Infusion reactions after receiving the broadly neutralizing antibody VRC01 or placebo to reduce HIV-1 acquisition : results from the Phase 2b antibody-mediated prevention randomized trials

Presented at Conference for Retroviruses and Opportunistic Infections; March 06–10, 2021.BACKGROUND : The antibody-mediated prevention (AMP) studies (HVTN 703/HPTN 081 and HVTN 704/HPTN 085) are harmonized phase 2b trials to assess HIV prevention efficacy and safety of intravenous infusion of anti-gp120 broadly neutralizing antibody VRC01. Antibodies for other indications can elicit infusion-related reactions (IRRs), often requiring premedication and limiting their application. We report on AMP study IRRs. METHODS : From 2016 to 2018, 2699 HIV-uninfected, at-risk men and transgender adults in the Americas and Switzerland (704/085) and 1924 at-risk heterosexual women in sub-Saharan Africa (703/081) were randomized 1:1:1 to VRC01 10 mg/kg, 30 mg/kg, or placebo. Participants received infusions every 8 weeks (n = 10/participant) over 72 weeks, with 104 weeks of follow-up. Safety assessments were conducted before and after infusion and at noninfusion visits. A total of 40,674 infusions were administered. RESULTS : Forty-seven participants (1.7%) experienced 49 IRRs in 704/085; 93 (4.8%) experienced 111 IRRs in 703/081 (P < 0.001). IRRs occurred more frequently in VRC01 than placebo recipients in 703/081 (P < 0.001). IRRs were associated with atopic history (P = 0.046) and with younger age (P = 0.023) in 703/081. Four clinical phenotypes of IRRs were observed: urticaria, dyspnea, dyspnea with rash, and “other.” Urticaria was most prevalent, occurring in 25 (0.9%) participants in 704/085 and 41 (2.1%) participants in 703/081. Most IRRs occurred with the initial infusion and incidence diminished through the last infusion. All reactions were managed successfully without sequelae. CONCLUSIONS : IRRs in the AMP studies were uncommon, typically mild or moderate, successfully managed at the research clinic, and resolved without sequelae. Analysis is ongoing to explore potential IRR mechanisms.Clinical trial funding from Janssen Vaccines.http://www.jaids.comhj2023School of Health Systems and Public Health (SHSPH

Establishing final infarct volume: stroke lesion evolution past 30 days is insignificant

BACKGROUND AND PURPOSE: Lesion volume measured on MRI has been used as an objective surrogate marker for outcome in clinical trials. However, lesion volumes vary over time because of edema and tissue loss. This study aims to determine if lesion volumes measured at 30 and 90 days after ictus significantly differ. METHODS: We performed a retrospective study of 18 patients who had acute (\u3c24\u3ehours) DWI and follow-up fluid-attenuated inversion recovery imaging at 5, 30, and 90 days. Two expert readers segmented lesions and the mean volumes of both reads were used in all statistical analyses. RESULTS: Patient age was 65.8 (SD, 13.7) years and median NIHSS at baseline was 11.5. Inter-rater variability for lesion volume measurements was 3.7 (5.8) mL. Acute DWI volume was 19.3 (17.3) mL. Fluid-attenuated inversion recovery volumes for 5, 30, and 90 days were 34.3 (23.5), 18.6 (14.0), and 15.9 (13.8) mL, respectively. These volumes differed significantly (P\u3c0.001). Linear regression revealed a strong correlation (r=0.96; P\u3c0.001) between lesion volumes at 30 and 90 days with a slope that did not vary significantly from 1.0 (P=0.448). CONCLUSIONS: Lesions continue to evolve between 5 and 90 days, but by 30 days lesion volume approaches final infarct volume. While clinical response is the most meaningful outcome measure, our findings suggest that lesion volumes measured at 30 days may provide a sufficient approximation for final infarct volume for use in early phase clinical trials

