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Vaccines, Volume 9, Issue 12 (December 2021) – 137 articles

Cover Story (view full-size image): The scarcity of alternative therapeutics against viral infections as efficient as vaccines makes them essential in such areas as animal care. Whole-pathogen inactivated vaccines present substantial biosafety and handling advantages and thus a higher market acceptance in the animal production industry, including in aquaculture. Viral nervous necrosis (VNN) caused by the nervous necrosis virus (NNV) affects a broad range of primarily marine fish species, with mass mortality rates among larvae and juveniles. Its genetic diversification may hinder the effective implementation of vaccines. The present study describes different rapid inactivation procedures for developing an inactivated vaccine against a new NNV isolate confirmed to possess deadly effects upon the European seabass (Dicentrarchus labrax), an important farmed fish species. View this paper
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18 pages, 5318 KiB  
Article
A Five Collagen-Related Gene Signature to Estimate the Prognosis and Immune Microenvironment in Clear Cell Renal Cell Cancer
by Xiaokai Shi, Xiao Zhou, Chuang Yue, Shenglin Gao, Zhiqin Sun, Chao Lu and Li Zuo
Vaccines 2021, 9(12), 1510; https://doi.org/10.3390/vaccines9121510 - 20 Dec 2021
Cited by 3 | Viewed by 2971
Abstract
Collagen is the main component of the extracellular matrix (ECM) and might play an important role in tumor microenvironments. However, the relationship between collagen and clear cell renal cell cancer (ccRCC) is still not fully clarified. Hence, we aimed to establish a collagen-related [...] Read more.
Collagen is the main component of the extracellular matrix (ECM) and might play an important role in tumor microenvironments. However, the relationship between collagen and clear cell renal cell cancer (ccRCC) is still not fully clarified. Hence, we aimed to establish a collagen-related signature to predict the prognosis and estimate the tumor immune microenvironment in ccRCC patients. Patients with a high risk score were often correlated with unfavorable overall survival (OS) and an immunosuppressive microenvironment. In addition, the collagen-related genetic signature was highly correlated with clinical pathological features and can be considered as an independent prognostic factor in ccRCC patients. Moreover, GSEA results show that patients with a high risk grade tend to be associated with epithelial–mesenchymal junctions (EMT) and immune responses. In this study, we developed a collagen-related gene signature, which might possess the potential to predict the prognosis and immune microenvironment of ccRCC patients and function as an independent prognostic factor in ccRCC. Full article
(This article belongs to the Special Issue Cancer Immunotherapy and Vaccines Research)
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<p>Identification of collagen-related signature to predict prognosis of ccRCC. (<b>A</b>) 25 hub genes dragged out from 257 collagen-related genes based on interaction degrees; (<b>B</b>) Establishment of a collagen-related risk model by univariate and multivariate cox regression; (<b>C</b>,<b>D</b>) Spearman correlation analysis of five collagen-related genes in train and test cohort. * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01.</p>
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<p>The gene expression profiles of five collagen-related genes in pan cancer based on TIMER database. (<b>A</b>–<b>E</b>) The differential expression between tumor and adjacent normal tissues for five collagen-related genes including COL4A4, COL7A1, COL9A2, FN1, and IL6 across all TCGA tumors. Distributions of gene expression levels are displayed using box plots, with statistical significance of differential expression evaluated using the Wilcoxon test. * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01 and *** <span class="html-italic">p</span> &lt; 0.001.</p>
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<p>Prognosis value of collagen-related signature in train and test cohort. (<b>A</b>,<b>B</b>) Risk curve of ccRCC patients in train and test cohort. The median risk score in train cohort was set as the cutoff value to separate patients into high and low risk groups. The cutoff value in train cohort was also used to calculate the risk score of patients in test cohort; (<b>C</b>,<b>D</b>) The heatmap showing five hub gene expression profiles in high and low risk groups from train and test cohort; (<b>E</b>,<b>F</b>) Patient status distribution in high and low risk groups; (<b>G</b>,<b>H</b>) The Kaplan–Meier overall survival curves for patients assigned to high and low risk groups based on the risk score.</p>
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<p>Collagen-related gene expression is correlated with clinicopathological features of ccRCC. (<b>A</b>,<b>B</b>) The heatmap showing five collagen-related gene expression profiles in different clinical stages from train and test cohorts; (<b>C</b>,<b>D</b>) The expression levels of five collagen-related genes in ccRCC with different clinical stages; (<b>E</b>–<b>G</b>) The heatmap and expression levels of five collagen-related genes in different T stage, M stage, and WHO grades from train and test cohorts; * <span class="html-italic">p</span> &lt; 0.05,** <span class="html-italic">p</span> &lt; 0.01 and *** <span class="html-italic">p</span> &lt; 0.001.</p>
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<p>Prognostic value of the collagen-related signature in ccRCC. (<b>A</b>,<b>B</b>) ROC curves showing the predictive efficiency of the collagen-related signature on the 1-,3- and 5-years survival rate; (<b>C</b>–<b>F</b>) Univariate and multivariate cox regression analysis evaluating the independent prognostic value of collagen-related signature in terms of OS in ccRCC patients.</p>
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<p>GSEA enrichment analysis between high and low risk groups. (<b>A</b>) The hallmark enrichment of high and low risk groups by GSEA method; GSEA revealing that genes in the high risk group were enriched for hallmarks of epithelial–mesenchymal transition (EMT) and immune response in train cohort; (<b>B</b>) The results were further validated by the test cohort.</p>
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<p>Immune landscape between low and high risk ccRCC patients. (<b>A</b>) Relative proportion of immune infiltration in high and low risk patients. (<b>B</b>,<b>C</b>) Box plots visualizing significantly different immune cells between high risk and low risk patients. (<b>D</b>) GSEA demonstrating that collagen-related signature correlated with immune-related biological function.</p>
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<p>High collagen-related risk score indicates an immunosuppressive microenvironment. (<b>A</b>,<b>B</b>) Heatmap of gene profiles involved in the negative regulation of the cancer immunity cycle in high and low risk groups in train and test cohorts; (<b>C</b>) Correlation between LAG3 expression and risk score; (<b>D</b>) LAG3 expression in high and low risk groups; (<b>E</b>) Correlation between CTLA-4 expression and risk score; (<b>F</b>) CTLA-4 expression in high and low risk groups; (<b>G</b>–<b>I</b>) PD1,TIGIT, and PD-L1 expression in high and low risk groups; (<b>J</b>) Tumor immunosuppressive cytokines expression in high and low risk groups; * <span class="html-italic">p</span> &lt; 0.05,** <span class="html-italic">p</span> &lt; 0.01 and *** <span class="html-italic">p</span> &lt; 0.001.</p>
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8 pages, 365 KiB  
Article
Mutagenic Distinction between the Receptor-Binding and Fusion Subunits of the SARS-CoV-2 Spike Glycoprotein and Its Upshot
by Robert Clark Penner
Vaccines 2021, 9(12), 1509; https://doi.org/10.3390/vaccines9121509 - 20 Dec 2021
Cited by 5 | Viewed by 2624
Abstract
We observe that a residue R of the spike glycoprotein of SARS-CoV-2 that has mutated in one or more of the current variants of concern or interest, or under monitoring, rarely participates in a backbone hydrogen bond if R lies in the S [...] Read more.
We observe that a residue R of the spike glycoprotein of SARS-CoV-2 that has mutated in one or more of the current variants of concern or interest, or under monitoring, rarely participates in a backbone hydrogen bond if R lies in the S1 subunit and usually participates in one if R lies in the S2 subunit. A partial explanation for this based upon free energy is explored as a potentially general principle in the mutagenesis of viral glycoproteins. This observation could help target future vaccine cargos for the evolving coronavirus as well as more generally. A related study of the Delta and Omicron variants suggests that Delta was an energetically necessary intermediary in the evolution from Wuhan-Hu-1 to Omicron. Full article
(This article belongs to the Special Issue Recent Advances in Research into Vaccine Technologies)
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<p>Plot of BFE by the residue across the PDB-covered spike, namely residues 27–1147 of S. Illustrated in orange are the respective residue ranges for the N-terminal domain, the receptor-binding domain, the <math display="inline"><semantics> <mrow> <msub> <mi mathvariant="normal">S</mi> <mn>1</mn> </msub> <mo>/</mo> <msub> <mi mathvariant="normal">S</mi> <mn>2</mn> </msub> </mrow> </semantics></math> cleavage, the <math display="inline"><semantics> <mrow> <msub> <mi mathvariant="normal">S</mi> <mn>2</mn> </msub> <mo>/</mo> <msubsup> <mi mathvariant="normal">S</mi> <mn>2</mn> <mo>′</mo> </msubsup> </mrow> </semantics></math> cleavage, and the first heptad repeat domain. The gray horizontal line indicates one “heat quantum” <math display="inline"><semantics> <mrow> <mi>k</mi> <mi>T</mi> <mo>≈</mo> <mn>0.6</mn> <mspace width="3.33333pt"/> </mrow> </semantics></math>kcal/mole below zero. One can confirm by comparison with the structure itself that the intersections of BFE with this line corresponds to <math display="inline"><semantics> <mi>α</mi> </semantics></math> helices and, in fact, ones whose backbone geometry is especially near ideal <math display="inline"><semantics> <mi>α</mi> </semantics></math> helices according to considerations of free energy.</p>
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<p>Comparison of BFE across the spike from the single mutation D614G [<a href="#B27-vaccines-09-01509" class="html-bibr">27</a>]. The BFE of Wuhan-Hu-1 is computed at each residue as the average of PDB structures 7KDG and 7KDH, which are stabilized in the prefusion conformation by mutations R682G, R683G, and R685G, plus the 2P mutation given by K986P and V987P; the BFE of the D614G mutation is computed as the average of structures 7KDK and 7KDL, analogously stabilized but also with the D614G mutation. In each case, missing or absent residues give null. Plotted is the difference of the former minus the latter. The Wuhan-Hu-1 BFE at residue 614, itself, is 2.26 kcal/mole compared to 2.12 kcal/mole for D614G, but despite this near equality at residue 614, the BFE across the entire spike is altered.</p>
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11 pages, 1310 KiB  
Article
Assessment of Post-Vaccination Antibody Response Eight Months after the Administration of BNT1622b2 Vaccine to Healthcare Workers with Particular Emphasis on the Impact of Previous COVID-19 Infection
by Blanka Wolszczak-Biedrzycka, Anna Bieńkowska and Justyna Dorf
Vaccines 2021, 9(12), 1508; https://doi.org/10.3390/vaccines9121508 - 20 Dec 2021
Cited by 16 | Viewed by 3603
Abstract
At the end of 2020, COVID-19 vaccination programs were initiated in many countries, including Poland. The first vaccine approved in Poland was the BNT162b2 mRNA preparation (Pfizer/BioNTech), and the first vaccinated group were healthcare workers. The aim of the present study was to [...] Read more.
At the end of 2020, COVID-19 vaccination programs were initiated in many countries, including Poland. The first vaccine approved in Poland was the BNT162b2 mRNA preparation (Pfizer/BioNTech), and the first vaccinated group were healthcare workers. The aim of the present study was to evaluate post-vaccine antibody titers 8 months after the second vaccine dose had been administered to a group of employees of the Hospital of the Ministry of the Interior and Administration in Olsztyn (Poland). The employees were divided into two groups: persons who had COVID-19 in the fourth quarter of 2020 and were vaccinated in January–February 2021, and persons without a history of COVID-19 who were vaccinated during the same period. The analyzed material was venous blood serum collected from 100 hospital employees on 23–28 September 2021. The level of anti-SARS-CoV-2 S antibodies was measured with a Roche Cobas e411 analyzer using the electrochemiluminescence (ECLIA) method. The study demonstrated that persons with a history of SARS-CoV-2 infection had significantly higher antibody levels (taking into account gender, age, type of work performed, and severity of post-vaccination symptoms) than employees without a history of COVID-19. The study also revealed that the type of work, age, gender, and the course of SARS-CoV-2 infection can influence the humoral immune response. The presented results may prove helpful in the context of administering additional vaccine doses. Full article
(This article belongs to the Topic Global Analysis of SARS-CoV-2 Serology)
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<p>(<b>A</b>) Comparison of total anti-SARS-CoV-2 antibodies level between group of women and men without history of COVID-19. The data are presented as median (minimum–maximum). (<b>B</b>) Comparison of total anti-SARS-CoV-2 antibodies level between groups of patients before and after the age of 50 without history of COVID-19. The data are presented as median (minimum–maximum). (<b>C</b>) Comparison of total anti-SARS-CoV-2 antibodies level between groups of patients with mild to moderate and severe symptoms after vaccination in patients without history of COVID-19. The data are presented as median (minimum–maximum). (<b>D</b>) Comparison of total anti-SARS-CoV-2 antibodies level between group of medical and non-medical workers without history of COVID-19. The data are presented as median (minimum–maximum).</p>
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<p>(<b>A</b>) Comparison of total anti-SARS-CoV-2 antibodies level between group of women and men with history of COVID-19. The data are presented as median (minimum–maximum). (<b>B</b>) Comparison of total anti-SARS-CoV-2 antibodies level between groups of patients before and after the age of 50 with history of COVID-19. The data are presented as median (minimum–maximum). (<b>C</b>) Comparison of total anti-SARS-CoV-2 antibodies level depending on the time between positive result of SARS-CoV2 PCR and vaccination date. The data are presented as median (minimum–maximum). (<b>D</b>) Comparison of total anti-SARS-CoV-2 antibodies level between groups of patients with mild to moderate and severe symptoms during COVID-19. The data are presented as median (minimum–maximum). (<b>E</b>) Comparison of total anti-SARS-CoV-2 antibodies level between groups of patients with mild to moderate and severe symptoms after vaccination in patients with history of COVID-19. The data are presented as median (minimum–maximum). (<b>F</b>) Comparison of total anti-SARS-CoV-2 antibodies level between group of medical and non-medical workers with history of COVID-19. The data are presented as median (minimum–maximum).</p>
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<p>(<b>A</b>) Comparison of total anti-SARS-CoV-2 antibodies level in the groups of women and men with and without history of COVID-19. The data are presented as median (minimum–maximum). (<b>B</b>) Comparison of total anti-SARS-CoV-2 antibodies level in groups of patients before and after the age of 50 with and without history of COVID-19. The data are presented as median (minimum–maximum). (<b>C</b>) Comparison of total anti-SARS-CoV-2 antibodies level in groups of patients with mild to moderate and severe symptoms after vaccination with and without history of COVID-19. The data are presented as median (minimum–maximum). (<b>D</b>) Comparison of total anti-SARS-CoV-2 antibodies level in groups of medical and non-medical workers with and without history of COVID-19. The data are presented as median (minimum–maximum).</p>
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16 pages, 568 KiB  
Review
Promising Expectations for Pneumococcal Vaccination during COVID-19
by Hyobin Im, Jinhui Ser, Uk Sim and Hoonsung Cho
Vaccines 2021, 9(12), 1507; https://doi.org/10.3390/vaccines9121507 - 20 Dec 2021
Cited by 13 | Viewed by 6329
Abstract
The emergence of new viral infections has increased over the decades. The novel virus is one such pathogen liable for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, popularly known as coronavirus disease 2019 (COVID-19). Most fatalities during the past century’s influenza pandemics [...] Read more.
