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Human immunodeficiency virus (HIV)-specific natural killer (CD3- cells), CD4, and CD8 T cellular responses were determined in 79 HIV‐1-infected women in response to HIV‐1 peptide pools (Gag, Pol, Nef, Reg, and Env) with use of a whole‐blood intracellular cytokine staining assay that measures interferon-γ and/or interleukin-2. HIV‐specific CD3- cell responses to any region (Env and Reg predominantly targeted) were associated with lower viral load (P = .031) and higher CD4 T cell count (P = .015). Env‐specific CD3- cell responses were stronger in women who had both Gag CD4 and CD8 T cell responses and, in turn, was associated with lower viral load (P = .005). CD3- cell responders had significantly higher representation of CD4 T cell responses to Env and Reg (P = .012 and P = .015, respectively) and higher magnitudes of CD4 T cell responses (P = .017 and P = .037, respectively) than did nonresponders. Peptide‐specific natural killer cells are associated with markers of less severe disease progression among HIV‐1-infected women (lower viral load and higher CD4 T cell count) and with stronger HIV‐specific T cell responses. [ABSTRACT FROM AUTHOR]

We assessed risk behaviour in a heterosexual cohort undergoing prescreening for the first Phase I/II HIV vaccine trials in Soweto. We developed a survey and collected self-reported data from HIV-negative potential volunteers. Of 488 participants, most were single and approximately half were from households with incomes below the poverty level. Males reported higher rates of heavy alcohol use (P < 0.001), marijuana use (P < 0.001) and other recreational drug use (P < 0.01). Males reported more sex partners than females in the previous six months (P < 0.001), as well as more casual/anonymous partners (P < 0.001) and one-night stands (P < 0.001). Multivariate analyses revealed substance use and male gender predicted higher risk behaviours, including <100% condom use with known/suspected HIV-positive partners, having casual/anonymous partners and having more than two partners. For this population, male volunteers may need increased risk-reduction counselling during Phase I/II trials and additional recruitment methods may be necessary to identify high-risk female volunteers for Phase III efficacy trials. [ABSTRACT FROM AUTHOR]

Under sufficient stresses, such as during dynamic loading, titanium experiences a phase transformation from hcp alpha phase to hexagonal omega phase. Omega phase is often retained in the microstructure after unloading, and has a strong influence on subsequent mechanical properties. Simulations suggest there are multiple pathways and underlying mechanisms for this transformation. Due to the incredibly short timescales involved, experimental measurements for model validation have been difficult. However, new capabilities at the Advanced Photon Source have enabled diffraction measurements during plate impact experiments to study the evolution of titanium during transformation. These high-rate data allow us to probe the mechanism and kinetics of phase transformations in new ways. Recent results will be presented and compared to post-mortem characterization of soft-recovered shocked specimens. Comparisons are made with previous tests where material was shock-loaded and soft recovered for microstructural analysis. Together these techniques create a consistent picture of material behavior during the shock-induced ff–! phase transformation in titanium.

For ductile metals, the process of dynamic fracture occurs through nucleation, growth and coalescence of voids. The stress required to nucleate these voids is inferred from the velocimetry data (using the acoustic approach) and termed as the spall strength. This is a key parameter that is used to evaluate a material’s susceptibility to damage and failure. However, it is also well recognized that the dynamic parameters used to generate the shock state such as pulse duration, tensile strain-rate and peak stress coupled with material microstructure itself affect the material response in a complex manner. Yet, it is impossible to capture all this information by assessing only the spall strength measured from simple one-dimensional Photon Doppler Velocimetry measurements. Although, there exist widely used corrections proposed by Kanel et. al. that allow for the inclusion of some of these complexities into the measured spall strength but still does not take the microstructure into account. In this work, we propose another scheme for normalization of spall strength with a damage area to capture the complexities included in the damage and failure process especially pertaining to microstructure. We will also demonstrate the application of this scheme by applying to examples of materials such as Copper, Copper-24 wt%Ag, Copper-15 wt% Nb and additively manufactured 316L SS.

For Certification and qualification of an engineering component generally involves meeting engineering and physics requirements tied to its functional requirements. In this paper, the results of a study quantifying the microstructure, mechanical behavior, and the dynamic damage evolution of Tantalum (Ta) fabricated using an EOS laser-powder-bed machine are presented. The microstructure and quasi-static mechanical behavior of the AM-Ta is detailed and compared / contrasted to wrought Ta. The dynamic damage evolution and failure response of the AM-Ta material, as well as wrought Ta, was probed using flyer-plate impact driven spallation experiments. The differences in the spallation response between the AM and wrought Ta were measured using in-situ velocimetry as well as post-mortem quantification of damage in “soft-recovered” samples. The damage evolution of the AM and wrought Ta were characterized using both optical metallography and electron-backscatter diffraction.

Spall fracture is a high-rate tensile damage phenomenon associated with impulsive and shock-load events. Typically, the material undergoes a sequence of compression followed by release into high rate (on the order of 104 s-1 and up) tension, causing voids to nucleate and grow, which can then coalesce into a crack and the material fails. We present a series of experiments on high purity, well characterized tantalum samples subjected to shock-loading via gas-gun plate impact. Through careful selection of the flyer-plate velocity and material we have independent control over the peak compressive stress and the tensile strain rate in the sample. At all times, the spall damage remains incipient, i.e. in the early stages of void formation and the material does not fully fracture. Velocimetry was used on the rear of the sample to record the wave-profiles and determine spall strength. Soft recovery and sectioning of the samples allowed the internal damage to be observed, quantifying the damage amount, distribution, and relationship to microstructural features with both optical and electron based microscopy.

Background: Single-dose nevirapine (sdNVP)-which prevents mother-to-child transmission of HIV-selects non-nucleoside reverse-transcriptase inhibitor (NNRTI) resistance mutations in the majority of women and HIV-infected infants receiving it. This open-label, randomised trial examined the efficacy of short-course zidovudine (AZT) and lamivudine (3TC) with sdNVP in reducing NNRTI resistance in mothers, and as a secondary objective, in infants, in a setting where sdNVP was standard-of-care.Methods and Findings: sdNVP alone, administered at the onset of labour and to the infant, was compared to sdNVP with AZT plus 3TC, given as combivir (CBV) for 4 (NVP/CBV4) or 7 (NVP/CBV7) days, initiated simultaneously with sdNVP in labour; their newborns received the same regimens. Women were randomised 1ratio1ratio1. HIV-1 resistance was assessed by population sequencing at: baseline, 2, and 6 wk after birth. An unplanned interim analysis resulted in early stopping of the sdNVP arm. 406 pregnant women were randomised and took study medication (sdNVP 74, NVP/CBV4 164, and NVP/CBV7 168). HIV-1 resistance mutations emerged in 59.2%, 11.7%, and 7.3% of women in the sdNVP, NVP/CBV4, and NVP/CBV7 arms by 6 wk postpartum; differences between NVP-only and both NVP/CBV arms were significant (p<0.0001), but the difference between NVP/CBV4 and NVP/CBV7 was not (p = 0.27). Estimated efficacy comparing combined CBV arms with sdNVP was 85.6%. Similar resistance reductions were seen in infants who were HIV-infected by their 6-wk visit.Conclusions: A short course of AZT plus 3TC, supplementing maternal and infant sdNVP, reduces emergent NNRTI resistance mutations in both mothers and their infants. However, this trial was not powered to detect small differences between the CBV arms.Trial Registration: www.ClinicalTrials.govNCT 00144183. [ABSTRACT FROM AUTHOR]

