Mosaic HIV-1 vaccine regimen in southern African women (Imbokodo/HVTN 705/HPX2008): a randomised, double-blind, placebo-controlled, phase 2b trial.

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.

Safety and Immunogenicity of a DNA Vaccine With Subtype C gp120 Protein Adjuvanted With MF59 or AS01B: A Phase 1/2a HIV-1 Vaccine Trial.

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.

Is HIV epidemic control by 2030 realistic?

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.

SARS-CoV-2 Viral Load in the Nasopharynx at Time of First Infection Among Unvaccinated Individuals: A Secondary Cross-Protocol Analysis of 4 Randomized Trials.

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.

Quantifying how single dose Ad26.COV2.S vaccine efficacy depends on Spike sequence features.

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.

Risk of COVID-19 after natural infection or vaccination.

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.

Clinical and Demographic Factors Associated With COVID-19, Severe COVID-19, and SARS-CoV-2 Infection in Adults: A Secondary Cross-Protocol Analysis of 4 Randomized Clinical Trials.

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.

Laboratory services in the context of prevention of mother-to-child transmission of HIV testing requirements in Copperbelt Province, Zambia: a qualitative inquiry.

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.

Risk Factors Associated with HIV Acquisition in Males Participating in HIV Vaccine Efficacy Trials in South Africa.

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.

Examining the Relationship Between Psychosocial Factors with Knowledge of HIV-Positive Status and Antiretroviral Therapy Exposure Among Adolescent Girls and Young Women Living with HIV in South Africa.

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.

Immune correlates analysis of the ENSEMBLE single Ad26.COV2.S dose vaccine efficacy clinical trial.

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 (ID50) 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 ID50; vaccine efficacy was 60% (43%, 72%) at non-quantifiable ID50 (<2.7 IU50 ml-1) and increased to 89% (78%, 96%) at ID50 = 96.3 IU50 ml-1. Comparison of the vaccine efficacy by ID50 titre curves for ENSEMBLE-US, the COVE trial of the mRNA-1273 vaccine and the COV002-UK trial of the AZD1222 vaccine supported the ID50 titre as a correlate of protection across trials and vaccine types.

Health system response to preventing mother-to-child transmission of HIV policy changes in Zambia: a health system dynamics analysis of primary health care facilities.

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.

Developing tuberculosis vaccines for people with HIV: consensus statements from an international expert panel.

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.

FCGR3A gene duplication, FcγRIIb-232TT and FcγRIIIb-HNA1a associate with an increased risk of vertical acquisition of HIV-1.

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.

Baseline host determinants of robust human HIV-1 vaccine-induced immune responses: A meta-analysis of 26 vaccine regimens.

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.

Analysis of the HIV Vaccine Trials Network 702 Phase 2b-3 HIV-1 Vaccine Trial in South Africa Assessing RV144 Antibody and T-Cell Correlates of HIV-1 Acquisition Risk.

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.

Immune Correlates Analysis of a Single Ad26.COV2.S Dose in the ENSEMBLE COVID-19 Vaccine Efficacy Clinical Trial.

Anti-spike IgG binding antibody, anti-receptor binding domain IgG antibody, and pseudovirus neutralizing antibody measurements four weeks post-vaccination were assessed as correlates of risk of moderate to severe-critical COVID-19 outcomes through 83 days post-vaccination and as correlates of protection following a single dose of Ad26.COV2.S COVID-19 vaccine in the placebo-controlled phase of ENSEMBLE, an international, randomized efficacy trial. Each marker had evidence as a correlate of risk and of protection, with strongest evidence for 50% inhibitory dilution (ID50) neutralizing antibody titer. The outcome hazard ratio was 0.49 (95% confidence interval 0.29, 0.81; p=0.006) per 10-fold increase in ID50; vaccine efficacy was 60% (43, 72%) at nonquantifiable ID50 (< 2.7 IU50/ml) and rose to 89% (78, 96%) at ID50 = 96.3 IU50/ml. Comparison of the vaccine efficacy by ID50 titer curves for ENSEMBLE-US, the COVE trial of the mRNA-1273 vaccine, and the COV002-UK trial of the AZD1222 vaccine supported consistency of the ID50 titer correlate of protection across trials and vaccine types.

High Asymptomatic Carriage With the Omicron Variant in South Africa.

We report a 23% asymptomatic severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) Omicron carriage rate in participants being enrolled into a clinical trial in South Africa, 15-fold higher than in trials before Omicron. We also found lower CD4 + T-cell counts in persons with human immunodeficiency virus (HIV) strongly correlated with increased odds of being SARS-CoV-2 polymerase chain reaction (PCR) positive.

Effectiveness of the Ad26.COV2.S vaccine in health-care workers in South Africa (the Sisonke study): results from a single-arm, open-label, phase 3B, implementation study.

BACKGROUND: We aimed to assess the effectiveness of a single dose of the Ad26.COV2.S vaccine (Johnson & Johnson) in health-care workers in South Africa during two waves of the South African COVID-19 epidemic. METHODS: In the single-arm, open-label, phase 3B implementation Sisonke study, health-care workers aged 18 years and older were invited for vaccination at one of 122 vaccination sites nationally. Participants received a single dose of 5 × 1010 viral particles of the Ad26.COV2.S vaccine. Vaccinated participants were linked with their person-level data from one of two national medical insurance schemes (scheme A and scheme B) and matched for COVID-19 risk with an unvaccinated member of the general population. The primary outcome was vaccine effectiveness against severe COVID-19, defined as COVID-19-related admission to hospital, hospitalisation requiring critical or intensive care, or death, in health-care workers compared with the general population, ascertained 28 days or more after vaccination or matching, up to data cutoff. This study is registered with the South African National Clinical Trial Registry, DOH-27-022021-6844, ClinicalTrials.gov, NCT04838795, and the Pan African Clinical Trials Registry, PACTR202102855526180, and is closed to accrual. FINDINGS: Between Feb 17 and May 17, 2021, 477 102 health-care workers were enrolled and vaccinated, of whom 357 401 (74·9%) were female and 119 701 (25·1%) were male, with a median age of 42·0 years (33·0-51·0). 215 813 vaccinated individuals were matched with 215 813 unvaccinated individuals. As of data cutoff (July 17, 2021), vaccine effectiveness derived from the total matched cohort was 83% (95% CI 75-89) to prevent COVID-19-related deaths, 75% (69-82) to prevent COVID-19-related hospital admissions requiring critical or intensive care, and 67% (62-71) to prevent COVID-19-related hospitalisations. The vaccine effectiveness for all three outcomes were consistent across scheme A and scheme B. The vaccine effectiveness was maintained in older health-care workers and those with comorbidities including HIV infection. During the course of the study, the beta (B.1.351) and then the delta (B.1.617.2) SARS-CoV-2 variants of concerns were dominant, and vaccine effectiveness remained consistent (for scheme A plus B vaccine effectiveness against COVID-19-related hospital admission during beta wave was 62% [95% CI 42-76] and during delta wave was 67% [62-71], and vaccine effectiveness against COVID-19-related death during beta wave was 86% [57-100] and during delta wave was 82% [74-89]). INTERPRETATION: The single-dose Ad26.COV2.S vaccine shows effectiveness against severe COVID-19 disease and COVID-19-related death after vaccination, and against both beta and delta variants, providing real-world evidence for its use globally. FUNDING: National Treasury of South Africa, the National Department of Health, Solidarity Response Fund NPC, The Michael & Susan Dell Foundation, The Elma Vaccines and Immunization Foundation, and the Bill & Melinda Gates Foundation.