RESUMEN
BACKGROUND: The ambitious goal to eliminate new pediatric HIV infections by 2030 requires accelerated prevention strategies in high-risk settings such as South Africa. One approach could be pre-exposure prophylaxis (PrEP) with broadly neutralizing anti-HIV-1 monoclonal antibodies (bNAbs). The aim of our study is to define the optimal dose(s), the ideal combination(s) of bNAbs in terms of potency and breadth, and timing of subcutaneous (SC) administration(s) to prevent breast milk transmission of HIV. METHODS: Two bNAbs, CAP256V2LS and VRC07-523LS, will be assessed in a sequential and randomized phase I, single-site, single-blind, dose-finding trial. We aim to investigate the 28-day safety and pharmacokinetics (PK) profile of incrementally higher doses of these bNAbs in breastfeeding HIV-1 exposed born without HIV neonates alongside standard of care antiretroviral (ARV) medication to prevent (infants) or treat (mothers) HIV infection. The trial design includes 3 steps and 7 arms (1, 2, 3, 4, 5, 6 and 6b) with 8 infants in each arm. The first step will evaluate the safety and PK profile of the bNAbs when given alone as a single subcutaneous (SC) administration at increasing mg/kg body weight doses within 96 h of birth: arms 1, 2 and 3 at doses of 5, 10, and 20 mg/kg of CAP256V2LS, respectively; arms 4 and 5 at doses of 20 and 30 mg/kg of VRC07-523LS, respectively. Step two will evaluate the safety and PK profile of a combination of the two bNAbs administered SC at fixed doses within 96 h of birth. Step three will evaluate the safety and PK profile of the two bNAbs administered SC in combination at fixed doses, after 3 months. Arms 1 and 6 will follow sequential recruitment, whereas randomization will occur sequentially between arms (a) 2 & 4 and (b) 3 & 5. Before each randomization, a safety pause will allow review of safety data of the preceding arms. DISCUSSION: The results of this trial will guide further studies on bNAbs to prevent breast milk transmission of HIV. PROTOCOL VERSION: Version 4.0 dated 15 March 2024. TRIAL REGISTRATION: Pan African Clinical Trial Registry (PACTR): PACTR202205715278722, 21 April 2022; South African National Clinical Trial Registry (SANCTR): DOH-27-062022-6058.
Asunto(s)
Anticuerpos Anti-VIH , Infecciones por VIH , VIH-1 , Humanos , Infecciones por VIH/prevención & control , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/transmisión , VIH-1/inmunología , Recién Nacido , Femenino , Anticuerpos Anti-VIH/administración & dosificación , Lactante , Inyecciones Subcutáneas , Anticuerpos Monoclonales/farmacocinética , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/inmunología , Profilaxis Pre-Exposición/métodos , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Sudáfrica , Anticuerpos ampliamente neutralizantes/inmunología , Anticuerpos ampliamente neutralizantes/administración & dosificación , Lactancia Materna , Fármacos Anti-VIH/farmacocinética , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/uso terapéutico , Método Simple Ciego , Anticuerpos Neutralizantes/inmunología , Masculino , Ensayos Clínicos Fase I como AsuntoRESUMEN
BACKGROUND: Broadly neutralizing antibodies (bnAbs) are a promising approach for HIV-1 prevention. In the Antibody Mediated Prevention (AMP) trials, a CD4-binding site targeting bnAb, VRC01, administered intravenously (IV), demonstrated 75% prevention efficacy against highly neutralization-sensitive viruses but was ineffective against less sensitive viruses. VRC07-523LS is a next-generation bnAb targeting the CD4-binding site and was engineered for increased neutralization breadth and half-life. We conducted a multicenter, randomized, partially blinded Phase I clinical trial to evaluate the safety and serum concentrations of VRC07-523LS, administered in multiple doses and routes to healthy adults without HIV. METHODS AND FINDINGS: Participants were recruited between 2 February 2018 and 9 October 2018. A total of 124 participants were randomized to receive 5 VRC07-523LS administrations via IV (T1: 2.5 mg/kg, T2: 5 mg/kg, T3: 20 mg/kg), subcutaneous (SC) (T4: 2.5 mg/kg, T5: 5 mg/kg), or intramuscular (IM) (T6: 2.5 mg/kg or P6: placebo) routes at 4-month intervals. Participants and site staff were blinded to VRC07-523LS versus placebo for the IM group, while all other doses and routes were open-label. Safety data were collected for 144 weeks following the first administration. VRC07-523LS serum concentrations were measured by ELISA through Day 112 in all participants and by binding antibody multiplex assay (BAMA) thereafter in 60 participants (10 per treatment group) through Day 784. Compartmental population pharmacokinetic (PK) analyses were conducted to evaluate the VRC07-523LS serum PK. Neutralization activity was measured in a TZM-bl assay and antidrug antibodies (ADAs) were assayed using a tiered bridging assay testing strategy. Injections and infusions were well tolerated, with mild pain or tenderness reported commonly in the SC and IM groups, and mild to moderate erythema or induration reported commonly in the SC groups. Infusion reactions were reported in 3 of 20 participants in the 20 mg/kg IV group. Peak geometric mean (GM) concentrations (95% confidence intervals [95% CIs]) following the first administration were 29.0 µg/mL (25.2, 33.4), 58.5 µg/mL (49.4, 69.3), and 257.2 µg/mL (127.5, 518.9) in T1-T3 with IV dosing; 10.8 µg/mL (8.8, 13.3) and 22.8 µg/mL (20.1, 25.9) in T4-T5 with SC dosing; and 16.4 µg/mL (14.7, 18.2) in T6 with IM dosing. Trough GM (95% CIs) concentrations immediately prior to the second administration were 3.4 µg/mL (2.5, 4.6), 6.5 µg/mL (5.6, 7.5), and 27.2 µg/mL (23.9, 31.0) with IV dosing; 0.97 µg/mL (0.65, 1.4) and 3.1 µg/mL (2.2, 4.3) with SC dosing, and 2.6 µg/mL (2.05, 3.31) with IM dosing. Peak VRC07-523LS serum concentrations increased linearly with the administered dose. At a given dose, peak and trough concentrations, as well as serum neutralization titers, were highest in the IV groups, reflecting the lower bioavailability following SC and IM administration. A single participant was found to have low titer ADA at a lone time point. VRC07-523LS has an estimated mean half-life of 42 days across all doses and routes (95% CI: 40.5, 43.5), over twice as long as VRC01 (15 days). CONCLUSIONS: VRC07-523LS was safe and well tolerated across a range of doses and routes and is a promising long-acting bnAb for inclusion in HIV-1 prevention regimens. TRIAL REGISTRATION: ClinicalTrials.gov/ NCT03387150 (posted on 21 December 2017).