QUESTION: In patients with serious mental disorders, is integrated medical care given in a mental health clinic better than usual care given in a general medicine clinic for improving outcomes?DesignRandomised (unclear allocation concealment*), unblinded*, controlled trial with 1 year of follow up.SettingA Veterans Affairs mental health clinic in West Haven, Connecticut, USA.Patients120 patients (mean age 45 y, 99% men) who had serious mental disorders and would benefit from primary care. Exclusion criteria included having a current primary care provider, urgent or multiple serious chronic problems, and medical hospital admissions in the past 6 months. Follow up was 100% for service use, quality of preventive care, and costs; random regression was used to account for missing health status data.Intervention59 patients were allocated to integrated care and 61 to usual care. For integrated care, clinic staff emphasised patient education, preventive services, and close contact with mental health care providers. Patients also received telephone reminders before appointments, and whenever possible, clinical appointments were scheduled immediately after mental health visits. When appointments were missed, clinic staff made active efforts to reschedule visits. Patients in the usual care group were assigned to a primary care provider.Main outcome measuresService use (medical and psychiatric visits), quality of preventive care (17 preventive measures), physical (physical component summary of the 36 Item Short Form Health Survey) and mental health status (Symptom Checklist 90 and Addiction Severity Index), and costs in US$.Main resultsAnalysis was by intention to treat. More patients in the integrated care group than the usual care group made primary care visits (p=0.006) (table) and received 15 of 17 preventive measures at 1 year (all p values < 0.05). Fewer patients in the integrated care group than the usual care group made emergency department visits at 1 year (p=0.04) (table). Improvement in physical health status over 1 year was greater in the integrated care group than the usual care group (mean change from baseline score 4.7 v -0.3, p < 0.001). Primary care costs per patient were greater in the integrated care group than the usual care group (US$1582 v $398, p=0.02), but total healthcare costs did not differ.ConclusionIn patients with serious mental disorders, integrated medical care given in a mental health clinic was better than usual care in a general medicine clinic for improving access to primary care services, quality of preventive care, and health related quality of life.*See glossary. [ABSTRACT FROM AUTHOR]

Background: Most people infected with HIV-1 are dually infected with herpes simplex virus type 2. Daily suppression of this herpes virus reduces plasma HIV-1 concentrations, but whether it delays HIV-1 disease progression is unknown. We investigated the effect of acyclovir on HIV-1 progression.Methods: In a trial with 14 sites in southern Africa and east Africa, 3381 heterosexual people who were dually infected with herpes simplex virus type 2 and HIV-1 were randomly assigned in a 1:1 ratio to acyclovir 400 mg orally twice daily or placebo, and were followed up for up to 24 months. Eligible participants had CD4 cell counts of 250 cells per mL or higher and were not taking antiretroviral therapy. We used block randomisation, and patients and investigators were masked to treatment allocation. Effect of acyclovir on HIV-1 disease progression was defined by a primary composite endpoint of first occurrence of CD4 cell counts of fewer than 200 cells per microL, antiretroviral therapy initiation, or non-trauma related death. As an exploratory analysis, we assessed the endpoint of CD4 falling to <350 cells per microL. Analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00194519.Findings: At enrollment, the median CD4 cell count was 462 cells per microL and median HIV-1 plasma RNA was 4.1 log(10) copies per microL. Acyclovir reduced risk of HIV-1 disease progression by 16%; 284 participants assigned acyclovir versus 324 assigned placebo reached the primary endpoint (hazard ratio [HR] 0.84, 95% CI 0.71-0.98, p=0.03). In those with CD4 counts >or=350 cells per microL, aciclovir delayed risk of CD4 cell counts falling to <350 cells per microL by 19% (0.81, 0.71-0.93, p=0.002)Interpretation: The role of suppression of herpes simplex virus type 2 in reduction of HIV-1 disease progression before initiation of antiretroviral therapy warrants consideration.Funding: Bill & Melinda Gates Foundation. [ABSTRACT FROM AUTHOR]

