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Research Square Jun 2024Tauopathies, including Alzheimer's disease (AD) and Frontotemporal Dementia (FTD), are histopathologically defined by the aggregation of hyperphosphorylated pathological...
Virus-like particle (VLP)-based vaccine targeting tau phosphorylated at Ser396/Ser404 (PHF1) site outperforms phosphorylated S199/S202 (AT8) site in reducing tau pathology and restoring cognitive deficits in the rTg4510 mouse model of tauopathy.
Tauopathies, including Alzheimer's disease (AD) and Frontotemporal Dementia (FTD), are histopathologically defined by the aggregation of hyperphosphorylated pathological tau (pTau) as neurofibrillary tangles in the brain. Site-specific phosphorylation of tau occurs early in the disease process and correlates with progressive cognitive decline, thus serving as targetable pathological epitopes for immunotherapeutic development. Previously, we developed a vaccine (Qβ-pT181) displaying phosphorylated Thr181 tau peptides on the surface of a Qβ bacteriophage virus-like particle (VLP) that induced robust antibody responses, cleared pathological tau, and rescued memory deficits in a transgenic mouse model of tauopathy. Here we report the characterization and comparison of two additional Qβ VLP-based vaccines targeting the dual phosphorylation sites Ser199/Ser202 (Qβ-AT8) and Ser396/Ser404 (Qβ-PHF1). Both Qβ-AT8 and Qβ-PHF1 vaccines elicited high-titer antibody responses against their pTau epitopes. However, only Qβ-PHF1 rescued cognitive deficits, reduced soluble and insoluble pathological tau, and reactive microgliosis in a 4-month rTg4510 model of FTD. Both sera from Qβ-AT8 and Qβ-PHF1 vaccinated mice were specifically reactive to tau pathology in human AD post-mortem brain sections. These studies further support the use of VLP-based immunotherapies to target pTau in AD and related tauopathies and provide potential insight into the clinical efficacy of various pTau epitopes in the development of immunotherapeutics.
PubMed: 38946961
DOI: 10.21203/rs.3.rs-4390998/v1 -
Progress in Community Health... 2024Incarcerated people have been disproportionately affected by the COVID-19 pandemic and face significant challenges to COVID-19 vaccine confidence.
BACKGROUND
Incarcerated people have been disproportionately affected by the COVID-19 pandemic and face significant challenges to COVID-19 vaccine confidence.
OBJECTIVES
(1) Describe our partnerships with community members directly impacted by incarceration, (2) discuss the partnership's process for co-developing and implementing project interventions to increase COVID-19 vaccine confidence, and (3) share lessons learned from this unique community-engaged partnership.
METHODS
An advisory board of 14 formerly incarcerated community members participated in this project. Their wisdom and experience led to the development and implementation of interventions to increase confidence in COVID-19 vaccines among incarcerated people.
LESSONS LEARNED
Valuable lessons learned were centering community, leaning into trusted sources of information, acknowledging historical and present harms, and investing in community-engaged work.
CONCLUSIONS
Centering lived experiences of those directly impacted by incarceration has been crucial to increasing vaccine confidence among this population. Doing so reinforced the importance of long-term investments in community-based collaborations with communities impacted by incarceration.
Topics: Humans; COVID-19 Vaccines; COVID-19; Prisoners; Prisons; Community-Based Participatory Research; Jails; SARS-CoV-2
PubMed: 38946565
DOI: No ID Found -
Immunology and Cell Biology Jun 2024In this article for the Highlight of 2023 series, we discuss recent advances in the fundamental biology of the germinal center response. These discoveries provide...
In this article for the Highlight of 2023 series, we discuss recent advances in the fundamental biology of the germinal center response. These discoveries provide important insights as to how the germinal center contributes to protection against infection, and also highlights opportunities for future vaccine development.
PubMed: 38946158
DOI: 10.1111/imcb.12800 -
Iranian Biomedical Journal Apr 2024The growing threat of antibiotic resistance and Klebsiella pneumoniae infection in healthcare settings highlights the urgent need for innovative solutions, such as...
BACKGROUND
The growing threat of antibiotic resistance and Klebsiella pneumoniae infection in healthcare settings highlights the urgent need for innovative solutions, such as vaccines, to address these challenges. This study sought to assess the potential of using K. pneumoniae OmpA as a vaccine candidate through both in silico and in vivo analyses.
