Safety, Tolerability, and Pharmacokinetics of Long-Acting Broadly Neutralizing HIV-1 Monoclonal Antibody VRC07-523LS in Newborn Infants Exposed to HIV-1

Overview

Journal J Pediatric Infect Dis Soc

Publisher Oxford University Press

Date 2025 Jan 17

PMID 39821046

Authors

Coleen K Cunningham

Elizabeth J McFarland

Petronella Muresan

Edmund V Capparelli

Charlotte Perlowski

Benjamin Johnston

Frederic Bone

Lynette Purdue

Dwight E Yin

Jack Moye

Hans M L Spiegel

Sai Majji

Gerhard B Theron

Hilda A Mujuru

Murli Purswani

Grace Alvarez

Jaime G Deville

Carrie Chambers

Emily Brown

Paul A Harding

Nicole H Tobin

Kwang Low

Lucio Gama

Affiliations

Soon will be listed here.

Abstract

Background: Vertical HIV-1 transmission despite antiretroviral therapy may be mitigated by the use of long-acting, broadly neutralizing, monoclonal antibodies (bNAb) such as VRC07-523LS. The present study was designed to determine the safety and pharmacokinetics of VRC07-523LS.

Methods: VRC07-523LS, 80 mg/dose, was administered subcutaneously after birth to non-breastfed (cohort 1; N = 11, enrolled in USA) and breastfed (cohort 2; N = 11, enrolled in South Africa and Zimbabwe) infants exposed to HIV-1. Breastfed infants (cohort 2) received a second 100-mg dose at 12 weeks if still receiving breastmilk. All infants received antiretroviral prophylaxis in addition to VRC07-523LS. VRC07-523LS levels were compared to VRC01 levels, as determined previously in this study.

Results: Local reactions (all grade ≤ 2) occurred after dose 1 in 18% of infants in cohort 1 and after doses 1 and 2 in 100% of infants in cohort 2. The VRC07-523LS dose at birth (mean 26 mg/kg) achieved a mean ± SD plasma level of 222.3 ± 71.6 mcg/mL by 24 hours and 18.4 ± 7.2 mcg/mL at week 12, prior to dose 2. The pre-established target of ≥ 10 mcg/mL at week 12 was met in 94% of infants. The terminal half-life of VRC07-523LS was observed to be 39.2 ± 5.0 days. At week 4 and week 8, bNAb levels were significantly higher (P ≤ .002) after one dose of VRC07-523LS, compared to one dose of VRC01 (20 mg/kg). No infant included in the study acquired HIV-1.

Conclusions: VRC07-523LS was well tolerated with pharmacokinetics that support further studies of potent long-acting bNAbs together with antiretrovirals to prevent HIV-1 acquisition in infants.

References

Jones J, Fleming-Dutra K, Prill M, Roper L, Brooks O, Sanchez P . Use of Nirsevimab for the Prevention of Respiratory Syncytial Virus Disease Among Infants and Young Children: Recommendations of the Advisory Committee on Immunization Practices - United States, 2023. MMWR Morb Mortal Wkly Rep. 2023; 72(34):920-925. PMC: 10468217. DOI: 10.15585/mmwr.mm7234a4. View

McFarland E, Cunningham C, Muresan P, Capparelli E, Perlowski C, Morgan P . Safety, Tolerability, and Pharmacokinetics of a Long-Acting Broadly Neutralizing Human Immunodeficiency Virus Type 1 (HIV-1) Monoclonal Antibody VRC01LS in HIV-1-Exposed Newborn Infants. J Infect Dis. 2021; 224(11):1916-1924. PMC: 8643399. DOI: 10.1093/infdis/jiab229. View

Casazza J, Cale E, Narpala S, Yamshchikov G, Coates E, Hendel C . Safety and tolerability of AAV8 delivery of a broadly neutralizing antibody in adults living with HIV: a phase 1, dose-escalation trial. Nat Med. 2022; 28(5):1022-1030. PMC: 9876739. DOI: 10.1038/s41591-022-01762-x. View

Gama L, Koup R . New-Generation High-Potency and Designer Antibodies: Role in HIV-1 Treatment. Annu Rev Med. 2017; 69:409-419. DOI: 10.1146/annurev-med-061016-041032. View

Roopenian D, Akilesh S . FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007; 7(9):715-25. DOI: 10.1038/nri2155. View

Dinh T, Delaney K, Goga A, Jackson D, Lombard C, Woldesenbet S . Impact of Maternal HIV Seroconversion during Pregnancy on Early Mother to Child Transmission of HIV (MTCT) Measured at 4-8 Weeks Postpartum in South Africa 2011-2012: A National Population-Based Evaluation. PLoS One. 2015; 10(5):e0125525. PMC: 4420458. DOI: 10.1371/journal.pone.0125525. View