Background: The HVTN 705 Imbokodo trial of 2636 people without HIV and assigned female sex at birth, conducted in southern Africa, evaluated a heterologous HIV-1 vaccine regimen: mosaic adenovirus 26-based vaccine (Ad26.Mos4.HIV) at Months 0, 3, 6, 12 and alum-adjuvanted clade C gp140 at Months 6, 12. Per-protocol vaccine efficacy (VE) against HIV-1 diagnosis from seven to 24 months was 14.1% (95% CI: -22.0% to 39.5%). Immune correlates analysis was performed for markers selected based on prior evidence in efficacy trials and/or nonhuman primate models., Methods: Humoral and cellular immune response markers at Month 7 were evaluated as immune correlates of risk and of protection in a breakthrough case-control cohort (n = 52 cases, 246 non-cases). Primary markers were IgG binding to vaccine-strain gp140, IgG3 binding to diverse Env antigens (IgG3 Env breadth), IgG3 binding to diverse V1V2 antigens (IgG3 V1V2 breadth), antibody-dependent phagocytosis against the vaccine-strain gp140, Env-specific CD4+ and CD8+ T-cell responses, and multi-epitope functions., Findings: No immune markers were statistically significant correlates of risk. IgG3 V1V2 breadth trended toward an inverse association: hazard ratio 0.70 (95% CI: 0.36 to 1.35; p = 0.29) per 10-fold increase and 0.51 (95% CI: 0.21 to 1.24; p = 0.14) in a Cox model with all primary markers. The VE estimate was 11.8% (95% CI: -17.9% to 34.0%) at all IgG3 V1V2 breadth values below 667 weighted geometric mean net MFI; just above this value, the VE estimate sharply increased to 62.6% (95% CI: -17.9% to 89.6%), and further increased to 80.9% (95% CI: -17.9% to 99.5%) at 1471 MFI, the 95th percentile of the marker distribution. Mediation analysis yielded a VE of 35.7% (95% CI: 15.0% to 51.3%) attributable to the vaccine's impact on this marker., Interpretation: The trend in association of greater IgG3 V1V2 antibody breadth with lower likelihood of HIV acquisition is consistent with the identification of antibodies against V1V2 as immune correlates in three other HIV vaccine efficacy trials and suggests that a greater emphasis should be placed on studying this region in the HIV-1 envelope as a vaccine immunogen., Funding: National Institute of Allergy and Infectious Diseases and Janssen Vaccines & Prevention BV., Competing Interests: Declaration of interests TvdK has a patent application with Johnson & Johnson and has stocks in Johnson & Johnson. BK received internal support for the present manuscript from her employer (Los Alamos National Laboratory). In the past 36 months, she received support for attending meetings and/or travel from NIH NIAID and from the Gates foundation. Her institution (LANL) had a patent on this work, although she did not receive any personal funds through this patent and was not involved with the licensing of the design to Johnson & Johnson. DHB has a patent on the mosaic HIV vaccine, but no royalties. FT was an employee of Janssen/Johnson & Johnson at the time the work was conducted and owns stock in Johnson & Johnson. LL received support from Janssen Infectious Diseases BV, Beerse, Belgium for travel expenses to attend HIV conferences and has stock or stock options in Johnson & Johnson. JvD, MGP, WW, TvdK and JHen are employees of Janssen/Johnson & Johnson and hold stock or stock options in Johnson & Johnson. WW has a patent planned, issued, or pending with Johnson & Johnson. SCDR had contracts in the past 36 months to perform immunogenicity testing for Janssen, Sanofi, and Moderna. HS and DJS were employees of Janssen Vaccines & Prevention BV and had stock and/or stock options in Johnson & Johnson at the time the work was conducted. SN was an employee of Janssen Infectious Diseases BV and had stock and/or stock options in Johnson & Johnson at the time the work was conducted. LP was an employee of Janssen Vaccines & Prevention BV at the time the work was conducted. GDT has received consulting fees for a scientific consulting session. All other authors have no potential competing interests to disclose. Funding for the Imbokodo Study and Correlates Group is the same as listed in “Acknowledgments” for the current work., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Coronavirus disease 2019 (COVID-19) vaccines reduce severe disease and mortality and may lessen transmission, measured by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load (VL). Evaluating vaccine associations in VL at COVID-19 diagnosis in 4 phase 3 randomized, placebo-controlled vaccine trials, July 2020 to July 2021, VL reductions were 2.78 log10 copies/mL (95% confidence interval [CI], 1.38-4.18; n = 60 placebo, 11 vaccine) and 2.12 log10 copies/mL (95% CI, 1.44-2.80; n = 594 placebo, 36 vaccine) for NVX-CoV2373 and mRNA-1273, respectively. Associations were not significant for AZD1222 (0.59 log10 copies/mL; 95% CI, -.19 to 1.36; n = 90 placebo, 78 vaccine) or Ad26.COV2.S (0.23 log10 copies/mL; 95% CI, -.01 to .47; n = 916 placebo, 424 vaccine). Thus, vaccines potentially decreased transmission when ancestral SARS-CoV-2 predominated. Clinical Trials Registration. NCT04470427, NCT04505722, NCT04516746, NCT04611802., Competing Interests: Potential conflicts of interest. A. F. had/has research grants from Pfizer, Merck, Janssen, CyanVac, VaxCo, Moderna, and BioFire Diagnostics; fees for advisory boards from GSK, ADMA Biologics, and Sanofi Pasteur; and fees for data safety monitoring board from Novavax. M. E. S. had/has grants from the National Institutes of Health (NIH) and National Institute of Allergy and Infectious Diseases (NIAID) during the conduct of the study (5UM1AI069470); grants from NIH/NIAID and Gates Foundation outside the submitted work; and grants to her institution from Merck Sharpe and Dohme, Sanofi, and Gilead outside of the submitted work. S. R. W. has received institutional funding from the NIH/NIAID; institutional grants or contracts from Sanofi Pasteur, Janssen Vaccines/Johnson & Johnson, Moderna Tx, Pfizer, Vir Biotechnology, and Worcester HIV Vaccine; has participated on data safety monitoring or advisory boards for Janssen Vaccines/Johnson & Johnson and BioNTech; and his spouse holds stock/stock options in Regeneron Pharmaceuticals. C. M. E. has received research grants from Merck and AstraZeneca; and has participated in Sanofi, Janssen, and Gilead advisory board meetings. N. R. is a paid safety consultant for ICON, CyanVac, and EMMES; served on selected advisory boards for Sanofi, Seqirus, Pfizer, and Moderna; and receives funds to their institution to conduct research from Sanofi, Lilly, Merck, Quidel, Immorna, Vaccine Company, and Pfizer. C. L. G. has received institutional funding from the NIH for the conduct of the Moderna and Novavax studies; and grants to her institution from Gilead and ViiV outside of the submitted work. K. L. K. has received institutional funding from the NIH for the conduct of the Moderna and Novavax studies (UM1 AI 148689); and from Novavax outside of the submitted work. J. A. G. is employed by and holds stock in AstraZeneca. E. A. H. received fees from Oxford University for time spent adjudicating end points for the AstraZeneca/Oxford SARS-CoV-2 vaccine trials conducted in the UK, South Africa, and Brazil. M. D. T. has received institutional funding from the NIH for the conduct of the Moderna and Novavax studies (UM1 AI 148689). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: An effective vaccine is required to end the HIV pandemic. We evaluated the safety and immunogenicity of a DNA (DNA-HIV-PT123) vaccine with low- or high-dose bivalent (TV1.C and 1086.C glycoprotein 120) subtype C envelope protein combinations, adjuvanted with MF59 or AS01B., Methods: HIV Vaccine Trials Network (HVTN)108 was a randomized, placebo-controlled, double-blind, phase 1/2a trial conducted in the United States and South Africa. HIV-negative adults were randomly assigned to 1 of 7 intervention arms or placebo to assess DNA prime with DNA/protein/adjuvant boosts, DNA/protein/adjuvant co-administration, and low-dose protein/adjuvant regimens. HVTN111 trial participants who received an identical regimen were also included. Outcomes included safety and immunogenicity 2 weeks and 6 months after final vaccination., Results: From June 2016 to July 2018, 400 participants were enrolled (N = 334 HVTN108, N = 66 HVTN111); 370 received vaccine and 30 received placebo. There were 48 grade 3 and 3 grade 4 reactogenicity events among 39/400 (9.8%) participants, and 32 mild/moderate-related adverse events in 23/400 (5.8%) participants. All intervention groups demonstrated high IgG response rates (>89%) and high magnitudes to HIV-1 Env gp120 and gp140 proteins; response rates for AS01B-adjuvanted groups approached 100%. V1V2 IgG magnitude, Fc-mediated functions, IgG3 Env response rates, and CD4+ T-cell response magnitudes and rates were higher in the AS01B-adjuvanted groups. The AS01B-adjuvanted low-dose protein elicited greater IgG responses than the higher protein dose., Conclusions: The vaccine regimens were generally well tolerated. Co-administration of DNA with AS01B-adjuvanted bivalent Env gp120 elicited the strongest humoral responses; AS01B-adjuvanted regimens elicited stronger CD4+ T-cell responses, justifying further evaluation.ClinicalTrials.gov registration: NCT02915016, registered 26 September 2016., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: HIV type 1 (HIV-1) remains a global health concern, with the greatest burden in sub-Saharan Africa. Despite 40 years of research, no vaccine candidate has shown durable and protective efficacy against HIV-1 acquisition. Although pre-exposure prophylaxis in groups with high vulnerability can be very effective, barriers to its use, such as perceived low acquisition risk, fear of stigma, and concerns about side-effects, remain. Thus, a population-based approach, such as an HIV-1 vaccine, is needed. The current study aimed to evaluate the efficacy and safety of a heterologous HIV-1 vaccine regimen, consisting of a tetravalent mosaic adenovirus 26-based vaccine (Ad26.Mos4.HIV) and aluminium phosphate-adjuvanted clade C glycoprotein (gp) 140, in young women at risk of acquiring HIV-1 in southern Africa., Methods: This randomised, double-blind, phase 2b study enrolled sexually active women without HIV-1 or HIV-2 aged 18-35 years at 23 clinical research sites in Malawi, Mozambique, South Africa, Zambia, and Zimbabwe. Participants were centrally randomly assigned (1:1) to receive intramuscular injections of vaccine or saline placebo in stratified permuted blocks via an interactive web response system. Study participants, study site personnel (except those with primary responsibility for study vaccine preparation and dispensing), and investigators were masked to treatment group allocation. The