel responsible for collecting safety data and analysing blood and stool samples were masked to group assignment. Personnel responsible for study product preparation and administration were not masked to group assignment. One dose (0·5 mL) of C difficile vaccine candidate or placebo vaccine was administered intramuscularly on days 0, 7, and 30. The primary outcome was the efficacy of the vaccine in preventing symptomatic C difficile infection, defined as having three or more loose stools in a period of 24 h or less, loose stools for 24 h or more, and a PCR-positive test for C difficile toxin B in a loose stool sample, within 3 years after the final vaccine dose. The primary outcome was measured in the modified intention-to-treat population (ie, all participants who received at least one injection of the assigned vaccine). The safety of the vaccine was assessed in the safety analysis set (ie, all participants who had received at least one injection, analysed according to the product received). This study is registered with WHO/ICTRP, number U111-1127-7162, and ClinicalTrials.gov, number NCT01887912, and has been terminated., Findings: Between July 30, 2013, and Nov 17, 2017, we enrolled and randomly assigned 9302 participants to the C difficile vaccine candidate group (n=6201) or to the placebo group (n=3101). 6173 (99·5%) participants in the C difficile vaccine candidate group and 3085 (99·5%) participants in the placebo group received at least one dose of the vaccine. The study was terminated after the first planned interim analysis because of futility. In the C difficile vaccine candidate group, 34 C difficile infections were reported over 11 697·2 person-years at risk (0·29 infections per 100 person-years [95% CI 0·20-0·41]) compared with 16 C difficile infections over 5789·4 person-years at risk in the placebo group (0·28 infections per 100 person-years [0·16-0·45]), indicating a vaccine efficacy of -5·2% (95% CI -104·1 to 43·5). In the C difficile vaccine candidate group, 2847 (46·6%) of 6113 participants reported an adverse event within 30 days of injection compared with 1282 (41·9%) of 3057 participants in the placebo group. The proportion of participants who had an adverse event leading to study discontinuation was 4·8% in both groups (296 participants in the C difficile vaccine candidate group and 146 participants in the placebo group). 1662 (27·2%) participants in the C difficile vaccine candidate group reported at least one serious adverse event compared with 851 (27·8%) participants in the placebo group., Interpretation: In adults at risk for C difficile infection, a bivalent C difficile toxoid vaccine did not prevent C difficile infection. Since the C difficile vaccine candidate met the criteria for futility, the study was terminated and clinical development of this vaccine candidate was stopped., Funding: Sanofi Pasteur., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Vaccine-related fowl cholera must be considered when flock mortality increases after use of a live Pasteurella multocida vaccine product. All registered live vaccines serotype as Heddleston 3,4; however, in some regions this is also the most common serotype of outbreak isolates in broiler breeders and turkeys. Therefore, serotyping may not be useful for diagnosing vaccine-related fowl cholera. This project sought to apply a vaccine-specific test to differentiate vaccine-related disease from naturally occurring outbreaks. Results indicate that vaccine strains were commonly isolated from broiler breeders exhibiting signs of fowl cholera postvaccination, but some of these isolates exhibited only serotype 4 antigenicity. The isolates' lipopolysaccharides, the target antigen for serotyping, contained compositional changes that may explain the varying serotype results and virulence of the commercial preparations. These results suggest that vaccine-related disease may be common in broiler breeders, and live commercial vaccine preparations need to be assessed for serotype and titer prior to use in order to reduce vaccine-related fowl cholera.

Increasing antibiotic resistance in bacteria causing endogenous infections has entailed a need for innovative approaches to therapy and prophylaxis of these infections and raised a new interest in vaccines for prevention of colonization and infection by typically antibiotic resistant pathogens. Nevertheless, there has been a long history of failures in late stage clinical development of this type of vaccines, which remains not fully understood. This article provides an overview on present and past vaccine developments targeting nosocomial bacterial pathogens; it further highlights the specific challenges associated with demonstrating clinical efficacy of these vaccines and the facts to be considered in future study designs. Notably, these vaccines are mainly applied to subjects with preexistent immunity to the target pathogen, transient or chronic immunosuppression and ill-defined microbiome status. Unpredictable attack rates and changing epidemiology as well as highly variable genetic and immunological strain characteristics complicate the development. In views of the clinical need, re-thinking of the study designs and expectations seems warranted: first of all, vaccine development needs to be footed on a clear rationale for choosing the immunological mechanism of action and the optimal time point for vaccination, e.g., (1) prevention (or reduction) of colonization vs. prevention of infection and (2) boosting of a preexistent immune response vs. altering the quality of the immune response. Furthermore, there are different, probably redundant, immunological and microbiological defense mechanisms that provide protection from infection. Their interplay is not well-understood but as a consequence their effect might superimpose vaccine-mediated resolution of infection and lead to failure to demonstrate efficacy. This implies that improved characterization of patient subpopulations within the trial population should be obtained by pro- and retrospective analyses of trial data on subject level. Statistical and systems biology approaches could help to define immune and microbiological biomarkers that discern populations that benefit from vaccination from those where vaccines might not be effective., (Copyright © 2020 Bekeredjian-Ding.)

Context: Recurrent urinary tract infections (rUTIs) can be a difficult condition to treat, and the role of vaccines is unclear., Objective: To systematically review the role of vaccines in the treatment of rUTIs, looking at efficacy, adverse events, and discontinuation from treatment., Evidence Acquisition: We systematically reviewed the role of vaccines for rUTIs using the Cochrane and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) methodologies for all English-language articles from inception of databases to July 2018. Data were collected for different vaccine types, short- (≤6 mo) and long-term (>6 mo) efficacy, and adverse effects with risk of bias assessment of included studies., Evidence Synthesis: After initial identification of 1680 articles, 36 abstracts were screened, 25 full-text articles were assessed, and 17 (including 3228 patients; 1970 in the vaccine group and 1258 in the comparison group) were included. There were three studies in Uromune, nine in OM-89/UroVaxom, four in Solco-Urovac, and one in ExPEC4 V groups. Uromune, UroVaxom, and Solco-Urovac reported on the short-term follow-up, and the overall efficacy for vaccination demonstrated a significant odds ratio (OR) of 0.17 (95% confidence interval [CI] 0.06-0.50). Uromune, UroVaxom, and ExPEC4 V reported on the long-term follow-up, and the overall efficacy for vaccination demonstrated a significant OR of 0.20 (95% CI 0.07-0.59). The reported side effects were mild and varied from 0% to 13% across studies, and treatment withdrawal or exclusion due to adverse events was reported in 11 patients., Conclusions: Vaccines seem to have a short-term role in the prevention of recurrent urinary tract infections with tolerable side effects. However, due to lack of uniformity of definitions and long-term follow-up, more work needs to be done with inclusion of other high-risk patient groups., Patient Summary: In this study, we look at the role of vaccines for recurrent urinary tract infections. We found that they seem to have a short-term role in the prevention of recurrent urinary tract infections and might play an increasing role in the future., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Brucellosis is an emergent and endemic zoonotic disease in Bosnia and Herzegovina. In this report we have diagnosed the first case of human brucellosis in Bosnia and Herzegovina, using molecular and microbiological tests, caused by live attenuated Brucella melitensis Rev.1 strain. The infection was caused through unintentional exposure to vaccination of small ruminants in Bosnia and Herzegovina and without any prior accidental self-injection of vaccine suspension., Competing Interests: No Conflict of Interest is declared, (Copyright (c) 2020 Jurica Arapovic, Silvio Spicic, Sanja Duvnjak, Maja Ostojic, Maja Arapovic, Jadranka Nikolic, Zeljko Cvetnic.)