Asunto(s)
Anticuerpos Neutralizantes , Anticuerpos Anti-VIH , Humanos , Masculino , Femenino , Adulto , Anticuerpos Neutralizantes/sangre , Anticuerpos Anti-VIH/sangre , Persona de Mediana Edad , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , VIH-1/inmunología , Adulto Joven , Anticuerpos ampliamente neutralizantes/administración & dosificación , Anticuerpos ampliamente neutralizantes/efectos adversos , Adolescente , Inyecciones IntramuscularesRESUMEN
The eradication of the viral reservoir represents the major obstacle to the development of a clinical cure for established HIV-1 infection. Here, we demonstrate that the administration of N-803 (brand name Anktiva) and broadly neutralizing antibodies (bNAbs) results in sustained viral control after discontinuation of antiretroviral therapy (ART) in simian-human AD8 (SHIV-AD8)-infected, ART-suppressed rhesus macaques. N-803+bNAbs treatment induced immune activation and transient viremia but only limited reductions in the SHIV reservoir. Upon ART discontinuation, viral rebound occurred in all animals, which was followed by durable control in approximately 70% of all N-803+bNAb-treated macaques. Viral control was correlated with the reprogramming of CD8+ T cells by N-803+bNAb synergy. Thus, complete eradication of the replication-competent viral reservoir is likely not a prerequisite for the induction of sustained remission after discontinuation of ART.
Asunto(s)
Antirretrovirales , Proteínas Recombinantes de Fusión , Síndrome de Inmunodeficiencia Adquirida del Simio , Virus de la Inmunodeficiencia de los Simios , Animales , Humanos , Antirretrovirales/uso terapéutico , Antirretrovirales/farmacología , Anticuerpos ampliamente neutralizantes/administración & dosificación , Linfocitos T CD8-positivos/virología , Inmunoterapia , Macaca mulatta , Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico , Síndrome de Inmunodeficiencia Adquirida del Simio/terapia , Carga Viral , Proteínas Recombinantes de Fusión/administración & dosificación , Proteínas Recombinantes de Fusión/farmacología , Inducción de Remisión , Quimioterapia CombinadaRESUMEN
Antiretroviral therapy is highly effective in suppressing human immunodeficiency virus (HIV)1. However, eradication of the virus in individuals with HIV has not been possible to date2. Given that HIV suppression requires life-long antiretroviral therapy, predominantly on a daily basis, there is a need to develop clinically effective alternatives that use long-acting antiviral agents to inhibit viral replication3. Here we report the results of a two-component clinical trial involving the passive transfer of two HIV-specific broadly neutralizing monoclonal antibodies, 3BNC117 and 10-1074. The first component was a randomized, double-blind, placebo-controlled trial that enrolled participants who initiated antiretroviral therapy during the acute/early phase of HIV infection. The second component was an open-label single-arm trial that enrolled individuals with viraemic control who were naive to antiretroviral therapy. Up to 8 infusions of 3BNC117 and 10-1074, administered over a period of 24 weeks, were well tolerated without any serious adverse events related to the infusions. Compared with the placebo, the combination broadly neutralizing monoclonal antibodies maintained complete suppression of plasma viraemia (for up to 43 weeks) after analytical treatment interruption, provided that no antibody-resistant HIV was detected at the baseline in the study participants. Similarly, potent HIV suppression was seen in the antiretroviral-therapy-naive study participants with viraemia carrying sensitive virus at the baseline. Our data demonstrate that combination therapy with broadly neutralizing monoclonal antibodies can provide long-term virological suppression without antiretroviral therapy in individuals with HIV, and our experience offers guidance for future clinical trials involving next-generation antibodies with long half-lives.