vaccine regimen consisted of Ad26.Mos4.HIV administered at months 0 and 3 followed by Ad26.Mos4.HIV administered concurrently with aluminium phosphate-adjuvanted clade C gp140 at months 6 and 12. The primary efficacy outcome was vaccine efficacy in preventing laboratory-confirmed HIV-1 acquisition diagnosed between visits at month 7 and month 24 after the first vaccination (VE[7-24]) in the per-protocol population, which included participants who had not acquired HIV-1 4 weeks after the third vaccination, received all planned vaccinations at the first three vaccination visits within the protocol-specified windows, and had no major protocol deviations that could affect vaccine efficacy. Primary safety outcomes were assessed in randomly assigned participants who received one study injection or more based on the actual injection received. The primary safety endpoints were the incidences of unsolicited adverse events (AEs), solicited local and systemic AEs, serious AEs, AEs of special interest, and AEs leading to discontinuation of vaccination. This trial is registered with ClinicalTrials.gov, NCT03060629, and is complete., Findings: Between Nov 3, 2017, and June 30, 2019, 2654 women were randomly assigned, of whom 2636 women (median age of 23 years [IQR 20-25]) were enrolled and received at least one study injection (1313 assigned vaccine, 1323 placebo; 1317 received vaccine, 1319 placebo). Analysis of the primary efficacy outcome in the per-protocol cohort included 1080 women in the vaccine group and 1108 women in the placebo group; the incidence of HIV-1 acquisition per 100 person-years over months 7-24 after the first vaccination was 3·38 (95% CI 2·54-4·41) in the vaccine group and 3·94 (3·04-5·03) in the placebo group, with an estimated VE(7-24) of 14·10% (95% CI -22·00 to 39·51; p=0·40). There were no serious unsolicited AEs, AEs of special interest, or deaths related to the study vaccine. In the vaccine group, 663 (50·3%) of 1317 participants had grade 1 or 2 solicited local AEs and ten (0·8%) of 1317 participants had grade 3 or 4 solicited local AEs. In the placebo group, 305 (23·1%) of 1319 participants had grade 1 or 2 solicited local AEs and three (0·2%) of 1319 participants had grade 3 or 4 solicited local AEs. 863 (65·5%) of 1317 participants in the vaccine group had grade 1 or 2 solicited systemic AEs and 34 (2·6%) of 1317 participants had grade 3 or 4 solicited systemic AEs. 763 (57·8%) of 1319 participants in the placebo group had grade 1 or 2 solicited systemic AEs and 20 (1·5%) of 1319 participants had grade 3 or 4 solicited systemic AEs. Overall, three (0·2%) of 1317 participants in the vaccine group and three (0·2%) of 1319 participants in the placebo group discontinued vaccination due to an unsolicited AE, and three (0·2%) of 1317 participants in the vaccine group and one (0·1%) of 1319 participants in the placebo group discontinued vaccination due to a solicited AE., Interpretation: The heterologous Ad26.Mos4.HIV and clade C gp140 vaccine regimen was safe and well tolerated but did not show efficacy in preventing HIV-1 acquisition in a population of young women in southern Africa at risk of HIV-1., Funding: Division of AIDS at the National Institute of Allergy and Infectious Diseases through the HIV Vaccine Trials Network, Bill & Melinda Gates Foundation, Janssen Vaccines & Prevention, US Army Medical Materiel Development Activity, and Ragon Institute., Competing Interests: Declaration of interests GEG's institution (the South African Medical Research Council) has received funding from the US National Institutes of Health (NIH) and the Bill & Melinda Gates Foundation. KM was a protocol co-chair for the Imbokodo trial. LL is a consultant for Janssen Infectious Diseases. SN, DJS, JvD, WW, JVH, HS, MGP, and FT were employees of Janssen Pharmaceuticals at the time of this study and are stockholders of Johnson & Johnson. AL's institution has received funding from the NIH; outside the submitted work, AL has received consulting fees from Harvard University, and his institution has received funding from Janssen Pharmaceuticals. PM is an employee and stockholder of CureVac. MJM's institution (Fred Hutchinson Cancer Center) has received funding, including for laboratory equipment purchases, from the HIV Vaccine Trials Network (HVTN) Laboratory Center (grant number 5UM1AI068618) and Seattle-Lausanne Clinical Trials Unit; outside the submitted work, her institution has received funding, including for laboratory equipment purchases, from the Scripps Consortium for HIV/AIDS Vaccine Development Subaward, National Institute of Allergy and Infectious Diseases (NIAID) Human Immunology Project Consortium 3, Bill & Melinda Gates Foundation Comprehensive Cellular Vaccine Immune Monitoring Consortium, and Bill & Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery; her institution has received funding, including for laboratory equipment purchases, supporting SARS-CoV-2 vaccine laboratory studies from the COVID-19 Prevention Network (NIAID), Janssen Pharmaceuticals, Infectious Diseases Clinical Research Consortium (NIAID), Sanofi Pasteur, Moderna, and Regeneron; her institution has received funding, including for laboratory equipment purchases, supporting HIV and other vaccine trials and laboratory studies from International AIDS Vaccine Initiative, Janssen Pharmaceuticals, and Vir Biotechnology; and she has participated in scientific advisory boards for the Ragon Institute and Keystone Symposia, and on a board of scientific counsellors for the NIH Vaccine Research Center. GDT's institution (Duke University) has received NIH funding through the HVTN (grant numbers 5UM1AI068614 and 5UM1AI068618); GDT has served as a consultant for and received funding to her institution through Janssen Pharmaceuticals; is a reviewer for the Gilead Research Scholar Program; and has served on the board of scientific counsellors for the NIH Vaccine Research Center. DHB is a co-inventor on HIV vaccine patents that have been licensed to Janssen Pharmaceuticals. SB has received grant funding from Gilead Sciences, Merck, GSK, and ViiV. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Rates of new HIV acquisition remain unacceptably high in most populations in low-income, middle-income, and high-income settings despite advances in treatment and prevention strategies. Although biomedical advances in primary prevention of new infections exist, systematic scale-up of these interventions has not occurred at the pace required to end AIDS by 2030. Low population coverage, adherence to oral pre-exposure prophylaxis in settings with high rates of HIV acquisition, and the fact that a significant proportion of new HIV infections occurs in populations not identified as high risk and are hence not targeted for prevention approaches impedes current prevention strategies. Although long-acting injectables and monoclonal antibodies are promising approaches to help reduce incidence, high cost and the need for high coverage rates mean that a vaccine or vaccine-like intervention still remains the most likely scenario to produce a population-level impact on HIV incidence, especially in countries with generalised epidemics. Current global efforts are not sufficient to meet 2030 HIV epidemic goals; acknowledgment of this issue is required to ensure persistent advocacy for population-based control of the ongoing HIV pandemic., Competing Interests: Declaration of interests SB receives grants paid to institution from Gilead, ViiV, GSK, and Merck. LC reports grants from the National Institute of Allergy and Infectious Diseases and National Institutes of Health paid to institution. GDT reports grants from National Institutes of Health paid to institution and contracts from Janssen, Regeneron, BioNTech, and Sanofi and honorariums for scientific advisory boards from Michelson Prizes, Gilead Scholars, University of Alabama, University of North Carolina, Emory University, and NIH Vaccine Research Center. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Importance: SARS-CoV-2 viral load (VL) in the nasopharynx is difficult to quantify and standardize across settings, but it may inform transmission potential and disease severity., Objective: To characterize VL at COVID-19 diagnosis among previously uninfected and unvaccinated individuals by evaluating the association of demographic and clinical characteristics, viral variant, and trial with VL, as well as the ability of VL to predict severe disease., Design, Setting, and Participants: This secondary cross-protocol analysis used individual-level data from placebo recipients from 4 harmonized, phase 3 COVID-19 vaccine efficacy trials sponsored by Moderna, AstraZeneca, Janssen, and Novavax. Participants were SARS-CoV-2 negative at baseline and acquired COVID-19 during the blinded phase of the trials. The setting included the US, Brazil, South Africa, Colombia, Argentina, Peru, Chile, and Mexico; start dates were July 27, 2020, to December 27, 2020; data cutoff dates were March 26, 2021, to July 30, 2021. Statistical analysis was performed from November 2022 to June 2023., Main Outcomes and Measures: Linear regression was used to assess the association of demographic and clinical characteristics, viral variant, and trial with polymerase chain reaction-measured log10 VL in nasal and/or nasopharyngeal swabs taken at the time of COVID-19 diagnosis., Results: Among 1667 participants studied (886 [53.1%] male; 995 [59.7%] enrolled in the US; mean [SD] age, 46.7 [14.7] years; 204 [12.2%] aged 65 years or older; 196 [11.8%] American Indian or Alaska Native, 150 [9%] Black or African American, 1112 [66.7%] White; 762 [45.7%] Hispanic or Latino), median (IQR) log10 VL at diagnosis was 6.18 (4.66-7.12) log10 copies/mL. Participant characteristics and viral variant explained only 5.9% of the variability in VL. The independent factor with the highest observed differences was trial: Janssen participants had 0.54 log10 copies/mL lower mean VL vs Moderna participants (95% CI, 0.20 to 0.87 log10 copies/mL lower). In the Janssen study, which captured the largest number of COVID-19 events and variants and used the most intensive post-COVID surveillance, neither VL at diagnosis nor averaged over days 1 to 28 post diagnosis was associated with COVID-19 severity., Conclusions and Relevance: In this study of placebo recipients from 4 randomized phase 3 trials, high variability was observed in SARS-CoV-2 VL at the time of COVID-19 diagnosis, and only a fraction was explained by individual participant characteristics or viral variant. These results suggest challenges for future studies of interventions seeking to influence VL and elevates the importance of standardized methods for specimen collection and viral load quantitation.

