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The Lancet. HIV Jul 2024Rates of new HIV acquisition remain unacceptably high in most populations in low-income, middle-income, and high-income settings despite advances in treatment and... (Review)
Review
Rates of new HIV acquisition remain unacceptably high in most populations in low-income, middle-income, and high-income settings despite advances in treatment and prevention strategies. Although biomedical advances in primary prevention of new infections exist, systematic scale-up of these interventions has not occurred at the pace required to end AIDS by 2030. Low population coverage, adherence to oral pre-exposure prophylaxis in settings with high rates of HIV acquisition, and the fact that a significant proportion of new HIV infections occurs in populations not identified as high risk and are hence not targeted for prevention approaches impedes current prevention strategies. Although long-acting injectables and monoclonal antibodies are promising approaches to help reduce incidence, high cost and the need for high coverage rates mean that a vaccine or vaccine-like intervention still remains the most likely scenario to produce a population-level impact on HIV incidence, especially in countries with generalised epidemics. Current global efforts are not sufficient to meet 2030 HIV epidemic goals; acknowledgment of this issue is required to ensure persistent advocacy for population-based control of the ongoing HIV pandemic.
Topics: Humans; HIV Infections; Epidemics; Pre-Exposure Prophylaxis; Incidence; Global Health
PubMed: 38925732
DOI: 10.1016/S2352-3018(24)00098-5 -
Antiviral Research Jun 2024Combinational antiretroviral therapy (cART) suppresses human immunodeficiency virus type 1 (HIV-1) viral replication and pathogenesis in acquired immunodeficiency...
Combinational antiretroviral therapy (cART) suppresses human immunodeficiency virus type 1 (HIV-1) viral replication and pathogenesis in acquired immunodeficiency syndrome (AIDS) patients. However, HIV-1 remains in the latent stage of infection by suppressing viral transcription, which hinders an HIV-1 cure. One approach for an HIV-1 cure is the "shock and kill" strategy. The strategy focuses on reactivating latent HIV-1, inducing the viral cytopathic effect and facilitating the immune clearance for the elimination of latent HIV-1 reservoirs. Here, we reported that the H3K4 trimethylation (H3K4me3)-specific demethylase KDM5A/B play a role in suppressing HIV-1 Tat/LTR-mediated viral transcription in HIV-1 latent cells. Furthermore, we evaluated the potential of KDM5-specific inhibitor JQKD82 as an HIV-1 "shock and kill" agent. Our results showed that JQKD82 increases the H3K4me3 level at HIV-1 5' LTR promoter regions, HIV-1 reactivation, and the cytopathic effects in an HIV-1-latent T cell model. In addition, we identified that the combination of JQKD82 and AZD5582, a non-canonical NF-κB activator, generates a synergistic impact on inducing HIV-1 lytic reactivation and cell death in the T cell. The latency-reversing potency of the JQKD82 and AZD5582 pair was also confirmed in peripheral blood mononuclear cells (PBMCs) isolated from HIV-1 aviremic patients and in an HIV-1 latent monocyte. In latently infected microglia (HC69) of the brain, either deletion or inhibition of KDM5A/B results in a reversal of the HIV-1 latency. Overall, we concluded that KDM5A/B function as a host repressor of the HIV-1 lytic reactivation and thus promote the latency and the survival of HIV-1 infected reservoirs.
PubMed: 38925368
DOI: 10.1016/j.antiviral.2024.105947 -
Nano Letters Jun 2024Enhancing the antitumor immune response and targeting ability of oncolytic viruses will improve the effect of tumor immunotherapy. Through infecting neural stem cells...
Enhancing the antitumor immune response and targeting ability of oncolytic viruses will improve the effect of tumor immunotherapy. Through infecting neural stem cells (NSCs) with a capsid dual-modified oncolytic adenovirus (CRAd), we obtained and characterized the "oncolytic extracellular vesicles" (CRAdEV) with improved targeted infection and tumor killing activity compared with CRAd. Both and studies revealed that CRAdEV activated innate immune cells and importantly enhanced the immunomodulatory effect compared to CRAd. We found that CRAdEV effectively increased the number of DCs and activated CD4 and CD8 T cells, significantly increased the number and activation of B cells, and produced higher levels of tumor-specific antibodies, thus eliciting enhanced antitumor activity compared with CRAd in a B16 xenograft immunocompetent mice model. This study provides a novel approach to oncolytic adenovirus modification and demonstrates the potential of "oncolytic extracellular vesicles" in antitumor immunotherapy.