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Fármacos Anti-VIH , Anticuerpos Neutralizantes , Anticuerpos Anti-VIH , Infecciones por VIH , VIH-1 , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Fármacos Anti-VIH/inmunología , Fármacos Anti-VIH/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Neutralizantes/efectos adversos , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/uso terapéutico , Anticuerpos ampliamente neutralizantes/administración & dosificación , Anticuerpos ampliamente neutralizantes/efectos adversos , Anticuerpos ampliamente neutralizantes/inmunología , Anticuerpos ampliamente neutralizantes/uso terapéutico , Método Doble Ciego , Anticuerpos Anti-VIH/administración & dosificación , Anticuerpos Anti-VIH/efectos adversos , Anticuerpos Anti-VIH/inmunología , Anticuerpos Anti-VIH/uso terapéutico , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/inmunología , VIH-1/aislamiento & purificación , Humanos , Carga Viral/efectos de los fármacos , Viremia/tratamiento farmacológico , Viremia/inmunología , Viremia/virologíaRESUMEN
PB2452, a neutralizing monoclonal antibody fragment that binds the antiplatelet drug ticagrelor with high affinity, is being developed as a ticagrelor reversal agent. To identify a clinically useful intravenous (i.v.) reversal regimen, a semimechanistic exposure-response model was developed during the PB2452 first-in-human phase I study. From a randomized, double-blind, placebo-controlled, single-dose trial to evaluate the safety, efficacy, and pharmacokinetics (PKs) of PB2452 in 61 healthy volunteers pretreated with ticagrelor, sequential dose cohort data were used to build and refine an exposure-response model that combined population PK models for ticagrelor (TICA), ticagrelor active metabolite (TAM), and PB2452, and related their binding relationships to the PK of uncomplexed TICA and TAM which is predictive of platelet inhibition. Platelet function was assessed by multiple assays. The model was developed using Bayesian methods in NONMEM. Human PK and pharmacodynamic data from sequential dose cohorts were used to initially define and then refine model parameters. Model simulations indicated that an initial i.v. bolus of PB2452, followed by a high-rate infusion, and then a slower-rate infusion would provide immediate and sustained reversal of the antiplatelet effects of ticagrelor. Based on model predictions, a 6 g i.v. bolus followed by 6 g infused over 4 h and then 6 g over 12 h was identified and tested in study subjects and shown to provide complete reversal within 5 min of infusion onset that was sustained for 20-24 h. The model is predictive of the reversal profile of PB2452 and will inform future trials of PB2452.
Asunto(s)
Reversión de la Anticoagulación/métodos , Anticuerpos ampliamente neutralizantes/administración & dosificación , Fragmentos de Inmunoglobulinas/administración & dosificación , Fragmentos de Inmunoglobulinas/farmacología , Ticagrelor/antagonistas & inhibidores , Adolescente , Adulto , Teorema de Bayes , Plaquetas/efectos de los fármacos , Anticuerpos ampliamente neutralizantes/farmacología , Anticuerpos ampliamente neutralizantes/uso terapéutico , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Voluntarios Sanos , Humanos , Fragmentos de Inmunoglobulinas/uso terapéutico , Masculino , Persona de Mediana Edad , Modelos Biológicos , Inhibidores de Agregación Plaquetaria/farmacología , Ticagrelor/administración & dosificación , Ticagrelor/farmacocinética , Ticagrelor/farmacología , Ticagrelor/uso terapéutico , Adulto JovenRESUMEN
Broadly neutralising antibodies (bNAbs) may play an important role in future strategies for HIV control. The development of anti-drug antibody (ADA) responses can reduce the efficacy of passively transferred bNAbs but the impact of ADA is imperfectly understood. We previously showed that therapeutic administration of the anti-HIV bNAb PGT121 (either WT or LALA version) controlled viraemia in pigtailed macaques with ongoing SHIV infection. We now report on 23 macaques that had multiple treatments with PGT121. We found that an increasing number of intravenous doses of PGT121 or human IgG1 isotype control antibodies (2-4 doses) results in anti-PGT121 ADA induction and low plasma concentrations of PGT121. ADA was associated with poor or absent suppression of SHIV viremia. Notably, ADA within macaque plasma recognised another human bNAb 10E8 but did not bind to the variable domains of PGT121, suggesting that ADA were primarily directed against the constant regions of the human antibodies. These findings have implications for the development of preclinical studies examining multiple infusions of human bNAbs.
Asunto(s)
Anticuerpos ampliamente neutralizantes/administración & dosificación , Anticuerpos Anti-VIH/administración & dosificación , Inmunoglobulina G/administración & dosificación , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Viremia/prevención & control , Animales , Anticuerpos ampliamente neutralizantes/sangre , Anticuerpos ampliamente neutralizantes/inmunología , Anticuerpos Anti-VIH/sangre , Anticuerpos Anti-VIH/inmunología , Macaca nemestrina/inmunología , Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología , Virus de la Inmunodeficiencia de los Simios/inmunología , Viremia/inmunologíaRESUMEN
Equine infectious anemia virus (EIAV) is a lentivirus similar to HIV that infects horses. Clinical and experimental studies demonstrating immune control of EIAV infection hold promise for efforts to produce an HIV vaccine. Antibody infusions have been shown to block both wild-type and mutant virus infection, but the mutant sometimes escapes. Using these data, we develop a mathematical model that describes the interactions between antibodies and both wild-type and mutant virus populations, in the context of continual virus mutation. The aim of this work is to determine whether repeated vaccinations through antibody infusions can reduce both the wild-type and mutant strains of the virus below one viral particle, and if so, to examine the vaccination period and number of infusions that ensure eradication. The antibody infusions are modelled using impulsive differential equations, a technique that offers insight into repeated vaccination by approximating the time-to-peak by an instantaneous change. We use impulsive theory to determine the maximal vaccination intervals that would be required to reduce the wild-type and mutant virus levels below one particle per horse. We show that seven boosts of the antibody vaccine are sufficient to eradicate both the wild-type and the mutant strains. In the case of a mutant virus infection that is given infusions of antibodies targeting wild-type virus (i.e., simulation of a heterologous infection), seven infusions were likewise sufficient to eradicate infection, based upon the data set. However, if the period between infusions was sufficiently increased, both the wild-type and mutant virus would eventually persist in the form of a periodic orbit. These results suggest a route forward to design antibody-based vaccine strategies to control viruses subject to mutant escape.