In the ENSEMBLE randomized, placebo-controlled phase 3 trial (NCT04505722), estimated single-dose Ad26.COV2.S vaccine efficacy (VE) was 56% against moderate to severe-critical COVID-19. SARS-CoV-2 Spike sequences were determined from 484 vaccine and 1,067 placebo recipients who acquired COVID-19. In this set of prespecified analyses, we show that in Latin America, VE was significantly lower against Lambda vs. Reference and against Lambda vs. non-Lambda [family-wise error rate (FWER) p < 0.05]. VE differed by residue match vs. mismatch to the vaccine-insert at 16 amino acid positions (4 FWER p < 0.05; 12 q-value ≤ 0.20); significantly decreased with physicochemical-weighted Hamming distance to the vaccine-strain sequence for Spike, receptor-binding domain, N-terminal domain, and S1 (FWER p < 0.001); differed (FWER ≤ 0.05) by distance to the vaccine strain measured by 9 antibody-epitope escape scores and 4 NTD neutralization-impacting features; and decreased (p = 0.011) with neutralization resistance level to vaccinee sera. VE against severe-critical COVID-19 was stable across most sequence features but lower against the most distant viruses., (© 2024. The Author(s).)

Background: While vaccines have established utility against COVID-19, phase 3 efficacy studies have generally not comprehensively evaluated protection provided by previous infection or hybrid immunity (previous infection plus vaccination). Individual patient data from US government-supported harmonized vaccine trials provide an unprecedented sample population to address this issue. We characterized the protective efficacy of previous SARS-CoV-2 infection and hybrid immunity against COVID-19 early in the pandemic over three-to six-month follow-up and compared with vaccine-associated protection., Methods: In this post-hoc cross-protocol analysis of the Moderna, AstraZeneca, Janssen, and Novavax COVID-19 vaccine clinical trials, we allocated participants into four groups based on previous-infection status at enrolment and treatment: no previous infection/placebo; previous infection/placebo; no previous infection/vaccine; and previous infection/vaccine. The main outcome was RT-PCR-confirmed COVID-19 >7-15 days (per original protocols) after final study injection. We calculated crude and adjusted efficacy measures., Findings: Previous infection/placebo participants had a 92% decreased risk of future COVID-19 compared to no previous infection/placebo participants (overall hazard ratio [HR] ratio: 0.08; 95% CI: 0.05-0.13). Among single-dose Janssen participants, hybrid immunity conferred greater protection than vaccine alone (HR: 0.03; 95% CI: 0.01-0.10). Too few infections were observed to draw statistical inferences comparing hybrid immunity to vaccine alone for other trials. Vaccination, previous infection, and hybrid immunity all provided near-complete protection against severe disease., Interpretation: Previous infection, any hybrid immunity, and two-dose vaccination all provided substantial protection against symptomatic and severe COVID-19 through the early Delta period. Thus, as a surrogate for natural infection, vaccination remains the safest approach to protection., Funding: National Institutes of Health., Competing Interests: Declaration of interests YiH, CY, TCSM, RMM, HMES, BG, GEG, PBG, JGK, LC, and DF declare no conflicts of interest. AMR declares unrelated grants or contracts from NIAID, I4kids, Society to Improve Diagnosis in Medicine, Beckwith Clinical Innovation Award, CTSI COVID-19 Pilot Award; unrelated consulting fees from Pfizer; unrelated support for attending meetings/travel from IDweek (2023); and an unrelated unpaid leadership role as the medical director of Human Milk Science Institute and Biobank. MBL declares unrelated grants or contracts from NIH VTEU paid to their institution. CaAR declares unrelated grants or contracts paid to their institution from Novavax and Moderna. ChAR declares unrelated grants or contracts paid to their institution from BioFire, Inc, GSK, Merck, Micron, MedImmune, Novavax, PaxVax, Regeneron, Pfizer, Sanofi-Pasteur, Janssen, Moderna, NIH, and CDC; unrelated royalties or licenses from Meissa Vaccines, Inc; and unrelated patent interests for “RSV Live-Attenuated Vaccine Candidates with Deleted G-Protein Mucin Domains” and “Chimeric RSV, Immunogenic, Compositions, and Methods of Use”. LRB declares unrelated grants or contracts paid to their institution from NIH/Harvard Medical School and Wellcome Trust/Gates Foundation; unrelated participation on a Data Safety Monitoring Board or Advisory Board for NIAID and FDA; and unrelated involvement in HIV and SARS-CoV-2 vaccine clinical trials conducted in collaboration with the NIH, HIV Vaccine Trials Network (HVTN), Covid Vaccine Prevention Network (CoVPN), International AIDS Vaccine Initiative (IAVI), Crucell/Janssen, Moderna, Military HIV Research Program (MHRP), the Gates Foundation, and Harvard Medical School. CLG declares unrelated grants or contracts paid to their institution from NIH. HEJ declares unrelated grants or contracts paid to their institution from NIH; and unrelated participation in multiple NIH-convened DSMBs. YuH declares unrelated grants or contracts paid to their institution from WHO and unrelated participation (with payment) on a Data Safety Monitoring Board or Advisory Board for WHV. BL is an employee of Moderna, Inc. IH is an employee of AstraZeneca and declares unrelated stock options held in AstraZeneca. FS is an employee of Janssen and declares unrelated stock received as compensation for past employment with GlaxoSmithKline. LMD is an employee of Novavax, Inc. KMN declares unrelated grants or contracts from Pfizer (no salary support) and NIH. PAG declares unrelated grants or contracts from NIH and patent interests for “Human monoclonal antibodies to SARS-COV-2 and use thereof”. SRW declares unrelated grants or contracts from Sanofi Pasteur, Moderna, Vir Biotechnology, Worcester HIV Vaccine, Pfizer, and Janssen Vaccines/Johnson & Johnson paid to their institution; unrelated support for attending meetings and/or travel from Sasnofi Pasteur; unrelated participation on a Data Safety Monitoring Board or Advisory Board for Janssen Vaccines/Johnson & Johnson; and that their spouse is an employee that holds stock/stock options at Regeneron Pharmaceuticals. KLK declares unrelated grants or contracts from NIAID. The CoVPN was funded by the NIH., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

