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Mucosal vaccination presents a promising complement to parenteral vaccination. Bacterium-like particles (BLPs), peptidoglycan structures prepared from lactic acid bacteria, are explored as potential nasal vaccine adjuvants for respiratory infections. To date, studies on BLP-adjuvanted nasal vaccines against intestinal infections have remained limited. In this study, we demonstrated the efficacy of intranasal BLP-adjuvanted vaccination in controlling intestinal infections using the Citrobacter rodentium (C. rodentium) model in C57BL/6 mice. Intranasal vaccination of Intimin, an adhesin critical for intimate bacterial adhesion to colonic epithelial cells, combined with BLP (BLP+I) elicited robust Intimin-specific intestinal secretory IgA production, reduced bacterial load in feces and almost completely inhibited colonic hyperplasia, a characteristic symptom of C. rodentium infection in mice. Conversely, parenteral vaccination with Alhydrogel-adjuvanted Intimin failed to induce intestinal Intimin-specific IgA production, resulting in poor protection against C. rodentium infection. This underscores the pivotal role of mucosal IgA responses elicited by intranasal immunization in its protective efficacy. As this study did not delineate the precise protective mechanism conferred by BLP+I intranasal immunization against C. rodentium infection, further elucidation of the mechanisms underlying intranasal BLP+I immunization is required., 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 © 2024 Elsevier Ltd. All rights reserved.)

An effective prophylactic vaccine for prevention of Neisseria gonorrhoeae infection would have a major impact on sexual and reproductive health worldwide. Interest in developing gonorrhoea vaccines is growing due to the reported high rates of N. gonorrhoeae infections globally, and the threat of antimicrobial resistance. Several gonorrhoea vaccine candidates are currently under evaluation and various mathematical models have been used to assess the potential population-level impact a gonorrhoea vaccine may have once available. Here we review key aspects of gonorrhoea vaccine mathematical modelling studies, including model structures, populations considered, and assumptions used as well as vaccine characteristics and implementation scenarios investigated. The predicted vaccine impact varied between studies, ranging from as little as ∼17 % reduction in N. gonorrhoeae prevalence after 30 years up to 100 % reduction after 5 years. However, all studies predicted that even a partially effective gonorrhoea vaccine could have a substantial impact in reducing N. gonorrhoeae prevalence or incidence, particularly when high coverage is achieved within either important risk groups or the overall sexually active population. As expected, higher vaccine efficacy against acquisition of N. gonorrhoeae and longer duration of protection were linked to greater reductions in infections. A vaccine that alters onward transmission could also substantially reduce infections. Several gaps and research needs have been identified by researchers in the field and via this narrative literature review. For example, future modelling to inform gonorrhoea vaccine development and implementation should consider additional populations that are at high risk of N. gonorrhoeae infection, especially in low- and middle-income settings, as well as the impact of vaccination on the potential adverse sexual and reproductive health outcomes of infection. In addition, more detailed and robust epidemiological, biological, and behavioural data is needed to enable more accurate and robust modelling of gonorrhoea vaccine impact to inform future scientific and public health decision-making., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Thilini Padeniya reports financial support was provided by National Institutes of Health. Kate Seib reports financial support was provided by National Institutes of Health. Kate Seib reports financial support was provided by National Health and Medical Research Council. If there are other authors, they 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 © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Neisseria gonorrhoeae infection (gonorrhoea) is a global public health challenge, causing substantial sexual and reproductive health consequences, such as infertility, pregnancy complications and increased acquisition or transmission of HIV. There is an urgency to controlling gonorrhoea because of increasing antimicrobial resistance to ceftriaxone, the last remaining treatment option, and the potential for gonorrhoea to become untreatable. No licensed gonococcal vaccine is available. Mounting observational evidence suggests that N. meningitidis serogroup B outer membrane vesicle-based vaccines may induce cross-protection against N. gonorrhoeae (estimated 30%-40% effectiveness using the 4CMenB vaccine). Clinical trials to determine the efficacy of the 4CMenB vaccine against N. gonorrhoeae are underway, as are Phase 1/2 studies of a new gonococcal-specific vaccine candidate. Ultimately, a gonococcal vaccine must be accessible, affordable and equitably dispensed, given that those most affected by gonorrhoea are also those who may be most disadvantaged in our societies, and most cases are in less-resourced settings. This vaccine value profile (VVP) provides a high level, holistic assessment of the current data to inform the potential public health, economic and societal value of pipeline vaccines. This was developed by a working group of subject matter experts from academia, non-profit organizations, public private partnerships and multi-lateral organizations. All contributors have extensive expertise on various elements of the N. gonorrhoeae VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using published data obtained from peer-reviewed journals or reports., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: JJO reports financial support from the World Health Organization and Australian National Health and Medical Research Foundation. Some of the authors are present or former staff members of the World Health Organization. The authors alone are responsible for the views expressed in this publication and they do not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated. All other 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 © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Klebsiella pneumoniae causes community- and healthcare-associated infections in children and adults. Globally in 2019, an estimated 1.27 million (95% Uncertainty Interval [UI]: 0.91-1.71) and 4.95 million (95% UI: 3.62-6.57) deaths were attributed to and associated with bacterial antimicrobial resistance (AMR), respectively. K. pneumoniae was the second leading pathogen in deaths attributed to AMR resistant bacteria. Furthermore, the rise of antimicrobial resistance in both community- and hospital-acquired infections is a concern for neonates and infants who are at high risk for invasive bacterial disease. There is a limited antibiotic pipeline for new antibiotics to treat multidrug resistant infections, and vaccines targeted against K. pneumoniae are considered to be of priority by the World Health Organization. Vaccination of pregnant women against K. pneumoniae could reduce the risk of invasive K.pneumoniae disease in their young offspring. In addition, vulnerable children, adolescents and adult populations at risk of K. pneumoniae disease with underlying diseases such as immunosuppression from underlying hematologic malignancy, chemotherapy, patients undergoing abdominal and/or urinary surgical procedures, or prolonged intensive care management are also potential target groups for a K. pneumoniae vaccine. A 'Vaccine Value Profile' (VVP) for K.pneumoniae, which contemplates vaccination of pregnant women to protect their babies from birth through to at least three months of age and other high-risk populations, provides a high-level, holistic assessment of the available information to inform the potential public health, economic and societal value of a pipeline of K. pneumoniae vaccines and other preventatives and therapeutics. This VVP was developed by a working group of subject matter experts from academia, non-profit organizations, public-private partnerships, and multi-lateral organizations, and in collaboration with stakeholders from the WHO. All contributors have extensive expertise on various elements of the K.pneumoniae VVP and collectively aimed to identify current research and knowledge gaps. The VVP was developed using only existing and publicly available information., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ziyaad Dangor reports financial support was provided by Bill & Melinda Gates Foundation. Ziyaad Dangor reports financial support was provided by World Health Organization. If there are other authors, they 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 © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Community-acquired pneumonia often stems from the macrolide-resistant strain of Mycoplasma pneumoniae, yet no effective vaccine exists against it., Methods: This study proposes a vaccine-immunoinformatics strategy for Mycoplasma pneumoniae and other pathogenic microbes. Specifically, dominant B and T cell epitopes of the Mycoplasma pneumoniae P30 adhesion protein were identified through immunoinformatics method. The vaccine sequence was then constructed by coupling with CTLA-4 extracellular region, a novel molecular adjuvant for antigen-presenting cells. Subsequently, the vaccine's physicochemical properties, antigenicity, and allergenicity were verified. Molecular dynamics modeling was employed to confirm interaction with TLR-2, TLR-4, B7-1, and B7-2. Finally, the vaccine underwent in silico cloning for expression., Results: The vaccine exhibited both antigenicity and non-allergenicity. Molecular dynamics simulation, post-docking with TLR-2, TLR-4, B7-1, and B7-2, demonstrated stable interaction between the vaccine and these molecules. In silico cloning confirmed effective expression of the vaccine gene in insect baculovirus vectors., Conclusion: This vaccine-immunoinformatics approach holds promise for the development of vaccines against Mycoplasma pneumoniae and other pathogenic non-viral and non-bacterial microbes., 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 © 2024 Elsevier Ltd. All rights reserved.)