Asunto(s)
Anticuerpos Antivirales/inmunología , Anticuerpos ampliamente neutralizantes/inmunología , Anemia Infecciosa Equina/terapia , Anemia Infecciosa Equina/virología , Inmunización Pasiva , Virus de la Anemia Infecciosa Equina/genética , Virus de la Anemia Infecciosa Equina/inmunología , Animales , Anticuerpos Antivirales/administración & dosificación , Anticuerpos ampliamente neutralizantes/administración & dosificación , Caballos , Virus de la Anemia Infecciosa Equina/fisiología , Modelos Biológicos , Mutación , Carga ViralRESUMEN
Human immunodeficiency virus (HIV)-1-specific broadly neutralizing monoclonal antibodies are currently under development to treat and prevent HIV-1 infection. We performed a single-center, randomized, double-blind, dose-escalation, placebo-controlled trial of a single administration of the HIV-1 V3-glycan-specific antibody PGT121 at 3, 10 and 30 mg kg-1 in HIV-uninfected adults and HIV-infected adults on antiretroviral therapy (ART), as well as a multicenter, open-label trial of one infusion of PGT121 at 30 mg kg-1 in viremic HIV-infected adults not on ART (no. NCT02960581). The primary endpoints were safety and tolerability, pharmacokinetics (PK) and antiviral activity in viremic HIV-infected adults not on ART. The secondary endpoints were changes in anti-PGT121 antibody titers and CD4+ T-cell count, and development of HIV-1 sequence variations associated with PGT121 resistance. Among 48 participants enrolled, no treatment-related serious adverse events, potential immune-mediated diseases or Grade 3 or higher adverse events were reported. The most common reactions among PGT121 recipients were intravenous/injection site tenderness, pain and headache. Absolute and relative CD4+ T-cell counts did not change following PGT121 infusion in HIV-infected participants. Neutralizing anti-drug antibodies were not elicited. PGT121 reduced plasma HIV RNA levels by a median of 1.77 log in viremic participants, with a viral load nadir at a median of 8.5 days. Two individuals with low baseline viral loads experienced ART-free viral suppression for ≥168 days following antibody infusion, and rebound viruses in these individuals demonstrated full or partial PGT121 sensitivity. The trial met the prespecified endpoints. These data suggest that further investigation of the potential of antibody-based therapeutic strategies for long-term suppression of HIV is warranted, including in individuals off ART and with low viral load.
Asunto(s)
Antivirales/administración & dosificación , Anticuerpos ampliamente neutralizantes/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , VIH-1/efectos de los fármacos , Adulto , Terapia Antirretroviral Altamente Activa , Antivirales/inmunología , Antivirales/farmacocinética , Anticuerpos ampliamente neutralizantes/inmunología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/virología , Método Doble Ciego , Femenino , Proteína gp120 de Envoltorio del VIH/antagonistas & inhibidores , Proteína gp120 de Envoltorio del VIH/inmunología , Infecciones por VIH/genética , Infecciones por VIH/patología , Infecciones por VIH/virología , VIH-1/patogenicidad , Humanos , Masculino , Persona de Mediana Edad , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/inmunología , Placebos , Carga Viral/efectos de los fármacos , Carga Viral/inmunología , Adulto JovenRESUMEN
The emergence of numerous variants of SARS-CoV-2, the causative agent of COVID-19, has presented new challenges to the global efforts to control the COVID-19 pandemic. Here, we obtain two cross-neutralizing antibodies (7D6 and 6D6) that target Sarbecoviruses' receptor-binding domain (RBD) with sub-picomolar affinities and potently neutralize authentic SARS-CoV-2. Crystal structures show that both antibodies bind a cryptic site different from that recognized by existing antibodies and highly conserved across Sarbecovirus isolates. Binding of these two antibodies to the RBD clashes with the adjacent N-terminal domain and disrupts the viral spike. Both antibodies confer good resistance to mutations in the currently circulating SARS-CoV-2 variants. Thus, our results have direct relevance to public health as options for passive antibody therapeutics and even active prophylactics. They can also inform the design of pan-sarbecovirus vaccines.
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Anticuerpos Antivirales/inmunología , Anticuerpos ampliamente neutralizantes/inmunología , COVID-19/terapia , Inmunización Pasiva/métodos , SARS-CoV-2/inmunología , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/aislamiento & purificación , Anticuerpos Monoclonales/metabolismo , Anticuerpos Antivirales/administración & dosificación , Anticuerpos Antivirales/aislamiento & purificación , Anticuerpos Antivirales/metabolismo , Sitios de Unión/genética , Sitios de Unión/inmunología , Anticuerpos ampliamente neutralizantes/administración & dosificación , Anticuerpos ampliamente neutralizantes/aislamiento & purificación , Anticuerpos ampliamente neutralizantes/metabolismo , Células CHO , COVID-19/epidemiología , COVID-19/inmunología , COVID-19/virología , Chlorocebus aethiops , Cricetulus , Epítopos/inmunología , Células HEK293 , Humanos , Ratones , Coronavirus del Síndrome Respiratorio de Oriente Medio/genética , Coronavirus del Síndrome Respiratorio de Oriente Medio/inmunología , Pruebas de Neutralización , Pandemias/prevención & control , Multimerización de Proteína , Receptores Virales/metabolismo , SARS-CoV-2/genética , Células Sf9 , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Células VeroAsunto(s)
Antibacterianos/uso terapéutico , Infecciones por Clostridium/tratamiento farmacológico , Infecciones por Clostridium/fisiopatología , Factores de Edad , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos ampliamente neutralizantes/administración & dosificación , Protocolos Clínicos , Infecciones por Clostridium/prevención & control , Método Doble Ciego , Interacciones Farmacológicas , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Recurrencia , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
Broadly neutralizing antibodies (bNAbs) directed to HIV-1 have shown promise at suppressing viremia in animal models. However, the use of bNAbs for the central nervous system (CNS) infection is confounded by poor penetration of the blood brain barrier (BBB). Typically, antibody concentrations in the CNS are extremely low; with levels in cerebrospinal fluid (CSF) only 0.1% of blood concentrations. Using a novel nanotechnology platform, which we term nanocapsules, we show effective transportation of the human bNAb PGT121 across the BBB in infant rhesus macaques upon systemic administration up to 1.6% of plasma concentration. We demonstrate that a single dose of PGT121 encased in nanocapsules when delivered at 48h post-infection delays early acute infection with SHIVSF162P3 in infants, with one of four animals demonstrating viral clearance. Importantly, the nanocapsule delivery of PGT121 improves suppression of SHIV infection in the CNS relative to controls.