In South Africa, HIV acquisition risk has been studied less in people assigned male at birth. We studied the associations between risk behaviors, clinical features and HIV incidence amongst males in two South African HIV preventive vaccine efficacy trials. We used Cox proportional hazards models to test for associations between demographics, sexual behaviors, clinical variables and HIV acquisition among males followed in the HVTN 503 (n = 219) and HVTN 702 (n = 1611) trials. Most males reported no male sexual partners (99.09% in HVTN 503) or identified as heterosexual (88.08% in HVTN 702). Annual HIV incidence was 1.39% in HVTN 503 (95% CI 0.76-2.32%) and 1.33% in HVTN 702 (95% CI 0.80-2.07%). Increased HIV acquisition was significantly associated with anal sex (HR 6.32, 95% CI 3.44-11.62), transactional sex (HR 3.42, 95% CI 1.80-6.50), and non-heterosexual identity (HR 16.23, 95%CI 8.13-32.41) in univariate analyses and non-heterosexual identity (HR 14.99, 95% CI 4.99-45.04; p < 0.01) in multivariate analysis. It is appropriate that prevention efforts in South Africa, although focused on the severe epidemic in young women, also encompass key male populations, including men who have sex with men, but also men who engage in anal or transactional sex., (© 2023. The Author(s).)

Introduction: Reliable and timely laboratory results are crucial for monitoring the Prevention of the Mother-to-Child Transmission (PMTCT) cascade, particularly to enable early HIV diagnosis and early intervention. We sought to explore whether and how laboratory services have been prepared to absorb new testing requirements following PMTCT Test-and-Treat policy changes in three districts of Zambia., Method: We employed in-depth interviews and thematic data analysis, informed by the health system dynamic framework. Twenty-Six health workers were purposively selected and a document review of laboratory services in the context of PMTCT was undertaken. All face-to-face interviews were conducted in three local government areas in the Copperbelt Province (one urban and two rural) between February 2019 and July 2020. We extracted notes and markings from the transcripts for coding. Different codes were sorted into potential themes and the data extracted were put within the identified themes. Trustworthiness was confirmed by keeping records of all data field notes, transcripts, and reflexive journals., Results: The findings revealed that the health system inputs (infrastructure and supplies, human resources, knowledge, and information and finance) and service delivery were unequal between the rural and urban sites, and this affected the ability of health facilities to apply the new testing requirements, especially, in the rural-based health facilities. The major barriers identified include gaps in the capacity of the existing laboratory system to perform crucial PMTCT clinical and surveillance functions in a coordinated manner and insufficient skilled human resources to absorb the increased testing demands. The centralized laboratory system for HIV testing of mothers and exposed neonates meant facilities had to send specimens to other facilities and districts which resulted in high turnaround time and hence delayed HIV diagnosis., Conclusion: New guidelines implemented without sufficient capacitation of health system laboratory capacity severely limited the effectiveness of PMTCT program implementation. This study documented the areas relating to health system inputs and laboratory service delivery where greater support to enable the absorption of the new testing requirements is needed., (© 2023. The Author(s).)

Importance: Current data identifying COVID-19 risk factors lack standardized outcomes and insufficiently control for confounders., Objective: To identify risk factors associated with COVID-19, severe COVID-19, and SARS-CoV-2 infection., Design, Setting, and Participants: This secondary cross-protocol analysis included 4 multicenter, international, randomized, blinded, placebo-controlled, COVID-19 vaccine efficacy trials with harmonized protocols established by the COVID-19 Prevention Network. Individual-level data from participants randomized to receive placebo within each trial were combined and analyzed. Enrollment began July 2020 and the last data cutoff was in July 2021. Participants included adults in stable health, at risk for SARS-CoV-2, and assigned to the placebo group within each vaccine trial. Data were analyzed from April 2022 to February 2023., Exposures: Comorbid conditions, demographic factors, and SARS-CoV-2 exposure risk at the time of enrollment., Main Outcomes and Measures: Coprimary outcomes were COVID-19 and severe COVID-19. Multivariate Cox proportional regression models estimated adjusted hazard ratios (aHRs) and 95% CIs for baseline covariates, accounting for trial, region, and calendar time. Secondary outcomes included severe COVID-19 among people with COVID-19, subclinical SARS-CoV-2 infection, and SARS-CoV-2 infection., Results: A total of 57 692 participants (median [range] age, 51 [18-95] years; 11 720 participants [20.3%] aged ≥65 years; 31 058 participants [53.8%] assigned male at birth) were included. The analysis population included 3270 American Indian or Alaska Native participants (5.7%), 7849 Black or African American participants (13.6%), 17 678 Hispanic or Latino participants (30.6%), and 40 745 White participants (70.6%). Annualized incidence was 13.9% (95% CI, 13.3%-14.4%) for COVID-19 and 2.0% (95% CI, 1.8%-2.2%) for severe COVID-19. Factors associated with increased rates of COVID-19 included workplace exposure (high vs low: aHR, 1.35 [95% CI, 1.16-1.58]; medium vs low: aHR, 1.41 [95% CI, 1.21-1.65]; P < .001) and living condition risk (very high vs low risk: aHR, 1.41 [95% CI, 1.21-1.66]; medium vs low risk: aHR, 1.19 [95% CI, 1.08-1.32]; P < .001). Factors associated with decreased rates of COVID-19 included previous SARS-CoV-2 infection (aHR, 0.13 [95% CI, 0.09-0.19]; P < .001), age 65 years or older (aHR vs age <65 years, 0.57 [95% CI, 0.50-0.64]; P < .001) and Black or African American race (aHR vs White race, 0.78 [95% CI, 0.67-0.91]; P = .002). Factors associated with increased rates of severe COVID-19 included race (American Indian or Alaska Native vs White: aHR, 2.61 [95% CI, 1.85-3.69]; multiracial vs White: aHR, 2.19 [95% CI, 1.50-3.20]; P < .001), diabetes (aHR, 1.54 [95% CI, 1.14-2.08]; P = .005) and at least 2 comorbidities (aHR vs none, 1.39 [95% CI, 1.09-1.76]; P = .008). In analyses restricted to participants who contracted COVID-19, increased severe COVID-19 rates were associated with age 65 years or older (aHR vs <65 years, 1.75 [95% CI, 1.32-2.31]; P < .001), race (American Indian or Alaska Native vs White: aHR, 1.98 [95% CI, 1.38-2.83]; Black or African American vs White: aHR, 1.49 [95% CI, 1.03-2.14]; multiracial: aHR, 1.81 [95% CI, 1.21-2.69]; overall P = .001), body mass index (aHR per 1-unit increase, 1.03 [95% CI, 1.01-1.04]; P = .001), and diabetes (aHR, 1.85 [95% CI, 1.37-2.49]; P < .001). Previous SARS-CoV-2 infection was associated with decreased severe COVID-19 rates (aHR, 0.04 [95% CI, 0.01-0.14]; P < .001)., Conclusions and Relevance: In this secondary cross-protocol analysis of 4 randomized clinical trials, exposure and demographic factors had the strongest associations with outcomes; results could inform mitigation strategies for SARS-CoV-2 and viruses with comparable epidemiological characteristics.