The emergence of new viral infections has increased over the decades. The novel virus is one such pathogen liable for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, popularly known as coronavirus disease 2019 (COVID-19). Most fatalities during the past century’s influenza pandemics have cooperated with bacterial co/secondary infections. Unfortunately, many reports have claimed that bacterial co-infection is also predominant in COVID-19 patients (COVID-19 associated co/secondary infection prevalence is up to 45.0%). In the COVID-19 pandemic, Streptococcus pneumoniae is the most common coinfecting pathogen. Half of the COVID-19 mortality cases showed co-infection, and pneumonia-related COVID-19 mortality in patients >65 years was 23%. The weakening of immune function caused by COVID-19 remains a high-risk factor for pneumococcal disease. Pneumococcal disease and COVID-19 also have similar risk factors. For example, underlying medical conditions on COVID-19 and pneumococcal diseases increase the risk for severe illness at any age; COVID-19 is now considered a primary risk factor for pneumococcal pneumonia and invasive pneumococcal disease. Thus, pneumococcal vaccination during the COVID-19 pandemic has become more critical than ever. This review presents positive studies of pneumococcal vaccination in patients with COVID-19 and other medical conditions and the correlational effects of pneumococcal disease with COVID-19 to prevent morbidity and mortality from co/secondary infections and superinfections. It also reports the importance and role of pneumococcal vaccination during the current COVID-19 pandemic era to strengthen the global health system. Full article
(This article belongs to the Topic Global Analysis of SARS-CoV-2 Serology)
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<p>The impact of comorbidities on the incidence of patients hospitalized with community-acquired pneumonia (CAP). CHF: congestive heart failure; COPD: chronic obstructive pulmonary disease.</p>
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16 pages, 3482 KiB  
Article
Mycoplasma suis Alpha-Enolase Subunit Vaccine Induces an Immune Response in Experimental Animals
by Shujiang Xue, Kangseok Seo, Miaosen Yang, Chengdu Cui, Meng Yang, Siyu Xiang, Zongbin Yan, Shengjun Wu, Jincheng Han, Xiaoyang Yu, Yunxiao Li and Xin Jin
Vaccines 2021, 9(12), 1506; https://doi.org/10.3390/vaccines9121506 - 20 Dec 2021
Cited by 8 | Viewed by 3896
Abstract
Recombinant protein technology has emerged as an excellent option for vaccine development. However, prior to our study, the immune induction ability of recombinant Mycoplasma suis alpha-enolase (rMseno) in animals remained unclear. The purpose of this study was to develop a rMseno protein subunit [...] Read more.
Recombinant protein technology has emerged as an excellent option for vaccine development. However, prior to our study, the immune induction ability of recombinant Mycoplasma suis alpha-enolase (rMseno) in animals remained unclear. The purpose of this study was to develop a rMseno protein subunit vaccine and to determine its ability to elicit an immunological response. To accomplish this, we cloned the gene into pET-15b, expressed it in BL21 cells, and purified it. Following the establishment of immunity, the immunogenicity and potential for protection of rMseno were evaluated in mice and piglets. The results demonstrate that anti-M. suis serum recognized the pure rMseno protein in both mice and piglets as evidenced by high levels of specific anti-rMseno antibodies, significantly increased levels of IFN-γ and IL-4 cytokines, and significantly increased T lymphocyte proliferation index. Piglets also had significantly increased levels of specific IgG1, IgG2a, CD4+, and CD8+ cells. The rMseno findings demonstrated a robust immunological response in mice and piglets, affording partial clinical protective efficacy in piglets. Full article
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<p>Overall flow.</p>
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<p>Western blotting to detect the purified recombinant protein. (<b>a</b>) M indicates the protein standard marker. The first lane presents the total protein before induction. Lanes 2 to 5 indicate the supernatant lysate of induced recombinant bacteria at 20 °C, the precipitate of the lysate of induced recombinant bacteria at 20 °C, the supernatant lysate of induced recombinant bacteria at 37 °C, and precipitate of the lysate of induced recombinant bacteria at 37 °C, respectively. (<b>b</b>) M indicates the protein standard marker. The first lane shows the total protein before induction. The second lane contains the filtered fluid containing the residual protein (excluding the target protein) from the supernatant of lysate of induced recombinant bacteria. The supernatant of the lysate of induced recombinant bacteria containing both bacterial proteins and the target protein is presented in the third lane. The fourth lane is target protein purified with elution buffer containing 100 mmol/L imidazole. The fifth lane is target protein purified with elution buffer containing 200 mmol/L imidazole. The wash buffer elution (50 mmol/L imidazole) is shown in the sixth lane (target protein and hybrid protein). The wash buffer elution containing 20 mmol/L imidazole is presented in the seventh lane (target protein and hybrid protein). (<b>c</b>) M indicates the standard protein marker. The first lane shows the purified rMseno protein.</p>
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<p>Antibody titers in sera of immunized mice. The OD<sub>405 nm</sub> was calculated for each group of mice (<span class="html-italic">n</span> = 5). An error bar shows the standard error of the mean. Mice in group A received the purified rMseno protein. Mice in group B received IPTG-induced <span class="html-italic">E. coli</span>-Mseno. Control group C received an equal volume of PBS. Control group D received uninduced recombinant <span class="html-italic">E. coli</span>-Mseno. Each group received three immunizations on day 0, day 14, and day 28. Antibody titers were determined until day 42. * <span class="html-italic">p</span> &lt; 0.05 presents a significant difference, and ** <span class="html-italic">p</span> &lt; 0.01 shows a highly significant difference.</p>
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<p>Serum IFN-γ and IL-4 levels in mice from different immunization groups. Each mouse in each group (<span class="html-italic">n</span> = 5 per group) was screened for IFN-γ and IL-4. Statistical comparisons were made between groups at all stages of immunization. (<b>a</b>) On day 14, IFN-γ levels in immune groups A and B were significantly increased (<span class="html-italic">p</span> &lt; 0.05). (<b>b</b>) On day 14, the levels of IL-4 in immune groups A and B were significantly increased (<span class="html-italic">p</span> &lt; 0.05). * <span class="html-italic">p</span> &lt; 0.05 presents a significant difference, and ** <span class="html-italic">p</span> &lt; 0.01 shows a highly significant difference.</p>
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<p>The proliferation of T lymphocytes in mice. The mice were divided into four groups (<span class="html-italic">n</span> = 5 per group) and stimulated with rMseno, <span class="html-italic">E. coli</span>-Mseno, PBS, <span class="html-italic">E. coli</span>, and ConA, respectively. Between groups, statistical comparisons were made using different stimulating factors. * <span class="html-italic">p</span> &lt; 0.05 presents a significant difference, and ** <span class="html-italic">p</span> &lt; 0.01 shows a highly significant difference.</p>
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<p>Antibody levels in the sera of piglets. The case groups were divided into groups A and B (<span class="html-italic">n</span> = 3 per group) immunized with rMseno and <span class="html-italic">E. coli</span>-Mseno, respectively. The control group (<span class="html-italic">n</span> = 3 per group) received an equal volume of PBS (C). Two stars above the black line indicate that immune groups A and B were highly significantly different compared to control group C at all points in time (7, 14, 21, 28, and 35 d). ** <span class="html-italic">p</span> &lt; 0.01 shows a highly significant difference.</p>
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<p>Serum IgG<sub>1</sub> and IgG<sub>2a</sub> levels of piglets in the different immunization groups. (<b>a</b>) From day 7, the differences between groups A and B (vaccinated) and group C (control) were highly significant, and the IgG<sub>1</sub> level gradually increased over time in the former two groups. (<b>b</b>) From day 7, the differences between groups A and B and group C were highly significant, and the IgG<sub>2a</sub> gradually increased over time in the former two groups. ** <span class="html-italic">p</span> &lt; 0.01 shows a highly significant difference.</p>
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<p>Serum IFN-γ and IL-4 levels in piglets from various immunization groups. (<b>a</b>) After the first immunization, the level of IFN-γ in group A was highly significantly different from that of group C (<span class="html-italic">p</span> &lt; 0.01 or <span class="html-italic">p</span> &lt; 0.001). (<b>b</b>) After the initial vaccination, the level of IL-4 in group A was highly significantly different than that of group C (<span class="html-italic">p</span> &lt; 0.01 or <span class="html-italic">p</span> &lt; 0.001). ** <span class="html-italic">p</span> &lt; 0.01 shows a highly significant difference, and *** <span class="html-italic">p</span> &lt; 0.001 shows an extremely significant difference.</p>
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<p>T lymphocytes were analyzed in the spleens of piglets from different immunization groups. The CD4<sup>+</sup> and CD8<sup>+</sup> levels were evaluated on day 35. * <span class="html-italic">p</span> &lt; 0.05 presents a significant difference, and ** <span class="html-italic">p</span> &lt; 0.01 shows a highly significant difference.</p>
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<p>The networks of interactions among alpha-enolase (ENO1) and other proteins (no clustering). Each node represents all the proteins produced by a single, protein-coding gene locus. An association means that the proteins most likely collaborate to perform a common function. The dots and lines are defined in the STRING manual. (<b>a</b>) An alpha-enolase interaction network based on <span class="html-italic">Sus scrofa</span>. (<b>b</b>) An alpha-enolase interaction network based on <span class="html-italic">Homo sapiens</span>. (<b>c</b>) An interaction network for alpha-enolase (ENO1), GAPDH, and OSGEP in <span class="html-italic">Sus scrofa</span>. (<b>d</b>) An interaction network for alpha-enolase (ENO1), GAPDH, OSGEP, PPA1, and HSPA1 in <span class="html-italic">Homo sapiens</span>.</p>
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17 pages, 393 KiB  
Article
Who Got Vaccinated for COVID-19? Evidence from Japan
by Toshihiro Okubo, Atsushi Inoue and Kozue Sekijima
Vaccines 2021, 9(12), 1505; https://doi.org/10.3390/vaccines9121505 - 20 Dec 2021
Cited by 14 | Viewed by 4046
Abstract
Vaccination has been critical to reducing infections and deaths during the coronavirus disease 2019 (COVID-19) pandemic. While previous studies have investigated attitudes toward taking a vaccine, studies on the determinants of COVID-19 vaccination behavior are scant. We examine what characteristics, including socioeconomic and [...] Read more.
Vaccination has been critical to reducing infections and deaths during the coronavirus disease 2019 (COVID-19) pandemic. While previous studies have investigated attitudes toward taking a vaccine, studies on the determinants of COVID-19 vaccination behavior are scant. We examine what characteristics, including socioeconomic and non-economic factors, are associated with vaccination behavior for COVID-19 in Japan. We use a large nationwide online survey with approximately 10,000 participants. As of September 2021, 85% of the respondents said that they had received or would receive a COVID-19 vaccine. Employing logistic regression analysis on vaccination behavior, we found that vaccination rates are higher among those who are older, married, educated, and/or work in a large company. On the other hand, vaccination rates tend to be lower among the self-employed, younger women, and those with poor mental health. Income did not significantly correlate with vaccination. Medical workers were found to have a relatively high rate of vaccination. Although attitude towards risk and time preference were not crucial factors for vaccination, fear of infection, infection prevention behavior, and agreement with government policies on behavioral restrictions in crisis situations positively correlated with vaccination. Full article
(This article belongs to the Section COVID-19 Vaccines and Vaccination)
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<p>Vaccination rate in Japan.</p>
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12 pages, 783 KiB  
Review
Innovations in the Insect Cell Expression System for Industrial Recombinant Vaccine Antigen Production
by Manon M. J. Cox
Vaccines 2021, 9(12), 1504; https://doi.org/10.3390/vaccines9121504 - 20 Dec 2021
Cited by 25 | Viewed by 7679
Abstract
The insect cell expression system has previously been proposed as the preferred biosecurity strategy for production of any vaccine, particularly for future influenza pandemic vaccines. The development and regulatory risk for new vaccine candidates is shortened as the platform is already in use [...] Read more.
The insect cell expression system has previously been proposed as the preferred biosecurity strategy for production of any vaccine, particularly for future influenza pandemic vaccines. The development and regulatory risk for new vaccine candidates is shortened as the platform is already in use for the manufacturing of the FDA-licensed seasonal recombinant influenza vaccine Flublok®. Large-scale production capacity is in place and could be used to produce other antigens as well. However, as demonstrated by the 2019 SARS-CoV-2 pandemic the insect cell expression system has limitations that need to be addressed to ensure that recombinant antigens will indeed play a role in combating future pandemics. The greatest challenge may be the ability to produce an adequate quantity of purified antigen in an accelerated manner. This review summarizes recent innovations in technology areas important for enhancing recombinant-protein production levels and shortening development timelines. Opportunities for increasing product concentrations through vector development, cell line engineering, or bioprocessing and for shortening timelines through standardization of manufacturing processes will be presented. Full article
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<p>Three stages of the baculovirus insect cell culture process. Cell maintenance, virus propagation, and protein production.</p>
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15 pages, 567 KiB  
Review
mRNA COVID-19 Vaccines and Long-Lived Plasma Cells: A Complicated Relationship
by Girolamo Giannotta and Nicola Giannotta
Vaccines 2021, 9(12), 1503; https://doi.org/10.3390/vaccines9121503 - 20 Dec 2021
Cited by 23 | Viewed by 11126
Abstract
mRNA COVID-19 vaccines have hegemonized the world market, and their administration to the population promises to stop the pandemic. However, the waning of the humoral immune response, which does not seem to last so many months after the completion of the vaccination program, [...] Read more.
mRNA COVID-19 vaccines have hegemonized the world market, and their administration to the population promises to stop the pandemic. However, the waning of the humoral immune response, which does not seem to last so many months after the completion of the vaccination program, has led us to study the molecular immunological mechanisms of waning immunity in the case of mRNA COVID-19 vaccines. We consulted the published scientific literature and from the few articles we found, we were convinced that there is an immunological memory problem after vaccination. Although mRNA vaccines have been demonstrated to induce antigen-specific memory B cells (MBCs) in the human population, there is no evidence that these vaccines induce the production of long-lived plasma cells (LLPCs), in a SARS-CoV-2 virus naïve population. This obstacle, in our point of view, is caused by the presence, in almost all subjects, of a cellular T and B cross-reactive memory produced during past exposures to the common cold coronaviruses. Due to this interference, it is difficult for a vaccination with the Spike protein alone, without adjuvants capable of prolonging the late phase of the generation of the immunological memory, to be able to determine the production of protective LLPCs. This would explain the possibility of previously and completely vaccinated subjects to become infected, already 4–6 months after the completion of the vaccination cycle. Full article
(This article belongs to the Special Issue Host Innate Immune Responses against SARS-CoV-2)
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<p>Fate of a naïve B cell after encountering the antigen in the germinal center.</p>
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11 pages, 660 KiB  
Case Report
Chronic Inflammatory Demyelinating Polyneuropathy after ChAdOx1 nCoV-19 Vaccination
by Caterina Francesca Bagella, Davide G. Corda, Pietro Zara, Antonio Emanuele Elia, Elisa Ruiu, Elia Sechi and Paolo Solla
Vaccines 2021, 9(12), 1502; https://doi.org/10.3390/vaccines9121502 - 19 Dec 2021
Cited by 19 | Viewed by 7152
Abstract
Recently several patients, who developed Guillain–Barré syndrome characterized by prominent bifacial weakness after ChAdOx1 nCoV-19 vaccination, were described from different centers. We recently observed a patient who developed a similar syndrome, later in the follow up he showed worsening of the neuropathy two [...] Read more.
