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Vaccines, Volume 7, Issue 1 (March 2019)

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Cover Story (view full-size image) African swine fever virus (ASFV) causes high morbidity and mortality in swine and its recent spread [...] Read more.
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Open AccessArticle Safety and Immunogenicity of the Heterosubtypic Influenza A Vaccine MVA-NP+M1 Manufactured on the AGE1.CR.pIX Avian Cell Line
Vaccines 2019, 7(1), 33; https://doi.org/10.3390/vaccines7010033 (registering DOI)
Received: 22 January 2019 / Revised: 27 February 2019 / Accepted: 5 March 2019 / Published: 22 March 2019
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Abstract
Seasonal influenza infections have a significant global impact leading to increased health and economic burden. The efficacy of currently available seasonal influenza vaccines targeting polymorphic surface antigens has historically been suboptimal. Cellular immune responses against highly conserved Influenza A virus antigens, such as [...] Read more.
Seasonal influenza infections have a significant global impact leading to increased health and economic burden. The efficacy of currently available seasonal influenza vaccines targeting polymorphic surface antigens has historically been suboptimal. Cellular immune responses against highly conserved Influenza A virus antigens, such as nucleoprotein (NP) and matrix protein-1 (M1), have previously been shown to be associated with protection from disease, whilst viral-vectored vaccines are an effective strategy to boost cell-mediated immunity. We have previously demonstrated that MVA encoding NP and M1 can induce potent and persistent T cell responses against influenza. In this Phase I study, we evaluated the safety and immunogenicity of MVA-NP+M1, which was newly manufactured on an immortalized cell line, in six healthy adult participants. The vaccine was well-tolerated with only mild to moderate adverse events that resolved spontaneously and were comparable to previous studies with the same vaccine manufactured in chick embryo fibroblasts. A significant increase in vaccine-specific T cell responses was detected seven days after immunization and was directed against both antigens in the vector insert. This small Phase I study supports progression of this vaccine to a Phase IIb study to assess immunogenicity and additional protective efficacy in older adults receiving licensed seasonal influenza vaccines. Full article
Open AccessReply Reply to “Comment on Effectiveness of a Group B Outer Membrane Vesicle Meningococcal Vaccine in Preventing Hospitalization from Gonorrhea in New Zealand: A Retrospective Cohort Study, Vaccines, 2019, 1, 5; doi:10.3390/vaccines7010005”
Received: 7 March 2019 / Accepted: 13 March 2019 / Published: 15 March 2019
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Abstract
Kenyon (2019) is correct to suggest that there is limited evidence of longer term effectiveness.[...] Full article
Open AccessComment Comment on “Effectiveness of a Group B outer membrane vesicle meningococcal vaccine in preventing hospitalization from gonorrhea in New Zealand: a retrospective cohort study, Vaccines, 2019, 1, 5; doi:10.3390/vaccines7010005”
Received: 18 February 2019 / Accepted: 13 March 2019 / Published: 14 March 2019
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Abstract
Available evidence suggests MeNZB™ is not associated with a durable effect against N. gonorrhoeae. Full article
Open AccessArticle Heterotypic Neuraminidase Antibodies Against Different A(H1N1) Strains are Elicited after Seasonal Influenza Vaccination
Received: 19 December 2018 / Revised: 1 March 2019 / Accepted: 9 March 2019 / Published: 13 March 2019
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Abstract
Neuraminidase (NA) content is not standardized in current seasonal influenza vaccines; neither anti-NA antibodies (anti-NA Abs) are measured nor is it well-defined as a correlate of humoral protection. In this work, the presence of NA1 antibodies against classical A(H1N1) and A(H1N1) pdm09 subtypes [...] Read more.
Neuraminidase (NA) content is not standardized in current seasonal influenza vaccines; neither anti-NA antibodies (anti-NA Abs) are measured nor is it well-defined as a correlate of humoral protection. In this work, the presence of NA1 antibodies against classical A(H1N1) and A(H1N1) pdm09 subtypes was studied before and after vaccination with seasonal vaccines containing A/California/07/2009 strain (A(H1N1) pdm09 subtype). By Enzyme-Linked Lectin Assay (ELLA; Consortium for the Standardization of Influenza Seroepidemiology), we analyzed serum samples from two different cohorts (adults and elderly). The presence of anti-NA Abs at titers ≥1/40 against classical A(H1N1) and A(H1N1) pdm09 subtypes were frequently found in both age groups, in 81.3% and 96.3% of adults and elderly, respectively. The higher titers of anti-NA Abs (NAI titers) were detected more frequently against classical A(H1N1) strains according to the expected age when the first flu infection takes place. In this way, an Original Antigenic Sin phenomenon related to NA seems to be part of the immune response against flu. Seasonal-vaccination induced homologous seroconversion against NA of A(H1N1) pdm09 subtype in 52.5% and 55.0%, and increased the Geometric Mean Titers (GMTs) in 70.0% and 78.8% of adults and elderly, respectively. Seasonal vaccination also induced a heterotypic anti-NA Abs response against classical A(H1N1) strains (seroconversion at least in 8.8% and 11.3% of adults and elderly, respectively, and an increase in GMTs of at least 28.0% in both age groups). These anti-NA Abs responses occur even though the seasonal vaccine does not contain a standardized amount of NA. This work demonstrates that seasonal vaccines containing the A(H1N1) pdm09 subtype induce a broad antibody response against NA1, that may be a target for future influenza vaccines. Our study is one of the first to analyze the presence of Abs against NA and the response mediated by NAI titers after seasonal influenza vaccination. Full article
(This article belongs to the Special Issue Pathogen-Host Interactions: Implications for Vaccine Design)
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Open AccessReview Plasmid DNA-Based Alphavirus Vaccines
Received: 14 February 2019 / Revised: 1 March 2019 / Accepted: 4 March 2019 / Published: 8 March 2019
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Abstract
Alphaviruses have been engineered as vectors for high-level transgene expression. Originally, alphavirus-based vectors were applied as recombinant replication-deficient particles, subjected to expression studies in mammalian and non-mammalian cell lines, primary cell cultures, and in vivo. However, vector engineering has expanded the application range [...] Read more.