Asunto(s)
Anticuerpos Antivirales/administración & dosificación , Encéfalo/virología , Anticuerpos ampliamente neutralizantes/administración & dosificación , Síndrome de Inmunodeficiencia Adquirida del Simio/virología , Carga Viral/efectos de los fármacos , Animales , Animales Recién Nacidos , Barrera Hematoencefálica , Encéfalo/efectos de los fármacos , Humanos , Macaca mulatta , Nanocápsulas , Virus de la Inmunodeficiencia de los SimiosRESUMEN
BackgroundVRC01, a potent, broadly neutralizing monoclonal antibody, inhibits simian-HIV infection in animal models. The HVTN 104 study assessed the safety and pharmacokinetics of VRC01 in humans. We extend the clinical evaluation to determine intravenously infused VRC01 distribution and protective function at mucosal sites of HIV-1 entry.MethodsHealthy, HIV-1-uninfected men (n = 7) and women (n = 5) receiving VRC01 every 2 months provided mucosal and serum samples once, 4-13 days after infusion. Eleven male and 8 female HIV-seronegative volunteers provided untreated control samples. VRC01 levels were measured in serum, secretions, and tissue, and HIV-1 inhibition was determined in tissue explants.ResultsMedian VRC01 levels were quantifiable in serum (96.2 µg/mL or 1.3 pg/ng protein), rectal tissue (0.11 pg/ng protein), rectal secretions (0.13 pg/ng protein), vaginal tissue (0.1 pg/ng protein), and cervical secretions (0.44 pg/ng protein) from all recipients. VRC01/IgG ratios in male serum correlated with those in paired rectal tissue (r = 0.893, P = 0.012) and rectal secretions (r = 0.9643, P = 0.003). Ex vivo HIV-1Bal26 challenge infected 4 of 21 rectal explants from VRC01 recipients versus 20 of 22 from controls (P = 0.005); HIV-1Du422.1 infected 20 of 21 rectal explants from VRC01 recipients and 12 of 12 from controls (P = 0.639). HIV-1Bal26 infected 0 of 14 vaginal explants of VRC01 recipients compared with 23 of 28 control explants (P = 0.003).ConclusionIntravenous VRC01 distributes into the female genital and male rectal mucosa and retains anti-HIV-1 functionality, inhibiting a highly neutralization-sensitive but not a highly resistant HIV-1 strain in mucosal tissue. These findings lend insight into VRC01 mucosal infiltration and provide perspective on in vivo protective efficacy.FundingNational Institute of Allergy and Infectious Diseases and Bill & Melinda Gates Foundation.
Asunto(s)
Anticuerpos Monoclonales/administración & dosificación , Anticuerpos ampliamente neutralizantes/administración & dosificación , Anticuerpos Anti-VIH/administración & dosificación , Infecciones por VIH/prevención & control , VIH-1/inmunología , VIH-1/patogenicidad , Recto/inmunología , Vagina/inmunología , Adulto , Anticuerpos Monoclonales/farmacocinética , Femenino , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Técnicas In Vitro , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Membrana Mucosa/inmunología , Membrana Mucosa/virología , Recto/virología , Vagina/virología , Adulto JovenRESUMEN
BACKGROUND: Perinatal human immunodeficiency virus type 1 (HIV-1) continues to occur due to barriers to effective antiretroviral prevention that might be mitigated by long-acting broadly neutralizing monoclonal antibodies (bNAbs). METHODS: An extended half-life bNAb, VRC01LS, was administered subcutaneously at 80 mg/dose after birth to HIV-1-exposed, nonbreastfed (cohort 1, n = 10) and breastfed (cohort 2, n = 11) infants. Cohort 2 received a second dose (100 mg) at 12 weeks. All received antiretroviral prophylaxis. VRC01LS levels were compared to VRC01 levels determined in a prior cohort. RESULTS: Local reactions (all grade ≤2) occurred in 67% and 20% after dose 1 and dose 2, respectively. The weight-banded dose (mean 28.8 mg/kg) of VRC01LS administered subcutaneously achieved a mean (standard deviation) plasma level of 222.3 (71.6) µg/mL by 24 hours and 44.0 (11.6) µg/mL at week 12, prior to dose 2. The preestablished target of ≥50 µg/mL was attained in 95% and 32% at weeks 8 and 12, respectively. The terminal half-life was 37-41 days. VRC01LS level after 1 dose was significantly greater (P <.002) than after a VRC01 dose (20 mg/kg). No infants acquired HIV-1. CONCLUSIONS: VRC01LS was well tolerated with pharmacokinetics that support further studies of more potent long-acting bNAbs as adjunct treatment with antiretrovirals to prevent infant HIV-1 transmission.