Recently several patients, who developed Guillain–Barré syndrome characterized by prominent bifacial weakness after ChAdOx1 nCoV-19 vaccination, were described from different centers. We recently observed a patient who developed a similar syndrome, later in the follow up he showed worsening of the neuropathy two months after the initial presentation. Repeat EMG showed reduced nerve sensory and motor conduction velocities of both upper and lower limbs, and a diagnosis of chronic inflammatory demyelinating polyneuropathy (typical CIDP) was made according to established criteria. Our report expands on the possible outcomes in patients who develop Guillain–Barrè syndrome after COVID-19 vaccinations and suggest that close monitoring after the acute phase is needed in these patients to exclude a chronic evolution of the disease, which has important implications for long-term treatment. Full article
(This article belongs to the Special Issue The COVID Vaccine)
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<p>Brain and spinal cord MRI findings. Axial post-gadolinium T1-weighted images of the brain showing enhancement of the right ((<b>A</b>), arrow) and left ((<b>B</b>), arrow) facial nerves. Sagittal T1-weighted images before (<b>C</b>) and after (<b>D</b>) gadolinium administration showing diffuse enhancement of the cauda equina and lower thoracic nerve roots.</p>
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14 pages, 3894 KiB  
Article
A Comparative Study on Delivery of Externally Attached DNA by Papillomavirus VLPs and Pseudoviruses
by Sarah Brendle, Nancy Cladel, Karla Balogh, Samina Alam, Neil Christensen, Craig Meyers and Jiafen Hu
Vaccines 2021, 9(12), 1501; https://doi.org/10.3390/vaccines9121501 - 18 Dec 2021
Cited by 3 | Viewed by 2835
Abstract
Human papillomavirus (HPV) 16 capsids have been chosen as a DNA delivery vehicle in many studies. Our preliminary studies suggest that HPV58 capsids could be better vehicles than HPV16 capsids to deliver encapsidated DNA in vitro and in vivo. In the current study, [...] Read more.
Human papillomavirus (HPV) 16 capsids have been chosen as a DNA delivery vehicle in many studies. Our preliminary studies suggest that HPV58 capsids could be better vehicles than HPV16 capsids to deliver encapsidated DNA in vitro and in vivo. In the current study, we compared HPV16, HPV58, and the cottontail rabbit papillomavirus (CRPV) capsids either as L1/L2 VLPs or pseudoviruses (PSVs) to deliver externally attached GFP-expressing DNA. Both rabbit and human cells were used to test whether there was a species-specific effect. DNA delivery efficiency was determined by quantifying either GFP-expressing cell populations or mean fluorescent intensities (MFI) by flow cytometry. Interestingly, CRPV and 58-VLPs and PSVs were significantly more efficient at delivering attached DNA when compared to 16-VLPs and PSVs. A capsid/DNA ratio of 2:1 showed the highest efficiency for delivering external DNA. The PSVs with papillomavirus DNA genomes also showed higher efficiency than those with irrelevant plasmid DNA. HPV16L1/58L2 hybrid VLPs displayed increased efficiency compared to HPV58L1/16L2 VLPs, suggesting that L2 may play a critical role in the delivery of attached DNA. Additionally, we demonstrated that VLPs increased in vivo infectivity of CRPV DNA in rabbits. We conclude that choosing CRPV or 58 capsids to deliver external DNA could improve DNA uptake in in vitro and in vivo models. Full article
(This article belongs to the Special Issue Development of Vaccines Based on Virus-Like Particles)
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<p>(<b>A</b>) Using HPV58 VLPs as an example, L1 and L2 contents were determined by ELISA assay using type-specific antibodies against L1 (H58.G5) and a cross-reacting rabbit antibody against L2 (R972). The corresponding protein concentration in each fraction was also determined by Bio-Rad protein assay (right axis mg/mL). (<b>B</b>) VLPs visualized by TEM should be empty particles, but many particles were filled with cellular DNAs and appear full. (<b>C</b>) GFP expression in rabbit cells (RLT) by HPV 16 and 58 L1-only VLPs and PSVs. As shown in the top panel, HPV 16 and 58 L1-only VLPs failed to deliver attached GFP into cultured cells. By contrast, GFP-positive cells were found when 16-PSV and 58-PSV delivered attached GFP DNA. 58-PSV showed comparable GFP expression to the commercial transfection kit. (<b>D</b>) Flow cytometry analysis was used to quantify GFP signals. Two parameters, the percentage of GFP positive population and mean fluorescent intensity (MFI) by geometric mean were analyzed, as shown here in a typical dataset. These two parameters correlated with each other and thus were used interchangeably for comparison among groups. (<b>E</b>) Significantly fewer rabbit cells (cell lines from two different rabbits) were GFP-positive by VLP-16 delivery when compared to HPV58- and CRPV-VLPs (<span class="html-italic">p</span> &lt; 0.05, unpaired Mann Whitney test, indicated by *). (<b>F</b>) We tested delivery of GFP DNA by HPV58-, 16-, and CRPV-VLPs in 293TT cells. CRPV-VLPs showed comparative efficiency when compared to 58-VLP (<span class="html-italic">p</span> &gt; 0.05, unpaired Mann Whitney test). The 16-VLPs showed significantly lower efficacy to deliver DNA when compared with both HPV 58- and CRPV-VLPs (<span class="html-italic">p</span> &lt; 0.05, unpaired Mann Whitney test, indicated by *). (<b>G</b>) To determine the stability of VLPs and PSVs, we tested fresh VLPs with those stored at −20 °C for a month. We observed that CRPV-VLP delivery efficiency decreased, while HPV16- and 58-VLPs maintained the same level of potency for delivery.</p>
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<p>(<b>A</b>) Using HPV58 VLPs as an example, L1 and L2 contents were determined by ELISA assay using type-specific antibodies against L1 (H58.G5) and a cross-reacting rabbit antibody against L2 (R972). The corresponding protein concentration in each fraction was also determined by Bio-Rad protein assay (right axis mg/mL). (<b>B</b>) VLPs visualized by TEM should be empty particles, but many particles were filled with cellular DNAs and appear full. (<b>C</b>) GFP expression in rabbit cells (RLT) by HPV 16 and 58 L1-only VLPs and PSVs. As shown in the top panel, HPV 16 and 58 L1-only VLPs failed to deliver attached GFP into cultured cells. By contrast, GFP-positive cells were found when 16-PSV and 58-PSV delivered attached GFP DNA. 58-PSV showed comparable GFP expression to the commercial transfection kit. (<b>D</b>) Flow cytometry analysis was used to quantify GFP signals. Two parameters, the percentage of GFP positive population and mean fluorescent intensity (MFI) by geometric mean were analyzed, as shown here in a typical dataset. These two parameters correlated with each other and thus were used interchangeably for comparison among groups. (<b>E</b>) Significantly fewer rabbit cells (cell lines from two different rabbits) were GFP-positive by VLP-16 delivery when compared to HPV58- and CRPV-VLPs (<span class="html-italic">p</span> &lt; 0.05, unpaired Mann Whitney test, indicated by *). (<b>F</b>) We tested delivery of GFP DNA by HPV58-, 16-, and CRPV-VLPs in 293TT cells. CRPV-VLPs showed comparative efficiency when compared to 58-VLP (<span class="html-italic">p</span> &gt; 0.05, unpaired Mann Whitney test). The 16-VLPs showed significantly lower efficacy to deliver DNA when compared with both HPV 58- and CRPV-VLPs (<span class="html-italic">p</span> &lt; 0.05, unpaired Mann Whitney test, indicated by *). (<b>G</b>) To determine the stability of VLPs and PSVs, we tested fresh VLPs with those stored at −20 °C for a month. We observed that CRPV-VLP delivery efficiency decreased, while HPV16- and 58-VLPs maintained the same level of potency for delivery.</p>
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<p>(<b>A</b>) PSV58 encapsidating an unrelated 5.5 kb DNA plasmid (PSV58/5.5 kb) showed improved delivery over VLP-58 (<span class="html-italic">p</span> &lt; 0.05, unpaired Mann Whitney test, indicated by *) that was also comparable to VLP-CRPV. (<b>B</b>) External GFP DNA delivered by PSV58 was more efficient than a commercial transfection reagent (<span class="html-italic">p</span> &lt; 0.05, unpaired Mann Whitney test, indicated by *). No difference was found between PSV58 alone, GFP DNA alone, and medium control (<span class="html-italic">p</span> &gt; 0.05, unpaired Mann Whitney test). (<b>C</b>) Efficiency of external DNA delivery is significantly higher by PSV58 containing the CRPV genome when compared to PSV58/5.5 kb (PCX expression vector, 5.5 kb) genome (<span class="html-italic">p</span> &lt; 0.05, unpaired Mann Whitney test, indicated by *).</p>
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<p>Dose curve to determine the optimal capsid/DNA ratio. (<b>A</b>) Different amounts of PSV58 (0.125, 0.25, 0.5, and 1 µg) were mixed with 0.5 µg of GFP DNA and added to SV40 LT immortalized rabbit cells (RLT). The 1 µg PSV-58 group showed increased numbers of positive cells when compared with the 0.125 and 0.25 µg groups (<span class="html-italic">p</span> &lt; 0.05, unpaired Mann Whitney test, indicated by *) (<b>B</b>) A range of GFP DNA was delivered by 1 µg of PSV58 to test for optimum delivery. An increased amount of GFP DNA did not show increased delivery efficiency; 1 µg PSV58 delivering 0.5 µg GFP DNA was the most efficient ratio for external DNA delivery.</p>
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<p>Delivery efficacy was determined by cell status. (<b>A</b>) Higher delivery efficacy was found in immortalized cells when compared to primary cells (<span class="html-italic">p</span> &lt; 0.05, unpaired Mann Whitney test, indicated by *). (<b>B</b>) Significantly higher delivery efficacy was found in PSV58 when compared with PSV16 (<span class="html-italic">p</span> &lt; 0.05, unpaired Mann Whitney test, indicated by *) in mouse dendritic cells.</p>
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<p>Delivery efficacy of external DNA is L2-dependent. Two hybrid VLPs, 16L1/58L2 and 58L1/16L2, were tested for attached DNA delivery with GFP DNA in rabbit and human cells. (<b>A</b>) The delivery efficiency of hybrid VLP-16L1/58L2 was partially restored in RLT cells when compared with VLP-58L1/16L2. Significantly more cells expressed GFP when delivered by VLP-16L1/58L2 (similar to VLP-58) when compared to VLP-58L1/16L2 (similar to VLP-16) in rabbit cells (<span class="html-italic">p</span> &lt; 0.05, unpaired Mann Whitney test, indicated by *). (<b>B</b>) Additionally, two more cell cultures (a rabbit cell line (I3) and a human cell line (SiHa)) were tested for hybrid VLP delivery. A similar pattern was found, as shown in RLT cells in the above experiments (<span class="html-italic">p</span> &lt; 0.05, unpaired Mann Whitney test, indicated by *).</p>
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11 pages, 6071 KiB  
Article
Attenuation of Antibody Titers from 3 to 6 Months after the Second Dose of the BNT162b2 Vaccine Depends on Sex, with Age and Smoking Risk Factors for Lower Antibody Titers at 6 Months
by Yushi Nomura, Michiru Sawahata, Yosikazu Nakamura, Ryousuke Koike, Otohiro Katsube, Koichi Hagiwara, Seiji Niho, Norihiro Masuda, Takaaki Tanaka and Kumiya Sugiyama
Vaccines 2021, 9(12), 1500; https://doi.org/10.3390/vaccines9121500 - 18 Dec 2021
Cited by 25 | Viewed by 3799
Abstract
Objective: We aimed to determine antibody titers at six months and their percentage change from three to six months after the second dose of the BNT162b2 coronavirus disease 2019 (COVID-19) mRNA vaccine (Pfizer/BioNTech) and to explore clinical variables associated with titers in Japan. [...] Read more.
Objective: We aimed to determine antibody titers at six months and their percentage change from three to six months after the second dose of the BNT162b2 coronavirus disease 2019 (COVID-19) mRNA vaccine (Pfizer/BioNTech) and to explore clinical variables associated with titers in Japan. Methods: We enrolled 365 healthcare workers (250 women, 115 men) whose three-month antibody titers were analyzed in our previous study and whose blood samples were collected 183 ± 15 days after the second dose. Participant characteristics, collected previously, were used. The relationships of these factors with antibody titers at six months and percentage changes in antibody titers from three to six months were analyzed. Results: Median age was 44 years. Median antibody titer at six months was 539 U/mL. Older participants had significantly lower antibody titers (20s, 752 U/mL; 60s–70s, 365 U/mL). In age-adjusted analysis, smoking was the only factor associated with lower antibody titers. Median percentage change in antibody titers from three to six months was −29.4%. The only factor significantly associated with the percentage change in Ab titers was not age or smoking, but sex (women, −31.6%; men, −25.1%). Conclusion: The most important factors associated with lower antibody titers at six months were age and smoking, as at three months, probably reflecting their effect on peak antibody titers. However, the only factor significantly associated with the attenuation in Ab titers from three to six months was sex, which reduced the sex difference seen during the first three months. Antibody titers may be affected by different factors at different time points. Full article
(This article belongs to the Special Issue Effectiveness, Safety and Immunogenicity of SARS-CoV-2 Vaccines)
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<p>Scatter plot of the distribution of Ab titers 6 months after the second vaccine dose according to age and smoking status. Older participants had significantly lower Ab titers. Closed and open circles show ever-smokers and never-smokers, respectively. Ever-smokers had lower Ab titers than never-smokers.</p>
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<p>Scatter plot of the distribution of the percentage change in Ab titers from 3 to 6 months after the second dose of the vaccine according to sex. The relationship between the percentage change after the vaccination and age is shown in (<b>A</b>), and the relationship between the percentage change and the Ab titer 6 months after the vaccination is shown in (<b>B</b>). No significant correlation was observed in (<b>A</b>), and age did not affect the attenuation of the Ab titers from 3 to 6 months after the vaccination. However, a significant correlation was observed in (<b>B</b>). Closed and open circles and continuous and broken lines show men and women, respectively.</p>
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14 pages, 1630 KiB  
Article
Nasal and Salivary Mucosal Humoral Immune Response Elicited by mRNA BNT162b2 COVID-19 Vaccine Compared to SARS-CoV-2 Natural Infection
by Mariapia Guerrieri, Beatrice Francavilla, Denise Fiorelli, Marzia Nuccetelli, Francesco Maria Passali, Luca Coppeta, Giuseppina Somma, Sergio Bernardini, Andrea Magrini and Stefano Di Girolamo
Vaccines 2021, 9(12), 1499; https://doi.org/10.3390/vaccines9121499 - 18 Dec 2021
Cited by 43 | Viewed by 7281 | Correction
Abstract
SARS-CoV-2 antibody assays are crucial in managing the COVID-19 pandemic. Approved mRNA COVID-19 vaccines are well known to induce a serum antibody responses against the spike protein and its RBD. Mucosal immunity plays a major role in the fight against COVID-19 directly at [...] Read more.