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. Healthy adults aged 18-50 years were assigned to receive a single intramuscular dose of cAd3-Marburg vaccine at either 1 × 10 or 1 × 10 particle units (pu). Primary safety endpoints included reactogenicity assessed for the first 7 days and all adverse events assessed for 28 days after vaccination. Secondary immunogenicity endpoints were assessment of binding antibody responses and T-cell responses against the Marburg virus glycoprotein insert, and assessment of neutralising antibody responses against the cAd3 vector 4 weeks after vaccination. This study is registered with ClinicalTrials.gov, NCT03475056. FINDINGS: Between Oct 9, 2018, and Jan 31, 2019, 40 healthy adults were enrolled and assigned to receive a single intramuscular dose of cAd3-Marburg vaccine at either 1 × 10 pu (n=20) or 1 × 10 pu (n=20). The cAd3-Marburg vaccine was safe, well tolerated, and immunogenic. All enrolled participants received cAd3-Marburg vaccine, with 37 (93%) participants completing follow-up visits; two (5%) participants moved from the area and one (3%) was lost to follow-up. No serious adverse events related to vaccination occurred. Mild to moderate reactogenicity was observed after vaccination, with symptoms of injection site pain and tenderness (27 [68%] of 40 participants), malaise (18 [45%] of 40 participants), headache (17 [43%] of 40 participants), and myalgia (14 [35%] of 40 participants) most commonly reported. Glycoprotein-specific antibodies were induced in 38 (95%) of 40 participants 4 weeks after vaccination, with geometric mean titres of 421 [95% CI 209-846] in the 1 × 10 pu group and 545 [276-1078] in the 1 × 10 pu group, and remained significantly elevated at 48 weeks compared with baseline titres (39 [95% CI 13-119] in the 1 ×10 pu group and 27 [95-156] in the 1 ×10 pu group; both p\u3c0·0001). T-cell responses to the glycoprotein insert and neutralising responses against the cAd3 vector were also increased at 4 weeks after vaccination. INTERPRETATION: This first-in-human trial of this cAd3-Marburg vaccine showed the agent is safe and immunogenic, with a safety profile similar to previously tested cAd3-vectored filovirus vaccines. 95% of participants produced a glycoprotein-specific antibody response at 4 weeks after a single vaccination, which remained in 70% of participants at 48 weeks. These findings represent a crucial step in the development of a vaccine for emergency deployment against a re-emerging pathogen that has recently expanded its reach to new regions. FUNDING: National Institutes of Health

HIV-1 neutralizing antibodies elicited in humans by a prefusion-stabilized envelope trimer form a reproducible class targeting fusion peptide

Summary: Elicitation of antibodies that neutralize the tier-2 neutralization-resistant isolates that typify HIV-1 transmission has been a long-sought goal. Success with prefusion-stabilized envelope trimers eliciting autologous neutralizing antibodies has been reported in multiple vaccine-test species, though not in humans. To investigate elicitation of HIV-1 neutralizing antibodies in humans, here, we analyze B cells from a phase I clinical trial of the “DS-SOSIP”-stabilized envelope trimer from strain BG505, identifying two antibodies, N751-2C06.01 and N751-2C09.01 (named for donor-lineage.clone), that neutralize the autologous tier-2 strain, BG505. Though derived from distinct lineages, these antibodies form a reproducible antibody class that targets the HIV-1 fusion peptide. Both antibodies are highly strain specific, which we attribute to their partial recognition of a BG505-specific glycan hole and to their binding requirements for a few BG505-specific residues. Prefusion-stabilized envelope trimers can thus elicit autologous tier-2 neutralizing antibodies in humans, with initially identified neutralizing antibodies recognizing the fusion-peptide site of vulnerability

Safety and pharmacokinetics of the Fc-modified HIV-1 human monoclonal antibody VRC01LS: A Phase 1 open-label clinical trial in healthy adults