Abstract: This article presents the World Health Organizations (WHO) evidence and recommendations for the use of Haemophilus influenzae type b vaccination from the WHO position paper on H. influenzae type b (Hib) Vaccination – July 2013 recently published in the Weekly Epidemiological Record [1]. This position paper summarizes the WHO position on the inclusion of Hib vaccines in all national immunization programmes, recent developments in the field and the potential of different Hib immunization schedules to further reduce morbidity and mortality. The current document replaces the position paper on the use of Hib vaccines published in 2006 [2]. Footnotes to this paper provide a number of core references. In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO's current position on the use of vaccines in the global context. This paper reflects the recommendations of WHO's Strategic Advisory Group of Experts (SAGE) on immunization. These recommendations were discussed by SAGE at its April 2013 meeting. Evidence presented at the meeting can be accessed at http://www.who.int/immunization/sage/previous/en/index.html. [Copyright &y& Elsevier]

Currently there is no human vaccine against Lyme borreliosis, and most research focuses on recombinant protein vaccines, as such a vaccine has been proven to be successful in the past. The expression of recombinant antigens in meningococcal Outer Membrane Vesicles (OMVs), with the OMV functioning both as adjuvant and delivery vehicle, greatly enhances their potential. Immunization studies in mice have shown that OMV-based vaccines can protect against various pathogens and an OMV-based meningococcal vaccine is approved and available for human use. Because of its surface localization in Borrelia and the detailed knowledge regarding its immunogenicity and structure, OspA was chosen as a suitable lipoprotein to be tested as an OMV-based vaccine against Lyme borreliosis. We have previously shown that the OMV-OspA vaccine was immunogenic in mice and here we assessed the efficacy of OMV-OspA. We generated a second-generation OMV-OspA vaccine and vaccinated C3H/HeN mice with (EDTA extracted) meningococcal OMVs expressing OspA from B. burgdorferi strain B31. The adjuvant effect of empty OMVs on recombinant OspA was tested as well. We subsequently challenged mice with a subcutaneous injection of B. burgdorferi. Average antibody end-point titers against the OspA-OMV construct were high, although lower compared to the antibodies raised against recombinant OspA. Interestingly, antibody titers between recombinant OspA adjuvanted with aluminum hydroxide and recombinant OspA with OMV as adjuvant were comparable. Finally, qPCR and culture data show that both the OspA-OMV and the vaccine based on recombinant OspA with OMV as adjuvant provided significant, yet partial protection, against Borrelia infection. OMV-based vaccines using Borrelia (lipo)proteins are an easy and feasible vaccination method protecting against B. burgdorferi infection and could be a promising strategy in humans., 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 © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: This first in human study was designed as an open label clinical trial to assess the safety and tolerability of Serum Institute of India Pvt. Ltd. (SIIPL) Tdap vaccine in healthy adult volunteers, aged 18-45 years., Methods: A total of 24 healthy adults were administered a 0.5 ml single dose of SIIPL Tdap vaccine intramuscularly, and were followed for one month for safety outcomes viz., immediate, solicited, unsolicited and serious adverse events., Results: 23 subjects completed the study in compliance with the study protocol. None of the participants experienced any immediate adverse events or any local or systemic solicited adverse events., Conclusion: Tdap vaccine manufactured by Serum Institute of India Pvt. Ltd. is safe and well tolerable in adults. It was concluded that further clinical development of this vaccine should continue to assess its safety and immunogenicity, in the target population. Clinical Trial Registration - CTRI/2017/03/008003., 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 © 2020. Published by Elsevier Ltd.)