SARS-CoV-2 antibody assays are crucial in managing the COVID-19 pandemic. Approved mRNA COVID-19 vaccines are well known to induce a serum antibody responses against the spike protein and its RBD. Mucosal immunity plays a major role in the fight against COVID-19 directly at the site of virus entry; however, vaccine abilities to elicit mucosal immune responses have not been reported. We detected anti-SARS-CoV-2 IgA-S1 and IgG-RBD in three study populations (healthy controls, vaccinated subjects, and subjects recovered from COVID-19 infection) on serum, saliva, and nasal secretions using two commercial immunoassays (ELISA for IgA-S1 and chemiluminescent assay for IgG-RBD). Our results show that the mRNA BNT162b2 vaccine Comirnaty (Pfizer/BioNTech, New York, NY, USA) determines the production of nasal and salivary IgA-S1 and IgG-RBD against SARS-CoV-2. This mucosal humoral immune response is stronger after the injection of the second vaccine dose compared to subjects recovered from COVID-19. Since there is a lack of validated assays on saliva and nasal secretions, this study shows that our pre-analytical and analytical procedures are consistent with the data. Our findings indicate that the mRNA COVID-19 vaccine elicits antigen-specific nasal and salivary immune responses, and that mucosal antibody assays could be used as candidates for non-invasive monitoring of vaccine-induced protection against viral infection. Full article
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<p>Anti SARS-CoV-2 IgA-S1 and anti SARS-CoV-2 IgG-RBD in serum samples. (<b>a</b>) Serum sample median levels of anti SARS-CoV-2 IgA-S1 in the three study groups expressed as COI (Cut off index). (<b>b</b>) Serum sample median levels of anti SARS-CoV-2 IgG-RBD in the three study groups, expressed as Binding Antibody Units (BAU/mL). In the COVID-19 group, the red rhombuses represent the hospitalized subjects. Statistical analysis and construction of figures were performed with GraphPad Prism 8 Software (GraphPad Software, San Diego, CA, USA). The D’Agostino and Pearson test, Shapiro–Wilk normality test, and Kolmogorov–Smirnov test were used to evaluate non-Gaussian distributions in all study populations. The continuous data were displayed as median and range. Non-parametric results were analyzed with the Mann–Whitney test. For all of the results, <span class="html-italic">p</span> &lt; 0.05 was considered statistically significant.</p>
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<p>Anti-SARS-CoV-2 IgA-S1 and anti-SARS-CoV-2 IgG-RBD in saliva samples. (<b>a</b>) Saliva sample median levels of anti-SARS-CoV-2 IgA-S1 in the three study groups, expressed as COI (Cut off index). (<b>b</b>) Saliva sample median levels of anti-SARS-CoV-2 IgG-RBD in the three study groups, expressed as Binding Antibody Units (BAU/mL). In the COVID-19 group, the red rhombuses represent the hospitalized subjects. Statistical analysis and construction of figures were performed with GraphPad Prism 8 Software (GraphPad Software, San Diego, CA, USA). The D’Agostino and Pearson test, the Shapiro-Wilk normality test, and the Kolmogorov–Smirnov test were used to evaluate non-Gaussian distributions in all of the study populations. The continuous data were displayed as median and range. Non-parametric results were analysed with the Mann–Whitney test. For all results, <span class="html-italic">p</span> &lt; 0.05 was considered statistically significant.</p>
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<p>Anti SARS-CoV-2 IgA-S1 and anti SARS-CoV-2 IgG-RBD in nasal fluid samples. (<b>a</b>) Nasal fluid sample median levels of anti SARS-CoV-2 IgA-S1 in the three study groups, expressed as COI (Cut off index). (<b>b</b>) Nasal fluid sample median levels of anti SARS-CoV-2 IgG-RBD in the three study groups, expressed as Binding Antibody Units (BAU/mL). In the COVID-19 group, the red rhombuses represent the hospitalized subjects. Statistical analysis and construction of figures were performed with GraphPad Prism 8 Software (GraphPad Software, San Diego, CA, USA). The D’Agostino and Pearson test, Shapiro–Wilk normality test, and Kolmogorov– Smirnov test were used to evaluate the non-Gaussian distributions in all of the study populations. The continuous data were displayed as median and range. Non-parametric results were analysed with the Mann–Whitney test. For all of the results, <span class="html-italic">p</span> &lt; 0.05 was considered statistically significant.</p>
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<p>Anti SARS-CoV-2 IgA-S1 and anti SARS-CoV-2 IgG-RBD in nasal fluid samples of subjects recovered from previous mild and severe COVID-19 infection. (<b>a</b>) Nasal secretions median levels of anti SARS-CoV-2 IgA-S1 in subjects with previous mild COVID-19 infection and severe infection, expressed as COI (Cut off index). (<b>b</b>) Nasal fluid samples median levels of anti SARS-CoV-2 IgG-RBD in subjects with previous mild COVID-19 infection and hospitalized subjects, respectively, expressed as Binding Antibody Units (BAU/mL). Statistical analysis and construction of figures were performed with GraphPad Prism 8 Software (GraphPad Software, San Diego, CA, USA). The D’Agostino and Pearson test, Shapiro–Wilk normality test, and Kolmogorov–Smirnov test were used to evaluate non-Gaussian distributions in all study populations. The error bars report the median, and 75° and 25° percentiles. The non-parametric results were analysed with the Mann–Whitney test. For all of the results, <span class="html-italic">p</span> &lt; 0.05 was considered statistically significant.</p>
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14 pages, 1368 KiB  
Article
COVID-19 Passport as a Factor Determining the Success of National Vaccination Campaigns: Does It Work? The Case of Lithuania vs. Poland
by Marcin Piotr Walkowiak, Justyna B. Walkowiak and Dariusz Walkowiak
Vaccines 2021, 9(12), 1498; https://doi.org/10.3390/vaccines9121498 - 18 Dec 2021
Cited by 44 | Viewed by 6065
Abstract
As the ongoing COVID-19 pandemic poses a global threat, it is of utmost importance that governments should find effective means of combating vaccine hesitancy and encouraging their citizens to vaccinate. In our article, we compare the vaccination outcomes in the past months in [...] Read more.
As the ongoing COVID-19 pandemic poses a global threat, it is of utmost importance that governments should find effective means of combating vaccine hesitancy and encouraging their citizens to vaccinate. In our article, we compare the vaccination outcomes in the past months in two neighbouring post-communist EU states, Lithuania and Poland. Both introduced COVID-19 certificates, but only the former followed with gradual limitations for those who failed to get vaccinated, beginning with restricted access to restaurants, sports facilities and indoor events, and finally banning residents without a certificate from entering supermarkets or larger shops and using most services. By contrast, in Poland, the certificate remained a tool for international travel only. We show using statistical data that Lithuania’s strict policy, regardless of its social implications, led to markedly higher vaccination outcomes in all age groups than those in Poland at the time. Full article
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<p>Vaccination rate of the European Economic Area—percentage of adults who received at least one dose of COVID-19 vaccine as of 30 September 2021, data for Germany presented in pre-unification borders, with Berlin excluded, based on Koch Institute [<a href="#B28-vaccines-09-01498" class="html-bibr">28</a>]; source of data on other EEA states: ECDC [<a href="#B29-vaccines-09-01498" class="html-bibr">29</a>].</p>
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<p>Share of the adult population that has received at least one dose of COVID-19 vaccine until a particular day, source of data: covidvax.live [<a href="#B30-vaccines-09-01498" class="html-bibr">30</a>].</p>
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<p>Vaccination rate increase between 30 June 2021 and 31 October 2021, as a percentage of the remaining population that got vaccinated. Source: Ministry of Health of the Republic of Lithuania.</p>
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25 pages, 1071 KiB  
Review
Bacterial-Based Cancer Therapy (BBCT): Recent Advances, Current Challenges, and Future Prospects for Cancer Immunotherapy
by Kajal H. Gupta, Christina Nowicki, Eileena F. Giurini, Amanda L. Marzo and Andrew Zloza
Vaccines 2021, 9(12), 1497; https://doi.org/10.3390/vaccines9121497 - 18 Dec 2021
Cited by 54 | Viewed by 10018
Abstract
Currently approximately 10 million people die each year due to cancer, and cancer is the cause of every sixth death worldwide. Tremendous efforts and progress have been made towards finding a cure for cancer. However, numerous challenges have been faced due to adverse [...] Read more.
Currently approximately 10 million people die each year due to cancer, and cancer is the cause of every sixth death worldwide. Tremendous efforts and progress have been made towards finding a cure for cancer. However, numerous challenges have been faced due to adverse effects of chemotherapy, radiotherapy, and alternative cancer therapies, including toxicity to non-cancerous cells, the inability of drugs to reach deep tumor tissue, and the persistent problem of increasing drug resistance in tumor cells. These challenges have increased the demand for the development of alternative approaches with greater selectivity and effectiveness against tumor cells. Cancer immunotherapy has made significant advancements towards eliminating cancer. Our understanding of cancer-directed immune responses and the mechanisms through which immune cells invade tumors have extensively helped us in the development of new therapies. Among immunotherapies, the application of bacteria and bacterial-based products has promising potential to be used as treatments that combat cancer. Bacterial targeting of tumors has been developed as a unique therapeutic option that meets the ongoing challenges of cancer treatment. In comparison with other cancer therapeutics, bacterial-based therapies have capabilities for suppressing cancer. Bacteria are known to accumulate and proliferate in the tumor microenvironment and initiate antitumor immune responses. We are currently well-informed regarding various methods by which bacteria can be manipulated by simple genetic engineering or synthetic bioengineering to induce the production of anti-cancer drugs. Further, bacterial-based cancer therapy (BBCT) can be either used as a monotherapy or in combination with other anticancer therapies for better clinical outcomes. Here, we review recent advances, current challenges, and prospects of bacteria and bacterial products in the development of BBCTs. Full article
(This article belongs to the Special Issue Cancer Immunotherapy and Vaccines Research)
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<p>Schematic summary of the various bacterial mechanisms utilized in BBCT. (1) Anaerobic facultative bacteria specifically target the hypoxic environment of tumors initiating an inflammatory reaction resulting in tumor destruction. (2) Bacteriobots for cancer therapy, which involve targeting controlled drug release, improved cell adhesion, and improved penetration into the cell. (3) Bacterial virulence factors (e.g., msbB, purl, relA, SpoT) can be bioengineered to reduce toxicity and increase tumor cell death. (4) Bacterial toxins, such as the bacterial secretory system (T1SS and T3SS), can be used to inhibit the growth of solid tumors. (5) Bacterial mutations help delivery of immunomodulators such as cytokines, chemokines, and small molecules along with immune checkpoint antibodies, which can stimulate anti-tumor responses. This figure was created using Biorender.com.</p>
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13 pages, 885 KiB  
Article
COVID-19 Vaccinations: Perceptions and Behaviours in People with Primary Ciliary Dyskinesia
by Eva S. L. Pedersen, Maria Christina Mallet, Yin Ting Lam, Sara Bellu, Isabelle Cizeau, Fiona Copeland, Trini Lopez Fernandez, Michele Manion, Amanda L. Harris, Jane S. Lucas, Francesca Santamaria, Myrofora Goutaki, Claudia E. Kuehni and COVID-PCD Patient Advisory Group
Vaccines 2021, 9(12), 1496; https://doi.org/10.3390/vaccines9121496 - 17 Dec 2021
Cited by 4 | Viewed by 3867
Abstract
Primary ciliary dyskinesia (PCD) is a rare genetic disease that causes recurrent respiratory infections. People with PCD may be at higher risk of severe coronavirus disease 2019 (COVID-19), and therefore vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is important. We studied [...] Read more.
Primary ciliary dyskinesia (PCD) is a rare genetic disease that causes recurrent respiratory infections. People with PCD may be at higher risk of severe coronavirus disease 2019 (COVID-19), and therefore vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is important. We studied vaccination willingness, speed of vaccination uptake, side effects, and changes in social contact behaviour after vaccination in people with PCD. We used data from COVID-PCD, an international participatory cohort study. A COVID-19 vaccination questionnaire was emailed to participants in May 2021 and 423 participants from 31 countries replied (median age: 30 years, range 1–85 years; 261 (62%) female). Vaccination uptake and willingness were high, with 273 of 287 adults (96%) being vaccinated or willing to be in June 2021; only 4% were hesitant. The most common reason for hesitancy was fear of side effects, reported by 88%. Mild side effects were common, but no participant reported severe side effects. Half of the participants changed their social behaviour after vaccination by seeing friends and family more often. The high vaccination willingness in the study population might reflect the extraordinary effort taken by PCD support groups to inform people about COVID-19 vaccination. Clear and specific information and involvement of representatives is important for high vaccine uptake. Full article
(This article belongs to the Section Epidemiology)
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<p>Reasons for getting vaccinated among participants who already got vaccinated or wanted to get vaccinated among adults (<span class="html-italic">n</span> = 272) and children and adolescents (<span class="html-italic">n</span> = 94). Responses rated from very important to unimportant. (COVID-PCD study, May 2021). Abbreviations: A = adults aged 18 years or above; C = children and adolescents below 18 years.</p>
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<p>Agreement (rated as somewhat or strongly) with reasons against getting vaccinated among those who did not want to get vaccinated against COVID-19 (<span class="html-italic">n</span> = 20) and those who were not sure whether to get vaccinated (<span class="html-italic">n</span> = 34). (COVID-PCD study, May 2021).</p>
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<p>Self-reported side effects after first (<span class="html-italic">n</span> = 238) and after second vaccine (<span class="html-italic">n</span> = 214) among vaccinated participants including 95% confidence intervals (COVID-PCD study, May 2021). Other side effects included nausea, vomiting, diarrhoea, stomachache, dizziness, chills, breathlessness, cough, congestion, and swollen lymph nodes.</p>
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<p>Proportion of participants who reported how they changed their social behaviour after first and second vaccinations compared to before getting vaccinated (<span class="html-italic">n</span> = 282) (COVID-PCD study, May 2021).</p>
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12 pages, 302 KiB  
Article
Austria’s Digital Vaccination Registry: Stakeholder Views and Implications for Governance
by Katharina T. Paul, Anna Janny and Katharina Riesinger
Vaccines 2021, 9(12), 1495; https://doi.org/10.3390/vaccines9121495 - 17 Dec 2021
Cited by 4 | Viewed by 3001
Abstract
In this study, we explore the recent setup of a digital vaccination record in Austria. Working from a social-scientific perspective, we find that the introduction of the electronic vaccination pass was substantially accelerated by the COVID-19 pandemic. Our interviews with key stakeholders ( [...] Read more.
In this study, we explore the recent setup of a digital vaccination record in Austria. Working from a social-scientific perspective, we find that the introduction of the electronic vaccination pass was substantially accelerated by the COVID-19 pandemic. Our interviews with key stakeholders (n = 16) indicated that three main factors drove this acceleration. The pandemic (1) sidelined historical conflicts regarding data ownership and invoked a shared sense of the value of data, (2) accentuated the need for enhanced administrative efficiency in an institutionally fragmented system, and (3) helped invoke the national vaccination registry as an indispensable infrastructure for public health governance with the potential to innovate its healthcare system in the long term. Full article
(This article belongs to the Special Issue Digital Innovation in Immunisation Programmes and Policies)
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<p>Immunization data governance in Austria.</p>
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10 pages, 510 KiB  
Article
Serological Response to SARS-CoV-2 Messenger RNA Vaccine: Real-World Evidence from Italian Adult Population
by Rosa Papadopoli, Caterina De Sarro, Caterina Palleria, Luca Gallelli, Claudia Pileggi and Giovambattista De Sarro
Vaccines 2021, 9(12), 1494; https://doi.org/10.3390/vaccines9121494 - 17 Dec 2021
Cited by 9 | Viewed by 2626
Abstract
Background: This study aims to investigate the extent of the BNT162b2 mRNA vaccine-induced antibodies against SARS-CoV-2 in a large cohort of Italian subjects belonging to the early vaccinated cohort in Italy. Methods: A prospective study was conducted between December 2020 and May 2021. [...] Read more.
