Hyaluronidase-enhanced subcutaneous delivery of bNAbs: a phase 1 randomized controlled clinical trial in HIV-uninfected women.

Broadly neutralizing antibodies (bNAbs) offer a promising strategy for HIV prevention. Subcutaneous (SC) administration is more feasible than intravenous delivery but may be limited by prolonged administration times and multiple injections. Here we report a pharmacokinetic (PK) modelling study, an unspecified exploratory analysis that involved 57 HIV-negative African women (median age 25 years; BMI range 18.

Dynamics of endemic virus re-emergence in children in the USA following the COVID-19 pandemic (2022-23): a prospective, multicentre, longitudinal, immunoepidemiological surveillance study.

Background: The Pandemic Response Repository through Microbial and Immune Surveillance and Epidemiology (PREMISE) programme was established to translate knowledge gained from global immunoepidemiological surveillance into a better understanding of population-level dynamics of emerging and re-emerging infections, as well as into the discovery and development of biomedical countermeasures against potential pandemic threats. As proof of principle for this approach, we conducted a longitudinal immunoepidemiological study in children in the USA, focusing on enterovirus D68 (EV-D68) infection dynamics but also capturing surveillance of a broad array of other endemic respiratory pathogens. Serendipitously, our sampling spanned the lifting of widespread COVID-19 non-pharmaceutical interventions (NPIs) in 2022-23, following a unique period during which virus exposure markedly diminished.

Pharmacokinetics Analysis of Serum and Rectal Tissue Concentrations of a Pair of Anti-HIV Monoclonal Antibodies, VRC01 and VRC01LS, in Adults without HIV.

VRC01 and VRC01LS are a pair of parental and LS-modified anti-HIV IgG1-backboned monoclonal antibodies. In a Phase 1 clinical trial HVTN 116, 79 participants without HIV received intravenously one dose of VRC01 (30 mg/kg, n = 16) or VRC01LS (30 mg/kg, n = 10), four doses of VRC01 (10 mg/kg, n = 23 or 30 mg/kg, n = 23) every 2 months, or three doses of VRC01LS (30 mg/kg, n = 7) every 3 months. Participants were followed for 6 (VRC01) or 12 (VRC01LS) months after the last dose.

Antigen persistence and TLR stimulation contribute to induction of a durable HIV-1-specific neutralizing antibody response.

HIV-1 Env glycoprotein (Env) immunogenicity is limited in part by structural instability and extensive glycan shielding and is likely the greatest obstacle to an HIV-1 vaccine. Stabilized Env trimers can elicit serum neutralizing antibodies, but the response is short-lived. Here we use Newcastle Disease Virus-like particle (NDV-VLP) platform to present stabilized versions of HIV-1 Env at high valency and in the context of varied conformational stability, adjuvants, dose, and antigen persistence.

Population pharmacokinetics of weight-based compared with fixed dosing of CAP256V2LS, a broadly neutralizing antibody for HIV prevention in women.

Introduction: In the development of broadly neutralizing monoclonal antibodies (bNAb) for HIV prevention, there is a need for simpler dosing strategies. This study assessed whether fixed dosing achieves comparable systemic bNAb concentrations to weight-based dosing across a range of weights.

Methods: The CAPRISA 012B trial was a first-in-human, Phase 1 dose-escalation study conducted in young, HIV-negative women (median age 25 years; IQR: 22-29) in South Africa, evaluating the subcutaneous administration of CAP256V2LS alone and in combination with VRC07-523LS.

Safety and pharmacokinetics of N6LS, a broadly neutralising monoclonal antibody for HIV: a phase 1, open-label, dose-escalation study in healthy adults.

Background: Broadly neutralising antibodies (bNAbs) have shown promise as both prevention and treatment strategies against HIV-1. The clinical effectiveness of bNAbs depends on enhancing their neutralisation breadth and extending their serum half-lives. In this study, we aimed to assess the safety, tolerability, pharmacokinetic profile, and neutralisation activity in serum of N6LS, a HIV-1 bNAb.

Prospective SARS-CoV-2 Booster Vaccination in Immunosuppressant-Treated Systemic Autoimmune Disease Patients in a Randomized Controlled Trial.

Background: Autoimmune disease patients on immunosuppressants exhibit reduced humoral responses to primary COVID-19 vaccination. Booster vaccine responses and the effects of holding immunosuppression around vaccination are less studied. We evaluated the efficacy and safety of additional vaccination in mycophenolate mofetil/mycophenolic acid (MMF/MPA)-, methotrexate (MTX)-, and B cell-depleting therapy (BCDT)-treated autoimmune disease patients, including the impact of withholding MMF/MPA and MTX.