Today, Coronavirus Disease 2019 (COVID-19) is a global public health emergency and vaccination measures to counter its diffusion are deemed necessary. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of the disease, unleashes a T-helper 2 immune response in those patients requiring intensive care. Here, we illustrate the immunological mechanism to train the immune system towards a more effective and less symptomatic T-helper 1 immune response, to be exploited against SARS-CoV-2., 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 © 2020 Elsevier Ltd. All rights reserved.)

Edwardsiellosis outbreaks cause significant losses in Japanese eel aquaculture. The causative agent, Edwardsiella tarda, is an intracellular pathogen, and the use of antibiotics has a limited effectiveness. As Japanese eels are sensitive to stress, injection vaccines are not recommended for treatment; immersion methods are less stressful, but not cost-effective. Alternatively, oral vaccination methods are more promising. The aim of this study was to develop a starch hydrogel-based oral (SHO) vaccine against edwardsiellosis in Japanese eel, using formalin-killed cells. To assess the protective effect, we compared SHO vaccine with the conventional formalin-killed cell (FKC) vaccine. A bacterial agglutination test showed that agglutination titers in SHO-vaccinated group were higher than in the FKC-vaccinated group. Japanese eel survival rate (%) was monitored after challenge by E. tarda at four weeks post-vaccination. Survival rates in the FKC group (60%, first trial; 70%, second trial) were lower than in SHO groups. Percentage survival rates in three SHO groups (first and second trials, respectively) were as follows: 70% and 80% in the group vaccinated once per day for one day; and 80% and 90% in both groups vaccinated for four and eight days. Additionally, a boost SHO vaccination at 46 days prompted a similar or even higher protection against edwardsiellosis than after the initial vaccination. Both FKC and SHO vaccination upregulated levels of pro-inflammatory cytokines (interleukin (IL)-6, tumor necrosis factor (TNF)-α), and host defense cytokine (interferon (IFN)-α) in all immunized groups of fish when compared with the control. These results reveal the immunostimulation effect of SHO vaccine in Japanese eel, emphasizing its potential as an oral vaccine in aquaculture., 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 © 2020 Elsevier Ltd. All rights reserved.)

Botulinum neurotoxins (BoNTs) are highly toxic proteins that mediate their effects by binding to neuronal receptors and block the neutralizing ability of therapeutic antibodies. Vaccination is currently the most effective strategy to prevent botulism. In this study, a series of recombinant functional domain antigens of BoNT/A were prepared and identified, and their immunoprotective efficacies were explored and compared. Our results showed that all antigens produced strong humoral immune responses, although their protective effects against the toxin were different. Only the Hc and HN-L antigens produced strong protective effects and afforded complete immunoprotection. In addition, the combined vaccine groups showed that there was no synergistic effect on immune responses after antigen combination, suggesting that the integrity of the toxin antigen or domain is crucial to the immune effects. Studies of the dose-dependent immunoprotective effects further confirmed that the Hc domain antigen afforded more effective protective potency than the HN-L antigen, equivalent to the immune effect of the full-length toxin (Hc + HN-L combination group). Overall, our results demonstrated that the Hc domain elicited a strong protective immune response and also provided basic data and theoretical support for the development of Hc-based BoNT/A subunit vaccine. Therefore, the receptor binding domain Hc is implicated as a promising target antigen of the BoNT/A recombinant subunit vaccine as an alternative to the toxoid vaccine., 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 © 2020 Elsevier Ltd. All rights reserved.)

Helicobacter pylori is a human class I carcinogen and no effective prophylactic or therapeutic H. pylori vaccine has yet been marketed. H. pylori can escape the host immune response, but the precise immune protection mechanisms in humans remain unknown. In this study, we developed a multivalent, subunit H. pylori vaccine candidate by formulating three commonly used H. pylori antigens, neutrophil-activating protein (NAP), urease subunit A (UreA) and subunit B (UreB) with the mucosal adjuvant, a double-mutant heat-labile toxin (dmLT) from Escherichia coli, and evaluated its immunogenicity and therapeutic efficacy in a mouse model of H. pylori infection. We found that oral immunization of H. pylori-infected mice significantly reduced gastric bacterial colonization at both 2 and 8 weeks after immunization. The reduction in bacterial burdens was accompanied with significantly increased serum antigen-specific IgG responses and mucosal IgA responses. Moreover, oral immunization also induced Th1/Th17 immune responses, which may play a synergistic role with the specific antibodies in the elimination of H. pylori. Thus, our vaccine candidate appears able to overcome the immune evasion mechanism of H. pylori, restore the suppression of Th2 immune responses with the induction of a strong humoral immune response. These results lay the foundation for the development of an optimized oral therapeutic H. pylori vaccine with increased immunogenicity of UreA and UreB, as well as providing long-term immunity., 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., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Toxoid vaccines against Clostridium difficile infections (CDI) appear promising in reducing the risk of developing toxin-mediated symptoms. We sought to evaluate the effectiveness and cost-effectiveness of a vaccine candidate in a hospital setting. We developed an agent-based simulation model of nosocomial CDI in a 300-bed hospital. Targeting high-risk patients for vaccination, we estimated the reduction of symptomatic CDI. Using the net reduction of CDI-associated isolation days, we evaluated the vaccine's cost-effectiveness from a healthcare provider perspective over a 2-year period with an average monthly incidence of 5 cases per 10,000 patient-days pre-vaccination. Assuming a vaccine efficacy in the range 60-90%, vaccinating 40% of high-risk patients pre-admission reduced symptomatic CDI by 16.6% (95% CI: 15.2, 17.9). When the vaccine coverage increased to 80%, the reduction of symptomatic CDI was 34.6% (95% CI: 33.7, 35.9). For a willingness to pay (WTP) of CDN$1000 (corresponding to the average costs of case isolation per day), vaccine was cost-effective for vaccination costs per individual (VCPI) up to CDN$111 in the scenario of 40% vaccine coverage. With the same WTP, vaccine was cost-effective for VCPI up to CDN$121 when the vaccine coverage increased to 80%. A significant portion (~80%) of hospital colonization is caused by environmental transmission of C. difficile, which markedly reduced the effectiveness of vaccine below its assumed efficacy. However, due to the number of CDI-associated isolation days averted, vaccination of high-risk patients can be cost-effective depending on the WTP and the VCPI., 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 © 2020 Elsevier Ltd. All rights reserved.)