Background: This study aims to investigate the extent of the BNT162b2 mRNA vaccine-induced antibodies against SARS-CoV-2 in a large cohort of Italian subjects belonging to the early vaccinated cohort in Italy. Methods: A prospective study was conducted between December 2020 and May 2021. Three blood samples were collected for each participant: one at the time of the first vaccine dose (T0), one at the time of the second vaccine dose, (T1) and the third 30 days after this last dose (T2). Results: We enrolled 2591 fully vaccinated subjects; 16.5% were frail subjects, and 9.8% were over 80 years old. Overall, 98.1% of subjects were seropositive when tested at T2, and 76.3% developed an anti-S IgG titer ≥4160 AU/mL, which is adequate to develop viral neutralizing antibodies. Seronegative subjects at T1 were more likely to remain seronegative at T2 or to develop a low–intermediate anti-S IgG titer (51–4159 AU/mL). Conclusions: In summary, vaccination leads to detectable anti-S IgG titer in nearly all vaccine recipients. Stratification of the seroconversion level could be useful to promptly identify high-risk groups who may not develop a viral neutralizing response, even in the presence of seroconversion, and therefore may remain at higher risk of infection, despite vaccination. Full article
(This article belongs to the Section COVID-19 Vaccines and Vaccination)
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<p>Percentage of seroconversion (anti-S IgG ≥ 50 AU/mL) 30 days after the conclusion of full course of BTN162b2 vaccination, by age and sex.</p>
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21 pages, 5181 KiB  
Protocol
Detection and Quantification of SARS-CoV-2 Receptor Binding Domain Neutralization by a Sensitive Competitive ELISA Assay
by Ahmed O. Shalash, Armira Azuar, Harrison Y. R. Madge, Naphak Modhiran, Alberto A. Amarilla, Benjamin Liang, Alexander A. Khromykh, Daniel Watterson, Paul R. Young, Istvan Toth and Mariusz Skwarczynski
Vaccines 2021, 9(12), 1493; https://doi.org/10.3390/vaccines9121493 - 16 Dec 2021
Cited by 8 | Viewed by 4699
Abstract
This protocol describes an ELISA-based procedure for accurate measurement of SARS-CoV-2 spike protein-receptor binding domain (RBD) neutralization efficacy by murine immune serum. The procedure requires a small amount of S-protein/RBD and angiotensin converting enzyme-2 (ACE2). A high-throughput, simple ELISA technique is employed. Plate-coated-RBDs [...] Read more.
This protocol describes an ELISA-based procedure for accurate measurement of SARS-CoV-2 spike protein-receptor binding domain (RBD) neutralization efficacy by murine immune serum. The procedure requires a small amount of S-protein/RBD and angiotensin converting enzyme-2 (ACE2). A high-throughput, simple ELISA technique is employed. Plate-coated-RBDs are allowed to interact with the serum, then soluble ACE2 is added, followed by secondary antibodies and substrate. The key steps in this procedure include (1) serum heat treatment to prevent non-specific interactions, (2) proper use of blank controls to detect side reactions and eliminate secondary antibody cross-reactivity, (3) the addition of an optimal amount of saturating ACE2 to maximize sensitivity and prevent non-competitive co-occurrence of RBD-ACE2 binding and neutralization, and (4) mechanistically derived neutralization calculation using a calibration curve. Even manually, the protocol can be completed in 16 h for >30 serum samples; this includes the 7.5 h of incubation time. This automatable, high-throughput, competitive ELISA assay can screen a large number of sera, and does not require sterile conditions or special containment measures, as live viruses are not employed. In comparison to the ‘gold standard’ assays (virus neutralization titers (VNT) or plaque reduction neutralization titers (PRNT)), which are laborious and time consuming and require special containment measures due to their use of live viruses. This simple, alternative neutralization efficacy assay can be a great asset for initial vaccine development stages. The assay successfully passed conventional validation parameters (sensitivity, specificity, precision, and accuracy) and results with moderately neutralizing murine sera correlated with VNT assay results (R2 = 0.975, n = 25), demonstrating high sensitivity. Full article
(This article belongs to the Special Issue The COVID Vaccine)
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<p>Schematic representation of various reported assay strategies. (<b>A</b>) This strategy involves coating ELISA plates with SARS-2-RBD, employing neutralizing sera or unknown Abs, applying known competing biotinylated neutralizing Abs, then adding chromogen-streptavidin followed by substrate for color generation and detection via plate common readers. (<b>B</b>) This strategy involves coating ELISA plates with ACE2, then employing a mixture of neutralizing sera and human IgG-Fc-RBD conjugate (<span class="html-italic">hFc</span>-RBD), followed by anti-human IgG-Fc-HRP-conjugated secondary Abs (Anti-<span class="html-italic">hFc</span>-2<sup>ry</sup> Ab-HRP) and substrate. (<b>C</b>) This strategy utilizes the capture ELISA principle, where anti-histidine rabbit Abs are coated onto the plates, followed by capture of the applied His-tagged RBD. Neutralizing sera or purified antibodies are applied, followed by human IgG-Fc-conjugated ACE2 (<span class="html-italic">hFc</span>-Ace2), then anti-<span class="html-italic">hFc</span>-2<sup>ry</sup> Ab-HRP and substrate. (<b>D</b>) Our strategy, which is reported herein, involves coating the ELISA plates with RBD, applying neutralizing sera and <span class="html-italic">hFc</span>-ACE2 (or biotin-tagged ACE2), then adding anti-<span class="html-italic">hFc</span>-2<sup>ry</sup> Ab-HRP (or chromogen-streptavidin), respectively, with substrate for color generation and detection.</p>
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<p>The binding affinity of ACE2 added to immobilized RBD. RBD (50 ng/100 µL per well) was immobilized on ELISA plates, then ACE2 solutions with various concentrations were added to the immobilized RBD. Bound ACE2 and saturation were determined from the OD<sub>450</sub> signal and fitted to a four-parameter logistic function, providing an R<sup>2</sup> = 0.99 and a binding affinity dissociation constant of <span class="html-italic">K<sub>D</sub></span> = 10 ng/100 µL, as determined at 50% of the maximum signal reading. The highest reading that resulted in significant OD increase corresponded to 250 ng/100 µL of <span class="html-italic">hFc</span>-ACE2. Therefore, a 5:1 concentration ratio of <span class="html-italic">hFc</span>-ACE2 to RBD (or 200 ng/100 µL, 4:1 ratio of ACE2/biotinylated-ACE2) is required for saturation with a statistically significant maximum OD signal (<span class="html-italic">p</span> &lt; 0.05). This corresponds to an equimolar ratio between the two proteins that achieves a 1:1 binding ratio. Asterisks represent the statistical significance level of each data point (compared to the preceding data point) using the student <span class="html-italic">t</span>-test, * <span class="html-italic">p</span> ≤ 0.05; ** <span class="html-italic">p</span> &lt; 0.01; *** <span class="html-italic">p</span> &lt; 0.001; ns is non-significant, <span class="html-italic">p</span> &gt; 0.05.</p>
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<p>Schematic diagram depicting the cELISA processing steps and expected outcomes. RBD antigen is coated onto sample plates and, in different amounts, onto a calibration curve plate. The wells are blocked with 2% BSA solution to prevent further non-specific binding.</p>
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<p>The correlated data belong to six groups of mice, comprising 24 different weakly-to-moderately neutralizing murine sera at different dilutions: (<b>A</b>) the correlation between combined group mean neutralization (%) values from the VNT assay and heat-inactivated sera cELISA assay was R<sup>2</sup> = 0.98, <span class="html-italic">n</span> = 10; (<b>B</b>) the correlation between individual mouse immune serum neutralization (%) values from the VNT assay and heat treated serum cELISA assay was R<sup>2</sup> = 0.975, <span class="html-italic">n</span> = 25; (<b>C</b>) the correlation between individual mouse immune serum neutralization (%) values from the VNT assay and untreated serum cELISA assay was R<sup>2</sup> = 0.54, <span class="html-italic">n</span> = 25; (<b>D</b>) the correlation between reciprocal serum dilutions that corresponded to 50% neutralization efficacy (<span class="html-italic">N</span><sub>50</sub>) between both assays (VNT and heat-treated serum cELISA) using heat-inactivated weak-to-moderately neutralizing murine sera profiles that were within the detectable range of both assays.</p>
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<p>Schematic depicting cELISA plates: calibration curve (CC)-plate and sample (S)-plate arrangement, orientation, and associated dilutions. The lowest calibration curve value (0.78%) corresponds to our assay’s detection limit. Accurate quantitation starts from ≥6.25%. S-plate sample rows have RBD, BSA block, serum, ACE2, and 2<sup>ry</sup> Ab. S-plate blank ACE2 rows have RBD, BSA block, the same serum, and 2<sup>ry</sup> Ab. CC-plate calibration curve rows have RBD (different amounts), BSA block, ACE2, and 2<sup>ry</sup> Ab. CC-plate background rows have BSA block, ACE2, and 2<sup>ry</sup> Ab. To check non-specific serum interactions (with ACE2 and/or 2<sup>ry</sup> Abs) and efficient washing (of ACE2 and 2<sup>ry</sup> Abs), background and blank ACE2 rows are employed.</p>
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<p>Schematic process diagram showing how to establish a calibration curve plot and interpolate the calibration curve using individual blank ACE2-corrected serum OD readings to obtain bound ACE2 (%) for each serum dilution.</p>
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<p>Schematic diagram depicting the processing of blank ACE2-corrected interpolated serum neutralization data from S-plates and the calibration curve (left panel), and plotting these against their corresponding reciprocal serum dilution values to obtain neutralization 50% (right panel dashed bold arrows) and nAb titers (right panel solid line thin arrows) for a given neutralizing serum sample.</p>
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<p>Sample of the calibration curve plate (CC-plate).</p>
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<p>Depicting results of CC- and S-plate using the calculation sheet, fitting of calibration curve replicates to sigmoidal function (<b>A</b>), fitting of individual mice serum neutralization <span class="html-italic">N</span>% (of RBD-ACE2 binding) as a function of serum dilution (<b>B</b>), and the resulting mean group nAb titer column graph (<b>C</b>).</p>
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25 pages, 23962 KiB  
Article
A Yellow Fever 17D Virus Replicon-Based Vaccine Platform for Emerging Coronaviruses
by Nadia Oreshkova, Sebenzile K. Myeni, Niraj Mishra, Irina C. Albulescu, Tim J. Dalebout, Eric J. Snijder, Peter J. Bredenbeek, Kai Dallmeier and Marjolein Kikkert
Vaccines 2021, 9(12), 1492; https://doi.org/10.3390/vaccines9121492 - 16 Dec 2021
Cited by 4 | Viewed by 4197
Abstract
The tremendous global impact of the current SARS-CoV-2 pandemic, as well as other current and recent outbreaks of (re)emerging viruses, emphasize the need for fast-track development of effective vaccines. Yellow fever virus 17D (YF17D) is a live-attenuated virus vaccine with an impressive efficacy [...] Read more.
The tremendous global impact of the current SARS-CoV-2 pandemic, as well as other current and recent outbreaks of (re)emerging viruses, emphasize the need for fast-track development of effective vaccines. Yellow fever virus 17D (YF17D) is a live-attenuated virus vaccine with an impressive efficacy record in humans, and therefore, it is a very attractive platform for the development of novel chimeric vaccines against various pathogens. In the present study, we generated a YF17D-based replicon vaccine platform by replacing the prM and E surface proteins of YF17D with antigenic subdomains from the spike (S) proteins of three different betacoronaviruses: MERS-CoV, SARS-CoV and MHV. The prM and E proteins were provided in trans for the packaging of these RNA replicons into single-round infectious particles capable of expressing coronavirus antigens in infected cells. YF17D replicon particles expressing the S1 regions of the MERS-CoV and SARS-CoV spike proteins were immunogenic in mice and elicited (neutralizing) antibody responses against both the YF17D vector and the coronavirus inserts. Thus, YF17D replicon-based vaccines, and their potential DNA- or mRNA-based derivatives, may constitute a promising and particularly safe vaccine platform for current and future emerging coronaviruses. Full article
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<p>Design and characterization of YF-replicons expressing the RBD or S1 domain of the MERS-CoV S protein. (<b>A</b>) Schematic representation of the YFV genome and that of a YF replicon, in which the sequences encoding the glycoproteins prM and E are replaced by a sequence encoding a foreign protein. (<b>B</b>) Schematic representation of the MERS-CoV spike protein and its subdomains; SS—signal sequence; TMA—transmembrane anchor. Cleavage site between S1 and S2 is illustrated with an asterisk. (<b>C</b>) Cartoon showing the membrane topology of the YFV (left panel) and YF replicon (right panel) polyprotein. The yellow arrows indicate cleavage sites in the viral/replicon polyprotein. The bars that traverse the membrane represent the transmembrane anchors (TMA) of the N-terminally located protein. The red circle highlights the prM amino acid sequence retained at the site of the luminal cleavage that releases the N-terminus of the foreign insert. (<b>D</b>) Western blot analysis confirming the expression and processing of YF-replicon polyproteins, as compared to YFV-17D, using a polyclonal serum against YFV. Arrows on the right indicate the viral proteins (blue) and the intracellular chaperon cyclophilin B (CypB), which was used as a loading control (black). (<b>E</b>,<b>F</b>) Western blot analysis of the expression and glycosylation status of the RBD (red arrow)/S1 (black arrow) domains (<b>E</b>) or the full-length S protein (<b>F</b>, black arrow), expressed from YF replicons as indicated. Treatment with PNGase revealed the expected glycosylated nature of each of these proteins.</p>
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<p>Immunofluorescent images of cells containing YF-replicons that express domains of the MERS-CoV S protein. Cells were either permeabilized with Triton X-100 for intracellular staining or left untreated for surface staining. (<b>A</b>) Surface and intracellular expression of the foreign domains RBD or S1. Cells were costained for protein disulfide isomerase (PDI) and MERS-CoV spike RBD. (<b>B</b>) Surface and intracellular expression of the RBD domain of MERS-CoV spike protein fused to either the SINV E2 TMR or the authentic YFV-E TMR in cells. Cells were costained for PDI. (<b>A</b>,<b>B</b>) PDI is stained red and RBD, green, and cell nuclei are visualized with DAPI staining (blue). A 63× objective (with immersion) was used to obtain the images.</p>
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<p>Characterization of MERS-CoV spike RBD- or S1-expressing replicons containing a furin cleavage site at the C-terminus of the insert. (<b>A</b>) Schematic representation of the YF-replicons with a consensus furin cleavage site, inserted at the C-terminus of the foreign domain RBD/S1 and upstream of the TMR. Successful furin cleavage results in the release of the RBD/S1 domain from the TMR and secretion in the medium. (<b>B</b>,<b>C</b>) Western blot analysis of cell lysates and supernatants of cells containing RBD- or S1-YF-replicons with or without engineered furin cleavage sites. Cell lysates were harvested at 1 day postelectroporation and are indicated by the “C” lanes. Supernatants were harvested 1 or 2 days postelectroporation and are indicated as “S d1” and “S d2”, respectively. The quantities of the cell lysates loaded on gel were normalized for the percentage of replicon-positive cells, as determined by flow cytometry (data not shown). The quantity of the supernatants was normalized to correspond to the amount of the loaded cells. The detected proteins are indicated on the right of the Western blot images. NS4B is a yellow fever virus protein and demonstrates the level of expression of the replicons. Intracellular chaperon cyclophilin B (CypB) was used as an internal control. (<b>D</b>) Amino acid sequence of the authentic C-terminal part of MERS-CoV S1 with its furin cleavage site (left box) and with the deletion of the furin cleavage site in the YF replicon (right box). (<b>E</b>) Amino acid sequence of the C-terminus of the RBD (upper left box, black letters) or S1 domains (lower left box, black letters) and the start of the downstream TMR (left boxes, pink letters) in the YF-replicons without furin cleavage sites and with introduced consensus furin cleavage sites (right boxes, yellow letters). The grey letters show the N-terminal 6 amino acids of the S2 domain of MERS-CoV spike used as a short spacer between the furin cleavage site and the downstream TMR. (<b>D</b>,<b>E</b>) Numbers illustrate amino acid position in the spike protein.</p>
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<p>Characterization of YF-replicons expressing various coronavirus inserts. (<b>A</b>) Schematic representation of the SARS-CoV and MHV S proteins. SS—signal sequence; TMA—transmembrane anchor. Cleavage site between S1 and S2 is illustrated with an asterisk. (<b>B</b>) Western blot analysis of the expression of the RBD or S1 domains of SARS-CoV and MHV, as well as mCherry, in lysates from cells containing the respective replicons. The quantities of the cell lysates loaded on gel were normalized for the percentage of replicon-positive cells, as determined by flow cytometry. (<b>C</b>) Western blot analysis of the glycosylation status of the RBD and S1 domains of SARS-CoV or mCherry after PNGase treatment of lysates from cells containing the respective YF-replicons. (<b>B</b>,<b>C</b>) Bands with the expected size for all inserts are indicated with colored rectangles: red for mCherry, light blue for MERS-CoV RBD, purple for MERS-CoV S1, light green for MHV RBD, and dark green for MHV S1. The antibodies used are shown on the right. A protein size marker is shown on the left. CypB and YFV NS4B were used as internal and replicon expression controls, respectively.</p>
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<p>Expression of MERS-CoV RBD, following infection with replicon particles. Supernatants from BHK-21cells that were electroporated with either a plasmid encoding YFV prM/E, in vitro transcribed replicon RNA expressing the MERS-CoV RBD (YFrepl-RBD) or both, were harvested 24 or 48 h postelectroporation and used to infect fresh BHK-21 cells. After 24 h of incubation, the cells were fixated and analyzed by immunofluorescence microscopy. The RBD domain is stained in red. A 20× objective was used to obtain the images.</p>
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<p>Humoral immune responses in mice, immunized with YF-replicons. (<b>A</b>) Schematic representation of the experimental design. (<b>B</b>–<b>D</b>) YFV-NS1-specific, (<b>E</b>,<b>F</b>) MERS-CoV S1-specific and (<b>G</b>) SARS-CoV S1-specific IgG antibodies, as measured by ELISA and expressed as endpoint titers. (<b>H</b>–<b>J</b>) Neutralizing titers against MERS-CoV (<b>H</b>,<b>I</b>) and against mouse-adapted SARS-CoV strain MA15 and a human-derived SARS-CoV strain Fr-1 (<b>J</b>) as measured by virus neutralization test and expressed as endpoint titers. The dotted lines indicate the lowest detectable titer (detection limit of the assay). All symbols represent individual titer values, and the geometric means are shown with horizontal lines. The YF-replicon used as a vaccine is shown above each graph. Statistical analysis was performed with nonparametric ANOVA (<b>B</b>–<b>D</b>) and with a <span class="html-italic">t</span>-test (<b>E</b>,<b>F</b>,<b>H</b>–<b>J</b>). Differences with <span class="html-italic">p</span> values ≤ 0.05 were considered significant and are shown where relevant. On the x-axis, days post-prime vaccination are shown.</p>
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16 pages, 1788 KiB  
Communication
Immunogenicity of a DNA-Based Sindbis Replicon Expressing Crimean–Congo Hemorrhagic Fever Virus Nucleoprotein
by Thomas Tipih, Mark Heise and Felicity Jane Burt
Vaccines 2021, 9(12), 1491; https://doi.org/10.3390/vaccines9121491 - 16 Dec 2021
Cited by 10 | Viewed by 3450
Abstract
Crimean–Congo hemorrhagic fever virus (CCHFV) infrequently causes hemorrhagic fever in humans with a case fatality rate of 30%. Currently, there is neither an internationally approved antiviral drug nor a vaccine against the virus. A replicon based on the Sindbis virus vector encoding the [...] Read more.
