BACKGROUND:Approximately 130 000 infants acquire HIV annually despite global maternal antiretroviral therapy scale-up. We evaluated the potential clinical impact and cost-effectiveness of offering long-acting, anti-HIV broadly neutralizing antibody (bNAb) prophylaxis to infants in three distinct settings. METHODS:We simulated infants in Côte d'Ivoire, South Africa, and Zimbabwe using the Cost-Effectiveness of Preventing AIDS Complications-Pediatric (CEPAC-P) model. We modeled strategies offering a three-bNAb combination in addition to WHO-recommended standard-of-care oral prophylaxis to infants: a) with known, WHO-defined high-risk HIV exposure at birth (HR-HIVE); b) with known HIV exposure at birth (HIVE); or c) with or without known HIV exposure (ALL). Modeled infants received 1-dose, 2-doses, or Extended (every 3 months through 18 months) bNAb dosing. Base case model inputs included 70% bNAb efficacy (sensitivity analysis range: 10-100%), 3-month efficacy duration/dosing interval (1-6 months), and $20/dose cost ($5-$100/dose). Outcomes included pediatric HIV infections, life expectancy, lifetime HIV-related costs, and incremental cost-effectiveness ratios (ICERs, in US$/year-of-life-saved [YLS], assuming a ≤ 50% GDP per capita cost-effectiveness threshold). FINDINGS:The base case model projects that bNAb strategies targeting HIVE and ALL infants would prevent 7-26% and 10-42% additional pediatric HIV infections, respectively, compared to standard-of-care alone, ranging by dosing approach. HIVE-Extended would be cost-effective (cost-saving compared to standard-of-care) in Côte d'Ivoire and Zimbabwe; ALL-Extended would be cost-effective in South Africa (ICER: $882/YLS). BNAb strategies targeting HR-HIVE infants would result in greater lifetime costs and smaller life expectancy gains than HIVE-Extended. Throughout most bNAb efficacies and costs evaluated in sensitivity analyses, targeting HIVE infants would be cost-effective in Côte d'Ivoire and Zimbabwe, and targeting ALL infants would be cost-effective in South Africa. INTERPRETATION:Adding long-acting bNAbs to current standard-of-care prophylaxis would be cost-effective, assuming plausible efficacies and costs. The cost-effective target population would vary by setting, largely driven by maternal antenatal HIV prevalence and postpartum incidence.

ABSTRACT Introduction Approximately 130 000 infants acquire HIV annually despite global maternal antiretroviral therapy scale-up. We evaluated the potential clinical impact and cost-effectiveness of offering long-acting, anti-HIV broadly neutralizing antibody (bNAb) prophylaxis to infants in three distinct settings. Methods We simulated infants in Côte d’Ivoire, South Africa, and Zimbabwe using the Cost-Effectiveness of Preventing AIDS Complications-Pediatric (CEPAC-P) model. We modeled strategies offering a three-bNAb combination in addition to WHO-recommended standard-of-care oral prophylaxis to infants: a) with known, WHO-defined high-risk HIV exposure at birth ( HR-HIVE ); b) with known HIV exposure at birth ( HIVE ); or c) with or without known HIV exposure ( ALL ). Modeled infants received 1-dose , 2-doses , or Extended (every 3 months through 18 months) bNAb dosing. Base case model inputs included 70% bNAb efficacy (sensitivity analysis range: 10-100%), 3-month efficacy duration/dosing interval (1-6 months), and $20/dose cost ($5-$100/dose). Outcomes included pediatric HIV infections, life expectancy, lifetime HIV-related costs, and incremental cost-effectiveness ratios (ICERs, in US$/year-of-life-saved [YLS], assuming a < 50% GDP per capita cost-effectiveness threshold). Results The base case model projects that bNAb strategies targeting HIVE and ALL infants would prevent 7-26% and 10-42% additional pediatric HIV infections, respectively, compared to standard-of-care alone, ranging by dosing approach. HIVE-Extended would be cost-effective (cost-saving compared to standard-of-care) in Côte d’Ivoire and Zimbabwe; ALL-Extended would be cost-effective in South Africa (ICER: $882/YLS). BNAb strategies targeting HR-HIVE infants would result in greater lifetime costs and smaller life expectancy gains than HIVE-Extended . Throughout most bNAb efficacies and costs evaluated in sensitivity analyses, targeting HIVE infants would be cost-effective in Côte d’Ivoire and Zimbabwe, and targeting ALL infants would be cost-effective in South Africa. Discussion Adding long-acting bNAbs to current standard-of-care prophylaxis would be cost-effective, assuming plausible efficacies and costs. The cost-effective target population would vary by setting, largely driven by maternal antenatal HIV prevalence and postpartum incidence.