Botulism is a paralytic disease caused by the intoxication of neurotoxins produced by Clostridium botulinum. Among the seven immunologically distinct serotypes of neurotoxins (BoNTs A - G), serotypes C and D, or a chimeric fusion termed C/D or D/C, are responsible for animal botulism. The most effective way to prevent botulism in cattle is through vaccination; however, the commercially available vaccines produced by detoxification of native neurotoxins are time-consuming and hazardous. To overcome these drawbacks, a non-toxic recombinant vaccine was developed as an alternative. In this study, the recombinant protein vaccine was produced using an Escherichia coli cell-based system. The formaldehyde-inactivated E. coli is able to induce 7.45 ± 1.77 and 6.6 ± 1.28 IU/mL neutralizing mean titers against BoNTs C and D in cattle, respectively, determined by mouse neutralization bioassay, and was deemed protective by the Brazilian legislation. Moreover, when the levels of anti-BoNT/C and D were compared with those achieved by the recombinant purified vaccines, no significant statistical difference was observed. Cattle vaccinated with the commercial vaccine developed 1.33 and 3.33 IU/mL neutralizing mean titers against BoNT serotypes C and D, respectively. To the best of our knowledge, this study is the first report on recombinant E. coli bacterin vaccine against botulism. The vaccine was safe and effective in generating protective antibodies and, thus, represents an industry-friendly alternative for the prevention of cattle botulism., 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 © 2020 Elsevier Ltd. All rights reserved.)

Clostridioides difficile infection is the leading cause of nosocomial diarrhoea globally. Immune responses to toxins produced by C. difficile are important in disease progression and outcome. Here, we analysed the anti-toxin A and anti-toxin B serum antibody proteomes following natural infection or vaccination with a C. difficile toxoid A/toxoid B vaccine using a modified miniaturised proteomic approach based on de novo mass spectrometric sequencing. Analysis of immunoglobulin variable region (IgV) subfamily expression in immunoprecipitated toxin A and toxin B antibodies from four and seven participants of a vaccine trial, respectively, revealed a polyclonal proteome with restricted IGHV, IGKV and IGLV subfamily usage. No dominant IGHV subfamily was observed in the toxin A response, however the dominant anti-toxin B heavy (H)-chain was encoded by IGHV3-23. Light (L)-chain usage was convergent for both anti-toxin A and anti-toxin B proteomes with IGKV3-11, 3-15, 3-20 and 4-1 shared among all subjects in both cohorts. Peptide mapping of common IgV families showed extensive public and private amino acid substitutions. The cohort responses to toxin A and toxin B showed limited similarity in shared IGHV subfamilies. L-chain subfamily usage was more similar in the anti-toxin A and anti-toxin B responses, however the mutational signatures for each subfamily were toxin-dependent. Samples taken both post vaccination (n = 5) or at baseline, indicating previous exposure (n = 2), showed similar anti-toxin B IgV subfamily usage and mutational profiles. In summary, this study provides the first sequence-based proteomic analysis of the antibody response to the major disease-mediating toxins of C. difficile, toxin A and toxin B, and demonstrates that despite the potential for extreme diversity, the immunoglobulin repertoire can raise convergent responses to specific pathogens whether through natural infection or following vaccination., Competing Interests: Declaration of Competing Interest N.G. Anosova declares the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Natalie G. Anosova is employed by Sanofi Pasteur and holds stock with the company. All the other 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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.)

Successful colonization of the mucosal epithelial cells is the key early step for Campylobacter jejuni (C. jejuni) pathogenesis in humans. A set of Surface Exposed Colonization Proteins (SECPs) are known to take leading role in bacterial adhesion and subsequent host pathogenesis. Among the major SECPs, the constitutively expressed C. jejuni surface lipoprotein Jejuni lipoprotein A (JlpA), interacts with intestinal heat shock protein 90α (Hsp90α) and contributes in disease progression by triggering pro-inflammatory responses via activation of NF-κB and p38 MAP kinase pathways. In addition to its ability to express on the surface, high sequence conservation of JlpA protein among different Campylobacter spp make it a suitable vaccine target against C. jejuni. Given that chickens are the primary source for C. jejuni infection in humans and persistent cecal colonization significantly contribute in pathogen transmission, we explicitly used chickens as a model to test the immune-protective efficacy of JlpA protein. Taking into account that gastro-intestinal tract is the major site for C. jejuni colonization, we chose to use mucosal (intragastric) route as mode for JlpA antigen delivery. To deliver JlpA via mucosal route, we engineered a food grade Lactic acid producing bacteria, Lactococcus lactis (L. lactis) to express functionally active JlpA protein in the surface. Further, we demonstrated its ability to substantially improve the antigen specific local immune responses in the intestine along with significant immune-protection against enteric colonization of C. jejuni in chickens., 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.)