PubMed: 38922640
DOI: 10.1021/acs.nanolett.4c02279 -
Pathogens (Basel, Switzerland) May 2024Vaccinations are vital as they protect us from various illness-causing agents. Despite all the advancements in vaccine-related research, developing improved and safer... (Review)
Review
Vaccinations are vital as they protect us from various illness-causing agents. Despite all the advancements in vaccine-related research, developing improved and safer vaccines against devastating infectious diseases including Ebola, tuberculosis and acquired immune deficiency syndrome (AIDS) remains a significant challenge. In addition, some of the current human vaccines can cause adverse reactions in some individuals, which limits their use for massive vaccination program. Therefore, it is necessary to design optimal vaccine candidates that can elicit appropriate immune responses but do not induce side effects. Subunit vaccines are relatively safe for the vaccination of humans, but they are unable to trigger an optimal protective immune response without an adjuvant. Although different types of adjuvants have been used for the formulation of vaccines to fight pathogens that have high antigenic diversity, due to the toxicity and safety issues associated with human-specific adjuvants, there are only a few adjuvants that have been approved for the formulation of human vaccines. Recently, nanoparticles (NPs) have gain specific attention and are commonly used as adjuvants for vaccine development as well as for drug delivery due to their excellent immune modulation properties. This review will focus on the current state of adjuvants in vaccine development, the mechanisms of human-compatible adjuvants and future research directions. We hope this review will provide valuable information to discovery novel adjuvants and drug delivery systems for developing novel vaccines and treatments.
PubMed: 38921739
DOI: 10.3390/pathogens13060441 -
Diseases (Basel, Switzerland) May 2024As mortality declined significantly during the fourth and fifth waves compared to previous waves, the question of the future role of COVID-19 vaccination arose among...
BACKGROUND
As mortality declined significantly during the fourth and fifth waves compared to previous waves, the question of the future role of COVID-19 vaccination arose among both experts and the public in South Africa. Turning attention away from the general public, now considered to be at very low risk of severe COVID-19 disease, a commonly held view was that the vaccination campaign should focus only on those who remain highly vulnerable to severe disease and death from COVID-19. Primary amongst this group are patients with common chronic diseases attending hospital outpatient departments. We hypothesized that providing COVID-19 vaccinations on-site at a central hospital will increase uptake for the patients with co-morbid chronic conditions who need them most in the Omicron phase of the pandemic.
AIM
Evaluate the acceptability, need, and uptake of a hospital-based vaccination site for patients attending the medical hospital outpatient departments.
OBJECTIVES
To assess vaccination uptake, coverage, and hesitancy in people attending a central hospital, to determine factors associated with and influencing vaccination uptake, and to document implementation and assess acceptability of the vaccination project among staff and persons attending the hospital.
METHODS
Mixed-methods study using quantitative and qualitative methods.
RESULTS
Of the 317 participants enrolled in the study, 229 (72%) had already received at least one dose of the COVID-19 vaccine. A total of 296 participants were eligible for a first vaccination, additional vaccination, or booster vaccination according to the South African Department of Health guidelines. Of those previously vaccinated, 65% opted for an additional dose on the day it was offered (same day). Only 13 previously unvaccinated participants (15% of vaccine naïve participants) opted for vaccination, increasing vaccine coverage with at least one dose from 72% to 76%. Approximately 24% ( = 75) of all participants refused vaccination (vaccine hesitant). Variables tested for an association with vaccination status demonstrated that age reached statistical significance. Emerging themes in the qualitative analysis included perceptions of vulnerability, vaccine safety and efficacy concerns, information gaps regarding vaccinations, the value of convenience in the decision to vaccinate, and the role of health promoters.
CONCLUSIONS
This study has shown that it is logistically acceptable to provide a vaccination site at a large hospital targeting patients attending outpatient services for chronic medical conditions. This service also benefits accompanying persons and hospital staff. Access and convenience of the vaccination site influence decision-making, increasing the opportunity to vaccinate. However, vaccine hesitancy is widespread with just under one-quarter of all those offered vaccinations remaining unvaccinated. Strengthening health education and patient-clinician engagement about the benefits of vaccination is essential to reach highly vulnerable populations routinely attending hospital outpatient departments with an appropriate vaccination program.