Crimean–Congo hemorrhagic fever virus (CCHFV) infrequently causes hemorrhagic fever in humans with a case fatality rate of 30%. Currently, there is neither an internationally approved antiviral drug nor a vaccine against the virus. A replicon based on the Sindbis virus vector encoding the complete open reading frame of a CCHFV nucleoprotein from a South African isolate was prepared and investigated as a possible candidate vaccine. The transcription of CCHFV RNA and recombinant protein production by the replicon were characterized in transfected baby hamster kidney cells. A replicon encoding CCHFV nucleoprotein inserted in plasmid DNA, pSinCCHF-52S, directed transcription of CCHFV RNA in the transfected cells. NIH-III heterozygous mice immunized with pSinCCHF-52S generated CCHFV IgG specific antibodies with notably higher levels of IgG2a compared to IgG1. Splenocytes from mice immunized with pSinCCHF-52S secreted IFN-γ and IL-2, low levels of IL-6 or IL-10, and no IL-4. No specific cytokine production was registered in splenocytes of mock-immunized mice (p < 0.05). Thus, our study demonstrated the expression of CCHFV nucleoprotein by a Sindbis virus vector and its immunogenicity in mice. The spectrum of cytokine production and antibody profile indicated predominantly Th1-type of an anti-CCHFV immune response. Further studies in CCHFV-susceptible animals are necessary to determine whether the induced immune response is protective. Full article
(This article belongs to the Special Issue Perspective Technologies of Vaccination and Immunotherapy)
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<p>BHK-21 cells transfected with pSinCCHF-52S encoding His-tagged CCHFV nucleoprotein (NP) fused to the polyhistidine tag were specifically stained with anti-His<sub>6</sub> antibody (<b>A</b>,<b>B</b>) and anti-CCHFV IgG human serum (<b>C</b>,<b>D</b>) in immunofluorescence test, and expressed protein with a molecular mass of 52 kDa stained with anti-His tag antibodies (<b>E</b>). BHK-21 cells transfected with replicon pSinCCHF-52S (<b>A</b>,<b>C</b>); mock-transfected BHK-21 cells (<b>B</b>,<b>D</b>); images were captured using the Olympus BX51 fluorescence microscope (USA) (×40). Western-blot analysis of CCHFV NP using mouse anti-His6 monoclonal antibody (<b>E</b>): Lane 1: MagicMark XP Western Protein Standard, Lane 2: BHK-21 cells transfected with pSinCCHF-52S, Lane 3: Mock-transfected BHK-21 cells. The position of the molecular mass marker is shown on the left.</p>
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<p>BHK-21 cells transfected with pSinCCHF-52S encoding His-tagged CCHFV nucleoprotein (NP) fused to the polyhistidine tag were specifically stained with anti-His<sub>6</sub> antibody (<b>A</b>,<b>B</b>) and anti-CCHFV IgG human serum (<b>C</b>,<b>D</b>) in immunofluorescence test, and expressed protein with a molecular mass of 52 kDa stained with anti-His tag antibodies (<b>E</b>). BHK-21 cells transfected with replicon pSinCCHF-52S (<b>A</b>,<b>C</b>); mock-transfected BHK-21 cells (<b>B</b>,<b>D</b>); images were captured using the Olympus BX51 fluorescence microscope (USA) (×40). Western-blot analysis of CCHFV NP using mouse anti-His6 monoclonal antibody (<b>E</b>): Lane 1: MagicMark XP Western Protein Standard, Lane 2: BHK-21 cells transfected with pSinCCHF-52S, Lane 3: Mock-transfected BHK-21 cells. The position of the molecular mass marker is shown on the left.</p>
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<p>Kinetics of CCHFV NP total RNA expression in BHK-21 cells electroporated with pSinCCHF-52S registered 4 to 48 h post-transfection. No CCHFV RNA was detected in cells after transfection with pSinGFP. * Signal was significantly higher than that generated by qRT-PCR of cells transfected with pSinGFP (&lt;1.0 × 10<sup>3</sup>; <span class="html-italic">p</span> &lt; 0.05; <a href="#app1-vaccines-09-01491" class="html-app">Supplementary Table S1</a>).</p>
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<p>Antibody responses induced by immunization with pSinCCHF-52S. Indirect immunofluorescence analysis of serum CCHFV NP IgG antibodies from pSinCCHF-52S immunized mice with and without Poly (I:C) (<b>A1</b>–<b>A5</b>): (<b>A1</b>) mouse 1, (<b>A2</b>) mouse 2, (<b>A3</b>) mouse 3, (<b>A4</b>) mouse 4, (<b>A5</b>) mouse 5 compared to mice immunized with pSinGFP (<b>B1</b>–<b>B3</b>): (<b>B1</b>) mouse 1, (<b>B2</b>) mouse 2, and (<b>B3</b>) mouse 3. (<b>C1</b>)<b>,</b> positive control. Images were captured using the Nikon ECLIPSE Ni-U fluorescence microscope (USA) (×20). Anti-CCHFV NP IgG endpoint titer (<b>C</b>). Anti-CCHFV NP IgG endpoint titer and IgG2a/IgG1 ratios (<b>D</b>). Mice (NIH; <span class="html-italic">n</span> = 5/group) were immunized three times intramuscularly with the prepared pSinCCHF-52S construct expressing CCHFV nucleoprotein with (<span class="html-italic">n</span> = 2) and without Poly (I:C) (<span class="html-italic">n</span> = 3). Serum anti-CCHFV NP IgG were analyzed using a commercially available indirect immunofluorescent assay. Data are expressed as the mean for five mice (pSinCCHF-52S) and three mice for pSinGFP and the standard error of the mean. * <span class="html-italic">p</span> &lt; 0.05 by Mann–Whitney U test.</p>
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<p>Immunization of mice with pSinCCHF-52S expressing NP protein of CCHFV (<span class="html-italic">n</span> = 5) induced specific production of IFN-γ (<span class="html-italic">p</span> = 0.0369) (<b>A</b>), IL-2 (<span class="html-italic">p</span> = 0.0495) (<b>B</b>), and an insignificant increase in production of TNF-a (<span class="html-italic">p</span> = 0.1) (<b>C</b>) as compared to cytokine responses in mice immunized with pSinGFP (<span class="html-italic">n</span> = 3). Murine splenocytes were stimulated with CCHFV antigen, as described in the Materials and Methods section. Cytokine expression was measured by ELISA using commercial kits (eBioscience, San Diego, CA, USA). Data are expressed as the mean for the group, with the standard error of the mean. * <span class="html-italic">p</span> &lt; 0.05.</p>
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31 pages, 6383 KiB  
Review
Vaccine Technologies and Platforms for Infectious Diseases: Current Progress, Challenges, and Opportunities
by Majed Ghattas, Garima Dwivedi, Marc Lavertu and Mohamad-Gabriel Alameh
Vaccines 2021, 9(12), 1490; https://doi.org/10.3390/vaccines9121490 - 16 Dec 2021
Cited by 88 | Viewed by 18840
Abstract
Vaccination is a key component of public health policy with demonstrated cost-effective benefits in protecting both human and animal populations. Vaccines can be manufactured under multiple forms including, inactivated (killed), toxoid, live attenuated, Virus-like Particles, synthetic peptide, polysaccharide, polysaccharide conjugate (glycoconjugate), viral vectored [...] Read more.
Vaccination is a key component of public health policy with demonstrated cost-effective benefits in protecting both human and animal populations. Vaccines can be manufactured under multiple forms including, inactivated (killed), toxoid, live attenuated, Virus-like Particles, synthetic peptide, polysaccharide, polysaccharide conjugate (glycoconjugate), viral vectored (vector-based), nucleic acids (DNA and mRNA) and bacterial vector/synthetic antigen presenting cells. Several processes are used in the manufacturing of vaccines and recent developments in medical/biomedical engineering, biology, immunology, and vaccinology have led to the emergence of innovative nucleic acid vaccines, a novel category added to conventional and subunit vaccines. In this review, we have summarized recent advances in vaccine technologies and platforms focusing on their mechanisms of action, advantages, and possible drawbacks. Full article
(This article belongs to the Section Vaccines against Tropical and other Infectious Diseases)
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<p>Schematic representation of common vaccine components, showing the typical vaccine components, including the active ingredients, stabilizers, adjuvants, preservatives, antibiotics, and trace components.</p>
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<p>Basics of the immune response to vaccines following intramuscular administration. Vaccine components (e.g., antigen, and/or adjuvant) are recognized and phagocytosed (or uptaken) by tissue resident innate immune cells, or antigen presenting cells (APCs), such as dendritic cells (DCs) and macrophages (Mϕs). The process of antigen and/or adjuvant recognition, phagocytosis, and intracellular processing of antigens induce APCs to mature (e.g., increased expression of clusters of differentiation (CDs) such as CD80, CD40, MHC…), and migrate to secondary lymphoid organs (SLO; e.g., draining lymph nodes (dLN), and the spleen). Incoming APCs encounter and interact with T lymphocytes through molecular recognition between the APCs major histocompatibility complex (MHC) and the T cell receptor (TCR); also known as signal 1. This interaction is stabilized through an additional set of interactions between receptors, or co-receptors, on both cell types (i.e., CD40-CD40L); also known as signal 2. Interaction between MHC-II and the TCR, co-receptors, and APC secreted cytokines (also known as signal 3) induces the activation of helper T cells (T<sub>h</sub> or CD4<sup>+</sup> T cells). In some cases, antigens may be cross-presented on class I MHC in addition to the canonical class II MHC presentation. The former interacts with the TCR of CD8<sup>+</sup> T cells, leading to their differentiation into effector (cytotoxic) T cells and memory CD8<sup>+</sup> T cells. CD4<sup>+</sup> T cells differentiate into one of the subclasses (e.g., Th2, Tfh, Th17, Th9…).</p>
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<p>Schematic representation of the different vaccine platforms for infectious diseases, showing different vaccine technologies against (<b>A</b>) viral, and (<b>B</b>) bacterial pathogens.</p>
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<p>Schematic representation of the production and purification process during manufacturing of Virus-like Particles (VLPs), shows (<b>A</b>) the manufacturing process of VLPs and (<b>B</b>) their expression in cell systems.</p>
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<p>Schematic representation of viral and bacterial structures, showing the typical components of enveloped and non-enveloped viruses (<b>Left</b>), and bacteria (<b>Right</b>).</p>
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<p>Schematic representation of the production and purification process during manufacturing of viral vectors. Modified viral plasmids that code for the vector components and the vaccine immunogen (transgene) are designed to co-transfect packaging cells. Within the cells, the plasmids are expressed, resulting in viral particles containing the vaccine immunogen. Particles assemble in the cytoplasm and are released into the media via cellular lysis before further purification, concentration, diafiltration, and characterization.</p>
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<p>Schematic representation of the production and purification process during manufacturing of DNA and mRNA vaccines. (<b>Top</b>): Plasmid DNA production: Designing the sequence is the first step in developing a genomic vaccine followed by high cell-density fermentation, gene synthesis, and subcloning. Cells are harvested, lysed, and purified using chromatography. DNA plasmids are then sequenced for quality assurance before being concentrated, filtered, and sterilized for DNA vaccine formulations. (<b>Bottom</b>): mRNA production: mRNA synthesis for RNA-based vaccines requires the linearization of the DNA plasmid to ensure a run-off transcription. Synthesis of mRNA from the DNA plasmid template is catalyzed by an in vitro transcription (IVT) enzymatic process. RNA polymerase (ex. T7 Polymerase), nucleotide triphosphates (NTPs) substrates, polymerase cofactor MgCl<sub>2</sub>, a pH buffer containing polyamine, and antioxidants are all components of the IVT procedure. Following QC check, the mRNA is concentrated, filtered, and sterilized.</p>
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<p>Conventional, self-amplifying, trans-amplifying, and circular RNA vaccine designs. 5′ 7-methylguanosine triphosphate (m7G), 5′ Untranslated region (5′UTR), 3′ untranslated region (3′UTR), and poly A tail are common in all RNA designs. (<b>A</b>) Conventional unmodified, and nucleoside modified mRNA encoding vaccine immunogen. (<b>B</b>) Self-amplifying RNA encoding replicase gene, a subgenomic promoter, and the vaccine immunogen. Replicase genes (e.g., Alphavirus nsP1-4) code for RNA dependent RNA polymerase complex (RdRP) that recognizes the subgenomic promoter sequences and amplifies vaccine immunogen. (<b>C</b>) Trans-amplifying mRNA relies on the same concept of the self-amplifying mRNA but uses two different RNA transcripts: a conventional RNA encoding replicase genes and, an RNA encoding subgenomic promoter along with the vaccine immunogen. (<b>D</b>) Circular RNA engineered to enable protein expression through the addition of internal ribosomal entry sites (IRES) (e.g., encephalomyocarditis virus IRES) and/or the incorporation of specific nucleoside modifications in the 5′ UTR.</p>
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21 pages, 9856 KiB  
Systematic Review
Effectiveness of the WHO-Authorized COVID-19 Vaccines: A Rapid Review of Global Reports till 30 June 2021
by Chang-Jie Cheng, Chun-Yi Lu, Ya-Hui Chang, Yu Sun, Hai-Jui Chu, Chun-Yu Lee, Chang-Hsiu Liu, Cheng-Huai Lin, Chien-Jung Lu and Chung-Yi Li
Vaccines 2021, 9(12), 1489; https://doi.org/10.3390/vaccines9121489 - 16 Dec 2021
Cited by 18 | Viewed by 4258
Abstract
Large clinical trials have proven the efficacy of the COVID-19 vaccine, and the number of studies about the effectiveness rapidly grew in the first half of the year after mass vaccination was administrated globally. This rapid review aims to provide evidence syntheses as [...] Read more.