This paper analyses farmers' behavioural responses to Government attempts to reduce the risk of disease transmission from badgers to cattle through badger vaccination. Evidence for two opposing behavioural adaptions is examined in response to the vaccination of badgers to reduce the risk of transmission to farmed cattle. Risk compensation theory suggests that interventions that reduce risk, such as vaccination, are counterbalanced by negative behavioural adaptions. By contrast, the spillover effect suggests that interventions can prompt further positive behaviours. The paper uses data from a longitudinal mixed methods study of farmers' attitudes to badger vaccination to prevent the spread of bovine tuberculosis, their reports of biosecurity practices, and cattle movement data in 5 areas of England, one of which experienced badger vaccination. Analysis finds limited evidence of spillover behaviours following vaccination. Lack of spillover is attributed to farmers' beliefs in the effectiveness of biosecurity and the lack of similarity between badger vaccination and vaccination for other animal diseases. Risk compensation behaviours are associated with farmers' beliefs as to who should manage animal disease. Rather than farmers' belief in vaccine effectiveness, it is more likely that farmers' low sense of being able to do anything to prevent disease influences their apparent risk compensation behaviours. These findings address the gap in the literature relating to farmers' behavioural adaptions to vaccine use in the management of animal disease., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The research examines the Badger Vaccination Deployment Project, funded by the Department for Environment, Food and Rural Affairs (Defra) and delivered by the Animal and Plant Health Agency (APHA). The authors received funding from Defra and assistance from APHA to conduct the research. The authors have received funding from Defra and APHA for other research related to the management of bovine Tuberculosis. One author (SD) is employed by the APHA., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

In our previous study, ten candidate proteins have been identified with immunogenicity and protection against Vibrio anguillarum in flounder (Paralichthys olivaceus). Among them, FlaC is the important outer protein in the flagellum with immunogenicity; VAA, OmpK and OmpR are protection proteins against V. anguillarum. In this paper, FlaC supplemented with VAA, OmpK or OmpR as bivalent subunit vaccine candidates, and their immune response of flounder and protective effects were evaluated, respectively. Recombinant(r) proteins of FlaC were mixed with rVAA, rOmpK and rOmpR, respectively, rVAA + rFlaC (AF), rOmpK + rFlaC (KF) and rOmpR + rFlaC (RF); formalin-killed cells (FKC) or PBS were injected to flounder, respectively. After immunization, the percentages of CD3 + T lymphocytes and surface membrane immunoglobulin-positive (sIg + ) B lymphocytes in peripheral blood lymphocytes (PBLs), total antibodies (TA), specific antibodies against V. anguillarum (VA), specific antibodies against bivalent recombinant proteins (PA), the expression of immune-related genes and relative percent survivals (RPS) were measured, respectively. The results showed that three bivalent vaccines candidates and FKC could induce the proliferation of sIg + B lymphocytes and CD3 + T lymphocytes in PBLs. The TA, VA and PA induced in bivalent vaccines candidates and FKC groups were significantly higher than that of the control group. CD3, IgM, CD4-1, CD4-2, CD8α and CD8β genes were up-regulated. After challenge with V. anguillarum, RPS in AF, KF, RF and FKC groups exhibited 62.6 ± 2.33%, 78.95 ± 3.01%, 75.45 ± 0.97%, and 56.71 ± 2.15% respectively. The results revealed that three bivalent vaccines candidates and FKC could induce the immune response in flounder, and have good protection against V. anguillarum, and KF can be an efficient bivalent subunit vaccine candidate., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: The number needed to vaccinate (NNV) is a measure that has been widely used in the scientific literature to draw conclusions about the usefulness and cost-effectiveness of various immunization programmes. The main objective of this review is to examine how and why the NNV has been used and reported in the published literature., Methods: Electronic databases were searched and records were screened against the eligibility criteria by two independent authors. We included papers that reported and interpreted NNV., Results: We identified 27 studies, the designs including observational studies, economic analyses, systematic reviews, and commentaries. The NNV has been used in the literature to describe three main themes: potential benefits of vaccination programmes, cost-effectiveness, and economic analyses, and modelling studies to compare different vaccination strategies., Conclusions: NNV has been used in a wide variety of ways in the literature, yet there are no defined thresholds for what is a favourable NNV. Furthermore, the generalizability of the NNV is usually limited. Further work is required to determine the most appropriate use of this measure., (Crown Copyright © 2015. Published by Elsevier Ltd. All rights reserved.)