Healthy United States-based adult volunteers with no history of travel to leprosy-endemic countries were enrolled for the first-in-human evaluation of LepVax (LEP-F1 + GLA-SE). In total 24 volunteers participated in an open-labelclinicaltrial, with 21 receiving three injections of LepVax consisting of either 2 µg or 10 µg recombinantpolyprotein LEP-F1 mixed with 5 µg of the GLA-SE adjuvant formulation. LepVax doses were provided by intramuscular injection on Days 0, 28, and 56, and safety was evaluated for one year following the final injection. LepVaxwas safe and well tolerated at both antigen doses. Immunological analyses indicated that similar LEP-F1-specific antibody and Th1 cytokine secretion (IFN-γ, IL-2, TNF) were induced by each of the antigen doses evaluated within LepVax. This clinicaltrialof the first definedvaccinecandidate for leprosy demonstrates that LepVax is safe and immunogenic in healthy subjects and supports its advancement to testing in leprosy-endemic regions., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Listeria monocytogenes is a promising therapeutic vaccine vector for cancer immunotherapy. Although highly attenuated, three cases of systemic listeriosis have been reported in people following treatment with Listeria-based therapeutic vaccines. This complication has thus far not been reported in canine patients., Case Presentation: A dog previously diagnosed with osteoblastic osteosarcoma was presented for care following administration of three doses of the Canine Osteosarcoma Vaccine-Live Listeria Vector. On routine staging chest radiographs, mild sternal lymphadenopathy and a right caudoventral thoracic mass effect were noted. Further evaluation of the mass effect with computed tomography and ultrasound revealed a cavitated mass associated with the 7th right rib. Aspirates of the mass cultured positive for Listeria monocytogenes. The mass and associated ribs were surgically removed. Histopathology was consistent with metastatic osteoblastic osteosarcoma. Treatment was continued with doxorubicin chemotherapy and at the time of publication, the dog was alive over 1 year following diagnosis with no evidence of further disease progression. Genotyping of the abscess-derived L. monocytogenes was consistent with the vaccine strain., Conclusions: This case represents the first veterinary case to describe development of a Listeria abscess following administration of a Listeria-based therapeutic vaccine.

New vaccine formulations that include novel strains of Mycoplasma hyopneumoniae and innovative adjuvants designed to induce cellular immunity could improve vaccine efficacy against this pathogen. The aim of this experimental study was to assess the efficacy of three experimental bacterin formulations based on M. hyopneumoniae field strain F7.2C which were able to induce cellular immunity. The formulations included a cationic liposome formulation with the Mincle receptor ligand trehalose 6,6-dibehenate (Lipo&#95;DDA:TDB), a squalene-in-water emulsion with Toll-like receptor (TLR) ligands targeting TLR1/2, TLR7/8 and TLR9 (SWE&#95;TLR), and a poly(lactic-co-glycolic acid) micro-particle formulation with the same TLR ligands (PLGA&#95;TLR). Four groups of 12 M. hyopneumoniae-free piglets were primo- (day (D) 0; 39 days of age) and booster vaccinated (D14) intramuscularly with either one of the three experimental bacterin formulations or PBS. The pigs were endotracheally inoculated with a highly and low virulent M. hyopneumoniae strain on D28 and D29, respectively, and euthanized on D56. The main efficacy parameters were: respiratory disease score (RDS; daily), macroscopic lung lesion score (D56) and log copies M. hyopneumoniae DNA determined with qPCR on bronchoalveolar lavage (BAL) fluid (D42, D56). All formulations were able to reduce clinical symptoms, lung lesions and the M. hyopneumoniae DNA load in the lung, with formulation SWE&#95;TLR being the most effective (RDS D28-D56 -61.90%, macroscopic lung lesions -88.38%, M. hyopneumoniae DNA load in BAL fluid (D42) -67.28%). Further experiments raised under field conditions are needed to confirm these results and to assess the effect of the vaccines on performance parameters.

Background: Chlamydia is the most common sexually transmitted bacterial infection worldwide. National screening programmes and antibiotic treatment have failed to decrease incidence, and to date no vaccines against genital chlamydia have been tested in clinical trials. We aimed to assess the safety and immunogenicity, in humans, of a novel chlamydia vaccine based on a recombinant protein subunit (CTH522) in a prime-boost immunisation schedule., Methods: This phase 1, first-in-human, double-blind, parallel, randomised, placebo-controlled trial was done at Hammersmith Hospital in London, UK, in healthy women aged 19-45 years. Participants were randomly assigned (3:3:1) to three groups: CTH522 adjuvanted with CAF01 liposomes (CTH522:CAF01), CTH522 adjuvanted with aluminium hydroxide (CTH522:AH), or placebo (saline). Participants received three intramuscular injections of 85 μg vaccine (with adjuvant) or placebo to the deltoid region of the arm at 0, 1, and 4 months, followed by two intranasal administrations of 30 μg unadjuvanted vaccine or placebo (one in each nostril) at months 4·5 and 5·0. The primary outcome was safety and the secondary outcome was humoral immunogenicity (anti-CTH522 IgG seroconversion). This study is registered with Clinicaltrials.gov, number NCT02787109., Findings: Between Aug 15, 2016, and Feb 13, 2017, 35 women were randomly assigned (15 to CTH522:CAF01, 15 to CTH522:AH, and five to placebo). 32 (91%) received all five vaccinations and all participants were included in the intention-to-treat analyses. No related serious adverse reactions were reported, and the most frequent adverse events were mild local injection-site reactions, which were reported in all (15 [100%] of 15) participants in the two vaccine groups and in three (60%) of five participants in the placebo group (p=0·0526 for both comparisons). Intranasal vaccination was not associated with a higher frequency of related local reactions (reported in seven [47%] of 15 participants in the active treatment groups vs three [60%] of five in the placebo group; p=1·000). Both CTH522:CAF01 and CTH522:AH induced anti-CTH522 IgG seroconversion in 15 (100%) of 15 participants after five immunisations, whereas no participants in the placebo group seroconverted. CTH522:CAF01 showed accelerated seroconversion, increased IgG titres, an enhanced mucosal antibody profile, and a more consistent cell-mediated immune response profile compared with CTH522:AH., Interpretation: CTH522 adjuvanted with either CAF01 or aluminium hydroxide appears to be safe and well tolerated. Both vaccines were immunogenic, although CTH522:CAF01 had a better immunogenicity profile, holding promise for further clinical development., Funding: European Commission and The Innovation Fund Denmark., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Immunization is one of the greatest public health achievements of the 20 th century. Vaccines have enabled the eradication of deadly diseases and decreased the morbidity and mortality associated with various infections. Most vaccines are safe to administer and cause only minor side effects. Although very rare, various glomerular diseases and acute kidney injury have been reported following immunization with certain vaccines including influenza, pneumococcal, and hepatitis B vaccines. This review summarizes these rare renal complications that have been published in the literature. Physicians and other health-care providers administrating vaccines should be aware of these very rare but possible renal side effects., Competing Interests: None