Alphaviruses have been engineered as vectors for high-level transgene expression. Originally, alphavirus-based vectors were applied as recombinant replication-deficient particles, subjected to expression studies in mammalian and non-mammalian cell lines, primary cell cultures, and in vivo. However, vector engineering has expanded the application range to plasmid DNA-based delivery and expression. Immunization studies with DNA-based alphavirus vectors have demonstrated tumor regression and protection against challenges with infectious agents and tumor cells in animal tumor models. The presence of the RNA replicon genes responsible for extensive RNA replication in the RNA/DNA layered alphavirus vectors provides superior transgene expression in comparison to conventional plasmid DNA-based expression. Immunization with alphavirus DNA vectors revealed that 1000-fold less DNA was required to elicit similar immune responses compared to conventional plasmid DNA. In addition to DNA-based delivery, immunization with recombinant alphavirus particles and RNA replicons has demonstrated efficacy in providing protection against lethal challenges by infectious agents and tumor cells. Full article
(This article belongs to the Special Issue Advances in DNA Vaccines)
Open AccessArticle Knowledge and Perceptions of Adverse Events Following Immunization among Healthcare Professionals in Africa: A Case Study from Ghana
Received: 19 October 2018 / Revised: 12 November 2018 / Accepted: 17 December 2018 / Published: 8 March 2019
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Abstract
The spontaneous reporting of suspected adverse events following immunization (AEFI) by healthcare professionals (HCPs) is vital in monitoring post-licensure vaccine safety. The main objective of this study was to assess the knowledge and perceptions of AEFIs among healthcare professionals (HCPs) in Africa, using [...] Read more.
The spontaneous reporting of suspected adverse events following immunization (AEFI) by healthcare professionals (HCPs) is vital in monitoring post-licensure vaccine safety. The main objective of this study was to assess the knowledge and perceptions of AEFIs among healthcare professionals (HCPs) in Africa, using the situation in Ghana as a case study. The study was of a cross-sectional quantitative design, and was carried out from 1 July 2017 to 31 December 2017 with doctors, pharmacists, and nurses as the study participants. A 28-item paper-based questionnaire, delivered by hand to study participants, was the data collection tool in the study. The study was conducted in 4 hospitals after ethical approval was granted. The desired sample size was 686; however, 453 consented to partake in the study. Data were analyzed using SPSS (software version 22, IBM, Armonk, NY, USA), and chi-square and binary logistic regression tests were used for tests of association between HCPs’ characteristics and their knowledge and perceptions. Detailed knowledge of AEFIs was ascertained with a set of 9 questions, with 8 or 9 correctly answered questions signifying high knowledge, 5 to 7 correctly answered questions signifying moderate knowledge, and below 5 correctly answered questions signifying low knowledge. A set of 10 questions also ascertained HCPs’ positive and negative perceptions of AEFI. Results revealed that knowledge of AEFIs was high in 49 (10.8%) participants, moderate in 213 (47.0%) participants, and low in 191 (42.2%) participants. There was no statistically significant correlation between AEFI knowledge and professions. The highest negative perception was the lack of desire to learn more about how to diagnose, report, investigate, and manage AEFI, whereas the lowest was the lack of belief that surveillance improves public trust in immunization programs. There was a general awareness of AEFIs among HCPs in this study. However, negative perceptions and the lack of highly knowledgeable HCPs regarding AEFIs were possible setbacks to AEFI diagnosis, management, prevention, and reporting. More training and sensitization of HCPs on AEFIs and vaccine safety will be beneficial in improving the situation. Future research should focus on assessing the training materials and methodology used in informing HCPs about AEFIs and vaccine safety. Full article
Open AccessArticle Simultaneous Administration of Recombinant Measles Viruses Expressing Respiratory Syncytial Virus Fusion (F) and Nucleo (N) Proteins Induced Humoral and Cellular Immune Responses in Cotton Rats
Received: 19 October 2018 / Revised: 24 February 2019 / Accepted: 27 February 2019 / Published: 4 March 2019
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Abstract
We previously reported that recombinant measles virus expressing the respiratory syncytial virus (RSV) fusion protein (F), MVAIK/RSV/F, induced neutralizing antibodies against RSV, and those expressing RSV-NP (MVAIK/RSV/NP) and M2-1 (MVAIK/RSV/M2-1) induced RSV-specific CD8+/IFN-γ+ cells, but not neutralizing antibodies. In the [...] Read more.
We previously reported that recombinant measles virus expressing the respiratory syncytial virus (RSV) fusion protein (F), MVAIK/RSV/F, induced neutralizing antibodies against RSV, and those expressing RSV-NP (MVAIK/RSV/NP) and M2-1 (MVAIK/RSV/M2-1) induced RSV-specific CD8+/IFN-γ+ cells, but not neutralizing antibodies. In the present study, MVAIK/RSV/F and MVAIK/RSV/NP were simultaneously administered to cotton rats and immune responses and protective effects were compared with MVAIK/RSV/F alone. Sufficient neutralizing antibodies against RSV and RSV-specific CD8+/IFN-γ+ cells were observed after re-immunization with simultaneous administration. After the RSV challenge, CD8+/IFN-γ+ increased in spleen cells obtained from the simultaneous immunization group in response to F and NP peptides. Higher numbers of CD8+/IFN-γ+ and CD4+/IFN-γ+ cells were detected in lung tissues from the simultaneous immunization group after the RSV challenge. No detectable RSV was recovered from lung homogenates in the immunized groups. Mild inflammatory reactions with the thickening of broncho-epithelial cells and the infiltration of inflammatory cells were observed in lung tissues obtained from cotton rats immunized with MVAIK/RSV/F alone after the RSV challenge. No inflammatory responses were observed after the RSV challenge in the simultaneous immunization groups. The present results indicate that combined administration with MVAIK/RSV/F and MVAIK/RSV/NP induces humoral and cellular immune responses and shows effective protection against RSV, suggesting the importance of cellular immunity. Full article
(This article belongs to the Special Issue Vaccines for Respiratory Syncytial Virus)
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Open AccessReview Will Attention by Vaccine Developers to the Host’s Nuclear Hormone Levels and Immunocompetence Improve Vaccine Success?
Received: 29 November 2018 / Revised: 16 February 2019 / Accepted: 21 February 2019 / Published: 27 February 2019
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Abstract
Despite extraordinary advances in fields of immunology and infectious diseases, vaccine development remains a challenge. The development of a respiratory syncytial virus vaccine, for example, has spanned more than 50 years of research with studies of more than 100 vaccine candidates. Dozens of [...] Read more.