<div><p>Background</p><p>VRC01 is a human broadly neutralizing monoclonal antibody (bnMAb) against the CD4-binding site of the HIV-1 envelope glycoprotein (Env) that is currently being evaluated in a Phase IIb adult HIV-1 prevention efficacy trial. VRC01LS is a modified version of VRC01, designed for extended serum half-life by increased binding affinity to the neonatal Fc receptor.</p><p>Methods and findings</p><p>This Phase I dose-escalation study of VRC01LS in HIV-negative healthy adults was conducted by the Vaccine Research Center (VRC) at the National Institutes of Health (NIH) Clinical Center (Bethesda, MD). The age range of the study volunteers was 21–50 years; 51% of study volunteers were male and 49% were female. Primary objectives were safety and tolerability of VRC01LS intravenous (IV) infusions at 5, 20, and 40 mg/kg infused once, 20 mg/kg given three times at 12-week intervals, and subcutaneous (SC) delivery at 5 mg/kg delivered once, or three times at 12-week intervals. Secondary objectives were pharmacokinetics (PK), serum neutralization activity, and development of antidrug antibodies. Enrollment began on November 16, 2015, and concluded on August 23, 2017. This report describes the safety data for the first 37 volunteers who received administrations of VRC01LS. There were no serious adverse events (SAEs) or dose-limiting toxicities. Mild malaise and myalgia were the most common adverse events (AEs). There were six AEs assessed as possibly related to VRC01LS administration, and all were mild in severity and resolved during the study. PK data were modeled based on the first dose of VRC01LS in the first 25 volunteers to complete their schedule of evaluations. The mean (±SD) serum concentration 12 weeks after one IV administration of 20 mg/kg or 40 mg/kg were 180 ± 43 μg/mL (<i>n</i> = 7) and 326 ± 35 μg/mL (<i>n</i> = 5), respectively. The mean (±SD) serum concentration 12 weeks after one IV and SC administration of 5 mg/kg were 40 ± 3 μg/mL (<i>n</i> = 2) and 25 ± 5 μg/mL (<i>n</i> = 9), respectively. Over the 5–40 mg/kg IV dose range (<i>n</i> = 16), the clearance was 36 ± 8 mL/d with an elimination half-life of 71 ± 18 days. VRC01LS retained its expected neutralizing activity in serum, and anti-VRC01 antibody responses were not detected. Potential limitations of this study include the small sample size typical of Phase I trials and the need to further describe the PK properties of VRC01LS administered on multiple occasions.</p><p>Conclusions</p><p>The human bnMAb VRC01LS was safe and well tolerated when delivered intravenously or subcutaneously. The half-life was more than 4-fold greater when compared to wild-type VRC01 historical data. The reduced clearance and extended half-life may make it possible to achieve therapeutic levels with less frequent and lower-dose administrations. This would potentially lower the costs of manufacturing and improve the practicality of using passively administered monoclonal antibodies (mAbs) for the prevention of HIV-1 infection.</p><p>Trial registration</p><p>ClinicalTrials.gov <a target="_blank">NCT02599896</a></p></div

Self-reported systemic reactogenicity up to 3 days after VRC01LS administration^*.

<p>Self-reported systemic reactogenicity up to 3 days after VRC01LS administration^{<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002493#t003fn001" target="_blank">*</a>}.</p

Maximum local reactogenicity up to day 7 after VRC01LS administration^*.

<p>Maximum local reactogenicity up to day 7 after VRC01LS administration^{<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1002493#t002fn001" target="_blank">*</a>}.</p

Neutralizing ability of VRC01LS is maintained in serum after infusion.

<p>(A) Serum inhibitory neutralization titers (ID₈₀) after VRC01LS infusion. Solid lines and closed squares indicate the reciprocal serum dilution that produces 80% virus neutralization for three viral strains. Dashed lines and open squares indicate predicted ID₈₀ based on the measured amount of VRC01LS in the serum and the known inhibitory concentration (IC₈₀) of VRC01LS for the viruses tested: MW965.26, 0.128 μg/mL; Q23.17, 0.298 μg/mL; and PVO.04, 1.66 μg/mL. All final time points were assessed 12 weeks after the final dose was administered. Values are the mean of duplicate wells run in the same plate. (B) Examples of serum and VRC01LS neutralization curves. Serum from day 2 and week 36 samples (closed circles) were used to generate neutralization curves (solid lines) that are compared to neutralization curves generated with uninfused VRC01LS IgG antibody (open circles and dashed lines) at different dilutions. The x-axis displays both the VRC01LS concentration acquired from serum and in vitro dilutions of uninfused antibody. IC₈₀, 80% inhibitory concentration; ID₈₀, dilution that produced 80% neutralization; IgG, immunoglobulin G; IV, intravenous; SC, subcutaneous.</p

CONSORT flow diagram of the VRC 606 trial.

<p>Thirty-seven volunteers were allocated to 6 groups. All volunteers who received at least one VRC01LS administration were analyzed for safety and reactogenicity. All volunteers who completed the per-protocol dosing schedule by the time of manuscript submission (<i>n</i> = 25) were additionally analyzed for pharmacokinetic parameters, serum neutralization activity, anti-drug antibodies, and IgG1 GM allotype. These 25 volunteers were all the volunteers in groups 1–4, the first six volunteers in group 5, and the first five volunteers in group 6. GM, genetic marker; IgG1, immunoglobulin G subclass 1; IV, intravenous; SC, subcutaneous; VRC, Vaccine Research Center.</p