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Frontiers in Immunology 2024Infectious diseases continue to pose significant global health challenges. In addition to the enduring burdens of ailments like malaria and HIV, the emergence of... (Review)
Review
Infectious diseases continue to pose significant global health challenges. In addition to the enduring burdens of ailments like malaria and HIV, the emergence of nosocomial outbreaks driven by antibiotic-resistant pathogens underscores the ongoing threats. Furthermore, recent infectious disease crises, exemplified by the Ebola and SARS-CoV-2 outbreaks, have intensified the pursuit of more effective and efficient diagnostic and therapeutic solutions. Among the promising options, antibodies have garnered significant attention due to their favorable structural characteristics and versatile applications. Notably, nanobodies (Nbs), the smallest functional single-domain antibodies of heavy-chain only antibodies produced by camelids, exhibit remarkable capabilities in stable antigen binding. They offer unique advantages such as ease of expression and modification and enhanced stability, as well as improved hydrophilicity compared to conventional antibody fragments (antigen-binding fragments (Fab) or single-chain variable fragments (scFv)) that can aggregate due to their low solubility. Nanobodies directly target antigen epitopes or can be engineered into multivalent Nbs and Nb-fusion proteins, expanding their therapeutic potential. This review is dedicated to charting the progress in Nb research, particularly those derived from camelids, and highlighting their diverse applications in treating infectious diseases, spanning both human and animal contexts.
Topics: Animals; Single-Domain Antibodies; Humans; Camelidae; Communicable Diseases; Camelids, New World; COVID-19
PubMed: 38827746
DOI: 10.3389/fimmu.2024.1334829 -
International Journal of Infectious... May 2024This study aimed to compare the humoral responses to mRNA COVID-19 vaccination in people living with HIV (PWH) and HIV-negative individuals.
Humoral response after mRNA COVID-19 primary vaccination and single booster dose in people living with HIV compared to controls: A French nationwide multicenter cohort study-ANRS0001s COV-POPART.
BACKGROUND
This study aimed to compare the humoral responses to mRNA COVID-19 vaccination in people living with HIV (PWH) and HIV-negative individuals.
METHODS
We included PWH with an undetectable viral load under ART and HIV-negative participants from the French nationwide ANRS COV-POPART cohort who had received two doses of vaccine as a primary vaccination. We compared humoral response between controls and PWH, stratified by CD4 cell count (<200/mm and ≥200/mm CD4 cell counts) at 1, 6, and 12 months after primary vaccination.
RESULTS
A total of 1776 participants were included in this analysis, 684 PWH (99% were on ART, median CD4 counts 673 cells/mm) and 1092 controls. At 1 month, after adjustment on age, sex, and BMI, PWH had lower seroneutralization titers than controls, and PWH with <200 CD4 cell/mm had lower anti-Spike SARS-CoV-2 IgG antibodies. Same results were found at 6 months. However, in participants who received a booster dose between 6 and 12 months postprimary vaccination, we did not observe differences between PWH and controls at 12 months.
CONCLUSION
PWH had high responses to primary mRNA COVID-19 vaccination. In those who received a booster dose after 6 months, the humoral response at 12 months increased to similar levels to controls, even in those with low CD4 counts at baseline.
PubMed: 38825164
DOI: 10.1016/j.ijid.2024.107110 -
PloS One 2024Health personnel (HP) are on the frontlines during response to public health emergencies like COVID-19. This risk of exposure suggests the need for safety in responding...
SARS-CoV-2 active infection and antibodies amongst health personnel during the outbreak in Cameroon: Strengthening the health system for response to future public health emergencies.
BACKGROUND
Health personnel (HP) are on the frontlines during response to public health emergencies like COVID-19. This risk of exposure suggests the need for safety in responding to any pandemic. Therefore, to ascertain the rate of SARS-CoV-2 infection and immunity, and their determinants amongst HP become relevant.
METHODS
A cross sectional health facility-based study was carried-out amongst HP in the Centre Region of Cameroon from 1st February to 30th June 2021. Characteristics and access to preventive tools were collected using face-to-face administered questionnaire. Nasopharyngeal swabs and whole blood were collected for PCR, IgG and IgM testing respectively. STATA version 17 software was used for data analysis. Determinants of COVID-19 infection were explored by estimating crude and adjusted Odd Ratio.