Despite extraordinary advances in fields of immunology and infectious diseases, vaccine development remains a challenge. The development of a respiratory syncytial virus vaccine, for example, has spanned more than 50 years of research with studies of more than 100 vaccine candidates. Dozens of attractive vaccine products have entered clinical trials, but none have completed the path to licensing. Human immunodeficiency virus vaccine development has proven equally difficult, as there is no licensed product after more than 30 years of pre-clinical and clinical research. Here, we examine vaccine development with attention to the host. We discuss how nuclear hormones, including vitamins and sex hormones, can influence responses to vaccines. We show how nuclear hormones interact with regulatory elements of immunoglobulin gene loci and how the deletion of estrogen response elements from gene enhancers will alter patterns of antibody isotype expression. Based on these findings, and findings that nuclear hormone levels are often insufficient or deficient among individuals in both developed and developing countries, we suggest that failed vaccine studies may in some cases reflect weaknesses of the host rather than the product. We encourage analyses of nuclear hormone levels and immunocompetence among study participants in clinical trials to ensure the success of future vaccine programs. Full article
(This article belongs to the Special Issue Vaccines for Respiratory Syncytial Virus)
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Open AccessEditorial Pneumococcal Vaccines: Challenges and Prospects
Received: 22 February 2019 / Accepted: 25 February 2019 / Published: 27 February 2019
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Abstract
Infections with the bacterium Streptococcus pneumoniae are one of the most common causes of morbidity and mortality in children less than five years of age worldwide, mostly in low- and middle-income countries (LMICs) [...] Full article
(This article belongs to the Special Issue Vaccines for Pneumococcal Infections)
Open AccessArticle Analysis of State-Specific Differences in Childhood Vaccination Coverage in Rural India
Received: 21 December 2018 / Revised: 19 February 2019 / Accepted: 21 February 2019 / Published: 24 February 2019
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Abstract
There is little research on state-level differences in child health outcomes in India. The aim of this study was to identify state-level characteristics that relate to childhood immunizations. Most state-level characteristics came from the 2011 Indian Census. Individual-level data and other state-level characteristics [...] Read more.
There is little research on state-level differences in child health outcomes in India. The aim of this study was to identify state-level characteristics that relate to childhood immunizations. Most state-level characteristics came from the 2011 Indian Census. Individual-level data and other state-level characteristics were obtained from the 2007–2008 District Level Household and Facility Survey. Predictors of full vaccination were assessed with logistic regression models. Among 86,882 children 12–36 months, 53.2% were fully vaccinated. Children living in bigger households (≥7 members), born in non-institutional settings, and female had lower odds of complete vaccination. Individuals living in states in the mid-range of poverty had lower odds of full vaccination compared to those in lower or higher poverty states (3rd vs. 1st quintile: odds ratio [OR]: 0.36, 95% confidence interval [CI]: 0.30, 0.42). Greater average population per primary health center was associated with decreased odds of full vaccination (5th vs. 1st quintile: OR: 0.37, 95% CI: 0.30, 0.47). Vaccination coverage in India can be explained by a complex interplay of individual- and state-level factors. Solutions to increasing vaccination must be multisectoral and acknowledge the cultural and socio-economic diversity that influences an individual child’s vaccination coverage along with within-state disparities. Full article
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Open AccessArticle Epitope-Specific Serological Assays for RSV: Conformation Matters
Received: 16 January 2019 / Revised: 13 February 2019 / Accepted: 22 February 2019 / Published: 23 February 2019
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Abstract
Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in children and older adults. An effective vaccine must elicit neutralizing antibodies targeting the RSV fusion (F) protein, which exists in two major conformations, pre-fusion (pre-F) and post-fusion (post-F). Although 50% of the surface [...] Read more.
Respiratory syncytial virus (RSV) causes substantial morbidity and mortality in children and older adults. An effective vaccine must elicit neutralizing antibodies targeting the RSV fusion (F) protein, which exists in two major conformations, pre-fusion (pre-F) and post-fusion (post-F). Although 50% of the surface is shared, pre-F contains highly neutralization-sensitive antigenic sites not present on post-F. Recent advancement of several subunit F-based vaccine trials has spurred interest in quantifying and understanding the protective potential of antibodies directed to individual antigenic sites. Monoclonal antibody competition ELISAs are being used to measure these endpoints, but the impact of F conformation and competition from antibodies binding to adjacent antigenic sites has not been thoroughly investigated. Since this information is critical for interpreting clinical trial outcomes and defining serological correlates of protection, we optimized assays to evaluate D25-competing antibodies (DCA) to antigenic site Ø on pre-F, and compared readouts of palivizumab-competing antibodies (PCA) to site II on both pre-F and post-F. We show that antibodies to adjacent antigenic sites can contribute to DCA and PCA readouts, and that cross-competition from non-targeted sites is especially confounding when PCA is measured using a post-F substrate. While measuring DCA and PCA levels may be useful to delineate the role of antibodies targeting the apex and side of the F protein, respectively, the assay limitations and caveats should be considered when conducting immune monitoring during vaccine trials and defining correlates of protection. Full article
(This article belongs to the Special Issue Vaccines for Respiratory Syncytial Virus)
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Open AccessReview Role of Type I Interferons on Filovirus Pathogenesis
Received: 17 December 2018 / Revised: 6 February 2019 / Accepted: 15 February 2019 / Published: 20 February 2019
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Abstract
Filoviruses, such as Ebola and Marburg virus, encode viral proteins with the ability to counteract the type I interferon (IFN-I) response. These IFN-I antagonist proteins are crucial to ensure virus replication, prevent an antiviral state in infected and bystander cells, and impair the [...] Read more.