Helicobacter pylori is an important pathogen of the human stomach, and the development of a protective vaccine has been an enticing goal for many years. The H. pylori antioxidant enzymes superoxide dismutase (SOD) and catalase (KatA) have been shown to be protective as vaccine antigens in mice, demonstrating that the organism's antioxidant enzyme system is a fruitful target for vaccine development. The research described here demonstrates that an additional antioxidant enzyme, thiolperoxidase (Tpx), is effective as a prophylactic vaccine antigen via both systemic and mucosal routes. The functional relationship between SOD, KatA and Tpx also provided an opportunity to investigate synergistic or additive effects when the three antigens were used in combination. Although the antigens still provided equivalent protection when administered in combination, no additional protection was observed. Moreover a decrease in antibody titres to the individual antigens was observed when delivered in combination via the nasal route, though not when injected subcutaneously. The findings of this paper demonstrate that the antioxidant system of H. pylori presents a particularly rich resource for vaccine development., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Reverse vaccinology aims to accelerate subunit vaccine design by rapidly predicting which proteins in a pathogenic bacterial proteome are putative protective antigens. Support vector machine classification is a machine learning approach that has been applied to solve numerous classification problems in biological sciences but has not previously been incorporated into a reverse vaccinology approach. A training data set of 136 bacterial protective antigens paired with 136 non-antigens was constructed and bioinformatic tools were used to annotate this data for predicted protein features, many of which are associated with antigenicity (i.e. extracellular localization, signal peptides and B-cell epitopes). Annotation was used to train support vector machine classifiers that exhibited a maximum accuracy of 92% for discriminating protective antigens from non-antigens as assessed by a leave-tenth-out cross-validation approach. These accuracies were superior to those achieved when annotating training data with auto and cross covariance transformations of z-descriptors for hydrophobicity, molecular size and polarity, or when classification was performed using regression methods. To further validate support vector machine classifiers, they were used to rank all the proteins in six bacterial proteomes for their antigenicity. Protective antigens from the training data were significantly recalled (enriched) in the top 75 ranked proteins for all six proteomes as assessed by a Fisher's exact test (p<0.05). This paper describes a superior workflow for performing reverse vaccinology studies and provides a benchmark training data set that can be used to evaluate future methodological improvements., (Published by Elsevier Ltd.)

The aim of research on infectious diseases is their prevention, and brucellosis and salmonellosis as such are classic examples of worldwide zoonoses for application of a systems biology approach for enhanced rational vaccine development. When used optimally, vaccines prevent disease manifestations, reduce transmission of disease, decrease the need for pharmaceutical intervention, and improve the health and welfare of animals, as well as indirectly protecting against zoonotic diseases of people. Advances in the last decade or so using comprehensive systems biology approaches linking genomics, proteomics, bioinformatics, and biotechnology with immunology, pathogenesis and vaccine formulation and delivery are expected to enable enhanced approaches to vaccine development. The goal of this paper is to evaluate the role of computational systems biology analysis of host:pathogen interactions (the interactome) as a tool for enhanced rational design of vaccines. Systems biology is bringing a new, more robust approach to veterinary vaccine design based upon a deeper understanding of the host-pathogen interactions and its impact on the host's molecular network of the immune system. A computational systems biology method was utilized to create interactome models of the host responses to Brucella melitensis (BMEL), Mycobacterium avium paratuberculosis (MAP), Salmonella enterica Typhimurium (STM), and a Salmonella mutant (isogenic ΔsipA, sopABDE2) and linked to the basis for rational development of vaccines for brucellosis and salmonellosis as reviewed by Adams et al. and Ficht et al. [1,2]. A bovine ligated ileal loop biological model was established to capture the host gene expression response at multiple time points post infection. New methods based on Dynamic Bayesian Network (DBN) machine learning were employed to conduct a comparative pathogenicity analysis of 219 signaling and metabolic pathways and 1620 gene ontology (GO) categories that defined the host's biosignatures to each infectious condition. Through this DBN computational approach, the method identified significantly perturbed pathways and GO category groups of genes that define the pathogenicity signatures of the infectious agent. Our preliminary results provide deeper understanding of the overall complexity of host innate immune response as well as the identification of host gene perturbations that defines a unique host temporal biosignature response to each pathogen. The application of advanced computational methods for developing interactome models based on DBNs has proven to be instrumental in elucidating novel host responses and improved functional biological insight into the host defensive mechanisms. Evaluating the unique differences in pathway and GO perturbations across pathogen conditions allowed the identification of plausible host-pathogen interaction mechanisms. Accordingly, a systems biology approach to study molecular pathway gene expression profiles of host cellular responses to microbial pathogens holds great promise as a methodology to identify, model and predict the overall dynamics of the host-pathogen interactome. Thus, we propose that such an approach has immediate application to the rational design of brucellosis and salmonellosis vaccines., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

A recombinant form of the outer membrane protein (A-layer protein) associated with atypical Aeromonas salmonicida was expressed, fused to a cellulose binding domain (CBD) isolated from Clostridium cellulovorans. The resultant chimerical protein was bound to either Sigmacell 20((R)) or Orbicell cellulose particles. Common goldfish were injected intraperitoneally with the cellulose-protein complex and blood serum antibody levels produced against A-protein were examined weekly by means of ELISA. These titers were compared to those induced by immunization of goldfish with the same protein, with or without Freund's incomplete adjuvant, as well as to a standard bacterin-adjuvant system. Small Orbicell beads (1-10 microM) induced antibody levels that were equal to the titers produced by the adjuvanted protein and bacterin formulae. In comparison, the larger Sigmacell particles (10-20 microM) proved to be poor immunopotentiators. The long-term titer elicited from a single injection of A-protein bound to Orbicell beads was equivalent to that induced by two injections. All the vaccinated fish demonstrated memory to the A-layer protein after exposure to a pathogenic load of atypical A. salmonicida with Orbicell treated fish displaying the highest titer. No direct correlation was found between the presence of anti-A-protein antibodies and protection against infection. The paper describes a simple and safe method to increase the potential immunogenicity of soluble recombinant proteins by employing relatively inexpensive cellulose particles.

In this paper, we describe for the first time the use of a fully recombinant sub-unit vaccine for plague. We have compared the protection afforded by the recombinant vaccine against Yersinia pestis in male and female mice of four inbred strains. We also determined the in vivo cellular memory and antibody response after one year. The recombinant vaccine was capable of inducing protective immunity, against subcutaneous and aerosol challenge, in mice from all four strains. Although, there was some breakthrough in the CBA males challenged with 10(7) median lethal dose (MLDs) the other mice regardless of sex or strain were well protected even at this extreme challenge dose. In both male and female mice, the specific IgG titres to both antigens peaked at day 28 and 35 and in female mice these titres were maintained for >1 year.