Virologic effects of broadly neutralizing antibodies VRC01LS and VRC07-523LS on chronic HIV-1 infection.

BACKGROUNDHIV-1-specific broadly neutralizing monoclonal antibodies (bNAbs) have emerged as promising interventions with the potential to effectively treat and prevent HIV-1 infections. We conducted a phase I clinical trial evaluating the potent CD4-binding site-specific (CD4bs-specific) bNAbs VRC01LS and VRC07-523LS in people with HIV-1 (PWH) not receiving antiretroviral therapy (ART).METHODSParticipants received a single intravenous 40 mg/kg dose of either VRC01LS (n = 7) or VRC07-523LS (n = 9) and did not initiate ART for a minimum of 14 days.

Structural basis for complement receptor engagement and virus neutralization through Epstein-Barr virus gp350.

Epstein-Barr virus (EBV) causes infectious mononucleosis and is associated with malignancies in humans. Viral infection of B cells is initiated by the viral glycoprotein 350 (gp350) binding to complement receptor 2 (CR2). Despite decades of effort, no vaccines or curative agents have been developed, partly due to lack of atomic-level understanding of the virus-host interface.

Neutralizing antibody correlate of protection against severe-critical COVID-19 in the ENSEMBLE single-dose Ad26.COV2.S vaccine efficacy trial.

Assessment of immune correlates of severe COVID-19 has been hampered by the low numbers of severe cases in COVID-19 vaccine efficacy (VE) trials. We assess neutralizing and binding antibody levels at 4 weeks post-Ad26.COV2.

Phase 1 dose-escalation trial evaluating a group 2 influenza hemagglutinin stabilized stem nanoparticle vaccine.

The relative conservation of the influenza hemagglutinin (HA) stem compared to that of the immunodominant HA head makes the HA stem an attractive target for broadly protective influenza vaccines. Here we report the first-in-human, dose-escalation, open-label trial (NCT04579250) evaluating an unadjuvanted group 2 stabilized stem ferritin nanoparticle vaccine based on the H10 A/Jiangxi-Donghu/346/2013 influenza HA, H10ssF, in healthy adults. Participants received a single 20 mcg dose (n = 3) or two 60 mcg doses 16 weeks apart (n = 22).

Subcutaneous Administration of a Monoclonal Antibody to Prevent Malaria.

Background: Subcutaneous administration of the monoclonal antibody L9LS protected adults against controlled infection in a phase 1 trial. Whether a monoclonal antibody administered subcutaneously can protect children from infection in a region where this organism is endemic is unclear.

Methods: We conducted a phase 2 trial in Mali to assess the safety and efficacy of subcutaneous administration of L9LS in children 6 to 10 years of age over a 6-month malaria season.

Phase 1 trial evaluating safety and pharmacokinetics of HIV-1 broadly neutralizing mAbs 10E8VLS and VRC07-523LS.

BACKGROUNDBroadly neutralizing monoclonal antibodies (bNAbs) represent a promising strategy for HIV-1 immunoprophylaxis and treatment. 10E8VLS and VRC07-523LS are bNAbs that target the highly conserved membrane-proximal external region (MPER) and the CD4-binding site of the HIV-1 viral envelope glycoprotein, respectively.METHODSIn this phase 1, open-label trial, we evaluated the safety and pharmacokinetics of 5 mg/kg 10E8VLS administered alone, or concurrently with 5 mg/kg VRC07-523LS, via s.

Immune responses to SARS-CoV-2 mRNA vaccination in people with idiopathic CD4 lymphopenia.

Background: The immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines is variable in individuals with different inborn errors of immunity or acquired immune deficiencies and is yet unknown in people with idiopathic CD4 lymphopenia (ICL).

Objective: We sought to determine the immunogenicity of mRNA vaccines in patients with ICL with a broad range of CD4 T-cell counts.

Methods: Samples were collected from 25 patients with ICL and 23 age- and sex-matched healthy volunteers (HVs) after their second or third SARS-CoV-2 mRNA vaccine dose.

Long trimer-immunization interval and appropriate adjuvant reduce immune responses to the soluble HIV-1-envelope trimer base.

Soluble 'SOSIP'-stabilized HIV-1 envelope glycoprotein (Env) trimers elicit dominant antibody responses targeting their glycan-free base regions, potentially diminishing neutralizing responses. Previously, using a nonhuman primate model, we demonstrated that priming with fusion peptide (FP)-carrier conjugate immunogens followed by boosting with Env trimers reduced the anti-base response. Further, we demonstrated that longer immunization intervals further reduced anti-base responses and increased neutralization breadth.