Large clinical trials have proven the efficacy of the COVID-19 vaccine, and the number of studies about the effectiveness rapidly grew in the first half of the year after mass vaccination was administrated globally. This rapid review aims to provide evidence syntheses as a means to complement the current evidence on the vaccine effectiveness (VE) against various outcomes in real-world settings. Databases (PubMed, EMBASE, and MedRxiv) were searched up to 30 June 2021, (PROSPERO ID: 266866). A total of 39 studies were included, covering over 15 million participants from 11 nations. Among the general population being fully vaccinated, the VE against symptomatic SARS-CoV-2 infection was estimated at 89–97%, 92% (95% CI, 78–97%), and 94% (95% CI, 86–97%) for BNT162b2, ChAdOx1, and mRNA-1273, respectively. As for the protective effects against B.1.617.2-related symptomatic infection, the VE was 88% (95% CI, 85.3–90.1%) by BNT162b2 and 67.0% (95% CI, 61.3–71.8%) by ChAdOx1 after full vaccination. This review revealed a consistently high effectiveness of certain vaccines among the general population in real-world settings. However, scarce data on the major variants of SARS-CoV-2 and the shortness of the study time may limit the conclusions to the mRNA vaccines and ChAdOx1. Full article
(This article belongs to the Special Issue The COVID Vaccine)
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<p>PRISMA flowchart of the literature searches.</p>
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<p>Vaccine effectiveness against overall SARS-CoV-2 infection.</p>
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<p>Vaccine effectiveness against various outcomes. (<b>A</b>) Vaccine effectiveness against asymptomatic infection. (<b>B</b>) Vaccine effectiveness against symptomatic infection. (<b>C</b>) Vaccine effectiveness against hospitalization. (<b>D</b>) Vaccine effectiveness against death. Abbreviations: RLCF: residents of long-term care facilities, SCC: subjects with comorbidity or chronic illness, 65PHC: individuals 65 years and older living at home but requiring practical help and personal care.</p>
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<p>Vaccine effectiveness against SARS-CoV-2 variants of concern.</p>
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13 pages, 2021 KiB  
Review
Neutrophil and Natural Killer Cell Interactions in Cancers: Dangerous Liaisons Instructing Immunosuppression and Angiogenesis
by Maria Teresa Palano, Matteo Gallazzi, Martina Cucchiara, Andrea De Lerma Barbaro, Daniela Gallo, Barbara Bassani, Antonino Bruno and Lorenzo Mortara
Vaccines 2021, 9(12), 1488; https://doi.org/10.3390/vaccines9121488 - 16 Dec 2021
Cited by 12 | Viewed by 5181
Abstract
The tumor immune microenvironment (TIME) has largely been reported to cooperate on tumor onset and progression, as a consequence of the phenotype/functional plasticity and adaptation capabilities of tumor-infiltrating and tumor-associated immune cells. Immune cells within the tumor micro (tissue-local) and macro (peripheral blood) [...] Read more.
The tumor immune microenvironment (TIME) has largely been reported to cooperate on tumor onset and progression, as a consequence of the phenotype/functional plasticity and adaptation capabilities of tumor-infiltrating and tumor-associated immune cells. Immune cells within the tumor micro (tissue-local) and macro (peripheral blood) environment closely interact by cell-to-cell contact and/or via soluble factors, also generating a tumor-permissive soil. These dangerous liaisons have been investigated for pillars of tumor immunology, such as tumor associated macrophages and T cell subsets. Here, we reviewed and discussed the contribution of selected innate immunity effector cells, namely neutrophils and natural killer cells, as “soloists” or by their “dangerous liaisons”, in favoring tumor progression by dissecting the cellular and molecular mechanisms involved. Full article
(This article belongs to the Special Issue Tumor Immunotherapy)
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<p><b>Neutrophil and NK cell subsets</b>. Human neutrophils (<b>A</b>) are characterized by CD11b, CD66b, CD14, and CD16 expression. Mimicking the M1 or M2-like macrophage polarization, neutrophils in the tumor microenvironment are also characterized by the capability to acquire two opposite phenotypes. N1 neutrophils (<b>B</b>) show anti-tumoral activities and are characterized by the expression of chemokine (C-C motif) ligand 3 (CCL3), tumor necrosis factor α (TNFα), arginase, and intercellular adhesion molecule 1 (ICAM1); in contrast, N2 neutrophils (<b>C</b>) work as tumor-promoters and express CC and CXC chemokines (CCL2, 3, 4, 8, 12 and 17 and CXCL1, 2, 8, and 16), vascular endothelial growth factor (VEGF), matrix metalloprotease 9 (MMP9), and CXCR4 receptor. Human NK cell subsets (<b>D</b>) are characterized by CD56 expression. Cytolytic NK cells express CD56 and CD16 (CD56<sup>dim</sup>CD16<sup>+</sup>) and can release perforin and granzyme; cytokine producer NK cells lose CD16 expression and increase CD56 expression (CD56<sup>brigth</sup>CD16<sup>−)</sup> with the production of cytokines including TNFα and interferon γ (IFNγ); the last subset is named decidual cells (dNKs) that displayed higher expression of CD56 with CD9 and CD49a markers (CD56<sup>superbrigth</sup>CD16<sup>−</sup>CD9<sup>+</sup>CD49a<sup>+</sup>) and support angiogenesis through the release of VEGF, placental growth factor (PlGF), and interleukin 6 (IL6). A similar subset named decidual-like NK cells is also found in the tumor microenvironment (TME).</p>
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<p><b>Neutrophil–NK cell crosstalk in tumor microenvironment</b>. Neutrophils can (<b>A</b>) induce reduction in CCR1 expression on NK cells, impairing the NK cells’ infiltration capability. Interference with PDL1-PD1 (<b>B</b>) interactions in the TME, resulting in reduced NK cell capability to release IFNγ. Neutrophils can also modulate the expression of activating receptor NKp46 on NK cells through (<b>C</b>) the release of different molecules that include: (i) neutrophil-derived Cathepsin G (CG) reduces NKp46 on NK cells; similar; (ii) reactive oxygen species (ROS) can downmodulate NKp46 on cytotoxic CD56<sup>dim</sup>CD16<sup>+</sup>NK cells while they can upregulate this receptor on cytokine-producer CD56<sup>brigth</sup>CD16<sup>−</sup> NK cells; (iii) elastase and lactoferrin release exert a wide effect increasing cytotoxicity and reducing angiogenesis. NK-derived IFNγ, a key mediator in TME, can be inversely modulated by ARG1 and IL12 from neutrophils (<b>D</b>). (i) Indeed, neutrophil-derived ARG1 can abrogate IFNγ released from NK, improving NK pro-angiogenic features; (ii) while neutrophil-derived IL12 through STAT4 activation increases IFNγ and perforin production by NK cells. NK cell–neutrophil crosstalk (<b>E</b>) can be modulated by NK-derived IFNγ, which acts by decreasing pro-angiogenic features of tumor associated neutrophils (TANs). Indeed, NK cells or IFNγ depletion increase TANs’ pro-angiogenic features.</p>
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<p><b>Neutrophil–NK cell crosstalk in angiogenesis modulation</b>. The bidirectional crosstalk between neutrophils and NK cells can negatively modulate angiogenesis thus (<b>A</b>) neutrophil derived IL12, 15, and 18 stimulate IP10, perforin, and granzyme production in NK cells that block FGF2 effect. In TME, NK cells can improve angiogenesis (<b>B</b>) through the production of IFNγ and granulocyte-macrophages colony-stimulating factor (GM-CSF), which results in neutrophil expression of CD11b, CD62L, and CD64 surface antigens and release or VEGF and MMP9, in a STAT3 and c-Myc dependent manner. Moreover, in neutrophils, CD64 expression is linked to increasing production of ARG1. On the other hand, (<b>C</b>) NK-derived IFNγ prevents VEGF release from neutrophils, reducing angiogenesis stimulation. Finally, panels B and C show how IFNγ, produced by NK cells, act as a double edge sword by exerting both pro-angiogenic and anti-angiogenic activities.</p>
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25 pages, 5098 KiB  
Article
Effects of Pope Francis’ Religious Authority and Media Coverage on Twitter User’s Attitudes toward COVID-19 Vaccination
by Arkadiusz Gaweł, Marzena Mańdziuk, Marek Żmudziński, Małgorzata Gosek, Marlena Krawczyk-Suszek, Mariusz Pisarski, Andrzej Adamski and Weronika Cyganik
Vaccines 2021, 9(12), 1487; https://doi.org/10.3390/vaccines9121487 - 16 Dec 2021
Cited by 8 | Viewed by 4312
Abstract
This paper is interdisciplinary and combines the research perspective of medical studies with that of media and social communication studies and theological studies. The main goal of this article is to determine [from arguments on all sides of the issue] whether, and to [...] Read more.
This paper is interdisciplinary and combines the research perspective of medical studies with that of media and social communication studies and theological studies. The main goal of this article is to determine [from arguments on all sides of the issue] whether, and to what extent, statements issued by a religious authority can be used as an argument in the COVID-19 vaccination campaign. The authors also want to find answers to the questions of how the pope’s comments affect public opinion when they concern the sphere of secular and everyday life, including issues related to health care. The main method used in this study is desktop research and the analysis of the Roman Catholic Church’s teaching on vaccination and on the types and significance of the pope’s statements on various topics. The auxiliary methods are sentiment analysis and network analysis made in the open source software Gephi. The authors are strongly interested in the communication and media aspect of the analyzed situation. Pope Francis’ voice on the COVID-19 vaccination has certainly been noticed and registered worldwide, but the effectiveness of his message and direct impact on Catholics’ decisions to accept or refuse the COVID-19 vaccination is quite questionable and would require further precise research. Comparing this to the regularities known from political marketing, one would think that the pope’s statement would not convince the firm opponents of vaccination. Full article
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<p>Most frequent words by type of sentiment. Made using the ggplot2 library in R (<a href="https://ggplot2.tidyverse.org/authors.html" target="_blank">https://ggplot2.tidyverse.org/authors.html</a>, accessed on 10 December 2021). The red bars represent sentiments found in tweets classified as negative using the tidytext library, while the blue bars represent positive tweets.</p>
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<p>Percentage of sentiments in all the words used in the tweets. Made using the ggplot2 library in R. The red bar shows the percentage of sentiment found in tweets classified as negative using the tidytext library, the blue bar shows the percentage of positive words in tweets—the percentage view.</p>
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<p>Number of tweets according to type. Made using the ggplot2 library in R. The green bar shows the number of tweets that do not contain charged tweets or the number of tweets for which the number of negative words used in the sentence equals the number of positive words. The blue bar shows the number of tweets in which the positive words used constitute the majority in the tweet, while the red bar is the opposite (the bar shows the number of tweets in a sentence in which the negative words used constitute the majority in that tweet).</p>
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<p>The most common bigrams. Made using ggplot2, tm and tidytext libraries in R.</p>
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<p>The most common trigrams. Made using ggplot2, tm and tidytext libraries in R.</p>
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<p>The most frequent emotions. Made using the ggplot2 and sentimentr libraries in R.</p>
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<p>The highest correlations with the word pope. Made using ggplot2 and widyr in R.</p>
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<p>The correlation of words above R &gt; 0.5. Made using ggraph and widyr in R.</p>
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<p>Twitter mentions graph (created in Force Atlas 2 and Fruchtenman Reingold layouts) represents Catholic and lay communities engaged in dissemination and discussion surrounding the Pope’s announcement. The initial announcements from Pontifex (Pope Francis Twitter’s account) and Catholic News Agency—represented by the blue areas in the centre—are re-broadcasted by large international news networks, such as CNN, Reuters, CBS, NBC, ABC, represented by purple, green orange and red areas to the right.</p>
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<p>Fruchtenman Reingold Twitter retweets graph reveals the prominent role of CNN (in purple and light green) in redistribution and embracement of the Vatican’s announcement. Catholic news sources are at the top of the graph (blue and teal); communities from Brazil and the Philippines in top left.</p>
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6 pages, 645 KiB  
Case Report
Immune Thrombocytopenia Induced by the Chimpanzee Adenovirus-Vectored Vaccine against SARS-CoV-2 Infection
by Po-Wei Liao, Chieh-Lin Jerry Teng and Cheng-Wei Chou
Vaccines 2021, 9(12), 1486; https://doi.org/10.3390/vaccines9121486 - 16 Dec 2021
Cited by 8 | Viewed by 2984
Abstract
We present a case of immune thrombocytopenia (ITP) induced by the chimpanzee adenovirus-vectored vaccine, without evidence of thrombosis, eight days after vaccine administration. The thrombocytopenia condition improved after administering steroid treatment. This adenovirus vaccine had been reported to induce rare side effects, such [...] Read more.
We present a case of immune thrombocytopenia (ITP) induced by the chimpanzee adenovirus-vectored vaccine, without evidence of thrombosis, eight days after vaccine administration. The thrombocytopenia condition improved after administering steroid treatment. This adenovirus vaccine had been reported to induce rare side effects, such as immune thrombotic thrombocytopenia. This case report showed that it could also induce immune thrombocytopenia without the presence of thrombosis. Therefore, we should be cautious of this rare side effect as global vaccine administrations against coronavirus disease increase. Full article
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<p>The peripheral blood smear and bone marrow aspiration findings. (<b>a</b>) The peripheral blood smear showed thrombocytopenia and no schistocyte. (<b>b</b>) The bone marrow aspiration showed normal morphology of megakaryocytes.</p>
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<p>Time course of the platelet count after first dose of ChAdOx1 nCoV-19 vaccine injection. The gray bar indicated that hydrocortisone was prescribed after the diagnosis of immune thrombocytopenia (ITP). The platelet count gradually recovered after hydrocortisone use without blood transfusion.</p>
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14 pages, 1322 KiB  
Article
Has Clinical and Epidemiological Varicella Burden Changed over Time in Children? Overview on Hospitalizations, Comorbidities and Costs from 2010 to 2017 in Italy
by Maria Francesca Piazza, Daniela Amicizia, Chiara Paganino, Francesca Marchini, Matteo Astengo, Federico Grammatico, Cecilia Trucchi, Paolo Romairone, Simona Simonetti, Camilla Sticchi and Filippo Ansaldi
Vaccines 2021, 9(12), 1485; https://doi.org/10.3390/vaccines9121485 - 15 Dec 2021
Cited by 4 | Viewed by 3256
Abstract
According to WHO estimates, varicella disease is responsible of a worldwide significant burden in terms of hospitalizations, complications, and deaths, with more than 90% of cases under 12 years old. This study aims at evaluating the clinical, epidemiological, and economic burden of varicella [...] Read more.