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Antirretrovirales/administración & dosificación , Anticuerpos Monoclonales/farmacocinética , Anticuerpos ampliamente neutralizantes/farmacología , Anticuerpos Anti-VIH , Infecciones por VIH/prevención & control , VIH-1/efectos de los fármacos , Transmisión Vertical de Enfermedad Infecciosa/prevención & control , Antirretrovirales/uso terapéutico , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos ampliamente neutralizantes/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Anticuerpos Anti-VIH/administración & dosificación , Anticuerpos Anti-VIH/efectos adversos , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , VIH-1/inmunología , VIH-1/patogenicidad , Semivida , Humanos , Recién Nacido , MasculinoRESUMEN
BACKGROUND: Staphylococcus aureus remains a common cause of ventilator-associated pneumonia, with little change in incidence over the past 15 years. We aimed to evaluate the efficacy of suvratoxumab, a monoclonal antibody targeting the α toxin, in reducing the incidence of S aureus pneumonia in patients in the intensive care unit (ICU) who are on mechanical ventilation. METHODS: We did a multicentre, randomised, double-blind, placebo-controlled, parallel-group, phase 2 pilot trial at 31 hospitals in Belgium, the Czech Republic, France, Germany, Greece, Hungary, Portugal, Spain, and Switzerland. Eligible patients were in the ICU, aged ≥18 years, were intubated and on mechanical ventilation, were positive for S aureus colonisation of the lower respiratory tract, as assessed by quantitative PCR (qPCR) analysis of endotracheal aspirate, and had not been diagnosed with new-onset pneumonia. Patients were excluded if they had confirmed or suspected acute ongoing staphylococcal disease; had received antibiotics for S aureus infection for more than 48 h within 72 h of randomisation; had a Clinical Pulmonary Infection Score of 6 or higher; had an acute physiology and chronic health evaluation II score of 25 or higher with a Glasgow coma scale (GCS) score of more than 5, or an acute physiology and chronic health evaluation II score of at least 30 with a GCS score of 5 or less; had a Sequential Organ Failure Assessment score of 9 or higher; or had active pulmonary disease that would impair the ability to diagnose pneumonia. Colonised patients were randomly assigned (1:1:1), by use of an interactive voice or web response system, to receive either a single intravenous infusion of suvratoxumab 2000 mg, suvratoxumab 5000 mg, or placebo. Randomisation was done in blocks of size four, stratified by country and by whether patients had received systemic antibiotics for S aureus infection. Patients, investigators, and study staff involved in the treatment or clinical evaluation of patients were masked to patient assignment. The primary efficacy endpoint was the incidence of S aureus pneumonia at 30 days, as determined by a masked independent endpoint adjudication committee, in all patients who received their assigned treatment (modified intention-to-treat [ITT] population). Primary safety endpoints were the incidence of treatment-emergent adverse events at 30 days, 90 days, and 190 days after treatment, and the incidence of treatment-emergent serious adverse events, adverse events of special interest, and new-onset chronic disease at 190 days after treatment. All primary safety endpoints were assessed in the modified ITT population. This trial is registered with ClinicalTrials.gov (NCT02296320) and the EudraCT database (2014-001097-34). FINDINGS: Between Oct 10, 2014, and April 1, 2018, 767 patients were screened, of whom 213 patients with confirmed S aureus colonisation of the lower respiratory tract were randomly assigned to the suvratoxumab 2000 mg group (n=15), the suvratoxumab 5000 mg group (n=96), or the placebo group (n=102). Two patients in the placebo group did not receive treatment after randomisation because their clinical conditions changed and they no longer met the eligibility criteria for dosing. As adjudicated by the data monitoring committee at an interim analysis, the suvratoxumab 2000 mg group was discontinued on the basis of predefined pharmacokinetic criteria. At 30 days after treatment, 17 (18%) of 96 patients in the suvratoxumab 5000 mg group and 26 (26%) of 100 patients in the placebo group had developed S aureus pneumonia (relative risk reduction 31·9% [90% CI -7·5 to 56·8], p=0·17). The incidence of treatment-emergent adverse events at 30 days were similar between the suvratoxumab 5000 mg group (87 [91%]) and the placebo group (90 [90%]). The incidence of treatment-emergent serious adverse events at 30 days were also similar between the suvratoxumab 5000 mg group (36 [38%]) and the placebo group (32 [32%]). No significant difference in the incidence of treatment-emergent adverse events between the two groups at 90 days (89 [93%] in the suvratoxumab 5000 mg group vs 92 [92%] in the placebo group) and at 190 days (93 [94%] vs 93 [93%]) was observed. 40 (40%) patients in the placebo group and 50 (52%) in the suvratoxumab 5000 mg group had a serious adverse event at 190 days. In the suvratoxumab 5000 mg group, one (1%) patient reported at least one treatment-emergent serious adverse event related to treatment, two (2%) patients reported an adverse event of special interest, and two (2%) reported a new-onset chronic disease. INTERPRETATION: In patients in the ICU receiving mechanical ventilation with qPCR-confirmed S aureus colonisation of the lower respiratory tract, the incidence of S aureus pneumonia at 30 days was not significantly lower following treatment with 5000 mg suvratoxumab than with placebo. Despite these negative results, monoclonal antibodies still represent one promising therapeutic option to reduce antibiotic consumption that require further exploration and studies. FUNDING: AstraZeneca, with support from the Innovative Medicines Initiative Joint Undertaking.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos ampliamente neutralizantes/uso terapéutico , Neumonía Asociada al Ventilador/prevención & control , Infecciones Estafilocócicas/prevención & control , Staphylococcus aureus/efectos de los fármacos , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Bélgica , Anticuerpos ampliamente neutralizantes/administración & dosificación , República Checa , Método Doble Ciego , Femenino , Francia , Alemania , Grecia , Humanos , Hungría , Pulmón , Masculino , Persona de Mediana Edad , Proyectos Piloto , Portugal , Respiración Artificial , España , Suiza , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Early in the coronavirus disease 2019 (COVID-19) pandemic, there was a concern over possible increase in antibiotic use due to coinfections among COVID-19 patients in the community. Here, we evaluate the changes in nationwide use of broad-spectrum antibiotics during the COVID-19 epidemic in South Korea. METHODS: We obtained national reimbursement data on the prescription of antibiotics, including penicillin with ß-lactamase inhibitors, cephalosporins, fluoroquinolones, and macrolides. We examined the number of antibiotic prescriptions compared with the previous 3 years in the same period from August to July. To quantify the impact of the COVID-19 epidemic on antibiotic use, we developed a regression model adjusting for changes of viral acute respiratory tract infections (ARTIs), which are an important factor driving antibiotic use. RESULTS: During the COVID-19 epidemic in South Korea, the broad-spectrum antibiotic use dropped by 15%-55% compared to the previous 3 years. Overall reduction in antibiotic use adjusting for ARTIs was estimated to be 14%-30%, with a larger impact in children. CONCLUSIONS: Our study found that broad-spectrum antibiotic use was substantially reduced during the COVID-19 epidemic in South Korea. This reduction can be in part due to reduced ARTIs as a result of stringent public health interventions including social distancing measures.