Immunization by bath immersion is likely the simplest method of fish vaccination. Although the route of immunogenicity has not been fully identified, immersion vaccination is clearly a useful labor-saving technique. In this study, microbubble (MB) treatment was assessed for its ability to improve the efficacy of bath immersion vaccination in the cyprinid loach. MBs are commonly defined as minute particles of gas with a diameter of less than 100 μm, which generated free radicals. Here, the efficacy of MB treatment for vaccination enhancement in the cyprinid loach was assessed in direct challenge experiments using the virulent Aeromonas hydrophila JUNAH strain; assessments comprised agglutination titer assay and non-specific parameter analysis. Agglutination titers were high in loaches that were immunized via injection with inactivated cells (FKC group); however, non-specific immune activation parameters (e.g., lysozyme, superoxide dismutase, and phagocytic activity) were more increased in loaches that were immunized via bath immersion with MB treatment. Moreover, MB-treated loaches showed comparable survival rates, relative to loaches immunized via injection with formalin inactivated cells. Thus, higher levels of non-specific immune parameters suggest increased efficacy of this vaccine approach. Improving the effectiveness of bath immersion vaccine will increase its affordability and ease of application in aquaculture., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Present day therapeutic modalities for viral warts are mostly ablative in nature, limited by high recurrence rates and are unsuitable for numerous lesions. Immunotherapy has the potential to overcome these limitations., Aims: This study aimed at comparing efficacy and safety of and quality of life changes with intradermal purified protein derivative (PPD) of tuberculin antigen and Mycobacterium w (Mw) vaccine in immunotherapy of warts., Methods: Patients with multiple (≥5) warts were randomized (1:1) into two groups (PPDand, Mw vaccine groups). Fortnightly, 0.1 ml of either medicine was injected intradermally over the deltoidregion till complete resolution or a maximum of six doses. Patients were followed-up for another 3 months for recurrence., Results: Sixty-four participants received either PPD or Mw vaccine. The number of warts were comparable at baseline (P = 0.089, Mann-Whitney test), and reduced significantly with treatment in both groups (P < 0.001, Friedman's ANOVA), as seen from the fourth follow-up onwards with Mw and fifth follow-up onwards with PPD (P < 0.05, Post hoc Dunn's test). Intergroup comparison showed significantly more (P < 0.05, Mann-Whitney test) reduction with Mw than PPD at the sixth and seventh follow-up. The size of warts also reduced significantly (P < 0.001) in both groups from the third follow-up onwards. Complete remission was more (P = 0.539, Fischer's exact test) in the Mw group (68.8%) than the PPD group (50%); and was significantly higher (P = 0.049, Mann-Whitney test) in patients having shorter duration of warts. Adverse events were significantly more (P < 0.001) with Mw including ulceration (50%), discharge (15.6%), pain-swelling-induration and scar at the injection site (97% each), whereas some of those receiving PPD noted erythema and scaling at the injection site (18.8%), and post-inflammatory hyperpigmentation (12.5%). No recurrence was seen till the end of the study., Limitation: Unicentric trial., Conclusion: Intradermal injection of Mw vaccine was more effective but had a higher incidence of adverse effects compared to PPD of tuberculin antigen in patients with warts., Competing Interests: None

We characterized five different vaccine candidates and a commercial vaccine in terms of safety, immunogenicity and using a systems vaccinology approach, with the aim to select novel vaccine candidates against Mycoplasma hyopneumoniae . Seven groups of six M. hyopneumoniae -free piglets were primo- and booster vaccinated with the different experimental bacterin formulations, the commercial vaccine Hyogen® as a positive control or PBS as a negative control. The experimental bacterin was formulated with cationic liposomes + c-di-AMP (Lipo&#95;AMP), cationic liposomes + Toll-like receptor (TLR) 2/1, TLR7, and TLR9 ligands (TLR ligands; Lipo&#95;TLR), micro-particles + TLR ligands (PLGA&#95;TLR), squalene-in-water emulsion + TLR ligands (SWE&#95;TLR), or DDA:TDB liposomes (Lipo&#95;DDA:TDB). Lipo&#95;DDA:TDB and Lipo&#95;AMP were the most potent in terms of serum antibody induction, and Lipo&#95;DDA:TDB, Lipo&#95;AMP, and SWE&#95;TLR significantly induced Th1 cytokine-secreting T-cells. Only PLGA&#95;TLR appeared to induce Th17 cells, but was unable to induce serum antibodies. The transcriptomic analyses demonstrated that the induction of inflammatory and myeloid cell blood transcriptional modules (BTM) in the first 24 h after vaccination correlated well with serum antibodies, while negative correlations with the same modules were found 7 days post-vaccination. Furthermore, many cell cycle and T-cell BTM upregulated at day seven correlated positively with adaptive immune responses. When comparing the delivery of the identical TLR ligands with the three formulations, we found SWE&#95;TLR to be more potent in the induction of an early innate immune response, while the liposomal formulation more strongly promoted late cell cycle and T-cell BTM. For the PLGA formulation we found signs of a delayed and weak perturbation of these BTM. Lipo&#95;AMP was found to be the most potent vaccine at inducing a BTM profile similar to that correlating with adaptive immune response in this and other studies. Taken together, we identified four promising vaccine candidates able to induce M. hyopneumoniae -specific antibody and T-cell responses. In addition, we have adapted a systems vaccinology approach developed for human to pigs and demonstrated its capacity in identifying early immune signatures in the blood relating to adaptive immune responses. This approach represents an important step in a more rational design of efficacious vaccines for pigs.