Adolescent girls and young women (AGYW) living with HIV have poor antiretroviral therapy (ART) outcomes. We examined the relationship between psychosocial factors with knowledge of HIV-positive status and antiretroviral therapy exposure among AGYW living with HIV in South Africa. Participants 15-24 years responded to a survey including socio-demographics, psychosocial factors, and HIV testing. Blood was collected to determine HIV status and ART exposure. Multivariable analyses were conducted using R. Of 568 participants with HIV, 356 had knowledge of their HIV-positive status. Social support from family [aOR 1.14 (95% CI 1.04-1.24)] or from a special person [aOR 1.12 (95% CI 1.02-1.23)] was associated with knowledge of HIV-positive status. Resilience [aOR 1.05 (95% CI 1.01-1.08)] was the only psychosocial factor associated with a higher odds of ART exposure. Social support and resilience may increase knowledge of HIV-positive status and ART exposure among South African AGYW., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Zambia is focusing on attaining HIV epidemic control by 2021, including eliminating Mother to Child Transmission (eMTCT) of HIV. However, there is little evidence to understand frontline healthcare workers' experience with the policy changes and the readiness of different health system elements to contribute to this goal., Objective: To understand frontline healthcare workers' experience of preventing mother-to-child transmission (PMTCT) of human immunodeficiency (HIV) policy changes and to explore the health system readiness to respond to rapid changes in PMTCT policy by using the health system dynamic framework., Method: We conducted a qualitative study in which 35 frontline healthcare workers were selected and interviewed using a snowball sampling technique. All transcripts were analysed through thematic content analysis and deductive coding. Themes were derived and presented according to the health system dynamics framework., Results: Among the ten elements of the health system dynamics framework, service delivery, context, and resources (i.e. infrastructure and supplies, knowledge and information, human resource, and finance) were critical in implementing the continuously evolving PMTCT policies. Furthermore, due to the fragmented primary health care platform in Zambia, non-governmental organisations (NGOs) were instrumental in ensuring that the PMTCT programme met the demand and requirements of the general population. Frontline healthcare workers who participated in the study described inequity in access to ART services due to the service delivery model employed in the selected study sites., Conclusion: The study highlights challenges when policies are implemented without consideration for the readiness, context, and capacity in which the policy is implemented. We offer lessons that can inform implementation of universal health coverage of antiretroviral therapy (ART), a strategy many countries have adopted, despite weak health systems.

Measuring immune correlates of disease acquisition and protection in the context of a clinical trial is a prerequisite for improved vaccine design. We analysed binding and neutralizing antibody measurements 4 weeks post vaccination as correlates of risk of moderate to severe-critical COVID-19 through 83 d post vaccination in the phase 3, double-blind placebo-controlled phase of ENSEMBLE, an international randomized efficacy trial of a single dose of Ad26.COV2.S. We also evaluated correlates of protection in the trial cohort. Of the three antibody immune markers we measured, we found most support for 50% inhibitory dilution (ID 50 ) neutralizing antibody titre as a correlate of risk and of protection. The outcome hazard ratio was 0.49 (95% confidence interval 0.29, 0.81; P = 0.006) per 10-fold increase in ID 50 ; vaccine efficacy was 60% (43%, 72%) at non-quantifiable ID 50 (<2.7 IU 50  ml -1 ) and increased to 89% (78%, 96%) at ID 50  = 96.3 IU 50  ml -1 . Comparison of the vaccine efficacy by ID 50 titre curves for ENSEMBLE-US, the COVE trial of the mRNA-1273 vaccine and the COV002-UK trial of the AZD1222 vaccine supported the ID 50 titre as a correlate of protection across trials and vaccine types., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

The Prevention of Mother-to-child Transmission (PMTCT) of HIV program in Zambia has undergone several policy iterations over the past 10 years. This qualitative study aimed to contribute towards addressing this knowledge gap by analysing the evolution and actors' influence during the policy process using the Walt and Gilson policy triangle as our evaluation framework. Document review and key informant interviews with policy makers were undertaken to identify the contextual factors that had shaped the PMTCT policy evolution in Zambia. Overall, the study revealed that over the past decade, at least five PMTCT policy changes have occurred, averaging three years per policy with extensive overlap between policies. This resulted in more than two policies being implemented at a given time. Pressure from the international community and scientific evidence were the main drivers of policy change in Zambia, with local actors being mainly reactive. Among international agencies, UNICEF and WHO were the key actors who had driven the policy changes as they had the power and resources. The rapid changes, negatively impacted the health system, disrupted service delivery, which was unprepared to effectively and efficiently shift from one policy to another.