Local cortical circuit function is regulated by diverse populations of GABAergic interneurons with distinct properties and extensive interconnectivity. Inhibitory-to-inhibitory interactions between interneuron populations may play key roles in shaping circuit operation according to behavioral context. A specialized population of GABAergic interneurons that co-express vasoactive intestinal peptide (VIP-INs) are activated during arousal and locomotion and innervate other local interneurons and pyramidal neurons. Although modulation of VIP-IN activity by behavioral state has been extensively studied, their role in regulating information processing and selectivity is less well understood. Using a combination of cellular imaging, short and long-term manipulation, and perceptual behavior, we examined the impact of VIP-INs on their synaptic target populations in the primary visual cortex of awake behaving mice. We find that loss of VIP-IN activity alters the behavioral state-dependent modulation of somatostatin-expressing interneurons (SST-INs) but not pyramidal neurons (PNs). In contrast, reduced VIP-IN activity disrupts visual feature selectivity for stimulus size in both populations. Inhibitory-to inhibitory interactions thus directly shape the selectivity of GABAergic interneurons for sensory stimuli. Moreover, the impact of VIP-IN activity on perceptual behavior varies with visual context and is more acute for small than large visual cues. VIP-INs thus contribute to both state-dependent modulation of cortical circuit activity and sensory context-dependent perceptual performance.

Cortical circuit function is regulated by extensively interconnected, diverse populations of GABAergic inter -neurons that may play key roles in shaping circuit operation according to behavioral context. A specialized population of interneurons that co-express vasoactive intestinal peptides (VIP-INs) are activated during arousal and innervate other INs and pyramidal neurons (PNs). Although state-dependent modulation of VIP-INs has been extensively studied, their role in regulating sensory processing is less well understood. We examined the impact of VIP-INs in the primary visual cortex of awake behaving mice. Loss of VIP-IN ac-tivity alters the behavioral state-dependent modulation of somatostatin-expressing INs (SST-INs) but not PNs. In contrast, reduced VIP-IN activity globally disrupts visual feature selectivity for stimulus size. More-over, the impact of VIP-INs on perceptual behavior varies with context and is more acute for small than large visual cues. VIP-INs thus contribute to both state-dependent modulation of cortical activity and sensory context-dependent perceptual performance.

Abstract 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.

Background Despite the advent of safe and effective coronavirus disease 2019 vaccines, pervasive inequities in global vaccination persist. Methods We projected health benefits and donor costs of delivering vaccines for up to 60% of the population in 91 low- and middle-income countries (LMICs). We modeled a highly contagious (Re at model start, 1.7), low-virulence (infection fatality ratio [IFR], 0.32%) “Omicron-like” variant and a similarly contagious “severe” variant (IFR, 0.59%) over 360 days, accounting for country-specific age structure and healthcare capacity. Costs included vaccination startup (US$630 million) and per-person procurement and delivery (US$12.46/person vaccinated). Results In the Omicron-like scenario, increasing current vaccination coverage to achieve at least 15% in each of the 91 LMICs would prevent 11 million new infections and 120 000 deaths, at a cost of US$0.95 billion, for an incremental cost-effectiveness ratio (ICER) of US$670/year of life saved (YLS). Increases in vaccination coverage to 60% would additionally prevent up to 68 million infections and 160 000 deaths, with ICERs <US$8000/YLS. ICERs were <US$4000/YLS under the more severe variant scenario and generally robust to assumptions about vaccine effectiveness, uptake, and costs. Conclusions Funding expanded COVID-19 vaccine delivery in LMICs would save hundreds of thousands of lives, be similarly or more cost-effective than other donor-funded global aid programs, and improve health equity.

SummaryDespite the advent of safe and highly effective COVID-19 vaccines1–4, pervasive inequities in global distribution persist5. In response, multinational partners have proposed programs to allocate vaccines to low- and middle-income countries (LMICs)6. Yet, there remains a substantial funding gap for such programs7. Further, the optimal vaccine supply is unknown and the cost-effectiveness of investments into global vaccination programs has not been described. We used a validated COVID-19 simulation model8 to project the health benefits and costs of reaching 20%-70% vaccine coverage in 91 LMICs. We show that funding 20% vaccine coverage over one year among 91 LMICs would prevent 294 million infections and 2 million deaths, with 26 million years of life saved at a cost of US$6.4 billion, for an incremental cost effectiveness ratio (ICER) of US$250/year of life saved (YLS). Increasing vaccine coverage up to 50% would prevent millions more infections and save hundreds of thousands of additional lives, with ICERs below US$8,000/YLS. Results were robust to variations in vaccine efficacy and hesitancy, but were more sensitive to assumptions about epidemic pace and vaccination costs. These results support efforts to fund vaccination programs in LMICs and complement arguments about health equity9, economic benefits10, and pandemic control11.