PubMed: 38920545
DOI: 10.3390/diseases12060113 -
Journal of Biological Inorganic... Jun 2024Encephalitozoon intestinalis is an opportunistic microsporidian parasite that primarily infects immunocompromised individuals, such as those with HIV/AIDS or undergoing...
Encephalitozoon intestinalis is an opportunistic microsporidian parasite that primarily infects immunocompromised individuals, such as those with HIV/AIDS or undergoing organ transplantation. Leishmaniasis is responsible for parasitic infections, particularly in developing countries. The disease has not been effectively controlled due to the lack of an effective vaccine and affordable treatment options. Current treatment options for E. intestinalis infection and leishmaniasis are limited and often associated with adverse side effects. There is no previous study in the literature on the antimicrosporidial activities of Ag(I)-N-heterocyclic carbene compounds. In this study, the in vitro antimicrosporidial activities of previously synthesized Ag(I)-N-heterocyclic carbene complexes were evaluated using E. intestinalis spores cultured in human renal epithelial cell lines (HEK-293). Inhibition of microsporidian replication was determined by spore counting. In addition, the effects of the compounds on Leishmania major promastigotes were assessed by measuring metabolic activity or cell viability using a tetrazolium reaction. Statistical analysis was performed to determine significant differences between treated and control groups. Our results showed that the growth of E. intestinalis and L. major promastigotes was inhibited by the tested compounds in a concentration-dependent manner. A significant decrease in parasite viability was observed at the highest concentrations. These results suggest that the compounds have potential anti-microsporidial and anti-leishmanial activity. Further research is required to elucidate the underlying mechanisms of action and to evaluate the efficacy of the compounds in animal models or clinical trials.
PubMed: 38918208
DOI: 10.1007/s00775-024-02063-z -
Journal of Acquired Immune Deficiency... Aug 2024An effective vaccine is required to end the HIV pandemic. We evaluated the safety and immunogenicity of a DNA (DNA-HIV-PT123) vaccine with low- or high-dose bivalent... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
An effective vaccine is required to end the HIV pandemic. We evaluated the safety and immunogenicity of a DNA (DNA-HIV-PT123) vaccine with low- or high-dose bivalent (TV1.C and 1086.C glycoprotein 120) subtype C envelope protein combinations, adjuvanted with MF59 or AS01B.
METHODS
HIV Vaccine Trials Network (HVTN)108 was a randomized, placebo-controlled, double-blind, phase 1/2a trial conducted in the United States and South Africa. HIV-negative adults were randomly assigned to 1 of 7 intervention arms or placebo to assess DNA prime with DNA/protein/adjuvant boosts, DNA/protein/adjuvant co-administration, and low-dose protein/adjuvant regimens. HVTN111 trial participants who received an identical regimen were also included. Outcomes included safety and immunogenicity 2 weeks and 6 months after final vaccination.
RESULTS
From June 2016 to July 2018, 400 participants were enrolled (N = 334 HVTN108, N = 66 HVTN111); 370 received vaccine and 30 received placebo. There were 48 grade 3 and 3 grade 4 reactogenicity events among 39/400 (9.8%) participants, and 32 mild/moderate-related adverse events in 23/400 (5.8%) participants. All intervention groups demonstrated high IgG response rates (>89%) and high magnitudes to HIV-1 Env gp120 and gp140 proteins; response rates for AS01B-adjuvanted groups approached 100%. V1V2 IgG magnitude, Fc-mediated functions, IgG3 Env response rates, and CD4+ T-cell response magnitudes and rates were higher in the AS01B-adjuvanted groups. The AS01B-adjuvanted low-dose protein elicited greater IgG responses than the higher protein dose.
CONCLUSIONS
The vaccine regimens were generally well tolerated. Co-administration of DNA with AS01B-adjuvanted bivalent Env gp120 elicited the strongest humoral responses; AS01B-adjuvanted regimens elicited stronger CD4+ T-cell responses, justifying further evaluation.ClinicalTrials.gov registration: NCT02915016, registered 26 September 2016.