B Gilbert P, Huang Y, deCamp A, Karuna S, Zhang Y, Magaret C . Neutralization titer biomarker for antibody-mediated prevention of HIV-1 acquisition. Nat Med. 2022; 28(9):1924-1932. PMC: 9499869. DOI: 10.1038/s41591-022-01953-6. View

Doria-Rose N, Bhiman J, Roark R, Schramm C, Gorman J, Chuang G . New Member of the V1V2-Directed CAP256-VRC26 Lineage That Shows Increased Breadth and Exceptional Potency. J Virol. 2015; 90(1):76-91. PMC: 4702551. DOI: 10.1128/JVI.01791-15. View

Larsen A, Magasana V, Dinh T, Ngandu N, Lombard C, Cheyip M . Longitudinal adherence to maternal antiretroviral therapy and infant Nevirapine prophylaxis from 6 weeks to 18 months postpartum amongst a cohort of mothers and infants in South Africa. BMC Infect Dis. 2019; 19(Suppl 1):789. PMC: 6745776. DOI: 10.1186/s12879-019-4341-4. View

10.

Corey L, B Gilbert P, Juraska M, Montefiori D, Morris L, Karuna S . Two Randomized Trials of Neutralizing Antibodies to Prevent HIV-1 Acquisition. N Engl J Med. 2021; 384(11):1003-1014. PMC: 8189692. DOI: 10.1056/NEJMoa2031738. View

11.

Mafaune H, Sacks E, Chadambuka A, Musarandega R, Tachiwenyika E, Simmonds F . Effectiveness of Maternal Transmission Risk Stratification in Identification of Infants for HIV Birth Testing: Lessons From Zimbabwe. J Acquir Immune Defic Syndr. 2020; 84 Suppl 1:S28-S33. PMC: 7302327. DOI: 10.1097/QAI.0000000000002373. View

12.

Gaebler C, Caskey M . Broadly Neutralizing Antihuman Immunodeficiency Virus Antibodies in Infants: Promising New Tools for Prevention of Mother-to-Child Transmission?. J Infect Dis. 2019; 222(4):525-527. DOI: 10.1093/infdis/jiz536. View

13.

Wu X, Yang Z, Li Y, Hogerkorp C, Schief W, Seaman M . Rational design of envelope identifies broadly neutralizing human monoclonal antibodies to HIV-1. Science. 2010; 329(5993):856-61. PMC: 2965066. DOI: 10.1126/science.1187659. View

14.

Bardeskar N, Ahir-Bist S, Mehta P, Samant-Mavani P, Nanavati R, Mania-Pramanik J . Anti-retroviral therapy failure in HIV-1 infected pregnant women and its associated risk of HIV transmission. Arch Gynecol Obstet. 2020; 302(5):1229-1235. DOI: 10.1007/s00404-020-05743-8. View

15.

Rudicell R, Kwon Y, Ko S, Pegu A, Louder M, Georgiev I . Enhanced potency of a broadly neutralizing HIV-1 antibody in vitro improves protection against lentiviral infection in vivo. J Virol. 2014; 88(21):12669-82. PMC: 4248941. DOI: 10.1128/JVI.02213-14. View

16.

Walker B . The AMP Trials - A Glass Half Full. N Engl J Med. 2021; 384(11):1068-1069. DOI: 10.1056/NEJMe2101131. View

17.

Ruel T, Penazzato M, Zech J, Archary M, Cressey T, Goga A . Novel Approaches to Postnatal Prophylaxis to Eliminate Vertical Transmission of HIV. Glob Health Sci Pract. 2023; 11(2). PMC: 10141432. DOI: 10.9745/GHSP-D-22-00401. View

18.

Gaudinski M, Houser K, Doria-Rose N, Chen G, Rothwell R, Berkowitz N . Safety and pharmacokinetics of broadly neutralising human monoclonal antibody VRC07-523LS in healthy adults: a phase 1 dose-escalation clinical trial. Lancet HIV. 2019; 6(10):e667-e679. PMC: 11100866. DOI: 10.1016/S2352-3018(19)30181-X. View

19.

Huang J, Kang B, Ishida E, Zhou T, Griesman T, Sheng Z . Identification of a CD4-Binding-Site Antibody to HIV that Evolved Near-Pan Neutralization Breadth. Immunity. 2016; 45(5):1108-1121. PMC: 5770152. DOI: 10.1016/j.immuni.2016.10.027. View

20.

Li J, Nikanjam M, Cunningham C, McFarland E, Coates E, Houser K . Model Informed Development of VRC01 in Newborn Infants Using a Population Pharmacokinetics Approach. Clin Pharmacol Ther. 2020; 109(1):184-192. PMC: 7902301. DOI: 10.1002/cpt.2026. View