Filoviruses, such as Ebola and Marburg virus, encode viral proteins with the ability to counteract the type I interferon (IFN-I) response. These IFN-I antagonist proteins are crucial to ensure virus replication, prevent an antiviral state in infected and bystander cells, and impair the ability of antigen-presenting cells to initiate adaptive immune responses. However, in recent years, a number of studies have underscored the conflicting data between in vitro studies and in vivo data obtained in animal models and clinical studies during outbreaks. This review aims to summarize these data and to discuss the relative contributions of IFN-α and IFN-β to filovirus pathogenesis in animal models and humans. Finally, we evaluate the putative utilization of IFN-I in post-exposure therapy and its implications as a biomarker of vaccine efficacy. Full article
(This article belongs to the Special Issue Pathogen-Host Interactions: Implications for Vaccine Design)
Open AccessArticle Comparison of Immune Responses to Different Versions of VLP Associated Stabilized RSV Pre-Fusion F Protein
Received: 14 January 2019 / Revised: 7 February 2019 / Accepted: 11 February 2019 / Published: 15 February 2019
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Abstract
Efforts to develop a vaccine for respiratory syncytial virus (RSV) have primarily focused on the RSV fusion protein. The pre-fusion conformation of this protein induces the most potent neutralizing antibodies and is the focus of recent efforts in vaccine development. Following the first [...] Read more.
Efforts to develop a vaccine for respiratory syncytial virus (RSV) have primarily focused on the RSV fusion protein. The pre-fusion conformation of this protein induces the most potent neutralizing antibodies and is the focus of recent efforts in vaccine development. Following the first identification of mutations in the RSV F protein (DS-Cav1 mutant protein) that stabilized the pre-fusion conformation, other mutant stabilized pre-fusion F proteins have been described. To determine if there are differences in alternate versions of stabilized pre-fusion F proteins, we explored the use, as vaccine candidates, of virus-like particles (VLPs) containing five different pre-fusion F proteins, including the DS-Cav1 protein. The expression of these five pre-F proteins, their assembly into VLPs, their pre-fusion conformation stability in VLPs, their reactivity with anti-F monoclonal antibodies, and their induction of immune responses after the immunization of mice, were characterized, comparing VLPs containing the DS-Cav1 pre-F protein with VLPs containing four alternative pre-fusion F proteins. The concentrations of anti-F IgG induced by each VLP that blocked the binding of prototype monoclonal antibodies using two different soluble pre-fusion F proteins as targets were measured. Our results indicate that both the conformation and immunogenicity of alternative VLP associated stabilized pre-fusion RSV F proteins are different from those of DS-Cav1 VLPs. Full article
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Open AccessReview Feasibility Analysis of Interleukin-13 as a Target for a Therapeutic Vaccine
Received: 11 January 2019 / Revised: 4 February 2019 / Accepted: 7 February 2019 / Published: 12 February 2019
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Abstract
Background: The development of therapeutic vaccines requires thorough knowledge of potential hazards associated with long-term inactivation of self-proteins. Among potential targets, interleukin 13 (IL-13) merits consideration, as monoclonal antibodies disrupting IL-13 signaling are proving to be exceedingly effective in common conditions such as [...] Read more.
Background: The development of therapeutic vaccines requires thorough knowledge of potential hazards associated with long-term inactivation of self-proteins. Among potential targets, interleukin 13 (IL-13) merits consideration, as monoclonal antibodies disrupting IL-13 signaling are proving to be exceedingly effective in common conditions such as atopic dermatitis. Objective: Given the mass publication of scientific data, an appraisal of safety aspects is challenging. Methods: We here provide a three-fold approach to survey clinically relevant information on off-target effects, both adverse and beneficial, that may potentially be encountered in patients undergoing long-term IL-13 inactivation. First, we review non-clinical data in vivo and in vitro. Second, we summarize safety data accumulating from patients dosed with anti-IL-13 drugs. Third, we exploit human mutation data as well as emerging large-scale genetic datasets (global exome data from 60,000 patients) to obtain information on any association of IL-13-inactivating genetic variants with disease states. In addition, we: (1) dissect the precise efficacy signals obtained with various drugs targeting IL-13 and/or IL-4, and (2) summarize unintended, but potentially beneficial effects of prolonged IL-13 inactivation on several functional systems. Results: Prolonged repression of IL-13 in several thousand patients so far has not uncovered any non-redundant functions of IL-13 in immune defense. Furthermore, missense mutations in the key genes IL-13, IL-13Rα1, IL-13Rα2, IL-4, IL-4Rα are common, while no case reports have been published on any immune deficiency or increased risk of neoplastic disease associated with such mutations, suggesting that these genes do not harbor non-redundant roles in adult outbred humans. In terms of efficacy, data from clinically used drugs strongly suggest that targeting IL-13 only, as opposed to IL-13 and IL-4, may be effective in eczema while being more selective. Importantly, several lines of evidence suggest that inhibition of IL-13 may in fact harbor potentially beneficial effects on non-targeted systems, including glucose metabolism, hepatic fibrosis, and atherosclerosis, suggesting that respective outcomes should be systematically captured in patients dosed with IL-13 interfering drugs. Collectively, available evidence suggests that IL-13 may fulfill safety requirements required for the target of a therapeutic vaccine. Full article
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Open AccessArticle Differential Response Following Infection of Mouse CNS with Virulent and Attenuated Vaccinia Virus Strains
Received: 15 November 2018 / Revised: 4 February 2019 / Accepted: 7 February 2019 / Published: 12 February 2019
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Abstract
Viral infections of the central nervous system (CNS) lead to a broad range of pathologies. CNS infections with Orthopox viruses have been mainly documented as an adverse reaction to smallpox vaccination with vaccinia virus. To date, there is insufficient data regarding the mechanisms [...] Read more.
Viral infections of the central nervous system (CNS) lead to a broad range of pathologies. CNS infections with Orthopox viruses have been mainly documented as an adverse reaction to smallpox vaccination with vaccinia virus. To date, there is insufficient data regarding the mechanisms underlying pathological viral replication or viral clearance. Therefore, informed risk assessment of vaccine adverse reactions or outcome prediction is limited. This work applied a model of viral infection of the CNS, comparing neurovirulent with attenuated strains. We followed various parameters along the disease and correlated viral load, morbidity, and mortality with tissue integrity, innate and adaptive immune response and functionality of the blood–brain barrier. Combining these data with whole brain RNA-seq analysis performed at different time points indicated that neurovirulence is associated with host immune silencing followed by induction of tissue damage-specific pathways. In contrast, brain infection with attenuated strains resulted in rapid and robust induction of innate and adaptive protective immunity, followed by viral clearance and recovery. This study significantly improves our understanding of the mechanisms and processes determining the consequence of viral CNS infection and highlights potential biomarkers associated with such outcomes. Full article
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Open AccessReview Complementary Role of CD4+ T Cells in Response to Pneumococcal Polysaccharide Vaccines in Humans
Received: 31 December 2018 / Revised: 31 January 2019 / Accepted: 4 February 2019 / Published: 11 February 2019
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Abstract
Bacterial pathogens expressing capsular polysaccharides are common causes of mucosal infections (pneumonia, intestinal), as well as often fatal, invasive infections (meningitis, bloodstream infections) in children and adults worldwide. These chemically simple but structurally complex carbohydrate structures on the bacterial surface confer resistance to [...] Read more.