Non-typeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mcat) are frequent pathogens in acute exacerbations of COPD. We assessed the safety, reactogenicity and immunogenicity of different investigational vaccine formulations containing surface proteins of NTHi (PD and PE-PilA) and Mcat (UspA2) in adults with smoking history ≥10 pack-years, to immunologically represent the COPD population. Participants received two doses 60 days apart in a randomised, observer-blind, placebo-controlled study (NCT02547974). In step 1, 30 healthy adults aged 18-40 years were randomised (1:1) to receive a non-adjuvanted formulation (10-10-PLAIN) or placebo. In step 2, 90 smokers/ex-smokers aged 50-70 years randomly (1:1:1) received an AS01-adjuvanted formulation containing either 10 µg of each antigen (10-10-AS01) or 10 µg of each NTHi antigen and 3.3 µg of Mcat antigen (10-3-AS01), or placebo. Incidences of solicited local adverse events (AEs) tended to be highest in the AS01-adjuvanted vaccine groups. Most solicited AEs had mild/moderate intensity. No vaccine-related serious AEs were reported. The 10-3-AS01 formulation induced the best humoral immune response against the NTHi antigens. Responses against the Mcat antigen were similar across groups, with waning immunogenicity after 30 days post-dose 2. The investigational NTHi-Mcat vaccine had an acceptable safety and reactogenicity profile and good immunogenicity in older adults with a smoking history., (Copyright © 2019 GlaxoSmithKline Biologicals SA. Published by Elsevier Ltd.. All rights reserved.)

Background: Clostridium difficile infection (CDI) is a major global cause of nosocomial and community-acquired infections. Despite potentially severe or fatal complications and frequent recurrence, no preventive vaccine is currently available. This randomized, observer-blinded, placebo-controlled phase 1 study in older Japanese adults evaluated safety and immunogenicity of an investigational C difficile vaccine containing a mixture of genetically detoxified and chemically inactivated toxoids, A and B., Methods: Healthy Japanese adults aged 65 to 85 years were randomized in a 3:3:2 ratio to receive 100 or 200 μg of C difficile vaccine or placebo, respectively, at 0, 1, and 6 months (month regimen) or 1, 8, and 30 days (day regimen). The primary objective was safety evaluation. Vaccine immunogenicity, the secondary objective, was determined by assessing toxin A- and toxin B-specific neutralizing antibody levels in human sera., Results: Local reactions were reported by up to 33.3% of subjects per dose in the month regimen; percentages were generally higher in the 200-μg group. Such reactions were all mild or moderate in severity and generally transient. No adverse events in the month regimen led to subject withdrawal, and no serious adverse events were considered vaccine related. Further enrollment and dosing in the day regimen were discontinued after 3 subjects in the 100-μg group reported severe redness after dose 2. In the month regimen study arm, immune responses as measured by toxin-neutralizing antibody geometric mean concentrations, geometric mean fold rises, and proportions of subjects achieving prespecified fold rises were generally higher in the 200-μg group, peaked at month 7, and remained elevated at month 12., Conclusions: The C difficile vaccine candidate was safe, well tolerated, and immunogenic when administered to healthy older Japanese adults at 0, 1, and 6 months. Results support continued development of the vaccine for the prevention of CDI. ClinicalTrials.gov identifier: NCT02725437., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Case Report: We report Gudair® vaccination (against ovine Johne's disease, Mycobacterium avium subsp. paratuberculosis) site reactions in sheep used as a surgical model in biomedical research and discuss the actual and potential impact these lesions may have on surgical procedures, particularly in otology. Nine female Merino-cross sheep (Ovis aries) were enrolled in a project designed to investigate the healing capabilities of the malleus bone in the middle ear. The sheep were 12-18 months of age. Eight sheep had lesions near the base of the right ear that were discovered when surgery was performed. The size of the lesions varied and all lesions had a thick capsule containing various amount of caseous material. Two lesions had a draining tract where purulent material was apparent at the lowest point. The prescapular lymph nodes were not palpable in any of the sheep. Aerobic growth of various organisms was reported from four sheep lesions when the purulent material was transferred to a broth media. Histopathological examination revealed intralesional Mycobacteria and focal caseous necrosis or granulomatous dermatitis and cellulitis in seven of the eight lesions. Mild necrotising to granulomatous dermatitis and cellulitis was described in the lesion where organisms were not found., Conclusions: The lesions were confirmed at the end of the study to be associated with the vaccination and did not cause any known adverse effects on the research. However, it is important to acknowledge the risk of contamination these lesions could have on a sterile surgical site., (© 2019 Australian Veterinary Association.)