Topics: Humans; AIDS Vaccines; Vaccines, DNA; Female; Male; Adult; Squalene; Polysorbates; HIV Envelope Protein gp120; Adjuvants, Immunologic; HIV-1; HIV Infections; HIV Antibodies; Double-Blind Method; Middle Aged; Young Adult; Adjuvants, Vaccine; South Africa; Immunogenicity, Vaccine; Adolescent; United States
PubMed: 38916429
DOI: 10.1097/QAI.0000000000003438 -
BioRxiv : the Preprint Server For... Jun 2024The global burden of infections due to the pathogenic fungus is substantial in persons with low CD4 T cell counts. Previously, we deleted three chitin deacetylase...
UNLABELLED
The global burden of infections due to the pathogenic fungus is substantial in persons with low CD4 T cell counts. Previously, we deleted three chitin deacetylase genes from to create a chitosan-deficient, avirulent strain, designated which, when used as a vaccine, protected mice from challenge with virulent strain KN99. Here, we explored the immunological basis for protection. Vaccine-mediated protection was maintained in mice lacking B cells or CD8 T cells. In contrast, protection was lost in mice lacking α/β T cells or CD4 T cells. Moreover, CD4 T cells from vaccinated mice conferred protection upon adoptive transfer to naive mice. Importantly, while monoclonal antibody-mediated depletion of CD4 T cells just prior to vaccination resulted in complete loss of protection, significant protection was retained in mice depleted of CD4 T cells after vaccination, but prior to challenge. Vaccine-mediated protection was lost in mice genetically deficient in IFNγ, TNFα, or IL-23p19. A robust influx of leukocytes and IFNγ- and TNFα-expressing CD4 T cells was seen in the lungs of vaccinated and challenged mice. Finally, a higher level of IFNγ production by lung cells stimulated ex vivo correlated with lower fungal burden in the lungs. Thus, while B cells and CD8 T cells are dispensable, IFNγ and CD4 T cells have overlapping roles in generating protective immunity prior to vaccination. However, once vaccinated, protection becomes less dependent on CD4 T cells, suggesting a strategy for vaccinating HIV persons prior to loss of CD4 T cells.
IMPORTANCE
The fungus is responsible for >100,000 deaths annually, mostly in persons with impaired CD4 T cell function such as AIDS. There are no approved human vaccines. We previously created a genetically engineered avirulent strain of , designated . When used as a vaccine, protects mice against a subsequent challenge with a virulent strain. Here, we defined components of the immune system responsible for vaccine-mediated protection. We found that while B cells and CD8 T cells were dispensible, protection was lost in mice genetically deficient in CD4 T cells, and the cytokines IFNγ, TNFα, or IL-23. A robust influx of cytokine-producing CD4 T cells was seen in the lungs of vaccinated mice following infection. Importantly, protection was retained in mice depleted of CD4 T cells following vaccination, suggesting a strategy to protect persons who are at risk for future CD4 T cell dysfunction.
PubMed: 38915489
DOI: 10.1101/2024.06.12.598760 -
NPJ Vaccines Jun 2024Gammaherpesviruses are oncogenic viruses that establish lifelong infections and are significant causes of morbidity and mortality. Vaccine strategies to limit...
Gammaherpesviruses are oncogenic viruses that establish lifelong infections and are significant causes of morbidity and mortality. Vaccine strategies to limit gammaherpesvirus infection and disease are in development, but there are no FDA-approved vaccines for Epstein-Barr or Kaposi sarcoma herpesvirus. As a new approach to gammaherpesvirus vaccination, we developed and tested a replication-deficient virus (RDV) platform, using murine gammaherpesvirus 68 (MHV68), a well-established mouse model for gammaherpesvirus pathogenesis studies and preclinical therapeutic evaluations. We employed codon-shuffling-based complementation to generate revertant-free RDV lacking expression of the essential replication and transactivator protein encoded by ORF50 to arrest viral gene expression early after de novo infection. Inoculation with RDV-50.stop exposes the host to intact virion particles and leads to limited lytic gene expression in infected cells yet does not produce additional infectious particles. Prime-boost vaccination of mice with RDV-50.stop elicited virus-specific neutralizing antibody and effector T cell responses in the lung and spleen. In contrast to vaccination with heat-inactivated WT MHV68, vaccination with RDV-50.stop resulted in a near complete abolishment of virus replication in the lung 7 days post-challenge and reduction of latency establishment in the spleen 16 days post-challenge with WT MHV68. Ifnar1 mice, which lack the type I interferon receptor, exhibit severe disease and high mortality upon infection with WT MHV68. RDV-50.stop vaccination of Ifnar1 mice prevented wasting and mortality upon challenge with WT MHV68. These results demonstrate that prime-boost vaccination with a gammaherpesvirus that is unable to undergo lytic replication offers protection against acute replication, impairs the establishment of latency, and prevents severe disease upon the WT virus challenge. Our study also reveals that the ability of a gammaherpesvirus to persist in vivo despite potent pre-existing immunity is an obstacle to obtaining sterilizing immunity.