Bacterial pathogens expressing capsular polysaccharides are common causes of mucosal infections (pneumonia, intestinal), as well as often fatal, invasive infections (meningitis, bloodstream infections) in children and adults worldwide. These chemically simple but structurally complex carbohydrate structures on the bacterial surface confer resistance to recognition and clearance by the immune system through a range of mechanisms. Such recognition of capsular polysaccharides may be reduced by their limited ability to directly stimulate B cells and the T cells that may facilitate these humoral responses. The capsules may promote the evasion of complement deposition and activation and may sterically shield the recognition of other subjacent protein antigens by innate factors. Antibodies to capsular polysaccharides, elicited by infection and vaccines, may overcome these obstacles and facilitate bacterial agglutination at mucosal surfaces, as well as the opsonization and clearance of these organisms in tissues and the systemic compartment. However, the immunogenicity of these antigens may be limited by their lack of direct recognition by T cells (“T-independent” antigens) and their restricted ability to generate effective memory responses. In this review, we consider the mechanisms by which polysaccharides may initiate B cell responses and specific antibody responses and the role of T cells, particularly CD4+ follicular helper (TFH) cells to support this process. In addition, we also consider more recent counterintuitive data that capsular polysaccharides themselves may bind major histocompatibility antigen HLA class II to provide a more physiologic mechanism of T cell enhancement of B cell responses to capsular polysaccharides. Defining the contributions of T cells in the generation of effective humoral responses to the capsular polysaccharides will have important implications for understanding and translating this immunobiology for the development of more effective vaccines, to prevent the morbidity and mortality associated with these common mucosal and invasive pathogens in populations at risk. Full article
(This article belongs to the Special Issue Pathogen-Host Interactions: Implications for Vaccine Design)
Open AccessArticle Immunogenicity and Immune Memory after a Pneumococcal Polysaccharide Vaccine Booster in a High-Risk Population Primed with 10-Valent or 13-Valent Pneumococcal Conjugate Vaccine: A Randomized Controlled Trial in Papua New Guinean Children
Received: 29 November 2018 / Revised: 30 January 2019 / Accepted: 30 January 2019 / Published: 4 February 2019
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Abstract
We investigated the immunogenicity, seroprotection rates and persistence of immune memory in young children at high risk of pneumococcal disease in Papua New Guinea (PNG). Children were primed with 10-valent (PCV10) or 13-valent pneumococcal conjugate vaccines (PCV13) at 1, 2 and 3 months [...] Read more.
We investigated the immunogenicity, seroprotection rates and persistence of immune memory in young children at high risk of pneumococcal disease in Papua New Guinea (PNG). Children were primed with 10-valent (PCV10) or 13-valent pneumococcal conjugate vaccines (PCV13) at 1, 2 and 3 months of age and randomized at 9 months to receive PPV (PCV10/PPV-vaccinated, n = 51; PCV13/PPV-vaccinated, n = 52) or no PPV (PCV10/PPV-naive, n = 57; PCV13/PPV-naive, n = 48). All children received a micro-dose of PPV at 23 months of age to study the capacity to respond to a pneumococcal challenge. PPV vaccination resulted in significantly increased IgG responses (1.4 to 10.5-fold change) at 10 months of age for all PPV-serotypes tested. Both PPV-vaccinated and PPV-naive children responded to the 23-month challenge and post-challenge seroprotection rates (IgG ≥ 0.35 μg/mL) were similar in the two groups (80–100% for 12 of 14 tested vaccine serotypes). These findings show that PPV is immunogenic in 9-month-old children at high risk of pneumococcal infections and does not affect the capacity to produce protective immune responses. Priming with currently available PCVs followed by a PPV booster in later infancy could offer improved protection to young children at high risk of severe pneumococcal infections caused by a broad range of serotypes. Full article
(This article belongs to the Special Issue Vaccines for Pneumococcal Infections)
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Open AccessArticle Development of Luciferase Immunoprecipitation Systems (LIPS) Assay to Detect IgG Antibodies against Human Respiratory Syncytial Virus G-Glycoprotein
Received: 29 November 2018 / Revised: 28 January 2019 / Accepted: 30 January 2019 / Published: 1 February 2019
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Abstract
Respiratory syncytial virus (RSV) causes severe lower respiratory tract disease in infants and the elderly. Although there is no licensed vaccine, RSV-F and -G glycoproteins are targets for vaccine development and therapeutics. We developed an assay that can detect anti-RSV-G IgG antibodies, either [...] Read more.
Respiratory syncytial virus (RSV) causes severe lower respiratory tract disease in infants and the elderly. Although there is no licensed vaccine, RSV-F and -G glycoproteins are targets for vaccine development and therapeutics. We developed an assay that can detect anti-RSV-G IgG antibodies, either as a biomarker of natural exposure or immunization. RSV genes encoding native and mutated G (mG) proteins from subgroups A and B strains were cloned, expressed as luciferase-tagged proteins, and tested individually to detect anti-RSV-G specific IgG antibodies using a high-throughput luciferase immunoprecipitation system (LIPS-G). RSV monoclonal antibodies and polyclonal antisera specifically bound in the LIPS-GA and/or -GB assays; whereas anti-RSV-F and -N, and antisera against measles virus or human metapneumovirus did not bind. Anti-RSV-GA and -GB IgG responses detected in mice infected intranasally with RSV-A or -B strains were subtype specific. Subtype specific anti-RSV-GA or -GB IgG responses were also detected using paired serum samples from infants while human adolescent serum samples reacted in both LIPS-GA and -GB assays, reflecting a broader experience. Full article
(This article belongs to the Special Issue Vaccines for Respiratory Syncytial Virus)
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Open AccessErratum Erratum: Thadi A.; et al. Early Investigations and Recent Advances in Intraperitoneal Immunotherapy for Peritoneal Metastasis. Vaccines 2018, 6, 54
Received: 24 January 2019 / Accepted: 24 January 2019 / Published: 31 January 2019
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Abstract
The authors wish to make the following corrections to this paper [...] Full article
Open AccessArticle PCV7- and PCV10-Vaccinated Otitis-Prone Children in New Zealand Have Similar Pneumococcal and Haemophilus influenzae Densities in Their Nasopharynx and Middle Ear
Received: 29 November 2018 / Revised: 17 January 2019 / Accepted: 29 January 2019 / Published: 31 January 2019
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Abstract
Otitis media (OM) is a major reason for antibiotic consumption and surgery in children. Nasopharyngeal carriage of otopathogens, Streptococcus pneumoniae and nontypeable Haemophilus influenzae (NTHi), is a prerequisite for development of OM, and increased nasopharyngeal otopathogen density correlates with disease onset. Vaccines can [...] Read more.