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Anticuerpos ampliamente neutralizantes/administración & dosificación , Anticuerpos ampliamente neutralizantes/uso terapéutico , COVID-19/epidemiología , Salud Pública , Infecciones del Sistema Respiratorio/tratamiento farmacológico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Programas de Optimización del Uso de los Antimicrobianos , Cefalosporinas , Niño , Preescolar , Femenino , Fluoroquinolonas , Hospitalización/estadística & datos numéricos , Humanos , Lactante , Recién Nacido , Macrólidos , Masculino , Persona de Mediana Edad , Pandemias , Penicilinas , República de Corea/epidemiología , Infecciones del Sistema Respiratorio/epidemiología , SARS-CoV-2 , Adulto JovenRESUMEN
PURPOSE OF REVIEW: The coronavirus disease 2019 (COVID-19) pandemic has caught the world unprepared, with no prevention or treatment strategies in place. In addition to the efforts to develop an effective vaccine, alternative approaches are essential to control this pandemic, which will most likely require multiple readily available solutions. Among them, monoclonal anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies have been isolated by multiple laboratories in record time facilitated by techniques that were first pioneered for HIV-1 antibody discovery. Here, we summarize how lessons learned from anti-HIV-1 antibody discovery have provided fundamental knowledge for the rapid development of anti-SARS-CoV-2 antibodies. RECENT FINDINGS: Research laboratories that successfully identified potent broadly neutralizing antibodies against HIV-1 have harnessed their antibody discovery techniques to isolate novel potent anti-SARS-CoV-2 antibodies, which have efficacy in animal models. These antibodies represent promising clinical candidates for treatment or prevention of COVID-19. SUMMARY: Passive transfer of antibodies is a promising approach when the elicitation of protective immune responses is difficult, as in the case of HIV-1 infection. Antibodies can also play a significant role in post-exposure prophylaxis, in high-risk populations that may not mount robust immune responses after vaccination, and in therapy. We provide a review of the recent approaches used for anti-SARS-CoV-2 antibody discovery and upcoming challenges in the field.
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Anticuerpos Antivirales/inmunología , Anticuerpos ampliamente neutralizantes/inmunología , COVID-19/virología , Infecciones por VIH/inmunología , VIH-1/inmunología , SARS-CoV-2/inmunología , Animales , Anticuerpos Antivirales/administración & dosificación , Investigación Biomédica/tendencias , Anticuerpos ampliamente neutralizantes/administración & dosificación , COVID-19/inmunología , Infecciones por VIH/virología , VIH-1/genética , Humanos , SARS-CoV-2/genética , Tratamiento Farmacológico de COVID-19RESUMEN
Penile acquisition of HIV accounts for most infections among men globally. Nevertheless, candidate HIV interventions for men advance to clinical trials without preclinical efficacy data, due primarily to a paucity of relevant animal models of penile HIV infection. Using our recently developed macaque model, we show that a single subcutaneous administration of broadly neutralizing antibody (bNAb) 10-1074 conferred durable protection against repeated penile exposures to simian-human immunodeficiency virus (SHIVSF162P3). Macaques co-administered bNAbs 10-1074 and 3BNC117, or 3BNC117 alone, also exhibited significant protection against repeated vaginal SHIVAD8-EO exposures. Regression modeling estimated that individual plasma bNAb concentrations of 5 µg ml-1 correlated with ≥99.9% relative reduction in SHIV infection probability via penile (10-1074) or vaginal (10-1074 or 3BNC117) challenge routes. These results demonstrate that comparably large reductions in penile and vaginal SHIV infection risk among macaques were achieved at clinically relevant plasma bNAb concentrations and inform dose selection for the development of bNAbs as long-acting pre-exposure prophylaxis candidates for use by men and women.