We recently described the use of ion exchange chromatography for analysis and the industrial scale preparation of pools of oligosaccharides of intermediate chain length from polysaccharides of Haemophilus influenzae type b (Hib) and Neisseria meningitidis groups A and C. These negatively charged "sized" oligosaccharides are activated and conjugated to the carrier protein (CRM197) to prepare the corresponding glycoconjugate vaccines. Characterization and accurate determination of the degree of polymerization (DP) of the pool of oligosaccharides is essential for the consistent production of these conjugate vaccines. This paper describes the colorimetric assays used for determination of the average DP of the Hib and meningococcal oligosaccharides, and the qualification of these assays achieved by size characterization of the respective oligosaccharides by use of physicochemical methods, including liquid chromatography, mass spectrometry (ionspray) and NMR spectroscopy.

The pneumococcus remains a major cause of morbidity and mortality in both underdeveloped and developed countries. Although there are licensed, safe vaccines against invasive pneumococcal disease currently available in the US and Europe, several major dilemmas are apparent. First, the efficacy of these vaccines in high risk immunocompetent adults is only moderate, with limited or no immunogenicity in very high risk, immunocompromised adults. Secondly, efficacy of the vaccine against pneumococcal pneumonia in adults is controversial. Thirdly, the current vaccines are not efficacious in children < 2 years of age, which is problematic given the high rate of invasive disease among this age group. The solution to these dilemmas may lie in the development of protein conjugate-polysaccharide vaccines. This paper briefly reviews the role of conjugate pneumococcal vaccines.

Background Evaluations of oral cholera vaccines (OCVs) have demonstrated their effectiveness in diverse settings. However, low vaccine uptake in some settings reduces the opportunity for prevention. This paper identifies the socioeconomic factors associated with vaccine uptake in a mass vaccination program. Methods This was a three-arm (vaccine, vaccine plus behavioral change, and non-intervention) cluster randomized trial conducted in Dhaka, Bangladesh. Socio-demographic and vaccination data were collected from 268,896 participants. A geographical information system (GIS) was used to design and implement the vaccination program. A logistic regression model was used to assess the association between vaccine uptake and socioeconomic characteristics. Results The GIS supported the implementation of the vaccination program by identifying ideal locations of vaccination centres for equitable population access, defining catchment areas of daily activities, and providing daily coverage maps during the campaign. Among 188,206 individuals in the intervention arms, 123,686 (66%) received two complete doses, and 64,520 (34%) received one or no doses of the OCV. The vaccine uptake rate was higher in females than males (aOR: 1.80; 95% CI = 1.75–1.84) and in younger (<15 years) than older participants (aOR: 2.19; 95% CI = 2.13–3.26). Individuals living in their own house or having a higher monthly family expenditure were more likely to receive the OCV (aOR: 1.60; 95% CI = 1.50–1.70 and aOR: 1.14; 95% CI = 1.10–1.18 respectively). Individuals using treated water for drinking or using own tap as the source of water were more likely to receive the OCV (aOR: 1.23; 95% CI = 1.17–1.29 and aOR: 1.14; 95% CI = 1.02–1.25 respectively) than their counterpart. Vaccine uptake was also significantly higher in participants residing farther away from health facilities (aOR: 95% 1.80; CI = 1.36–2.37). Conclusion The GIS was useful in designing field activities, facilitating vaccine delivery and identifying socioeconomic drivers of vaccine uptake in the urban area of Bangladesh. Addressing these socioeconomic drivers may help improve OCV uptake, thereby effectiveness of the OCV in a community. [ABSTRACT FROM AUTHOR]

Haemophilus parasuis ( H. parasuis ) is the etiological agent of swine Glässer’s disease, which leads to significant economic loss in swine industry over the world. Subunit vaccine based on outer membrane protein is one of the promising choices to protect pigs against H. parasuis infection despite low immunity efficiency. In this paper, outer membrane protein 16 (Omp16) of H. parasuis encapsulated by alginate-chitosan microspheres as antigen carriers was explored for the first time in a mouse model. Our results showed that the microspheres with Omp16 induced significant higher H. parasuis -specific antibodies, and higher titers of IL-2, IL-4, and IFN-γ than those by Omp16-FIA in treated mice ( p < 0.05). Moreover, H. parasuis load in the tissues from liver, spleen, and lung of mice immunized with microspheres containing Omp16 was significantly decreased ( p < 0.05) than that in the same counterpart tissues of control groups. In addition, 80% mice treated with Omp16 and 70% mice with Omp16-FIA were survived after challenged with H. parasuis virulent strain LY02 (serovar 5). Therefore, Omp16-based microsphere vaccine induces both humoral and cellular immune responses and provides promising protection against H. parasuis infection in mice. [ABSTRACT FROM AUTHOR]