METHODS
The study examined the OmpA protein sequence for subcellular localization, antigenicity, allergenicity, similarity to the human proteome, physicochemical properties, B-cell epitopes, MHC binding sites, tertiary structure predictions, molecular docking, and immune response simulations. The ompA gene was cloned into the pET-28a (+) vector, expressed, purified and confirmed using Western blotting analysis. IgG levels in the serum of the immunized mice were measured using ELISA with dilutions ranging from 1:100 to 1:6400, targeting rOmpA and K. pneumoniae ATCC 13883. The sensitivity and specificity of the ELISA method were also assessed.
RESULTS
The bioinformatics analysis identified rOmpA as a promising vaccine candidate. The immunized group demonstrated significant production of specific total IgG antibodies against rOmpA and K. pneumoniae ATCC1 13883, as compared to the control group (p < 0.0001). The titers of antibodies produced in response to bacterial exposure did not show any significant difference when compared to the anti-rOmpA antibodies (p > 0.05). The ELISA test sensitivity was 1:3200, and the antibodies in the serum could accurately recognize K. pneumoniae cells.
CONCLUSION
This study is a significant advancement in the development of a potential vaccine against K. pneumoniae that relies on OmpA. Nevertheless, additional experimental analyses are required.
PubMed: 38946021
DOI: 10.61186/ibj.4023 -
Japanese Journal of Infectious Diseases Jun 2024Persistent inflammation in chronic HIV infection may affect immune responses against SARS-CoV-2 infection. Plasma levels of multiple proinflammatory cytokines during...
Persistent inflammation in chronic HIV infection may affect immune responses against SARS-CoV-2 infection. Plasma levels of multiple proinflammatory cytokines during acute SARS-CoV-2 infection were assessed in people with HIV (PWH) with effective cART. There were no significant differences in any of the tested cytokines between COVID-19 severity in PWH, while most of them were significantly higher in individuals with severe disease in HIV-uninfected individuals, suggesting that excess cytokines release by hyper-inflammatory responses does not occur in severe COVID-19 with HIV infection. The strong associations between the cytokines observed in HIV-uninfected individuals, especially between IFN-α/TNF-α and other cytokines, were lost in PWH. The steady state plasma levels of IP-10, ICAM-1, and CD62E were significantly higher in PWH, indicating that PWH are in an enhanced inflammatory state. Loss of the several inter-cytokine correlations were observed in in vitro LPS stimuli-driven cytokines production in PWH. These data suggest that inflammatory responses during SARS-CoV-2 infection in PWH are distinct from those in HIV-uninfected individuals, partially due to the underlying inflammatory state and/or impairment of innate immune cells.
PubMed: 38945856
DOI: 10.7883/yoken.JJID.2024.184 -
International Journal of Infectious... Jun 2024The emergence of new SARS-CoV-2 variants has led to the development of Omicron-targeting bivalent mRNA vaccines. It is crucial to understand how bivalent vaccines may...
OBJECTIVES
The emergence of new SARS-CoV-2 variants has led to the development of Omicron-targeting bivalent mRNA vaccines. It is crucial to understand how bivalent vaccines may improve antibody responses against new variants.
METHODS
A total of 107 participants, who had three COVID-19 WT mRNA vaccine doses, were recruited, and given either a monovalent (WT) or a bivalent mRNA vaccination (Pfizer/BioNTech Bivalent (WT and BA.4/BA.5) or Moderna Bivalent (WT and BA.1)). Blood samples were taken before booster and at 28 days post-booster.
RESULTS
We found significantly lower fold change in serum binding IgA responses against BA.1, BA.5 and EG.5.1 spike in the bivalent booster group, compared with the monovalent (WT) booster group, following vaccination. However, this was only observed in individuals with prior infection. The relative fold change in serum binding IgA response was more skewed towards WT over variant (BA.1, BA.5 or EG.5.1) spike in previously infected bivalent-booster-vaccinees, as compared with previously infected monovalent-(WT)-booster-vaccinees.
CONCLUSION
The findings suggest imprinting of antibody responses that is shaped by the first vaccination (WT spike). Previous infection also affects the boosting effect of follow-up vaccination. Studies are needed to understand how to induce a robust and long-lasting IgA immunity for protection against COVID-19 infection.
PubMed: 38945433
DOI: 10.1016/j.ijid.2024.107147 -
Clinical Microbiology and Infection :... Jun 2024Herpesviruses represent common and significant infectious complications after allogeneic hematopoietic cell transplantation (HCT). In the last decade, major advances in... (Review)
Review
BACKGROUND
Herpesviruses represent common and significant infectious complications after allogeneic hematopoietic cell transplantation (HCT). In the last decade, major advances in the prevention and treatment of these infections were accomplished.