New tuberculosis vaccine candidates that are in the development pipeline need to be studied in people with HIV, who are at high risk of acquiring Mycobacterium tuberculosis infection and tuberculosis disease and tend to develop less robust vaccine-induced immune responses. To address the gaps in developing tuberculosis vaccines for people with HIV, a series of symposia was held that posed six framing questions to a panel of international experts: What is the use case or rationale for developing tuberculosis vaccines? What is the landscape of tuberculosis vaccines? Which vaccine candidates should be prioritised? What are the tuberculosis vaccine trial design considerations? What is the role of immunological correlates of protection? What are the gaps in preclinical models for studying tuberculosis vaccines? The international expert panel formulated consensus statements to each of the framing questions, with the intention of informing tuberculosis vaccine development and the prioritisation of clinical trials for inclusion of people with HIV., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: The identification of baseline host determinants that associate with robust HIV-1 vaccine-induced immune responses could aid HIV-1 vaccine development. We aimed to assess both the collective and relative performance of baseline characteristics in classifying individual participants in nine different Phase 1-2 HIV-1 vaccine clinical trials (26 vaccine regimens, conducted in Africa and in the Americas) as High HIV-1 vaccine responders., Methods: This was a meta-analysis of individual participant data, with studies chosen based on participant-level (vs. study-level summary) data availability within the HIV-1 Vaccine Trials Network. We assessed the performance of 25 baseline characteristics (demographics, safety haematological measurements, vital signs, assay background measurements) and estimated the relative importance of each characteristic in classifying 831 participants as High (defined as within the top 25th percentile among positive responders or above the assay upper limit of quantification) versus Non-High responders. Immune response outcomes included HIV-1-specific serum IgG binding antibodies and Env-specific CD4+ T-cell responses assessed two weeks post-last dose, all measured at central HVTN laboratories. Three variable importance approaches based on SuperLearner ensemble machine learning were considered., Findings: Overall, 30.1%, 50.5%, 36.2%, and 13.9% of participants were categorized as High responders for gp120 IgG, gp140 IgG, gp41 IgG, and Env-specific CD4+ T-cell vaccine-induced responses, respectively. When including all baseline characteristics, moderate performance was achieved for the classification of High responder status for the binding antibody responses, with cross-validated areas under the ROC curve (CV-AUC) of 0.72 (95% CI: 0.68, 0.76) for gp120 IgG, 0.73 (0.69, 0.76) for gp140 IgG, and 0.67 (95% CI: 0.63, 0.72) for gp41 IgG. In contrast, the collection of all baseline characteristics yielded little improvement over chance for predicting High Env-specific CD4+ T-cell responses [CV-AUC: 0.53 (0.48, 0.58)]. While estimated variable importance patterns differed across the three approaches, female sex assigned at birth, lower height, and higher total white blood cell count emerged as significant predictors of High responder status across multiple immune response outcomes using Approach 1. Of these three baseline variables, total white blood cell count ranked highly across all three approaches for predicting vaccine-induced gp41 and gp140 High responder status., Interpretation: The identified features should be studied further in pursuit of intervention strategies to improve vaccine responses and may be adjusted for in analyses of immune response data to enhance statistical power., Funding: National Institute of Allergy and Infectious Diseases (UM1AI068635 to YH, UM1AI068614 to GDT, UM1AI068618 to MJM, and UM1 AI069511 to MCK), the Duke CFAR P30 AI064518 to GDT, and National Institute of Dental and Craniofacial Research (R01DE027245 to JJK). This work was also supported by the Bill and Melinda Gates Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of any of the funding sources., Competing Interests: Declaration of interests Y.H. declares contract payments to her institution from the World Health Organization to conduct statistical analysis work (outside the scope of the current work; related to COVID-19 vaccines) and plan to submit the results for publication, within the past 36 months, as well as service to WHV as an SMB (payment directly to her) within the past 36 months. K.E.S. and J.H. declare coverage of travel expenses for attendance at the HVTN Full Group Meeting in 2022 (reimbursement by the HVTN); K.E.S. additionally declares payment of a registration fee for virtual seminar attendance directly to Keystone Symposium by the HVTN. S.D.R. declares contracts awarded to his institution from Battelle and from Janssen, and grants awarded to his institution from the Gates Medical Research Institute and from the Paul G. Allen Family Foundation, within the past 36 months. P.A.G. declares consulting fees received from Johnson and Johnson within the past 36 months, as well as a patent for a COVID-19 monoclonal antibody that is not yet clinically available. K.W.C. declares funding from the Bill and Melinda Gates Foundation in the form of payments to her institution within the last 36 months. B.D.W. declares grant payments made to his institution within the past 36 months from the following entities: Centers for Disease Control and Prevention, Patient-Centered Outcomes Research Institute, National Institute of Mental Health, National Institute of Allergy and Infectious Diseases, National Cancer Institute, and the National Institute of General Medical Studies; an honorarium for delivering an invited webinar to the American Statistical Association: Statistical Learning and Data Science Section; travel support through a grant from the National Institute of Mental Health; and retirement accounts invested in mutual funds operated by Vanguard and by TIAA (he does not choose individual stocks). L.-G.B. declares payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Gilead Sciences, Janssen, and Merck PTY LTD within the past 36 months, as well as participation on a Data Safety Monitoring Board or Advisory Board for the PrEPVAC study within the past 36 months. G.D.T. declares consulting fees received from Axon and from Janssen (not related to this work), serving as an Advisory Board member for the NIH VRC, UNC CFAR, and Johns Hopkins (not related to this work), and serving as a scientific review member for Gilead (not related to this work), all within the past 36 months, as well as travel as part of research funding (more than 3 years prior, with funding paid to her institution). J.T. declares consulting fees from Vaccitech within the past 36 months., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Some mother-to-child transmission (MTCT) studies suggest that allelic variations of Fc gamma receptors (FcγR) play a role in infant HIV-1 acquisition, but findings are inconsistent. To address the limitations of previous studies, the present study investigates the association between perinatal HIV-1 transmission and FcγR variability in three cohorts of South African infants born to women living with HIV-1., Methods: This nested case-control study combines FCGR genotypic data from three perinatal cohorts at two hospitals in Johannesburg, South Africa. Children with perinatally-acquired HIV-1 (cases, n = 395) were compared to HIV-1-exposed uninfected children (controls, n = 312). All study participants were black South Africans and received nevirapine for prevention of MTCT. Functional variants were genotyped using a multiplex ligation-dependent probe amplification assay, and their representation compared between groups using logistic regression analyses., Results: FCGR3A gene duplication associated with HIV-1 acquisition (OR = 10.27; 95% CI 2.00-52.65; P = 0.005) as did the FcγRIIb-232TT genotype even after adjusting for FCGR3A copy number and FCGR3B genotype (AOR = 1.72; 95%CI 1.07-2.76; P = 0.024). The association between FcγRIIb-232TT genotype and HIV-1 acquisition was further strengthened (AOR = 2.28; 95%CI 1.11-4.69; P = 0.024) if adjusted separately for FCGR2C c.134-96C>T. Homozygous FcγRIIIb-HNA1a did not significantly associate with HIV-1 acquisition in a univariate model (OR = 1.42; 95%CI 0.94-2.16; P = 0.098) but attained significance after adjustment for FCGR3A copy number and FCGR2B genotype (AOR = 1.55; 95%CI 1.01-2.38; P = 0.044). Both FcγRIIb-232TT (AOR = 1.83; 95%CI 1.13-2.97; P = 0.014) and homozygous FcγRIIIb-HNA1a (AOR = 1.66; 95%CI 1.07-2.57; P = 0.025) retained significance when birthweight and breastfeeding were added to the model. The common FCGR2A and FCGR3A polymorphisms did not associate with HIV-1 acquisition., Conclusions: Collectively, our findings suggest that the FcγRIIb-232TT genotype exerts a controlling influence on infant susceptibility to HIV-1 infection. We also show a role for less studied variants-FCGR3A duplication and homozygous HNA1a. These findings provide additional insight into a role for FcγRs in HIV-1 infection in children., Competing Interests: The authors have declared that no competing interests exist.

Background: The ALVAC/gp120 + MF59 vaccines in the HIV Vaccine Trials Network (HVTN) 702 efficacy trial did not prevent human immunodeficiency virus-1 (HIV-1) acquisition. Vaccine-matched immunological endpoints that were correlates of HIV-1 acquisition risk in RV144 were measured in HVTN 702 and evaluated as correlates of HIV-1 acquisition., Methods: Among 1893 HVTN 702 female vaccinees, 60 HIV-1-seropositive cases and 60 matched seronegative noncases were sampled. HIV-specific CD4+ T-cell and binding antibody responses were measured 2 weeks after fourth and fifth immunizations. Cox proportional hazards models assessed prespecified responses as predictors of HIV-1 acquisition., Results: The HVTN 702 Env-specific CD4+ T-cell response rate was significantly higher than in RV144 (63% vs 40%, P = .03) with significantly lower IgG binding antibody response rate and magnitude to 1086.C V1V2 (67% vs 100%, P < .001; Pmag < .001). Although no significant univariate associations were observed between any T-cell or binding antibody response and HIV-1 acquisition, significant interactions were observed (multiplicity-adjusted P ≤.03). Among vaccinees with high IgG A244 V1V2 binding antibody responses, vaccine-matched CD4+ T-cell endpoints associated with decreased HIV-1 acquisition (estimated hazard ratios = 0.40-0.49 per 1-SD increase in CD4+ T-cell endpoint)., Conclusions: HVTN 702 and RV144 had distinct immunogenicity profiles. However, both identified significant correlations (univariate or interaction) for IgG V1V2 and polyfunctional CD4+ T cells with HIV-1 acquisition. Clinical Trials Registration . NCT02968849., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)