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ISSN / EISSN : 2076-393X / 2076-393X
Published by: MDPI (10.3390)
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Published: 17 May 2022
by MDPI
Abstract:
Membrane trafficking is emerging as an attractive therapeutic strategy for cancer. Recent reports have found a connection between Wnt signaling, receptor-mediated endocytosis, V-ATPase, lysosomal activity, and macropinocytosis through the canonical Wnt pathway. In macropinocytic cells, a massive internalization of the plasma membrane can lead to the loss of cell-surface cadherins, integrins, and other antigens that mediate cell–cell adhesion, favoring an invasive phenotype. V-ATPase is a key regulator in maintaining proper membrane trafficking, homeostasis, and the earliest developmental decisions in the Xenopus vertebrate development model system. Here, we review how the interference of membrane trafficking with membrane trafficking inhibitors might be clinically relevant in humans.
Published: 17 May 2022
by MDPI
Abstract:
In 2017, Poland introduced the 10-valent pneumococcal conjugate vaccine (PCV) into its national immunization schedule. This prospective study was conducted between March and June 2020 to determine the impact of vaccination on prevalence of the nasopharyngeal carriage of S. pneumoniae in 176 healthy children and to determine how conjugate vaccines indirectly affect colonization of nasopharyngeal microbiota. Pneumococcal isolates were analyzed by serotyping and antimicrobial resistance tests. Nasopharyngeal microbiota were detected and identified using the culture method and real-time PCR amplification primers and hydrolysis-probe detection with the 16S rRNA gene as the target. In the vaccinated group of children, colonization was in 24.2% of children, compared to 21.4% in the unvaccinated group. Serotypes 23A and 23B constituted 41.5% of the isolates. Serotypes belonging to PCV10 and PCV13 constituted 4.9% and 17.1% of the isolates, respectively. S. pneumoniae isolates were resistant to penicillin (34.1%), erythromycin (31.7%), and co-trimoxazole (26.8%). Microbial DNA qPCR array correlated to increased amounts of Streptococcus mitis and S. sanguinis in vaccinated children, with reduced amounts of C. pseudodiphtericum, S. aureus, and M. catarrhalis. Introduction of PCV for routine infant immunization was associated with significant reductions in nasopharyngeal carriage of PCV serotypes and resistant strains amongst vaccine serotypes, yet carriage of non-PCV serotypes increased modestly, particularly serotype 23B.
, , , , , , , , on behalf of the Partners In Health Cross-Site COVID-19 Cohort Research Network
Published: 17 May 2022
by MDPI
Abstract:
Current low COVID-19 vaccination rates in low- and middle-income countries reflect an inequitable global vaccine distribution; however, local attitudes towards the COVID-19 vaccine are an important factor to meet vaccination benchmarks. We describe attitudes toward the uptake of the COVID-19 vaccine and perceptions among patients with NCDs and their caregivers using cross-sectional data collected through telephone interviews in Neno, Malawi. Out of 126 survey respondents, 71% were patients, and 29% were caregivers. Twenty-two percent of respondents had received at least one dose at the interview (95% CI: 15–30%), with 19% being fully vaccinated. Only 24% (95% CI: 12–40%) of unvaccinated respondents reported that they would accept an approved vaccine if it were offered today. Vaccines were perceived as unsafe or designed to harm and commonly associated with death, severe disability, infertility, and evil. However, over two-thirds reported high levels of trust in health care workers (73%) and community health workers (72%) as sources of information for the COVID-19 vaccine. Although the uptake of COVID-19 vaccine in this vulnerable population was three times than the national average, a low intention to be vaccinated persists among the unvaccinated. Strong trust in health care workers suggests that community engagement could help increase vaccine acceptance.
Published: 17 May 2022
by MDPI
Abstract:
Over 1.5 million preventable new hepatitis B infections continue to occur each year and there are an estimated 296 million people living with chronic hepatitis B infection worldwide, resulting in more than 820,000 deaths annually due to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B vaccination remains the cornerstone of public health policy to prevent HCC and a vital component of the global hepatitis B elimination response. The WHO has set a 90% vaccination target to achieve hepatitis B elimination by 2030; however, there is wide variability in reported birth dose coverage, with global coverage at only 42%. In this review, we outline the global trends in hepatitis B vaccination coverage and the impact of hepatitis B vaccination on HCC incidence and discuss the challenges and enabling factors for achieving WHO 2030 hepatitis B vaccination coverage targets.
