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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 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). In a Phase 1 randomised clinical trial, Stephen Walsh and colleagues assess the safety and pharmacokinetics of VRC07-523LS which has been engineered for improved breadth, potency, and a longer half-life. Author summary: Why was this study done?: Broadly neutralizing antibodies (bnAbs), which can block HIV-1 infection in laboratory settings, have considerable promise for HIV-1 prevention in people. In the Antibody Mediated Prevention (AMP) trials, a CD4-binding site (CD4bs) targeting bnAb, VRC01, was found to have 75% prevention efficacy against highly neutralization-sensitive viruses. Most circulating isolates of HIV-1 are less sensitive, and VRC01 was ineffective against those viruses. Our clinical trial was done to assess the safety and drug levels of another CD4bs bnAb called VRC07-523LS, which has been engineered for improved breadth, potency, and a longer half-life. What did the researchers do and find?: We administered VRC07-523LS to healthy volunteers without HIV using multiple routes (intravenous [IV], subcutaneous [SC], and intramuscular [IM]) and at doses ranging from 2.5 mg/kg to 20 mg/kg. VRC07-523LS was safe and well tolerated over more than 30 months of follow-up. At any 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. VRC07-523LS has a half-life of about 42 days, which is over twice as long as VRC01 (15 days). What do these findings mean?: 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. The main limitations of our study are the small sizes of the individual groups and missing blood draws at the later time points due to COVID-19 restrictions, both of which lead to uncertainty in our estimates of drug levels and pharmacokinetic parameters. Presented in part at: HIV R4P 2021 Virtual (Abstract OA03.01), Cape Town, South Africa, January 2021; and IAS 2022 (Abstract PESUA14), Montréal, Canada, July 2022. [ABSTRACT FROM AUTHOR]