Broadly neutralizing monoclonal antibodies for HIV prevention

Miner, Maurine D.; Corey, Lawrence; Montefiori, David C.

doi:10.1002/jia2.25829

Cited by 29 publications

(23 citation statements)

References 82 publications

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“…This study, together with our previous LASV challenge studies in animal models (28,36,41), demonstrates an opportunity for therapeutic treatment of LF, a WHO and CEPI priority infectious disease. More broadly and consistent with developing concepts on other viruses (42)(43)(44)(45)(46), our study illustrates the importance of cocktail selection to include antibodies with compatible epitopes and complementary mechanisms of neutralization.…”

Section: Discussionsupporting

confidence: 82%

A cocktail of protective antibodies subverts the dense glycan shield of Lassa virus

Buck

Zandonatti

et al. 2022

Sci. Transl. Med.

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Developing potent therapeutics and effective vaccines are the ultimate goals in controlling infectious diseases. Lassa virus (LASV), the causative pathogen of Lassa fever (LF), infects hundreds of thousands annually, but effective antivirals or vaccines against LASV infection are still lacking. Furthermore, neutralizing antibodies against LASV are rare. Here, we describe biochemical analyses and high-resolution cryo-electron microscopy structures of a therapeutic cocktail of three broadly protective antibodies that target the LASV glycoprotein complex (GPC), previously identified from survivors of multiple LASV infections. Structural and mechanistic analyses reveal compatible neutralizing epitopes and complementary neutralization mechanisms that offer high potency, broad range, and resistance to escape. These antibodies either circumvent or exploit specific glycans comprising the extensive glycan shield of GPC. Further, they require mammalian glycosylation, native GPC cleavage, and proper GPC trimerization. These findings guided engineering of a next-generation GPC antigen suitable for future neutralizing antibody and vaccine discovery. Together, these results explain protective mechanisms of rare, broad, and potent antibodies and identify a strategy for the rational design of therapeutic modalities against LF and related infectious diseases.

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Section: Discussionsupporting

confidence: 82%

A cocktail of protective antibodies subverts the dense glycan shield of Lassa virus

Buck

Zandonatti

et al. 2022

Sci. Transl. Med.

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“…The degree of genetic variation, along with the inability of the host immune system to eradicate HIV, makes the development of an HIV vaccine quite difficult. Over the last decade focus has turned to the development of broadly neutralizing antibodies (bNAbs) that are able to inhibit replication of most genetic variants of HIV ( 49 ). A current vaccine development strategy includes development of candidate vaccines that can induce the host to produce bNAbs in vivo as a strategy to provide protection against HIV challenge ( 50 ).…”

Section: How Did This Happen?mentioning

confidence: 99%

Wonder of wonders, miracle of miracles: the unprecedented speed of COVID-19 science

Saag

2022

Physiological Reviews

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“…VRC01LS and VRC07‐523LS) have demonstrated safety, tolerability and potentially protective levels for 3 months when given subcutaneously to HIV‐exposed uninfected infants soon after birth and during infancy in clinical trials [7, 8]. There are at least 10 bNAbs moving forward in clinical trials both as prophylaxis and as treatment, although the timeline for regulatory approval is uncertain [9]. Several of these bNAbs, alone and in combination, possess in vitro neutralizing activity with greater breadth and potency than VRC01, and are nearing readiness for clinical use [10, 11].…”

Section: Introductionmentioning

confidence: 99%

Cost‐effectiveness of broadly neutralizing antibody prophylaxis for HIV‐exposed infants in sub‐Saharan African settings

et al. 2023

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Introduction Infant HIV prophylaxis with broadly neutralizing anti‐HIV antibodies (bNAbs) could provide long‐acting protection against vertical transmission. We sought to estimate the potential clinical impact and cost‐effectiveness of hypothetical bNAb prophylaxis programmes for children known to be HIV exposed at birth in three sub‐Saharan African settings. Methods We conducted a cost‐effectiveness analysis using the CEPAC‐Pediatric model, simulating cohorts of infants from birth through death in Côte d'Ivoire, South Africa and Zimbabwe. These settings were selected to reflect a broad range of HIV care cascade characteristics, antenatal HIV prevalence and budgetary constraints. We modelled strategies targeting bNAbs to only WHO‐designated “high‐risk” HIV‐exposed infants (HR‐HIVE) or to all HIV‐exposed infants (HIVE). We compared four prophylaxis approaches within each target population: standard of care oral antiretroviral prophylaxis (SOC), and SOC plus bNAbs at birth (1‐dose), at birth and 3 months (2‐doses), or every 3 months throughout breastfeeding (Extended). Base‐case model inputs included bNAb efficacy (60%/dose), effect duration (3 months/dose) and costs ($60/dose), based on published literature. Outcomes included paediatric HIV incidence and incremental cost‐effectiveness ratios (ICERs) calculated from discounted life expectancy and lifetime HIV‐related costs. Results The model projects that bNAbs would reduce absolute infant HIV incidence by 0.3–2.2% (9.6–34.9% relative reduction), varying by country, prophylaxis approach and target population. In all three settings, HR‐HIVE–1‐dose would be cost‐saving compared to SOC. Using a 50% GDP per capita ICER threshold, HIVE‐Extended would be cost‐effective in all three settings with ICERs of $497/YLS in Côte d'Ivoire, $464/YLS in South Africa and $455/YLS in Zimbabwe. In all three settings, bNAb strategies would remain cost‐effective at costs up to $200/dose if efficacy is ≥30%. If the bNAb effect duration were reduced to 1 month, the cost‐effective strategy would become HR‐HIVE–1‐dose in Côte d'Ivoire and Zimbabwe and HR‐HIVE–2‐doses in South Africa. Findings regarding the cost‐effectiveness of bNAb implementation strategies remained robust in sensitivity analyses regarding breastfeeding duration, maternal engagement in postpartum care, early infant diagnosis uptake and antiretroviral treatment costs. Conclusions At current efficacy and cost estimates, bNAb prophylaxis for HIV‐exposed children in sub‐Saharan African settings would be a cost‐effective intervention to reduce vertical HIV transmission.

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Broadly neutralizing monoclonal antibodies for HIV prevention

Cited by 29 publications

References 82 publications

A cocktail of protective antibodies subverts the dense glycan shield of Lassa virus

A cocktail of protective antibodies subverts the dense glycan shield of Lassa virus

Wonder of wonders, miracle of miracles: the unprecedented speed of COVID-19 science

Cost‐effectiveness of broadly neutralizing antibody prophylaxis for HIV‐exposed infants in sub‐Saharan African settings

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