Published: 17 May 2022
by MDPI
Abstract:
The SARS-CoV-2 variant Omicron has spread world-wide and is responsible for rapid increases in infections, including in populations with high vaccination rates. Here, we analysed in the sera of vaccinated individuals the antibody binding to the receptor-binding domain (RBD) of the spike protein and the neutralization of wild-type (WT), Delta (B.1.617.2), and Omicron (B.1.1.529; BA.1) pseudotyped vectors. Although sera from individuals immunized with vector vaccines (Vaxzevria; AZ and COVID-19 Janssen, Ad26.COV2.S; J&J) were able to bind and neutralize WT and Delta, they showed only background levels towards Omicron. In contrast, mRNA (Comirnaty; BNT) or heterologous (AZ/BNT) vaccines induced weak, but detectable responses against Omicron. While RBD-binding antibody levels decreased significantly six months after full vaccination, the SARS-CoV-2 RBD-directed avidity remained constant. However, this still coincided with a significant decrease in neutralization activity against all variants. A third booster vaccination with BNT significantly increased the humoral immune responses against all tested variants, including Omicron. In conclusion, only vaccination schedules that included at least one dose of mRNA vaccine and especially an mRNA booster vaccination induced sufficient antibody levels with neutralization capacity against multiple variants, including Omicron.
Published: 17 May 2022
by MDPI
Abstract:
Immunosuppressive therapy increases the risk of pneumococcal disease. This risk can be mitigated by pneumococcal vaccination. The objective of this study was to investigate the immunogenicity of the 13-valent pneumococcal conjugate vaccine (PCV13), followed by the 23-valent pneumococcal polysaccharide vaccine (PPSV23), in adults with and without immunosuppressive therapy. We performed a prospective cohort study among adults using conventional immunomodulators (cIM), biological immunomodulators (bIM), combination therapy, and controls during 12 months. The primary outcome was seroprotection, defined as the proportion of patients with a postimmunization IgG concentration of ≥1.3 µg/mL for at least 70% (17/24) of the serotypes of PCV13+PPSV23. We included 214 participants. For all 24 vaccine serotypes, IgG levels increased significantly in both treatment subgroups and controls, with peak seroprotection rates of 44% (combination therapy), 58% (cIM), 57% (bIM), and 82% (controls). By month 12, seroprotection had decreased to 24%, 48%, 39%, and 63%, respectively. Although pneumococcal vaccination with PCV13+PPSV23 was immunogenic in all treatment groups, impaired vaccination responses were observed in patients using immunosuppressive medication. Apart from the obvious recommendation to administer vaccines before such medication is started, alternative vaccination strategies, such as additional PCV13 doses or higher-valent pneumococcal vaccines, should be investigated.
Published: 17 May 2022
by MDPI
Abstract:
Waning immunity against SARS-CoV-2 and the emergence of variants, especially of the most distant variant, Omicron, affect titers of neutralizing antibodies in the sera of vaccinated individuals. Thus, two vaccinations with the mRNA vaccine BNT162b fail to induce neutralizing antibodies against the Omicron variant. A first booster vaccination increases Omicron-RBD-binding IgG and IgA and neutralizing capacity. In comparison, the Wuhan isolate titers of the Omicron variant binding antibodies are 8.5 lower. After a third vaccination, induction of Omicron-RBD- and Wuhan-RBD-binding antibodies follows the same kinetic. Five to six months after the third vaccination, there are still Omicron-RBD-binding antibodies detectable, but 35.9 percent of the analyzed sera fail to neutralize the Omicron variant, while all sera efficiently neutralize the Delta isolate. In the case of the Wuhan-RBD, a significantly larger number of stable antigen–antibody complexes is formed than in Omicron-RBD. A fourth vaccination with mRNA-1273 temporarily restores levels of Omicron-, Delta- and Wuhan-specific antibodies. Comparing different booster strategies revealed that the breadth of the immune response is not affected by the vaccination regimen. Taken together, these data indicate that booster vaccinations (third and fourth dose) increase the breadth of the immune response, but there is a qualitative difference of antibodies with respect to the stability of antigen–antibody complexes and persistence of antibody titers.