Otitis media (OM) is a major reason for antibiotic consumption and surgery in children. Nasopharyngeal carriage of otopathogens, Streptococcus pneumoniae and nontypeable Haemophilus influenzae (NTHi), is a prerequisite for development of OM, and increased nasopharyngeal otopathogen density correlates with disease onset. Vaccines can reduce or eliminate otopathogen carriage, as demonstrated for pneumococcal serotypes included in pneumococcal conjugate vaccines (PCV). The 10-valent PCV (PCV10) includes an NTHi carrier protein, and in 2011 superseded 7-valent PCV on the New Zealand Immunisation Program. Data are conflicting on whether PCV10 provides protection against NTHi carriage or disease. Assessing this in otitis-prone cohorts is important for OM prevention. We compared otopathogen density in the nasopharynx and middle ear of New Zealand PCV7-vaccinated and PCV10-vaccinated otitis-prone and non-otitis-prone children to determine PCV10 impact on NTHi and S. pneumoniae carriage. We applied qPCR to specimens collected from 217 PCV7-vaccinated children (147 otitis-prone and 70 non-otitis-prone) and 240 PCV10-vaccinated children (178 otitis-prone and 62 non-otitis-prone). After correcting for age and day-care attendance, no difference was observed between NTHi density in the nasopharynx of PCV7-vaccinated versus PCV10-vaccinated otitis-prone (p = 0.563) or non-otitis-prone (p = 0.513) children. In contrast, pneumococcal nasopharyngeal density was higher in PCV10-vaccinated otitis-prone children than PCV7-vaccinated otitis-prone children (p = 0.003). There was no difference in otopathogen density in middle ear effusion from PCV7-vaccinated versus PCV10-vaccinated otitis-prone children (NTHi p = 0.918; S. pneumoniae p = 0.415). When pneumococcal carriage was assessed by vaccine serotypes (VT) and non-vaccine serotypes (NVT), there was no difference in VT density (p = 0.546) or NVT density (p = 0.315) between all PCV7-vaccinated versus all PCV10-vaccinated children. In summary, PCV10 did not reduce NTHi density in the nasopharynx or middle ear, and was associated with increased pneumococcal nasopharyngeal density in otitis-prone children in New Zealand. Development of therapies that prevent or reduce otopathogen colonisation density in the nasopharynx are warranted to reduce the burden of OM. Full article
(This article belongs to the Special Issue Vaccines for Pneumococcal Infections)
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Open AccessReview The Role of Serotype-Specific Immunological Memory in Pneumococcal Vaccination: Current Knowledge and Future Prospects
Received: 30 November 2018 / Revised: 30 December 2018 / Accepted: 28 January 2019 / Published: 29 January 2019
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Abstract
Streptococcus pneumoniae (S. pneumoniae, pneumococcus) is a major cause of morbidity and mortality worldwide. Achieving long-term immunity against S. pneumoniae through immunization is an important public health priority. Long-term protection after immunization is thought to rely both on protective serum antibody [...] Read more.
Streptococcus pneumoniae (S. pneumoniae, pneumococcus) is a major cause of morbidity and mortality worldwide. Achieving long-term immunity against S. pneumoniae through immunization is an important public health priority. Long-term protection after immunization is thought to rely both on protective serum antibody levels and immunological memory in the form of antigen-specific memory B cells (MBCs). Although the ability to achieve protective antibody levels shortly after pneumococcal vaccination has been well documented for the various infant immunization schedules currently in use worldwide, the examination of immunological memory in the form of antigen-specific MBCs has been much more limited. Such responses are critical for long-term protection against pneumococcal colonization and disease. This review summarizes the published literature on the MBC response to primary or booster immunization with either pneumococcal polysaccharide vaccine (PPV23) or pneumococcal conjugate vaccines (PCVs), aiming to elucidate the immunological mechanisms that determine the magnitude and longevity of vaccine protection against pneumococcus. There is evidence that PCVs induce the production of antigen-specific MBCs, whereas immunization with PPV23 does not result in the formation of MBCs. Increased understanding of the immunological factors that facilitate the induction, maintenance and recall of MBCs in response to pneumococcal vaccination could enable the use of MBC enumeration as novel correlates of protection against S. pneumoniae. Ongoing studies that examine MBC response to pneumococcal vaccination in high burden settings will be extremely important in our understanding of long-term protection induced by pneumococcal conjugate vaccines. Full article
(This article belongs to the Special Issue Vaccines for Pneumococcal Infections)
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Open AccessArticle DNA-Protein Vaccination Strategy Does Not Protect from Challenge with African Swine Fever Virus Armenia 2007 Strain
Received: 22 October 2018 / Revised: 14 January 2019 / Accepted: 23 January 2019 / Published: 28 January 2019
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Abstract
African swine fever virus (ASFV) causes high morbidity and mortality in swine (Sus scrofa), for which there is no commercially available vaccine. Recent outbreaks of the virus in Trans-Caucasus countries, Eastern Europe, Belgium and China highlight the urgent need to develop [...] Read more.