RESULTS
Out of 510 HP reached, 458 were enrolled with mean age of 35 (±10) years. Thirty-four (7.4%) were PCR-positive to SARS-CoV-2 with 73.5% being clinicians versus 9 (26.4%) non-clinicians (p = 0.05). Sero-positivity to SARS-CoV-2 IgG/IgM was 40.2% (184/458), with 84.2% being clinicians versus 29 (15.8%) non-clinicians (p = 0.733). Amongst the 34 HP with PCR-positivity, 16 (47%) had no antibodies, while, 15 (44%) were IgG only. An estimate of HP (43.7%) had at least an evidence of PCR, IgG or IgM contact to COVID-19. Determinants of PCR-positivity was being clinical staff (AOR = 0.29, P = 0.039); and that of IgG/IgM were being non clinical staff (AOR = 0.41, p = 0.018) and regular use of face masks (AOR = 0.44, p = 0.001). HP trained on IPC (24%) were mainly from peripheral level (74.7%, p = 0.002).
CONCLUSION
Active infections were within the range of pandemic control (<10%). However, around two-fifths of participants have had contact with the virus, indicating that HP remains a population at risk of COVID-19 and other similarly-transmitted epidemic prone diseases, and also an important source of transmission. There is need of vaccine to achieve protectiveness, and optimal response also requires capacity building to improve the health system when challenged by a future pandemic.
Topics: Humans; COVID-19; Cameroon; Health Personnel; Male; Adult; Female; SARS-CoV-2; Cross-Sectional Studies; Antibodies, Viral; Middle Aged; Public Health; Disease Outbreaks; Immunoglobulin G; Immunoglobulin M
PubMed: 38820301
DOI: 10.1371/journal.pone.0304477 -
Nature Immunology Jun 2024Current prophylactic human immunodeficiency virus 1 (HIV-1) vaccine research aims to elicit broadly neutralizing antibodies (bnAbs). Membrane-proximal external region...
Current prophylactic human immunodeficiency virus 1 (HIV-1) vaccine research aims to elicit broadly neutralizing antibodies (bnAbs). Membrane-proximal external region (MPER)-targeting bnAbs, such as 10E8, provide exceptionally broad neutralization, but some are autoreactive. Here, we generated humanized B cell antigen receptor knock-in mouse models to test whether a series of germline-targeting immunogens could drive MPER-specific precursors toward bnAbs. We found that recruitment of 10E8 precursors to germinal centers (GCs) required a minimum affinity for germline-targeting immunogens, but the GC residency of MPER precursors was brief due to displacement by higher-affinity endogenous B cell competitors. Higher-affinity germline-targeting immunogens extended the GC residency of MPER precursors, but robust long-term GC residency and maturation were only observed for MPER-HuGL18, an MPER precursor clonotype able to close the affinity gap with endogenous B cell competitors in the GC. Thus, germline-targeting immunogens could induce MPER-targeting antibodies, and B cell residency in the GC may be regulated by a precursor-competitor affinity gap.
Topics: Germinal Center; Animals; Mice; Humans; B-Lymphocytes; HIV-1; HIV Antibodies; Antibody Affinity; Antibodies, Neutralizing; HIV Infections; AIDS Vaccines; Receptors, Antigen, B-Cell; Gene Knock-In Techniques; Mice, Transgenic; Broadly Neutralizing Antibodies; Mice, Inbred C57BL
PubMed: 38816616
DOI: 10.1038/s41590-024-01844-7 -
Nature Immunology Jun 2024A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high...
A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high antigenic diversity is the design of priming immunogens that induce rare bnAb-precursor B cells. The high neutralization breadth of the HIV bnAb 10E8 makes elicitation of 10E8-class bnAbs desirable; however, the recessed epitope within gp41 makes envelope trimers poor priming immunogens and requires that 10E8-class bnAbs possess a long heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. We developed germline-targeting epitope scaffolds with affinity for 10E8-class precursors and engineered nanoparticles for multivalent display. Scaffolds exhibited epitope structural mimicry and bound bnAb-precursor human naive B cells in ex vivo screens, protein nanoparticles induced bnAb-precursor responses in stringent mouse models and rhesus macaques, and mRNA-encoded nanoparticles triggered similar responses in mice. Thus, germline-targeting epitope scaffold nanoparticles can elicit rare bnAb-precursor B cells with predefined binding specificities and HCDR3 features.