Extended safety and tolerability of subcutaneous CAP256V2LS and VRC07-523LS in HIV-negative women: study protocol for the randomised, placebo-controlled double-blinded, phase 2 CAPRISA 012C trial.

Introduction: Women-controlled HIV prevention technologies that overcome adherence challenges of available daily oral pre-exposure prophylaxis and give women a choice of options are urgently needed. Broadly neutralising monoclonal antibodies (bnAbs) administered passively may offer a valuable non-antiretroviral biological intervention for HIV prevention. Animal and human studies have demonstrated that bnAbs which neutralise HIV can prevent infection.

Soluble prefusion-closed HIV-envelope trimers with glycan-covered bases.

Soluble HIV-1-envelope (Env) trimers elicit immune responses that target their solvent-exposed protein bases, the result of removing these trimers from their native membrane-bound context. To assess whether glycosylation could limit these base responses, we introduced sequons encoding potential -linked glycosylation sites (PNGSs) into base-proximal regions. Expression and antigenic analyses indicated trimers bearing six-introduced PNGSs to have reduced base recognition.

Deep Phenotyping of Neurologic Postacute Sequelae of SARS-CoV-2 Infection.

Background And Objectives: SARS-CoV-2 infection has been associated with a syndrome of long-term neurologic sequelae that is poorly characterized. We aimed to describe and characterize in-depth features of neurologic postacute sequelae of SARS-CoV-2 infection (neuro-PASC).

Methods: Between October 2020 and April 2021, 12 participants were seen at the NIH Clinical Center under an observational study to characterize ongoing neurologic abnormalities after SARS-CoV-2 infection.

An influenza hemagglutinin stem nanoparticle vaccine induces cross-group 1 neutralizing antibodies in healthy adults.

Influenza vaccines could be improved by platforms inducing cross-reactive immunity. Immunodominance of the influenza hemagglutinin (HA) head in currently licensed vaccines impedes induction of cross-reactive neutralizing stem-directed antibodies. A vaccine without the variable HA head domain has the potential to focus the immune response on the conserved HA stem.

An influenza H1 hemagglutinin stem-only immunogen elicits a broadly cross-reactive B cell response in humans.

Current yearly seasonal influenza vaccines primarily induce an antibody response directed against the immunodominant but continually diversifying hemagglutinin (HA) head region. These antibody responses provide protection against the vaccinating strain but little cross-protection against other influenza strains or subtypes. To focus the immune response on subdominant but more conserved epitopes on the HA stem that might protect against a broad range of influenza strains, we developed a stabilized H1 stem immunogen lacking the immunodominant head displayed on a ferritin nanoparticle (H1ssF).

Safety and pharmacokinetics of escalating doses of neutralising monoclonal antibody CAP256V2LS administered with and without VRC07-523LS in HIV-negative women in South Africa (CAPRISA 012B): a phase 1, dose-escalation, randomised controlled trial.

Background: Young women in sub-Saharan Africa continue to bear a high burden of HIV infection. Combination anti-HIV monoclonal antibodies are a potential HIV prevention technology that could overcome adherence challenges of daily oral pre-exposure prophylaxis. In this phase 1 clinical trial we aimed to determine the safety and pharmacokinetic profile of the broadly neutralising monoclonal antibody CAP256V2LS.

Kinetics of the Antibody Response to Symptomatic SARS-CoV-2 Infection in Vaccinated and Unvaccinated Individuals in the Blinded Phase of the mRNA-1273 COVID-19 Vaccine Efficacy Trial.

Background: Hybrid immunity is associated with more durable protection against coronavirus disease 2019 (COVID-19). We describe the antibody responses following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in vaccinated and unvaccinated individuals.

Methods: The 55 vaccine arm COVID-19 cases diagnosed during the blinded phase of the Coronavirus Efficacy trial were matched with 55 placebo arm COVID-19 cases.

Safety, tolerability, and immunogenicity of the chimpanzee adenovirus type 3-vectored Marburg virus (cAd3-Marburg) vaccine in healthy adults in the USA: a first-in-human, phase 1, open-label, dose-escalation trial.

Background: WHO has identified Marburg virus as an emerging virus requiring urgent vaccine research and development, particularly due to its recent emergence in Ghana. We report results from a first-in-human clinical trial evaluating a replication-deficient recombinant chimpanzee adenovirus type 3 (cAd3)-vectored vaccine encoding a wild-type Marburg virus Angola glycoprotein (cAd3-Marburg) in healthy adults.

Methods: We did a first-in-human, phase 1, open-label, dose-escalation trial of the cAd3-Marburg vaccine at the Walter Reed Army Institute of Research Clinical Trials Center in the USA.