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Vacunas contra el SIDA/administración & dosificación , Anticuerpos ampliamente neutralizantes/administración & dosificación , Anticuerpos Anti-VIH/administración & dosificación , Síndrome de Inmunodeficiencia Adquirida del Simio/prevención & control , Síndrome de Inmunodeficiencia Adquirida del Simio/transmisión , Virus de la Inmunodeficiencia de los Simios/inmunología , Vacunas contra el SIDA/sangre , Animales , Anticuerpos ampliamente neutralizantes/sangre , Modelos Animales de Enfermedad , Femenino , Anticuerpos Anti-VIH/sangre , Infecciones por VIH/prevención & control , Infecciones por VIH/transmisión , Semivida , Inmunización Pasiva , Macaca mulatta , Masculino , Pene/inmunología , Pene/virología , Profilaxis Pre-Exposición , Vagina/inmunología , Vagina/virologíaRESUMEN
Toll-like receptors (TLRs) are a family of pattern recognition receptors and part of the first line of defense against invading microbes. In humans, we know of 10 different TLRs, which are expressed to varying degrees in immune cell subsets. Engaging TLRs through their specific ligands leads to activation of the innate immune system and secondarily priming of the adaptive immune system. Because of these unique properties, TLR agonists have been investigated as immunotherapy in cancer treatment for many years, but in recent years there has also been growing interest in the use of TLR agonists in the context of human immunodeficiency virus type 1 (HIV-1) cure research. The primary obstacle to curing HIV-1 is the presence of a latent viral reservoir in transcriptionally silent immune cells. Due to the very limited transcription of the integrated HIV-1 proviruses, latently infected cells cannot be targeted and cleared by immune effector mechanisms. TLR agonists are very interesting in this context because of their potential dual effects as latency reverting agents (LRAs) and immune modulatory compounds. Here, we review preclinical and clinical data on the impact of TLR stimulation on HIV-1 latency as well as antiviral and HIV-1-specific immunity. We also focus on the promising role of TLR agonists in combination strategies in HIV-1 cure research. Different combinations of TLR agonists and broadly neutralizing antibodies or TLRs agonists as adjuvants in HIV-1 vaccines have shown very encouraging results in non-human primate experiments and these concepts are now moving into clinical testing.
Asunto(s)
Infecciones por VIH/inmunología , Infecciones por VIH/terapia , VIH-1 , Inmunoterapia/métodos , Receptores Toll-Like/agonistas , Vacunas contra el SIDA/administración & dosificación , Adyuvantes Inmunológicos/administración & dosificación , Animales , Fármacos Anti-VIH/farmacología , Anticuerpos ampliamente neutralizantes/administración & dosificación , Ensayos Clínicos como Asunto , Anticuerpos Anti-VIH/administración & dosificación , VIH-1/efectos de los fármacos , VIH-1/inmunología , VIH-1/fisiología , Humanos , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Factores Inmunológicos/farmacología , Técnicas In Vitro , Modelos Inmunológicos , Primates , Pteridinas/farmacología , Receptor Toll-Like 3/agonistas , Receptor Toll-Like 7/agonistas , Receptor Toll-Like 9/agonistas , Latencia del Virus/efectos de los fármacos , Latencia del Virus/inmunologíaRESUMEN
The correlation of HIV-specific antibody-dependent cellular cytotoxicity (ADCC) responses with protection from and delayed progression of HIV-1 infection provides a rationale to leverage ADCC-mediating antibodies for treatment purposes. We evaluated ADCC mediated by different combinations of 2 to 6 neutralizing and non-neutralizing anti-HIV-1 Envelope (Env) mAbs, using concentrations ≤ 1 µg/mL, to identify combinations effective at targeting latent reservoir HIV-1 viruses from 10 individuals. We found that within 2 hours, combinations of 3 mAbs mediated more than 30% killing of HIV-infected primary CD4+ T cells in the presence of autologous NK cells, with the combination of A32 (C1C2), DH511.2K3 (MPER), and PGT121 (V3) mAbs being the most effective. Increasing the incubation of target and effector cells in the presence of mAb combinations from 2 to 24 hours resulted in increased specific killing of infected cells, even with neutralization-resistant viruses. The same combination eliminated reactivated latently HIV-1-infected cells in an ex vivo quantitative viral outgrowth assay. Therefore, administration of a combination of 3 mAbs should be considered in planning in vivo studies seeking to eliminate persistently HIV-1-infected cells.
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Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Anti-VIH/administración & dosificación , Infecciones por VIH/inmunología , Infecciones por VIH/terapia , VIH-1/inmunología , Adulto , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/inmunología , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Anticuerpos ampliamente neutralizantes/administración & dosificación , Anticuerpos ampliamente neutralizantes/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/virología , Reservorios de Enfermedades/virología , Femenino , Anticuerpos Anti-VIH/inmunología , VIH-1/fisiología , Humanos , Inmunoterapia/métodos , Técnicas In Vitro , Células Asesinas Naturales/inmunología , Cinética , Masculino , Persona de Mediana Edad , Pruebas de Neutralización , Latencia del Virus/inmunologíaRESUMEN
The MODIFY I/II trials demonstrated that bezlotoxumab, a human monoclonal antibody against Clostridioides difficile toxin B, given during antibiotic treatment for Clostridioides difficile infection (CDI) significantly reduced C. difficile recurrence (rCDI) in adults at high risk for rCDI. Efficacy of CDI-directed intervention may depend on ribotype regional epidemiology, and patient characteristics. This post hoc analysis assessed the efficacy of bezlotoxumab in the subgroup of MODIFY I/II trial participants enrolled in Europe. Data from the bezlotoxumab (10 mg/kg single intravenous infusion) and placebo (0.9% saline) groups from MODIFY I/II were compared to assess initial clinical cure (ICC), rCDI, all-cause, and CDI-associated rehospitalizations within 30 days of discharge, and mortality through 12 weeks post-infusion. Of 1554 worldwide participants, 606 were from Europe (bezlotoxumab n = 313, 51%; placebo n = 292; 48%). Baseline characteristics were generally similar across groups, although there were more immunocompromised participants in the bezlotoxumab group (27.2%) compared with placebo (20.1%). Fifty-five percent of participants were female, and 86% were hospitalized at randomization. The rate of ICC was similar between treatment groups. The rate of rCDI in the bezlotoxumab group was lower compared with placebo among European participants overall, and among those with ≥ 1 risk factor for rCDI. Bezlotoxumab reduced 30-day CDI-associated rehospitalizations compared with placebo. These results are consistent with overall results from the MODIFY trials and demonstrate that bezlotoxumab reduces rCDI and CDI-associated rehospitalizations in European patients with CDI. MODIFY I/II (NCT01241552 and NCT01513239).