Topics: Animals; Humans; HIV Envelope Protein gp41; HIV Antibodies; Mice; AIDS Vaccines; Macaca mulatta; Antibodies, Neutralizing; HIV-1; HIV Infections; Vaccination; Broadly Neutralizing Antibodies; B-Lymphocytes; Nanoparticles; Female; Complementarity Determining Regions; Epitopes
PubMed: 38816615
DOI: 10.1038/s41590-024-01833-w -
The Lancet. HIV Jun 2024Allogeneic haematopoietic stem-cell transplantation (allo-HSCT) markedly reduces HIV reservoirs, but the mechanisms by which this occurs are only partly understood. In... (Observational Study)
Observational Study
Dynamics of virological and immunological markers of HIV persistence after allogeneic haematopoietic stem-cell transplantation in the IciStem cohort: a prospective observational cohort study.
BACKGROUND
Allogeneic haematopoietic stem-cell transplantation (allo-HSCT) markedly reduces HIV reservoirs, but the mechanisms by which this occurs are only partly understood. In this study, we aimed to describe the dynamics of virological and immunological markers of HIV persistence after allo-HSCT.
METHODS
In this prospective observational cohort study, we analysed the viral reservoir and serological dynamics in IciStem cohort participants with HIV who had undergone allo-HSCT and were receiving antiretroviral therapy, ten of whom had received cells from donors with the CCR5Δ32 mutation. Participants from Belgium, Canada, Germany, Italy, the Netherlands, Spain, Switzerland, and the UK were included in the cohort both prospectively and retrospectively between June 1, 2014 and April 30, 2019. In the first 6 months after allo-HSCT, participants had monthly assessments, with annual assessments thereafter, with the protocol tailored to accommodate for the individual health status of each participant. HIV reservoirs were measured in blood and tissues and HIV-specific antibodies were measured in plasma. We used the Wilcoxon signed-rank test to compare data collected before and after allo-HSCT in participants for whom longitudinal data were available. When the paired test was not possible, we used the Mann-Whitney U test. We developed a mathematical model to study the factors influencing HIV reservoir reduction in people with HIV after allo-HSCT.
FINDINGS
We included 30 people with HIV with haematological malignancies who received a transplant between Sept 1, 2009 and April 30, 2019 and were enrolled within the IciStem cohort and included in this analysis. HIV reservoirs in peripheral blood were reduced immediately after full donor chimerism was achieved, generally accompanied by undetectable HIV-DNA in bone marrow, ileum, lymph nodes, and cerebrospinal fluid, regardless of donor CCR5 genotype. HIV-specific antibody levels and functionality values declined more slowly than direct HIV reservoir values, decaying significantly only months after full donor chimerism. Mathematical modelling suggests that allogeneic immunity mediated by donor cells is the main viral reservoir depletion mechanism after massive reservoir reduction during conditioning chemotherapy before allo-HSCT (half-life of latently infected replication-competent cells decreased from 44 months to 1·5 months).
INTERPRETATION
Our work provides, for the first time, data on the effects of allo-HSCT in the context of HIV infection. Additionally, we raise the question of which marker can serve as the last reporter of the residual viraemia, postulating that the absence of T-cell immune responses might be a more reliable marker than antibody decline after allo-HSCT.
FUNDING
amfAR (American Foundation for AIDS Research; ARCHE Program), National Institutes of Health, National Institute of Allergy and Infectious Diseases, and Dutch Aidsfonds.
Topics: Humans; Hematopoietic Stem Cell Transplantation; HIV Infections; Male; Prospective Studies; Female; Adult; Middle Aged; HIV-1; Transplantation, Homologous; Biomarkers; Viral Load; HIV Antibodies
PubMed: 38816141
DOI: 10.1016/S2352-3018(24)00090-0 -
The Lancet. Microbe Jun 2024Serial measurement of virological and immunological biomarkers in patients admitted to hospital with COVID-19 can give valuable insight into the pathogenic roles of... (Randomized Controlled Trial)
Randomized Controlled Trial
Early trajectories of virological and immunological biomarkers and clinical outcomes in patients admitted to hospital for COVID-19: an international, prospective cohort study.