Chlamydia abortus is responsible for enzootic abortion (known as ovine enzootic abortion (OEA) and enzootic abortion of ewes (EAE)) in both sheep and goats and has major economic implications for the farming industry worldwide. A virulence-attenuated mutant strain of C. abortus (strain 1B) is currently commercially available as a live attenuated vaccine for immunization of sheep and goats in several European countries. Following an abortion storm in a French flock of 200 ewes that occurred two years after vaccination of 36 replacement ewes with the commercial 1B vaccine strain, the vaginal swabs of 3 vaccinated and 7 unvaccinated aborted ewes and 12 of the 13 dead fetuses were found to be positive for C. abortus by real-time PCR. Genotyping of the samples, using vaccine-specific SNP markers, identified all as positive for the vaccine-type strain. The recent vaccination of this flock with the attenuated commercial vaccine strain, the large number of abortion cases observed in ewes irrespective of vaccination status, the high C. abortus load detected in vaginal swabs or abortion tissues and the identification of specific vaccine-type markers in these samples strongly suggest that the 1B strain has been transmitted from vaccinated to naïve animals, thus mimicking a natural wild-type infection., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Intramuscular immunisation with a vaccine composed of three recombinant Helicobacter pylori antigens-vacuolating cytotoxin A (VacA), cytotoxin-associated antigen (CagA), and neutrophil-activating protein (NAP)-prevented infection in animal models and was well tolerated and highly immunogenic in healthy adults. We aimed to assess the efficacy of the vaccine in prevention of a H pylori infection after challenge with a CagA-positive strain (BCM 300) in healthy volunteers., Methods: In this randomised phase 1/2, observer-blind, placebo-controlled, single-centre study, healthy non-pregnant adults aged 18-40 years who were confirmed negative for H pylori infection were randomly assigned (3:4) to three intramuscular doses of either placebo or vaccine at 0, 1, and 2 months. Randomisation was via a computer-generated list with study numbers ensuring the correct ratio within a block size of seven. Participants were consecutively assigned in a double-blind manner to existing study numbers of the study protocol. Investigators and participants were blinded to allocation throughout the study. One month after the third immunisation, participants underwent challenge with a CagA-positive H pylori strain, which, for safety reasons, was initially administered in a subset of participants. The primary efficacy outcome was the efficacy of the vaccine as measured by the proportion of participants infected with H pylori 12 weeks after the challenge. At the end of the study, participants infected with H pylori were treated for 14 days with combination therapy consisting of a proton pump inhibitor and two antibiotics twice daily. Safety and immunogenicity were monitored at pre-established visits. This trial is registered with ClinicalTrials.gov, number NCT00736476, and is completed., Findings: 63 patients were randomly assigned, 27 to placebo and 36 to the vaccine. 34 participants (19 in the vaccinated group and 15 in the placebo group) underwent infectious challenge, all but one of whom experienced transient mild-to-moderate epigastric symptoms. 12 weeks after infectious challenge, six (32%) of 19 people in the vaccinated group and six (40%) of 15 people in the placebo group remained positive for H pylori. Eradication was successful in everyone who remained infected at 12 weeks. The geometric mean concentrations of antibodies specific to CagA (202 [95% CI 69-588] vs 4·73 [95% CI 1·41-16]; p=0·001), VacA (1469 [838-2577] vs 73 [39-138]; p=0·001), and NAP (208 [139-313] vs 8·01 [5·05-13]; p=0·001) were significantly higher in the vaccine group than in the placebo group 12 weeks after infectious challenge., Interpretation: Compared with placebo, the vaccine did not confer additional protection against H pylori infection after challenge with a CagA-positive strain, despite increased systemic humoral responses to key H pylori antigens. The finding of spontaneous clearance of H pylori infection in more than half the participants in the placebo group is remarkable and suggests important immune protection in the healthy adult population., Funding: Novartis Vaccine and Diagnostics., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objective: The aim of this study was the scientific evaluation of an intradermal vaccination method in comparison to an intramuscular vaccination against Mycoplasma hyopneumoniae in suckling piglets with regard to skin reactions, performance parameters and procedural aspects. Possible effects on animal welfare should be deduced., Material and Methods: Under field conditions, 672 suckling piglets in three batches were vaccinated; 338 intradermally and 334 intramuscularly. In addition to a detailed scoring of the integument, the injection site with the local reaction was evaluated, scoring the swelling size (score 0-5), and rubor and incrustation (score 0-3). Moreover, piglets were weighed individually 1 day before vaccination and 8 days later. In addition, the time required for each vaccination was documented., Results: On the first day after vaccination, 71.3 % of the intramuscularly vaccinated piglets and 2.7 % of the intradermally vaccinated piglets displayed no swelling at the vaccination site. No differences remained by the 7th day after vaccination. Daily weight gain did not differ significantly between the piglets in the intramuscularly (248 g) and intradermally (258 g) vaccinated groups. Intradermal vaccination took a mean of 11 seconds per piglet, while 17 seconds were required for intramuscular vaccination., Conclusions and Clinical Relevance: In this first study, no negative effects of the intradermal vaccination on performance parameters and no long-standing skin reactions were detected in the suckling piglets. Skin reactions were related to the desired immune reaction of the intradermal vaccination, but were no longer present after 7 days. Moreover, with regard to procedural aspects, the intradermal vaccination offered time saving advantages. To evaluate further possible effects on animal welfare, further analyses via video recordings are required., Competing Interests: Es bestehen keine geschützten, finanziellen, beruflichen oder anderen persönlichen Interessen an einem Produkt, einem Service und/oder einer Firma, welche die in diesem Manuskript dargestellten Inhalte oder Meinungen beeinflussen könnten., (Georg Thieme Verlag KG Stuttgart · New York.)

For almost a century, aluminum (Al) in the form of Al oxyhydroxide (a crystalline compound), Al hydroxyphosphate (an amorphous Al phosphate hydroxide), Al phosphate, and Al potassium sulfate has been used to improve the immunogenicity of vaccines. Al is currently included in vaccines against tetanus, hepatitis A, hepatitis B, human papillomavirus, Haemophilus influenzae type b, and infections due to Streptococcus pneumoniae and Neisseria meningitidis. Official health authorities consider the inclusion of Al in most of the presently recommended vaccines to be extremely effective and sufficiently safe. However, the inclusion of Al salts in vaccines has been debated for several years because of studies that seem to indicate that chronic Al exposure through vaccine administration can interfere with cellular and metabolic processes leading to severe neurologic diseases. Children, who in their first years of life receive several vaccine doses over a reduced period of time, would be most susceptible to any risk that might be associated with vaccines or vaccine components. The main aim of this paper was to discuss the data presently available regarding Al neurotoxicity and the risk for children receiving vaccines or other pharmaceutical preparations containing Al. Analysis of the literature showed that no apparent reason exists to support the elimination of Al from vaccines for fear of neurotoxicity. The only problem that deserves attention is the suggested relationship between Al oxyhydroxide-containing vaccines and macrophagic myofaciitis or myalgic encephalomyelitis/chronic fatigue syndrome. Currently, definitive conclusions cannot be drawn on these risks and further studies must be conducted. Until then, Al remains the best solution to improve vaccine efficacy., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Riemerella anatipestifer (RA) infections cause major economic losses in the duck industry. In this study, we developed an RA vaccine to control virulent serotype 1 and 2 RA, which predominate in worldwide prevalence. We established a strategy for vaccine candidate screening, and selected strains D15-RDA-92 (serotype 1) and D14-RDA-8 (serotype 2). These strains were characterized by ≤50% embryo mortality and <3.0 serum resistance assay values in in vitro screening. We evaluated the protective efficacy of live bivalent RA vaccines against virulent homologous serotype RA. Ducklings received two oral immunizations with the bivalent vaccine and showed significant protection against two virulent strains (serotypes 1 and 2) at 21 days post-immunization. No death or clinical signs of diarrhea, tremors, or limb swelling were observed in the immunized ducks. In a safety evaluation, ducks immunized with 100 times higher doses showed no clinical signs, mortality, gross lesions, or histological lesions, and body weight of the ducks showed no significant difference compared to that of negative controls. In addition, IgA analysis showed a significant increase in secretory IgA antibodies generated in the trachea and duodenum of orally immunized ducks at 28 days of age. The IgA might be involved in one of the major immune responses to RA and contributes to protecting against virulent RA. In this study, we developed monovalent and bivalent RA vaccines that were safe in ducks and provided significant protective efficacy against virulent homologous RA strains., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Gut infections triggered by pathogenic bacteria lead to most frequently occurring diarrhea in humans accounting for million deaths annually. Currently, only a few licensed vaccines are available against these pathogens for mostly travelers moving to diarrheal endemic areas. Besides commercialized vaccines, there are many formulations that are either under clinical or pre-clinical stages of development and despite several efforts to improve safety, immunogenicity and efficacy, none of them can confer long-term protective immunity, for which repeated booster doses are always recommended. Further in many countries, financial, social and political constraints have jeopardized vaccine development program against these pathogens that enforce us to gather knowledge on safety, tolerability, immunogenicity and protective efficacy regarding the same. In this review, we analyze safety and efficacy issues of vaccines against five major gut bacteria causing enteric infections. The article also simultaneously describes several barriers for vaccine development and further discusses possible strategies to enhance immunogenicity and efficacy.