Published: 16 May 2022
by MDPI
Abstract:
Virus-like particles (VLPs) are highly immunogenic and versatile subunit vaccines composed of multimeric viral proteins that mimic the whole virus but lack genetic material. Due to the lack of infectivity, VLPs are being developed as safe and effective vaccines against various infectious diseases. In this study, we generated a chimeric VLP-based COVID-19 vaccine stably produced by HEK293T cells. The chimeric VLPs contain the influenza virus A matrix (M1) proteins and the SARS-CoV-2 Wuhan strain spike (S) proteins with a deletion of the polybasic furin cleavage motif and a replacement of the transmembrane and cytoplasmic tail with that of the influenza virus hemagglutinin (HA). These resulting chimeric S-M1 VLPs, displaying S and M1, were observed to be enveloped particles that are heterogeneous in shape and size. The intramuscular vaccination of BALB/c mice in a prime-boost regimen elicited high titers of S-specific IgG and neutralizing antibodies. After immunization and a challenge with SARS-CoV-2 in K18-hACE2 mice, the S-M1 VLP vaccination resulted in a drastic reduction in viremia, as well as a decreased viral load in the lungs and improved survival rates compared to the control mice. Balanced Th1 and Th2 responses of activated S-specific T-cells were observed. Moderate degrees of inflammation and viral RNA in the lungs and brains were observed in the vaccinated group; however, brain lesion scores were less than in the PBS control. Overall, we demonstrate the immunogenicity of a chimeric VLP-based COVID-19 vaccine which confers strong protection against SARS-CoV-2 viremia in mice.
Published: 16 May 2022
by MDPI
Abstract:
Recently, long synthetic peptides or in silico-predicted epitope peptides have been used to identify T cell epitopes, but these approaches may not be suitable for investigating naturally processed epitopes. Here, mRNAs, including fragments or predicted epitope sequences of HCMV pp65 antigen, were generated by in vitro transcription following transcriptionally active PCR. Then, artificial antigen-presenting cells (aAPCs) expressing a single HLA allotype were transfected with mRNAs to identify epitopes in donors with T cell responses that recognize pp65 antigen restricted to HLA-A*02:01, -A*02:06, or -B*07:02. T cells restricted to a particular HLA allotype showed positive responses in some of the 10 fragment antigens. Among predicted epitopes within these positive fragments, three epitopes of HLA-A*02:01, -A*02:06, and -B*07:02 were confirmed. In addition, T cells expanded by anti-CD3 stimulation for two weeks could also be effectively used for the identification of these T cell epitopes, although there were individual differences. These results demonstrated that fragment antigens and epitopes can be rapidly generated using mRNA, and naturally processed antigenic regions can be detected using aAPCs without a T cell cloning procedure. This method will help to identify novel T cell epitopes for developing immunotherapy and vaccines against infectious diseases and cancer.
Published: 16 May 2022
by MDPI
Abstract:
Infectious laryngotracheitis (ILT) is caused by Gallid herpesvirus-1 (GaHV-1) or infectious laryngotracheitis virus (ILTV) and was first described in Canadian poultry flocks. In Canada, ILTV infection is endemic in backyard flocks, and commercial poultry encounters ILT outbreaks sporadically. A common practice to control ILT is the use of live attenuated vaccines. However, outbreaks still occur in poultry flocks globally due to ILTV vaccine strains reverting to virulence and emergence of new ILTV strains due to recombination in addition to circulating wildtype strains. Recent studies reported that most of the ILT outbreaks in Canada were induced by the chicken-embryo-origin (CEO) live attenuated vaccine revertant strains with the involvement of a small percentage of wildtype ILTV. It is not known if the host responses induced by these two ILTV strains are different. The objective of the study was to compare the host responses elicited by CEO revertant and wildtype ILTV strains in chickens. We infected 3-week-old specific pathogen-free chickens with the two types of ILTV isolates and subsequently evaluated the severity of clinical and pathological manifestations, in addition to host responses. We observed that both of the isolates show high pathogenicity by inducing several clinical and pathological manifestations. A significant recruitment of immune cells at both 3 and 7 days post-infection (dpi) was observed in the tracheal mucosa and the lung tissues of the infected chickens with wildtype and CEO vaccine revertant ILTV isolates when compared to uninfected controls. Overall, this study provides a better understanding of the mechanism of host responses against ILTV infection.
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