Background A vaccine against serogroup B Neisseria meningitidis , major cause of bacterial meningitis in children and adults, has recently been developed. In a context of an increasing parental mistrust against vaccinations, understanding the reason for their choices is crucial in order to improve immunization coverage. Our study aimed at evaluating parental attitudes and perceptions towards serogroup B meningococcal invasive disease vaccination. Methods A prospective observational study was conducted in different French independent-practice medical offices (general practitioners and paediatricians) and nurseries between May 1 and December 31, 2013, using a questionnaire distributed in electronic and paper forms to parents having at least one child between the ages of 2 months and 16 years old. Results 1270 parents were included, of whom 671 (52.8%) spontaneously stated to be in favour of this vaccination. Their choice was mainly justified by the severity of the disease (63.8%) and the desire to protect their child (51.7%). In multivariate analysis, the young age of parents (OR 0.949 per additional year; p < 10 −3 ), the history of vaccination against serogroup C meningococcal invasive diseases (OR 6.755; p < 10 −3 ), and the prior knowledge of the vaccine (OR 2.081; p = 0.001) were associated with vaccination acceptance. The main reasons for refusal were the lack of hindsight on this new vaccine (50.6%) and the fear of side effects (45.5%). After objective information on the disease and the vaccine, only 6.3% of the entire responding population would refuse to consider vaccination. Conclusions The spontaneous acceptance rate of vaccination against serogroup B meningococcal invasive disease is insufficient. However, after objective information by their physician or public health authorities, only a few parents would in the end be completely resistant. [ABSTRACT FROM AUTHOR]

The incidence of Haemophilus Influenzae type b (Hib) disease in developed countries has decreased since the introduction of Hib conjugate vaccines in their National Immunization Programs (NIP). In countries where Hib vaccination is not applied routinely, due to limited availability and high cost of the vaccines, invasive Hib disease is still a cause of mortality. Through the development of a production process for a Hib conjugate vaccine and related quality control tests and the transfer of this technology to emerging vaccine manufacturers in developing countries, a substantial contribution was made to the availability and affordability of Hib conjugate vaccines in these countries. Technology transfer is considered to be one of the fastest ways to get access to the technology needed for the production of vaccines. The first Hib conjugate vaccine based on the transferred technology was licensed in 2007, since then more Hib vaccines based on this technology were licensed. This paper describes the successful development and transfer of Hib conjugate vaccine technology to vaccine manufacturers in India, China and Indonesia. By describing the lessons learned in this process, it is hoped that other technology transfer projects can benefit from the knowledge and experience gained. [ABSTRACT FROM AUTHOR]

Abstract: This paper seeks to give some preliminary evidence on the potential outcome of the pneumococcal vaccine Advance Market Commitment (AMC), with a focus on its impact on innovation in ‘emerging’ vaccine manufacturers in developing countries. The evidence is derived from a series of interviews with executives at industrial vaccine developing organizations with pneumococcal vaccines in their R&D portfolio, including both multinational pharmaceutical companies and ‘emerging’ manufacturers. The main findings are that so far there is no evidence to support any claim that the AMC is speeding innovation of pneumococcal vaccines, or that it is contributing to productive capacity expansion. Representatives of emerging manufacturers consistently state that the AMC is either irrelevant or inappropriate for supporting their innovative activities on pneumococcal vaccines. [Copyright &y& Elsevier]

Abstract: We reanalyzed data from a phase III trial for the killed oral cholera vaccine to test two hypotheses: there will be a greater impact of the vaccine in areas where there is a low force of infection, and the spatial pattern of disease transmission will change after a mass vaccination campaign. Spatial regression was used to test these hypotheses accounting for spatial heterogeneity in disease and vaccine coverage. The results of the analyses confirm both hypotheses. The paper also shows how spatial analysis can be used to understand the impact of vaccination when there are spatially heterogeneous disease distributions. [Copyright &y& Elsevier]

Abstract: Epidemic meningococcal meningitis is a priority disease for prevention and control in Africa. The current World Health Organization (WHO) approach to the control of meningitis epidemics is based on early detection of cases and emergency vaccination of the population at risk with meningococcal polysaccharide (PS) vaccines. But this is a tall order for the developing nations of Africa where experts operate from an ineffective health system. Although the widespread use of meningococal polysaccharide vaccines has had a major and much appreciated public health impact on the disease it has not prevented epidemics of this dreaded infection. The current partnership between WHO and the PATH aims to develop, evaluate and introduce an appropriate and affordable meningococcal conjugate vaccine that could potentially provide for a means of preventing epidemic meningitis caused by N. meningitidis group A. In this paper, we review the prospects and challenges facing the introduction of the mono-valent conjugate vaccine in Africa. [Copyright &y& Elsevier]

Abstract: Conjugate vaccines exist that offer protection against disease caused by Haemophilus influenzae type b (Hib), and selected serogroups/serotypes of Neisseria meningitidis and Streptococcus pneumoniae. These vaccines are not only able to prevent serious disease, but they also provide protection against asymptomatic carriage. The resulting herd immunity effects have been striking, and have played an important role in the public health success of conjugate vaccination programmes. The aim of this paper is to review the state of the current evidence on conjugate vaccines and to identify important areas for further study, in order to inform the debate regarding the best use of these vaccines. [Copyright &y& Elsevier]

Abstract: Killed whole cell vaccines for plague were first produced as long ago as the late 1890s and modified versions of these are still used, with evidence that they are efficacious against bubonic plague. Renewed efforts with modern technology have yielded new candidate vaccines which are less reactogenic, can be produced in a conventional pharmaceutical manufacturing plant and are protective against the life-threatening pneumonic form of the disease. This paper reviews the progress towards an improved vaccine for plague and assesses the likely impact of a prophylactic vaccine for bubonic and pneumonic plague. [Copyright &y& Elsevier]

Abstract: Meningococcal C conjugate vaccine was introduced in the UK in November 1999 together with a comprehensive meningococcal surveillance strategy to support and inform the vaccine programme. These surveillance data have provided important information on the long-term effectiveness of the programme, through direct and indirect protection, and on the prevalent serotypes and serosubtypes causing invasive meningococcal infection subsequent to vaccine introduction. The MCC immunization programme has been extremely successful in controlling serogroup C disease and continues to be evaluated. The aim of this paper is to review the experiences in England and Wales over the past 9 years. [Copyright &y& Elsevier]