VNP20009 is a genetically modified strain of Salmonella typhimurium and has a good anticancer effect wildly used in tumour therapy on animal models. For its clinical application, an accurate bio-safety assessment on sensitive models is necessary. In this study, we use TNFR1 KO mice as a susceptive model to assess the virulence of bacterial VNP20009 and its derivative ΔhtrA. By intraperitoneal administration of Salmonella, the increased lethality was observed in TNFR1 KO mice infected with VNP20009, but not with ΔhtrA. We performed a systemically comparative analysis of their toxicity, and ΔhtrA shows a better bio-safety for TNFR1 KO mice. Since the macrophages with TNFR1 deficiency exhibit a reduced ability of bacteria clearance, ΔhtrA with lower survival ability in normal macrophages restores its viability in TNFR1 KO macrophages. Thus, ΔhtrA was further tested for its antitumour effect in TNFR1 KO mice bearing a B16F10 melanoma model. It displays a moderate antitumour effect, suggesting ΔhtrA instead of VNP20009 might be a promising candidate for bacteria-mediated tumour therapy specific to those with low immunity., Significant and Impact of the Study: VNP20009 is attenuated Salmonella with a good safety widely used for tumour-targeting bacterial therapies. Little is known about its toxicity in hosts with low immunity. This study is the first systemically comparative analysis of their toxicity of VNP20009 and its mutant ΔhtrA in TNFR1-KO mice. Research on toxicity of tumour-targeting Salmonella in mice with immunodeficiency can facilitate the optimization of bacterial therapies with reduced adverse effects in future clinical trials., (© 2018 The Society for Applied Microbiology.)

Vaccines containing live attenuated bacterial or viral organisms are currently being investigated as potential therapy for locally advanced or metastatic cancers. However, the use of such live organisms in an immunocompromised population, such as patients who recently or are currently receiving chemotherapy, raises the concern that these organisms can themselves disseminate and cause frank infection. We report a hereunto unreported phenomenon of anti-cancer vaccines (containing live attenuated organisms) leading to frank, disseminated infection. We submit that occurrence of this phenomenon must be watched for by all members of the interdisciplinary cancer treatment team., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: It is important to examine the risk of Acute disseminated encephalomyelitis (ADEM) after vaccination., Methods: We conducted a nested case-control study between January 2011 and December 2015. Four controls per case were matched for age, gender, address. An independent expert committee validated the diagnoses of cases and controls. Data on vaccinations were obtained from computerized vaccination records. The analyses were conducted with the use of conditional logistic regression., Results: The analyses include 272 cases of ADEM and 1096 controls. No increase in the risk of ADEM was observed for vaccination against hepatitis B, influenza, polio(live), diphtheria, pertuss(acellular), tetanusis, measles, mumps, rubella, Japanese Encephalitis, meningitis, hepatitis A, varicella and rabies vaccines. Vaccine was associated with a statistically significant increase in risk in the 31-60-day exposure interval (OR, 4.04 [95% CI, 1.07-12.69]), but not the 0-30 and 61-180-day interval. There was no association between vaccine received and the recurrence of ADEM., Conclusions: Findings from the present study do not demonstrate an association of vaccines with an increased risk of ADEM and its recurrence among either paediatric (≤18 years) or adult (>18 years) individuals within the 180 days after vaccinations. The finding in children in the 31-60 day risk interval is likely coincidental and was not confirmed in separate self-control analyses., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: The live, temperature-attenuated vaccine strain 1B of Chlamydia abortus, the aetiological agent of ovine enzootic abortion (OEA), has been implicated in cases of vaccine breakdown. The aim of this study was to understand the nature of this attenuation through sequencing of the vaccine parent strain (AB7) and the derived mutant strains 1B and 1H, as well as to clarify the role of the vaccine strain in causing disease through comparative whole genome analysis., Methods: Whole genome sequencing was performed on: vaccine parent strain AB7; N-methyl-N'-nitro-N-nitrosoguanidine (NTG)-induced temperature attenuated mutant strain 1B grown from the commercial live vaccines Cevac Chlamydia and Enzovax; strain 1H a reverted NTG mutant; and 5 strains isolated from cases of OEA originating from animals from the original vaccine safety trial (2 strains) or from vaccinated ewes or ewes exposed to vaccinated animals (3 strains)., Results: We confirmed that AB7 is in a different lineage from the reference strain S26/3. The genome of vaccine strain 1B contains ten single nucleotide polymorphisms (SNPs) created by the NTG treatment, which are identical to those found in strain 1H. The strains from OEA cases also cluster phylogenetically very tightly with these vaccine strains., Conclusions: The results show that C. abortus vaccine strain 1B has an identical genome sequence to the non-attenuated "reverted mutant" strain 1H. Thus, the protection of the 1B vaccine is unlikely to be due to the NTG induced SNPs and is more likely caused by the administration of high doses of C. abortus elementary bodies that stimulate protective immunity. Vaccine-identical strains were also isolated from cases of disease, as well as strains which had acquired 1-3 SNPs, including an animal that had not been vaccinated with either of the commercial live OEA vaccines, indicating that the 1B vaccine strain may be circulating and causing disease., (Copyright © 2018. Published by Elsevier Ltd.)