BACKGROUND
Serial measurement of virological and immunological biomarkers in patients admitted to hospital with COVID-19 can give valuable insight into the pathogenic roles of viral replication and immune dysregulation. We aimed to characterise biomarker trajectories and their associations with clinical outcomes.
METHODS
In this international, prospective cohort study, patients admitted to hospital with COVID-19 and enrolled in the Therapeutics for Inpatients with COVID-19 platform trial within the Accelerating COVID-19 Therapeutic Interventions and Vaccines programme between Aug 5, 2020 and Sept 30, 2021 were included. Participants were included from 108 sites in Denmark, Greece, Poland, Singapore, Spain, Switzerland, Uganda, the UK, and the USA, and randomised to placebo or one of four neutralising monoclonal antibodies: bamlanivimab (Aug 5 to Oct 13, 2020), sotrovimab (Dec 16, 2020, to March 1, 2021), amubarvimab-romlusevimab (Dec 16, 2020, to March 1, 2021), and tixagevimab-cilgavimab (Feb 10 to Sept 30, 2021). This trial included an analysis of 2149 participants with plasma nucleocapsid antigen, anti-nucleocapsid antibody, C-reactive protein (CRP), IL-6, and D-dimer measured at baseline and day 1, day 3, and day 5 of enrolment. Day-90 follow-up status was available for 1790 participants. Biomarker trajectories were evaluated for associations with baseline characteristics, a 7-day pulmonary ordinal outcome, 90-day mortality, and 90-day rate of sustained recovery.
FINDINGS
The study included 2149 participants. Participant median age was 57 years (IQR 46-68), 1246 (58·0%) of 2149 participants were male and 903 (42·0%) were female; 1792 (83·4%) had at least one comorbidity, and 1764 (82·1%) were unvaccinated. Mortality to day 90 was 172 (8·0%) of 2149 and 189 (8·8%) participants had sustained recovery. A pattern of less favourable trajectories of low anti-nucleocapsid antibody, high plasma nucleocapsid antigen, and high inflammatory markers over the first 5 days was observed for high-risk baseline clinical characteristics or factors related to SARS-CoV-2 infection. For example, participants with chronic kidney disease demonstrated plasma nucleocapsid antigen 424% higher (95% CI 319-559), CRP 174% higher (150-202), IL-6 173% higher (144-208), D-dimer 149% higher (134-165), and anti-nucleocapsid antibody 39% lower (60-18) to day 5 than those without chronic kidney disease. Participants in the highest quartile for plasma nucleocapsid antigen, CRP, and IL-6 at baseline and day 5 had worse clinical outcomes, including 90-day all-cause mortality (plasma nucleocapsid antigen hazard ratio (HR) 4·50 (95% CI 3·29-6·15), CRP HR 3·37 (2·30-4·94), and IL-6 HR 5·67 (4·12-7·80). This risk persisted for plasma nucleocapsid antigen and CRP after adjustment for baseline biomarker values and other baseline factors.
INTERPRETATION
Patients admitted to hospital with less favourable 5-day biomarker trajectories had worse prognosis, suggesting that persistent viral burden might drive inflammation in the pathogenesis of COVID-19, identifying patients that might benefit from escalation of antiviral or anti-inflammatory treatment.
FUNDING
US National Institutes of Health.
Topics: Humans; COVID-19; Prospective Studies; Male; Female; Biomarkers; Middle Aged; SARS-CoV-2; Aged; Hospitalization; Fibrin Fibrinogen Degradation Products; Antibodies, Monoclonal, Humanized; Interleukin-6; C-Reactive Protein; Pandemics; Coronavirus Infections; Pneumonia, Viral; Treatment Outcome
PubMed: 38815595
DOI: 10.1016/S2666-5247(24)00015-6 -
AIDS (London, England) Jul 2024
Topics: Humans; HIV Infections; COVID-19 Vaccines; COVID-19; SARS-CoV-2; mRNA Vaccines; Vaccines, Synthetic; Antibodies, Viral
PubMed: 38814720
DOI: 10.1097/01.aids.0001010204.00856.15 -
Open Forum Infectious Diseases May 2024Syphilis diagnosis in the emergency department (ED) setting is often missed due to the lack of ED-specific testing strategies. We characterized ED patients with...