PubMed: 38914546
DOI: 10.1038/s41541-024-00908-x -
Sexually Transmitted Infections Jun 2024Populations who seek HIV pre-exposure prophylaxis (PrEP) are disproportionately affected by hepatitis A virus (HAV), hepatitis B virus (HBV) and human papillomavirus...
HIV pre-exposure prophylaxis and opportunities for vaccination against hepatitis A virus, hepatitis B virus and human papillomavirus: an analysis of the Ontario PrEP cohort study.
OBJECTIVES
Populations who seek HIV pre-exposure prophylaxis (PrEP) are disproportionately affected by hepatitis A virus (HAV), hepatitis B virus (HBV) and human papillomavirus (HPV). We examined immunity/vaccination against these infections among participants in the Ontario PrEP cohort study (ON-PrEP).
METHODS
ON-PrEP is a prospective cohort of HIV-negative PrEP users from 10 Ontario clinics. We descriptively analysed baseline immunity/vaccination against HAV (IgG reactive), HBV (hepatitis B surface antibody >10) and HPV (self-reported three-dose vaccination). We further performed multivariable logistic regression to identify characteristics associated with baseline immunity/vaccination. We used cumulative incidence functions to describe vaccine uptake among participants non-immune at baseline.
RESULTS
Of 633 eligible participants, 59.1% were white, 85.8% were male and 79.6% were gay. We found baseline evidence of immunity/vaccination against HAV, HBV and HPV in 69.2%, 81.2% and 16.8% of PrEP-experienced participants and 58.9%, 70.3% and 10.4% of PrEP-naïve participants, respectively. Characteristics associated with baseline HAV immunity were greater PrEP duration (adjusted OR (aOR) 1.41/year, 95% CI 1.09 to 1.84), frequent sexually transmitted and bloodborne infection (STBBI) testing (aOR 2.38, 95% CI 1.15 to 4.92) and HBV immunity (aOR 3.53, 95% CI 2.09 to 5.98). Characteristics associated with baseline HBV immunity were living in Toronto (aOR 3.54, 95% CI 1.87 to 6.70) or Ottawa (aOR 2.76, 95% CI 1.41 to 5.40), self-identifying as racialised (aOR 2.23, 95% CI 1.19 to 4.18), greater PrEP duration (aOR 1.39/year, 95% CI 1.02 to 1.90) and HAV immunity (aOR 3.75, 95% CI 2.19 to 6.41). Characteristics associated with baseline HPV vaccination were being aged ≤26 years (aOR 9.28, 95% CI 2.11 to 40.77), annual income between CAD$60 000 and CAD$119 000 (aOR 3.42, 95% CI 1.40 to 8.34), frequent STBBI testing (aOR 7.00, 95% CI 1.38 to 35.46) and HAV immunity (aOR 6.96, 95% CI 2.00 to 24.25). Among those non-immune at baseline, overall cumulative probability of immunity/vaccination was 0.70, 0.60 and 0.53 among PrEP-experienced participants and 0.93, 0.80 and 0.70 among PrEP-naïve participants for HAV, HBV and HPV, respectively.
CONCLUSIONS
Baseline immunity to HAV/HBV was common, and a sizeable proportion of non-immune participants were vaccinated during follow-up. However, HPV vaccination was uncommon. Continued efforts should be made to remove barriers to HPV vaccination such as cost, inclusion in clinical guidelines and provider recommendation.
PubMed: 38914474
DOI: 10.1136/sextrans-2023-055961