Mycoplasma gallisepticum (MG) is an important pathogen of poultry worldwide that causes chronic respiratory disease (CRD) in chickens and infectious sinusitis in turkeys. Vaxsafe MG (strain ts-11) is a live attenuated temperature sensitive vaccine that has been proven to be effective in controlling CRD in chickens, but it is not efficacious in turkeys. The gapA gene, which encodes a mature cytadhesin protein with a molecular weight of approximately 105 kDa, is not expressed in strain ts-11 because a 20 base pair reiterated sequence introduces a frame shift and causes premature truncation of the translated peptide. A GapA positive clone, MG ts-304, isolated from strain ts-11 has been shown to have enhanced efficacy in chickens. Here we describe studies we conducted to assess the safety and efficacy of the MG ts-304 vaccine candidate in turkeys. We found that MG ts-304 was able to colonise the trachea of 3-week-old turkeys and was safe, even at a tenfold overdose, inducing no adverse clinical signs of respiratory disease or significant gross lesions in the respiratory tract (air sacs or trachea), and was poorly transmissible to in-contact birds. We also showed that it was efficacious when administered to 3-week-old turkeys, inducing protective immunity against challenge with the M.gallisepticum wild-type strain Ap3AS. MG ts-304 is therefore a promising live attenuated vaccine candidate for use in turkeys., (Copyright © 2018. Published by Elsevier Ltd.)

Objectives: We undertook an open-label, uncontrolled study of investigational recombinant botulinum vaccine for botulinum neurotoxin (BoNT) serotypes A and B (rBV A/B) to assess its safety and immunogenicity in healthy volunteers who had been previously immunized with investigational pentavalent botulinum toxoid. Study participants who wished to do so could donate their hyperimmune plasma for production of Human Botulism Immune Globulin Intravenous (BIG-IV, BabyBIG®)., Study Design: A single 0.5 ml (mL), 40-microgram intramuscular injection of rBV A/B was administered to study participants. Post-vaccination sera collected at approximately 2-week intervals were evaluated for anti-BoNT/A and anti-BoNT/B neutralizing antibody concentrations (NAC). Local and systemic treatment-emergent adverse events (TEAEs) were identified by clinical and laboratory monitoring for 12 weeks post-vaccination with a final telephone follow-up for additional safety assessment at 6 months. The primary endpoint for immunogenicity was a ≥4-fold rise in NAC in ≥50% of participants by Week 4 post-vaccination., Results: All 45 enrolled participants completed the study. Forty-two of 45 participants (93.3%) experienced at least one TEAE. Overall, 138 of 218 (63.3%) reported TEAEs were treatment-related, the majority of which were mild injection-site reactions. No serious or unexpected adverse events occurred. The study achieved its primary immunogenicity endpoint with 37/45 (82.2%) participants and 39/45 (86.7%) participants having a ≥4-fold rise in NAC to anti-BoNT/A and to anti-BoNT/B, respectively, by Week 4 post-vaccination., Conclusion: A single 0.5 mL dose of rBV A/B was safe, well-tolerated and immunogenic in participants previously immunized with pentavalent botulinum toxoid. The tolerability and immunogenicity characteristics of rBV A/B vaccination of individuals with existing BoNT immunity support its potential future use to provide occupational protection to botulism laboratory workers. Almost all study participants donated hyperimmune plasma for production of BIG-IV. ClinicalTrials.gov registration number: NCT01701999., (Copyright © 2018. Published by Elsevier Ltd.)

Guidelines recommend vaccination starting 12 months after autologous hematopoietic stem cell transplant (aHCT), but there is varying practice for patients on maintenance therapy, with some centers not immunizing at all. Because of decreased vaccine rates among the general population causing loss of herd immunity, we aimed to establish the safety and efficacy of revaccinating multiple myeloma patients on lenalidomide maintenance (LM). Of the 122 patients who were vaccinated after aHCT between 2010 and 2014 at Memorial Sloan Kettering Cancer Center, 91 (75%) were on LM. Vaccine responses were defined by increases between pre- and postvaccination titers. Reponses varied by vaccine type with 76% responding to pertussis, 70% diphtheria, 60% tetanus, 71% Haemophilus influenzae, and 58% pneumococcal. All patients retained minimal levels of polio immunity, but 27% responded with increased titers. Fewer patients received hepatitis A and B, but of those who did, 30% responded to hepatitis A and 40% to hepatitis B. No differences were seen in rates of response for those on LM at time of vaccination compared with those who were not. There were no vaccine-related adverse effects. Reimmunization with inactivated vaccines in patients on LM is therefore both safe and effective, offering this population immunity to vaccine-preventable diseases., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