African swine fever virus (ASFV) causes high morbidity and mortality in swine (Sus scrofa), for which there is no commercially available vaccine. Recent outbreaks of the virus in Trans-Caucasus countries, Eastern Europe, Belgium and China highlight the urgent need to develop effective vaccines against ASFV. Previously, we evaluated the immunogenicity of a vaccination strategy designed to test various combinations of ASFV antigens encoded by DNA plasmids and recombinant proteins with the aim to activate both humoral and cellular immunity. Based on our previous results, the objective of this study was to test the combined DNA-protein vaccine strategy using a cocktail of the most immunogenic antigens against virulent ASFV challenge. Pigs were vaccinated three times with a cocktail that included ASFV plasmid DNA (CD2v, p72, p32, +/−p17) and recombinant proteins (p15, p35, p54, +/−p17). Three weeks after the third immunization, all pigs were challenged with the virulent ASFV Armenia 2007 strain. The results showed that vaccinated pigs were not protected from ASFV infection or disease. Compared to the non-vaccinated controls, earlier onset of clinical signs, viremia, and death were observed for the vaccinated animals following virulent ASFV challenge. ASFV induced pathology was also enhanced in the vaccinated pigs. Furthermore, while the vaccinated pigs developed antigen-specific antibodies, immunized pig sera at the time of challenge lacked the capacity to neutralize virus, and instead was observed to enhance ASFV infection in vitro. The results of this work points to a putative immune enhancement mechanism involved in ASFV pathogenesis that warrants further investigation. This pilot study provides insight for the selection of appropriate combinations of ASFV antigens for the development of a rationally-designed, safe, and efficacious vaccine for ASF. Full article
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Open AccessReview T-Cell Response to Viral Hemorrhagic Fevers
Received: 18 December 2018 / Revised: 15 January 2019 / Accepted: 19 January 2019 / Published: 22 January 2019
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Abstract
Viral hemorrhagic fevers (VHF) are a group of clinically similar diseases that can be caused by enveloped RNA viruses primarily from the families Arenaviridae, Filoviridae, Hantaviridae, and Flaviviridae. Clinically, this group of diseases has in common fever, fatigue, dizziness, [...] Read more.
Viral hemorrhagic fevers (VHF) are a group of clinically similar diseases that can be caused by enveloped RNA viruses primarily from the families Arenaviridae, Filoviridae, Hantaviridae, and Flaviviridae. Clinically, this group of diseases has in common fever, fatigue, dizziness, muscle aches, and other associated symptoms that can progress to vascular leakage, bleeding and multi-organ failure. Most of these viruses are zoonotic causing asymptomatic infections in the primary host, but in human beings, the infection can be lethal. Clinical and experimental evidence suggest that the T-cell response is needed for protection against VHF, but can also cause damage to the host, and play an important role in disease pathogenesis. Here, we present a review of the T-cell immune responses to VHF and insights into the possible ways to improve counter-measures for these viral agents. Full article
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Open AccessReview Time to Micromanage the Pathogen-Host-Vector Interface: Considerations for Vaccine Development
Received: 31 October 2018 / Revised: 10 January 2019 / Accepted: 16 January 2019 / Published: 21 January 2019
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Abstract
The current increase in vector-borne disease worldwide necessitates novel approaches to vaccine development targeted to pathogens delivered by blood-feeding arthropod vectors into the host skin. A concept that is gaining traction in recent years is the contribution of the vector or vector-derived components, [...] Read more.
The current increase in vector-borne disease worldwide necessitates novel approaches to vaccine development targeted to pathogens delivered by blood-feeding arthropod vectors into the host skin. A concept that is gaining traction in recent years is the contribution of the vector or vector-derived components, like salivary proteins, to host-pathogen interactions. Indeed, the triad of vector-host-pathogen interactions in the skin microenvironment can influence host innate and adaptive responses alike, providing an advantage to the pathogen to establish infection. A better understanding of this “bite site” microenvironment, along with how host and vector local microbiomes immunomodulate responses to pathogens, is required for future vaccines for vector-borne diseases. Microneedle administration of such vaccines may more closely mimic vector deposition of pathogen and saliva into the skin with the added benefit of near painless vaccine delivery. Focusing on the ‘micro’–from microenvironments to microbiomes to microneedles–may yield an improved generation of vector-borne disease vaccines in today’s increasingly complex world. Full article
(This article belongs to the Special Issue Pathogen-Host Interactions: Implications for Vaccine Design)
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Open AccessReview Novel Protein-Based Pneumococcal Vaccines: Assessing the Use of Distinct Protein Fragments Instead of Full-Length Proteins as Vaccine Antigens
Received: 30 November 2018 / Revised: 15 January 2019 / Accepted: 16 January 2019 / Published: 19 January 2019
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Abstract
Non-serotype-specific protein-based pneumococcal vaccines have received extensive research focus due to the limitations of polysaccharide-based vaccines. Pneumococcal proteins (PnPs), universally expressed among serotypes, may induce broader immune responses, stimulating humoral and cellular immunity, while being easier to manufacture and less expensive. Such an [...] Read more.
Non-serotype-specific protein-based pneumococcal vaccines have received extensive research focus due to the limitations of polysaccharide-based vaccines. Pneumococcal proteins (PnPs), universally expressed among serotypes, may induce broader immune responses, stimulating humoral and cellular immunity, while being easier to manufacture and less expensive. Such an approach has raised issues mainly associated with sequence/level of expression variability, chemical instability, as well as possible undesirable reactogenicity and autoimmune properties. A step forward employs the identification of highly-conserved antigenic regions within PnPs with the potential to retain the benefits of protein antigens. Besides, their low-cost and stable construction facilitates the combination of several antigenic regions or peptides that may impair different stages of pneumococcal disease offering even wider serotype coverage and more efficient protection. This review discusses the up-to-date progress on PnPs that are currently under clinical evaluation and the challenges for their licensure. Focus is given on the progress on the identification of antigenic regions/peptides within PnPs and their evaluation as vaccine candidates, accessing their potential to overcome the issues associated with full-length protein antigens. Particular mention is given of the use of newer delivery system technologies including conjugation to Toll-like receptors (TLRs) and reformulation into nanoparticles to enhance the poor immunogenicity of such antigens. Full article
(This article belongs to the Special Issue Vaccines for Pneumococcal Infections)
Open AccessCommunication Measles at Work: Status of Measles Vaccination at a Multinational Company
Received: 16 November 2018 / Revised: 15 January 2019 / Accepted: 15 January 2019 / Published: 16 January 2019
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Abstract
Background: This study aims to evaluate the status of measles vaccination among employees working for a multinational company. It also assesses the effectiveness of an on-site prevention campaign. In keeping with the guidelines of the World Health Organization regarding measles awareness, the Federal [...] Read more.