BACKGROUND
Syphilis diagnosis in the emergency department (ED) setting is often missed due to the lack of ED-specific testing strategies. We characterized ED patients with high-titer syphilis infections (HTSIs) with the goal of defining a screening strategy that most parsimoniously identifies undiagnosed, untreated syphilis infections.
METHODS
Unlinked, de-identified remnant serum samples from patients attending an urban ED, between 10 January and 9 February 2022, were tested using a three-tier testing algorithm, and sociodemographic variables were extracted from ED administrative database prior to testing. Patients who tested positive for treponemal antibodies in the first tier and positive at high titer (≥1:8) for nontreponemal antibodies in the second tier were classified as HTSI. Human immunodeficiency virus (HIV) status was determined with Bio-Rad enzyme-linked immunosorbent assay and confirmatory assays. Exact logistic regression and classification and regression tree (CART) analyses were performed to determine factors associated with HTSI and derive screening strategies.
RESULTS
Among 1951 unique patients tested, 23 (1.2% [95% confidence interval, .8%-1.8%]) had HTSI. Of those, 18 (78%) lacked a primary care physician, 5 (22%) were HIV positive, and 8 (35%) were women of reproductive age (18-49 years). CART analysis (area under the curve of 0.67) showed that using a screening strategy that measured syphilis antibodies in patients with HIV, without a primary care physician, and women of reproductive age would have identified most patients with HTSI (21/23 [91%]).
CONCLUSIONS
We show a high prevalence of HTSI in an urban ED and propose a feasible, novel screening strategy to curtail community transmission and prevent long-term complications.
PubMed: 38813260
DOI: 10.1093/ofid/ofae207 -
Frontiers in Immunology 2024HIV-1 infection may produce a detrimental effect on the immune response. Early start of antiretroviral therapy (ART) is recommended to preserve the integrity of the...
INTRODUCTION
HIV-1 infection may produce a detrimental effect on the immune response. Early start of antiretroviral therapy (ART) is recommended to preserve the integrity of the immune system. In fact, people with HIV (PWH) and normal CD4/CD8 ratio appear not to be more susceptible to severe forms of COVID-19 than the general population and they usually present a good seroconversion rate in response to vaccination against SARS-CoV-2. However, few studies have fully characterized the development of cytotoxic immune populations in response to COVID-19 vaccination in these individuals.
METHODS
In this study, we recruited PWH with median time of HIV-1 infection of 6 years, median CD4/CD8 ratio of 1.0, good adherence to ART, persistently undetectable viral load, and negative serology against SARS-CoV-2, who then received the complete vaccination schedule against COVID-19. Blood samples were taken before vaccination against COVID-19 and one month after receiving the complete vaccination schedule.
RESULTS
PWH produced high levels of IgG against SARS-CoV-2 in response to vaccination that were comparable to healthy donors, with a significantly higher neutralization capacity. Interestingly, the cytotoxic activity of PBMCs from PWH against SARS-CoV-2-infected cells was higher than healthy donors before receiving the vaccination schedule, pointing out the pre-existence of activated cell populations with likely unspecific antiviral activity. The characterization of these cytotoxic cell populations revealed high levels of Tgd cells with degranulation capacity against SARS-CoV-2-infected cells. In response to vaccination, the degranulation capacity of CD8+ T cells also increased in PWH but not in healthy donors.
DISCUSSION
The full vaccination schedule against COVID-19 did not modify the ability to respond against HIV-1-infected cells in PWH and these individuals did not show more susceptibility to breakthrough infection with SARS-CoV-2 than healthy donors after 12 months of follow-up. These results revealed the development of protective cell populations with broad-spectrum antiviral activity in PWH with normal CD4/CD8 ratio and confirmed the importance of early ART and treatment adherence to avoid immune dysfunctions.
Topics: Humans; SARS-CoV-2; COVID-19; HIV Infections; Male; Female; Middle Aged; Adult; CD4-CD8 Ratio; COVID-19 Vaccines; CD8-Positive T-Lymphocytes; Antibodies, Viral; HIV-1; Cytotoxicity, Immunologic; Immunoglobulin G; T-Lymphocytes, Cytotoxic; Vaccination
PubMed: 38812512
DOI: 10.3389/fimmu.2024.1362621