OBJECTIVES
The aim of this paper is to review the recent advances in the prophylaxis and treatment of herpesvirus infections after allogeneic HCT, to assess the persisting challenges, and to offer future directions for prevention and management of these infections.
SOURCES
We searched PubMed for relevant literature regarding specific herpesviruses complicating allogeneic HCT through March 2024.
CONTENT
The largest advances in this past decade were witnessed for cytomegalovirus (CMV) with the advent of letermovir for primary prophylaxis and the development of maribavir as an option for refractory and/or resistant CMV infections in transplant recipients. For Varicella Zoster Virus, prevention of reactivation with the recombinant zoster vaccine offers an additional prophylactic intervention. Pritelivir is being explored for treatment of drug resistant or refractory Herpes Simplex Virus infections. While rituximab is now an established option for preemptive therapy for Epstein Barr Virus, HHV-6 remains the most elusive virus of the herpesvirus family, with lack of evidence supporting benefit of any agent for prophylaxis or for optimal preemptive therapy.
IMPLICATIONS
While considerable advances have been achieved for the treatment and prevention of herpes virus infections, most notably with CMV, the coming years should hold additional opportunities to tame the beast in these herpesviruses post allogeneic HCT, with the advent of new antivirals, cell-mediated immunity testing, and cytotoxic T lymphocytes infusions.
PubMed: 38945270
DOI: 10.1016/j.cmi.2024.06.020 -
The Lancet. Infectious Diseases Jun 2024
PubMed: 38945150
DOI: 10.1016/S1473-3099(24)00415-8 -
Vaccine Jun 2024Infectious bursal disease virus (IBDV) is an acute and highly infectious RNA virus known for its immunosuppressive capabilities, chiefly inflicting rapid damage to the...
Infectious bursal disease virus (IBDV) is an acute and highly infectious RNA virus known for its immunosuppressive capabilities, chiefly inflicting rapid damage to the bursa of Fabricius (BF) of chickens. Current clinical control of IBDV infection relies on vaccination. However, the emergence of novel variant IBDV (nVarIBDV) has posed a threat to the poultry industry across the globe, underscoring the great demand for innovative and effective vaccines. Our previous studies have highlighted the critical role of IBDV VP5 as an apoptosis-inducer in host cells. In this study, we engineered IBDV mutants via a reverse genetic system to introduce amino acid mutations in VP5. We found that the mutant IBDV-VP5/3m strain caused reduced host cell mortality, and that strategic mutations in VP5 reduced IBDV replication early after infection, thereby delaying cell death. Furthermore, inoculation of chickens with IBDV-VP5/3m effectively reduced damage to BF and induced neutralizing antibody production comparable to that of parental IBDV WT strain. Importantly, vaccination with IBDV-VP5/3m protected chickens against challenges with nVarIBDV, an emerging IBDV variant strain in China, reducing nVarIBDV loads in BF while alleviating bursal atrophy and splenomegaly, suggesting that IBDV-VP5/3m might serve as a novel vaccine candidate that could be further developed as an effective vaccine for clinical control of IBD. This study provides a new clue to the development of novel and effective vaccines.
PubMed: 38944579
DOI: 10.1016/j.vaccine.2024.06.048 -
Vaccine Jun 2024Maternal immunisation is a powerful tool to protect both pregnant women and their children. A new maternal RSV vaccine holds promise to protect newborns from...
Maternal immunisation is a powerful tool to protect both pregnant women and their children. A new maternal RSV vaccine holds promise to protect newborns from RSV-associated illness in the first few months of life, but no official recommendation has been made in Germany. Since RSV causes a significant burden of paediatric hospital admissions, we consider it a pertinent opportunity to review barriers to maternal vaccination in Germany, which might also apply to other settings. Access to vaccination for pregnant women in Germany is shaped by an interplay of legal, regulatory, institutional, and sociocultural factors, with a less permissive clinical research environment, delays in recommendation and roll-out, and lower acceptance by healthcare professionals and the population. Actionable recommendations to improve availability and uptake include coordination with other national regulatory bodies to reduce delays, awareness and literacy campaigns for health professionals and the general public, and capacity building for vaccine clinical research.
PubMed: 38944576
DOI: 10.1016/j.vaccine.2024.06.061