According to WHO estimates, varicella disease is responsible of a worldwide significant burden in terms of hospitalizations, complications, and deaths, with more than 90% of cases under 12 years old. This study aims at evaluating the clinical, epidemiological, and economic burden of varicella in Ligurian children, about comorbidities, organizational variables, and vaccination coverages from 2010 to 2017, in terms of Emergency Department accesses and hospitalizations. The overall hospitalization rate was 179.76 (per 100,000 inhab.), with a gradual but significant decline since 2015, when universal varicella vaccination was introduced in Liguria (p < 0.0001). The risk of being hospitalized for complicated varicella in subjects with at least one comorbidity was significantly higher than in subjects without comorbidities (p = 0.0016). The economic analysis showed higher costs in subjects with complicated varicella who were 0–3 years old. This age group showed higher costs also considering extra-hospital costs for both outpatient procedures and pharmaceutical costs (p < 0.0001). The results confirm the relevant burden of varicella, especially in the 0–3 age group and in children with comorbidities. Thus, vaccination with the achievement of adequate vaccination coverages is confirmed to be a necessary control strategy to reduce hospitalizations and associated complications with important economic benefits. Full article
(This article belongs to the Collection Vaccines against Infectious Diseases)
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<p>Number of hospitalizations due to varicella and hospitalization rate per 100,000 inhabitants in the Liguria region in Ligurian children aged 0–17 years old.</p>
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<p>Varicella ED accesses/hospitalizations per 100,000 inhabitants and vaccination coverage (VC) in Liguria at 24, 36 months and 5–6 years of age.</p>
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<p>Monthly hospitalization rates of varicella in Ligurian subjects aged 0–17 years old, study period 2010–2017.</p>
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9 pages, 1058 KiB  
Review
Undetectable Anti-HBs Antibodies: Need of a Booster Dose for HIV-1-Infected Individuals
by Yonas Bekele, Jay A. Berzofsky and Francesca Chiodi
Vaccines 2021, 9(12), 1484; https://doi.org/10.3390/vaccines9121484 - 15 Dec 2021
Cited by 2 | Viewed by 5073
Abstract
HBV vaccination effectively prevents HBV transmission and the development of liver cancer. Disease progression and liver-related complications are more common in HIV-1/HBV co-infected than HBV mono-infected individuals. A considerable body of literature, which will be reviewed here, indicates that response to HBV vaccine [...] Read more.
HBV vaccination effectively prevents HBV transmission and the development of liver cancer. Disease progression and liver-related complications are more common in HIV-1/HBV co-infected than HBV mono-infected individuals. A considerable body of literature, which will be reviewed here, indicates that response to HBV vaccine is suboptimal in HIV-1-infected individuals and that the poor maintenance of protective immunity to HBV vaccines in these individuals is an important medical issue. Several factors affect HBV vaccine response during HIV-1 infection including CD4+ T cell counts, B cell response, vaccine formulation, schedules, and timing of antiretroviral therapy (ART). The initial response to HBV vaccination also plays a critical role in the sustainability of antibody responses in both HIV-1-infected and uninfected vaccinees. Thus, regular follow-up for antibody titer and a booster dose is warranted to prevent HBV transmission in HIV-1 infected people. Full article
(This article belongs to the Special Issue Hepatitis and Vaccines)
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<p>Correlation of anti-HBs titer at 1 and 6 months from completed HBV vaccination. Three doses of HBV vaccine were administered to children who were negative for HBsAg and previously unvaccinated, and periphery blood was collected at 1 month and 6 months after the last vaccination. Direct correlation of anti-HBs titers at 1 month and 6 months from the last vaccination dose in both healthy controls (<b>A</b>) and ART-treated HIV-1 infected (<b>B</b>) children. Anti-HBs: Hepatitis B surface antibody; IU/L: international units per liter (Modified from [<a href="#B8-vaccines-09-01484" class="html-bibr">8</a>,<a href="#B33-vaccines-09-01484" class="html-bibr">33</a>]).</p>
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<p>Immune responses to HBV vaccine. Antigen captured and processed by antigen-presenting cells (APCs); the processed antigen activates B cells and T cells. B-Tfh cells interact at the border of the GC for the generation of short-lived plasma cells and antibodies, and in the GC for the generation of long-lived plasma cells and development of memory B cells. In HIV-1 infection, inefficient interaction between B-Tfh cells was reported due to exhaustion of cells by direct and indirect effects of HIV-1. NB: naïve B cells, MB: memory B cells; AM: Activated memory B cells; TLB: Tissue-like memory B cells; Tfh: T follicular helper; IL: interleukin; GC: germinal center (Created with BioRender.com).</p>
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17 pages, 50888 KiB  
Article
Single-Dose Vaccination of Recombinant Chimeric Newcastle Disease Virus (NDV) LaSota Vaccine Strain Expressing Infectious Bursal Disease Virus (IBDV) VP2 Gene Provides Full Protection against Genotype VII NDV and IBDV Challenge
by Qilong Qiao, Mingzhen Song, Congcong Song, Yihang Zhang, Xiangdong Wang, Qing Huang, Baiyu Wang, Panpan Yang, Shiyi Zhao, Yongtao Li, Zeng Wang and Jun Zhao
Vaccines 2021, 9(12), 1483; https://doi.org/10.3390/vaccines9121483 - 15 Dec 2021
Cited by 15 | Viewed by 4015
Abstract
Newcastle disease virus (NDV) and infectious bursal disease virus (IBDV) are the two most important and widespread viruses causing huge economic losses in the global poultry industry. Outbreaks of genotype VII NDV and IBDV variants in vaccinated poultry flocks call for genetically matched [...] Read more.
Newcastle disease virus (NDV) and infectious bursal disease virus (IBDV) are the two most important and widespread viruses causing huge economic losses in the global poultry industry. Outbreaks of genotype VII NDV and IBDV variants in vaccinated poultry flocks call for genetically matched vaccines. In the present study, a genetic matched chimeric NDV LaSota vaccine strain expressing VP2 gene of IBDV variant, rLaS-VIIF/HN-VP2 was generated for the first time, in which both the F and HN genes of LaSota were replaced with those of the genotype VII NDV strain FJSW. The cleavage site of the FJSW strain F protein in the rLaS-VIIF/HN-VP2 genome was mutated to the avirulent motif found in LaSota. Expression of IBDV VP2 protein was confirmed by western blot. The rLaS-VIIF/HN-VP2 maintained the efficient replication ability in embryonated eggs, low pathogenicity and genetic stability comparable to that of parental LaSota virus. One dose oculonasal vaccination of one-week-old SPF chickens with rLaS-VIIF/HN-VP2 induced full protection against genotype VII NDV and IBDV lethal challenge. These results indicate that the rLaS-VIIF/HN-VP2 is a promising bivalent vaccine to prevent infections of IBDV and genotype VII NDV. Full article
(This article belongs to the Section Veterinary Vaccines)
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<p>Diagram of cDNA construct for recombinant chimeric LaSota expressing IBDV VP2 gene: The VP2 gene of a novel IBDV variant SHG19 strain was inserted between P and M genes in the pGEM-PM plasmid. The generated pGEM-PM-VP2 plasmid was cut with ApaI and PmlI, and the fragment containing VP2gene was cloned into ApaI and PmlI digested pNDFL-VII-F/HN to make pNDFL-VII-7F/HN-VP2 construct.</p>
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<p>Growth kinetics of recombinant rLaS-VIIF/HN-VP2 and LaSota in SPF eggs: 10<sup>2</sup> EID<sub>50</sub> (50% egg infections dose, EID<sub>50</sub>) of NDV LaSota strain and the 25th passage rLaS-VIIF/HN-VP2 was inoculated into the allantoic cavity of 10-day-old embryonated SPF eggs. The allantoic fluid was harvested at 12, 24, 36, 48, 60, 72, and 96 h post-infection (hpi). The EID<sub>50</sub> of the virus at each time point was measured.</p>
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<p>Western blotting analysis of IBDV VP2 protein expression by recombinant virus: IBDV VP2 protein expressed by the rLaS-VIIF/HN-VP2 was detected by western blot using anti-IBDV VP2 monoclonal antibody. M. Pre-stained protein molecular weight standards; Lane 1. rLaS-VIIF/HN-VP2-infected chicken embryo allantoic fluid; Lane 2. LaSota LaSota-infected chicken embryo allantoic fluid.</p>
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<p>Antibody responses against genotype VII NDV and IBDV in chickens immunized oculonasally with live rLaS-VIIF/HN-VP2: (<b>A</b>) HI antibody titers against genotype VII NDV. Mean HI titer plus standard deviation of each group were show; (<b>B</b>) ELISA antibody titers against IBDV. Mean antibody titers plus standard deviation are shown.</p>
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<p>Survival rates of chickens post genotype VII velogenic NDV and variant IBDV strain challenge: Half of the chickens in rLaS-VIIF/HN-VP2 vaccinated and placebo control group were oculonasally challenged with 10<sup>5</sup> ELD<sub>50</sub>/chicken of velogenic genotype VII NDV isolate FJSW (<b>A</b>) and 10<sup>4</sup> ELD<sub>50</sub>/chicken of IBDV TL strain (<b>B</b>), respectively.</p>
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<p>Representative postmortem examinations of chickens challenged with virulent IBDV TL strain: (<b>A</b>) Postmortem examination of unvaccinated chickens showed hemorrhages in the thigh, swelling and paleness of the kidneys, and urate deposits in the ureters. (<b>B</b>) The bursa of Fabricius of all unvaccinated chickens appeared severe atrophy and had a gelatinous yellowish transudate covering the mucosal surface. Chickens immunized with the live rLaS-VIIF/HN-VP2 did not show obvious gross lesions.</p>
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<p>Typical microscopic lesions of lymphoid organs from chickens after virulent IBDV TL strain challenge. The microscopic lesions in unvaccinated chickens occurred primarily in the lymphoid tissues. There was severe depletion, degeneration, and necrosis of lymphocytes in the medullary area of bursal follicles. The main lesions in spleen and cecal tonsil included lymphoid necrosis in the germinal follicles and the periarteriolar lymphoid sheath. No obvious tissue damages were seen in the lymphoid organs of chickens vaccinated with the live rLaS-VIIF/HN-VP2 and uninfected controls (H&amp;E stain, original magnification 400×).</p>
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<p>Typical microscopic lesions of in different organs from chickens after virulent genotype VII NDV FJSW challenge: The histological lesions presented by the unvaccinated chickens included interstitial chronic inflammatory infiltrate in lung; necrosis with lymphoid depletion of spleen, cecal tonsil and bursa of Fabricius; necrosis of epithelium of intestine and proventriculus. Organs of chickens vaccinated with the live rLaS-VIIF/HN-VP2 and the uninfected controls did not exhibit obvious microscopic lesions. (H&amp;E stain, original magnification 400×).</p>
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<p>Viral loads in different tissues of chickens challenged with virulent IBDV TL strain and genotype VII NDV FJSW strain. Viral loads in the lung, trachea, spleen, duodenum, proventriculus, cecal tonsil, and bursa of Fabricius tissue samples were quantitated by a SYBR Green I quantitative real-time PCR. (<b>A</b>) IBDV viral loads in bursa of Fabricius tissues were quantitated by using IBDV VP1 as an indicator for the presence of viral RNA. (<b>B</b>) Genotype VII NDV viral loads in different tissues were determined using genotype VII NDV HN gene as an indicator. The viral loads were reported as gene copies / mg of tissue, and presented as the mean viral loads plus standard deviation. Asterisks (**) indicate significant difference in viral loads (<span class="html-italic">p</span> &lt; 0.01).</p>
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18 pages, 318 KiB  
Review
Oral Cholera Vaccine Efficacy and Effectiveness
by Katerina Rok Song, Jacqueline Kyungah Lim, Se Eun Park, Tarun Saluja, Sung-Il Cho, Tram Anh Wartel and Julia Lynch
Vaccines 2021, 9(12), 1482; https://doi.org/10.3390/vaccines9121482 - 15 Dec 2021
Cited by 31 | Viewed by 7051
Abstract
Although measuring vaccine efficacy through the conventional phase III study design, randomized, double-blinded controlled trial serves as the “gold standard”, effectiveness studies, conducted in the context of a public health program, seek to broaden the understanding of the impact of a vaccine in [...] Read more.
Although measuring vaccine efficacy through the conventional phase III study design, randomized, double-blinded controlled trial serves as the “gold standard”, effectiveness studies, conducted in the context of a public health program, seek to broaden the understanding of the impact of a vaccine in a real world setting including both individual and population level impacts. Cholera is an acute diarrheal infection caused by the ingestion of food or water contaminated with the bacterium Vibrio cholerae. Since the 1980s, either killed or live oral cholera vaccines (OCVs) have been developed and efficacy and effectiveness studies have been conducted on OCV. Although the results of OCV effectiveness studies sometimes showed outliers, the tendency seen is for effectiveness of the vaccine used in public health settings to be somewhat higher than estimated in randomized controlled trials due to the influence of indirect herd protection. Efficacy and Effectiveness studies both generate important information about the vaccine performance characteristics and its impact when used in real world populations at risk for the disease. Full article
(This article belongs to the Special Issue Vaccine Efficacy and Vaccine Effectiveness)
10 pages, 405 KiB  
Review
Optimising COVID-19 Vaccination Policy to Mitigate SARS-CoV-2 Transmission within Schools in Zimbabwe
by Grant Murewanhema, Solomon Mukwenha, Tafadzwa Dzinamarira, Zindoga Mukandavire, Diego Cuadros, Roda Madziva, Innocent Chingombe, Munyaradzi Mapingure, Helena Herrera and Godfrey Musuka
Vaccines 2021, 9(12), 1481; https://doi.org/10.3390/vaccines9121481 - 15 Dec 2021
Cited by 6 | Viewed by 4449
Abstract
The COVID-19 pandemic has disrupted the learning of millions of children across the world. Since March 2020 when the first cases of COVID-19 were reported in Zimbabwe, the country, like many others, has gone through periods of closing and re-opening of schools as [...] Read more.
The COVID-19 pandemic has disrupted the learning of millions of children across the world. Since March 2020 when the first cases of COVID-19 were reported in Zimbabwe, the country, like many others, has gone through periods of closing and re-opening of schools as part of the national COVID-19 control and mitigation measures. Schools promote the social, mental, physical, and moral development of children. With this viewpoint, the authors argue that schools should not be closed to provide a measured and efficient response to the threats posed by the COVID-19 epidemic. Rather, infection prevention and control strategies, including vaccination of learners and teachers, and surveillance in schools should be heightened. The use of multiple prevention strategies discussed in this viewpoint has shown that when outbreaks in school settings are adequately managed, the transmission usually is low. The information presented here suggests that schools should remain open due to the preponderance of evidence indicating the overriding positive impacts of this policy on the health, development, and wellbeing of children. Full article
(This article belongs to the Special Issue Vaccination of Adolescents)
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Figure 1

Figure 1
<p>COVID-19 cases in Zimbabwean schools during the third academic term. Source: Ministry of Health and Child Care [<a href="#B14-vaccines-09-01481" class="html-bibr">14</a>].</p>
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