In this study, we conducted an investigation to determine the true prevalence of coxiellosis in sheep in central-eastern Tunisia. A total of 492 veterinary samples taken from 110 flocks were screened for coxiellosis using IS1111-based real-time PCR assay. Sheep sera were tested using an indirect enzyme-linked immunosorbent assay. Based on molecular and serological results, the true adjusted animal and herd-level prevalence of coxiellosis were 11.8% and 20.21%, respectively. Bacterial excretion was observed in 17 flocks, and 19 females showed evidence of Coxiella burnetii shedding (100%). In addition, a statistically significant association was found between vaginal and milk shedding for sheep. Multivariable logistic regression analysis at the animal-population level indicated that strata and vaccination variables were found to be associated with coxiellosis. Besides, it was shown that this infection increased when the intensive farm was exposed to carnivores and when the cleaning practices were not respected, while it decreased when a suitable quarantine was introduced for any introduction of a new animal. Good hygiene and sanitation practices on-farm should be handled as strategies to deal with this zoonotic pathogen in herds., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose: To obtain safety and preliminary efficacy data of the combination of ADXS11-001, live attenuated Listeria monocytogenes bacterium, with mitomycin, 5-fluorouracil (5-FU), and intensity modulated radiation therapy in locally advanced anal cancer., Patients and Methods: Eligibility included patients with previously untreated, nonmetastatic anal cancer with a primary tumor >4 cm or node-positive disease. Patients received 2 cycles of mitomycin and 5-FU concurrent with 54.0 Gy intensity modulated radiation therapy. One intravenous dose of ADXS11-001 (1 × 10 9  colony-forming units) was administered before chemoradiation; 3 additional monthly doses were given after chemoradiation., Results: Ten patients were treated, including 1 with N2 and 4 with N3 disease. Two patients had grade 3 acute toxicities after the initial dose of ADXS11-001, including chills/rigors (n = 2), back pain (n = 1), and hyponatremia (n = 1). All ADXS11-001 toxicities occurred within 24 hours of administration. There was no apparent increase in chemoradiation toxicities or myelosuppression. One patient had a grade 5 cardiopulmonary event shortly after beginning 5-FU treatment. All 9 assessable patients had complete clinical responses by sigmoidoscopy. Eight of 9 patients (89%) are progression-free at a median follow-up of 42 months., Conclusions: Preliminary data show that ADXS11-001 can be safely administered with standard chemoradiation for anal cancer. Further studies of listeria-based immunotherapy with radiation are warranted., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Tiger puffer (Takifugu rubripes) is becoming an economic promising aquaculture species in China. However, the development of Tiger puffer breeding industry is restricted by some serious aquatic disease such as vibriosis. An effective live attenuated vaccine MVAV6203 was developed in our previous studies by curing the virulence plasmid pEIB1 and unmarked inframe-deletion of the aroC gene from the virulent V. anguillarum. Here, we evaluated whether this live vaccine was suitable for Tiger puffer against disease caused by Vibrio genus. The live vaccine show virulence attenuation in both juvenile and adult fish vaccinated with either a single or high dose (50-fold single dose). In addition, administration of the live vaccine shew limited growth in fish and did not affect fish body weight significantly, with no adverse impact on growth between vaccinated and saline control fish. Furthermore, increased expression of cytokines involved in pro-inflammatory (IL-1β, TNFα and IL-6), cell-mediated immunity inducing (IL-12p35, IL-12p40 and IL-18), antiviral/intracellular pathogen killing (I-IFN-1, IFN-γ and Mx), peripheral T cell expansion and survival controlling (IL-2, IL-7 and IL-15) and antigen processing maker and anti-inflammatory (MHC I and IL-10) were elicited significantly after the vaccination. These cellular responses correlate with protection against virulent strain challenge and high RPS of 90.67% and 80.31% in juvenile and adult fish were obtained, respectively. These data indicated for the first time that the live attenuated V. anguillarum vaccine is suitably applied for the development of an effective and safe vaccine for prevention of vibriosis in Tiger puffer aquaculture industry., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Objectives: To determine the effectiveness of Uromune ® in preventing recurrent urinary tract infections (UTIs) in women., Patients and Methods: A total of 77 women with microbiology-proven recurrent UTIs were given Uromune sublingual vaccine for a period of 3 months. Time to first UTI recurrence since treatment and adverse events were prospectively recorded in a follow-up period of up to 12 months., Results: Of the 77 women, 75 completed the treatment. Of the 75 women who completed treatment, 59 (78%) had no subsequent UTIs in the follow-up period. Prior to treatment, all women had experienced a minimum of three or more episodes of UTI during the preceding 12 months. Proportionally, the majority of recurrences occurred in postmenopausal women. One patient had to stop treatment because of an adverse event (rash over face and neck)., Conclusion: This prospective study suggests that Uromune is safe and effective at preventing UTIs in women. Further research is required in larger groups of patients for longer treatment times. An international double-blind randomized control trial comparing Uromune with placebo is currently underway., (© 2017 The Authors BJU International © 2017 BJU International Published by John Wiley & Sons Ltd.)

Q-Vax®, a whole cell formalin inactivated vaccine, is currently the only licensed Q fever vaccine for humans world-wide. Efficacy is high, although vaccine failures have been described for those vaccinated within the incubation of a naturally acquired infection. In Australia, it is widely used to prevent occupational acquisition of Q fever and is the mainstay for outbreak control. A retrospective review of all notified cases of acute Q fever to the Victorian department of health, 1993-2013, revealed 34 of 659 cases were previously vaccinated and 10 cases were positive on pre-vaccination screening, precluding vaccination. Twenty-one cases described high-risk exposures for C. burnetii prior to and within 15 days post vaccination and are likely to have been vaccinated within the incubation period of a natural infection. Thirteen cases described symptom onset more than 15 days post vaccination and thus may represent the first described series of Q-Vax vaccine failures following appropriate vaccination., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Control of the important poultry pathogen Mycoplasma gallisepticum is highly dependent on safe and efficacious attenuated vaccines. In order to assess a novel vaccine candidate we evaluated the safety and efficacy of the M. gallisepticum mutant 26-1. The oppD 1 gene in this mutant has been interrupted by a signature-tagged transposon and previous studies have shown that it can colonise the respiratory tract of chickens without inducing significant disease. The capacity of the oppD 1 mutant to induce protective immunity in the respiratory tract after vaccination by eye-drop was assessed by challenging vaccinated birds with an aerosol of the virulent M. gallisepticum strain Ap3AS. Vaccination with the oppD 1 mutant was shown to fully protect against the lesions caused by pathogenic M. gallisepticum in the air sacs and tracheas. It also protected against the effect of infection on weight gain, and partially protected against colonisation of the trachea by virulent M. gallisepticum. These results indicate that a M. gallisepticum mutant with the oppD 1 gene knocked out could be used as a live attenuated vaccine as it is both safe and efficacious when administered by eyedrop to chickens., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Giant condyloma acuminatum occurs infrequently in children and adolescents. It is a challenging condition which is difficult to treat with both surgical and medical modalities. We present a case of a 15-year-old boy with giant condyloma acuminatum of the glans penis refractory to several therapeutic modalities. The lesions were treated successfully with a novel combination of Mycobacterium indicus pranii immunotherapy and acitretin. There was no recurrence of lesions after two years of follow-up.

This report summarises Australian passive surveillance data for adverse events following immunisation (AEFI) for 2015 reported to the Therapeutic Goods Administration and compares them to long-term trends. There were 2,924 AEFI records for vaccines administered in 2015; an annual AEFI reporting rate of 12.3 per 100,000 population. There was a decline of 7% in the overall AEFI reporting rate in 2015 compared with 2014. This decline in reported adverse events in 2015 compared to the previous year was mainly attributable to fewer reports following the HPV vaccine and replacement of monovalent vaccines (Hib, MenCCV and varicella) with combination vaccines such as Hib-MenC, and MMRV. AEFI reporting rates for most individual vaccines were lower in 2015 compared with 2014. The most commonly reported reactions were injection site reaction (26%), pyrexia (17%), rash (16%), vomiting (8%) and headache (7%). The majority of AEFI reports (85%) were described as non-serious events. There were two deaths reported, but no clear causal relationship with vaccination was found., (This work is copyright. You may download, display, print and reproduce the whole or part of this work in unaltered form for your own personal use or, if you are part of an organisation, for internal use within your organisation, but only if you or your organisation do not use the reproduction for any commercial purpose and retain this copyright notice and all disclaimer notices as part of that reproduction. Apart from rights to use as permitted by the Copyright Act 1968 or allowed by this copyright notice, all other rights are reserved and you are not allowed to reproduce the whole or any part of this work in any way (electronic or otherwise) without first being given the specific written permission from the Commonwealth to do so. Requests and inquiries concerning reproduction and rights are to be sent to the Online, Services and External Relations Branch, Department of Health, GPO Box 9848, Canberra ACT 2601, or by email to copyright@health.gov.au.)