Background: This study aims to evaluate the status of measles vaccination among employees working for a multinational company. It also assesses the effectiveness of an on-site prevention campaign. In keeping with the guidelines of the World Health Organization regarding measles awareness, the Federal Office of Public Health in Switzerland aims to eliminate measles by 2020. Methods: A questionnaire about measles vaccination was sent by e-mail and via a fluid survey. Logistic regression models examined the associations between explicative variables and the status of complete measles immunization. The status of complete measles immunization was used as the primary outcome. Results: 17% of the participants were not aware of their measles immunization status, 14% had had only one dose of the vaccination, and only 24% had two doses. Male employees had a lower probability of being vaccinated against measles than women [aOR = 0.62; 95% CI: 0.43–0.86]. Employees of Swiss and African origin had a higher probability of being vaccinated than employees of European origin (aOR = 1.94; 95% CI: 1.13–3.33). Conclusions: Based on the results of the questionnaire, further efforts are needed to promote measles vaccination through awareness campaigns so that employees become more aware of the importance of measles immunization. Full article
Open AccessReview Utility of the Neonatal Calf Model for Testing Vaccines and Intervention Strategies for Use against Human RSV Infection
Received: 29 November 2018 / Revised: 26 December 2018 / Accepted: 4 January 2019 / Published: 8 January 2019
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Abstract
Respiratory syncytial virus (RSV) is a significant cause of pediatric respiratory tract infections. It is estimated that two-thirds of infants are infected with RSV during the first year of life and it is one of the leading causes of death in this age [...] Read more.
Respiratory syncytial virus (RSV) is a significant cause of pediatric respiratory tract infections. It is estimated that two-thirds of infants are infected with RSV during the first year of life and it is one of the leading causes of death in this age group worldwide. Similarly, bovine RSV is a primary viral pathogen in cases of pneumonia in young calves and plays a significant role in bovine respiratory disease complex. Importantly, naturally occurring infection of calves with bovine RSV shares many features in common with human RSV infection. Herein, we update our current understanding of RSV infection in cattle, with particular focus on similarities between the calf and human infection, and the recent reports in which the neonatal calf has been employed for the development and testing of vaccines and therapeutics which may be applied to hRSV infection in humans. Full article
(This article belongs to the Special Issue Vaccines for Respiratory Syncytial Virus)
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Open AccessEditorial Acknowledgement to Reviewers of Vaccines in 2018
Received: 8 January 2019 / Accepted: 8 January 2019 / Published: 8 January 2019
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Abstract
Rigorous peer-review is the corner-stone of high-quality academic publishing. [...] Full article
Open AccessArticle Effectiveness of a Group B Outer Membrane Vesicle Meningococcal Vaccine in Preventing Hospitalization from Gonorrhea in New Zealand: A Retrospective Cohort Study
Received: 28 June 2018 / Revised: 19 December 2018 / Accepted: 24 December 2018 / Published: 5 January 2019
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Abstract
Gonorrhea is a major global public health problem with emergence of multiple drug-resistant strains with no effective vaccine. This retrospective cohort study aimed to estimate the effectiveness of the New Zealand meningococcal B vaccine against gonorrhea-associated hospitalization. The cohort consisted of individuals born [...] Read more.
Gonorrhea is a major global public health problem with emergence of multiple drug-resistant strains with no effective vaccine. This retrospective cohort study aimed to estimate the effectiveness of the New Zealand meningococcal B vaccine against gonorrhea-associated hospitalization. The cohort consisted of individuals born from 1984 to 1999 residing in New Zealand. Therefore, it was eligible for meningococcal B vaccination from 2004 to 2008. Administrative datasets of demographics, customs, hospitalization, education, income tax, and immunization were linked using the national Integrated Data Infrastructure. The primary outcome was hospitalization with a primary diagnosis of gonorrhea. Cox’s proportional hazards models were applied with a Firth correction for rare outcomes to generate estimates of hazard ratios. Vaccine effectiveness estimates were calculated as 1-Hazard Ratio expressed as a percentage. There were 1,143,897 eligible cohort members with 135 missing information on gender, 16,245 missing ethnicity, and 197,502 missing deprivation. Therefore, only 935,496 cohort members were included in the analysis. After adjustment for gender, ethnicity, and deprivation, vaccine effectiveness (MeNZB™) against hospitalization caused by gonorrhea was estimated to be 24% (95% CI 1–42%). In conclusion, the data suggests vaccination with MeNZB™ significantly reduced the rate of hospitalization from gonorrhea. This supports prior research indicating possible cross protection of this vaccine against gonorrhea acquisition and disease in the outpatient setting. Full article
Open AccessCommunication Should Pneumococcal Serotype 3 Be Included in Serotype-Specific Immunoassays?
Received: 31 October 2018 / Revised: 21 December 2018 / Accepted: 2 January 2019 / Published: 3 January 2019
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Abstract
Since the introduction of the 13-valent pneumococcal conjugate vaccine, a number of studies have demonstrated the limited efficacy of the pneumococcal serotype 3 component of this vaccine. Evidence from seven countries (Denmark, France, Greece, Portugal, Sweden, UK, US) shows limited or no effectiveness [...] Read more.
Since the introduction of the 13-valent pneumococcal conjugate vaccine, a number of studies have demonstrated the limited efficacy of the pneumococcal serotype 3 component of this vaccine. Evidence from seven countries (Denmark, France, Greece, Portugal, Sweden, UK, US) shows limited or no effectiveness of the 13-valent pneumococcal conjugate vaccine against serotype 3 invasive pneumococcal disease and carriage. The serotype 3 capsule has some unique characteristics that may serve to explain this lack of efficacy—capsular polysaccharide is abundantly expressed, leading to a greater thickness of capsule, and free capsular polysaccharide may be released during growth. The serotype 3 component of the Luminex multiplex assay demonstrates inferior inter-laboratory reproducibility than other components and results may not be reliable. This communication outlines this evidence and discusses whether it is necessary to include serotype 3 in the assay in the future. Full article
(This article belongs to the Special Issue Vaccines for Pneumococcal Infections)
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