Association Between SARS-CoV-2 Viral Load and COVID-19 Vaccination in 4 Phase 3 Trials.

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.

Omicron COVID-19 immune correlates analysis of a third dose of mRNA-1273 in the COVE trial.

In the phase 3 Coronavirus Efficacy (COVE) trial (NCT04470427), post-dose two Ancestral Spike-specific binding (bAb) and neutralizing (nAb) antibodies were shown to be correlates of risk (CoR) and of protection against Ancestral-lineage COVID-19 in SARS-CoV-2 naive participants. In the SARS-CoV-2 Omicron era, Omicron subvariants with varying degrees of immune escape now dominate, seropositivity rates are high, and booster doses are administered, raising questions on whether and how these developments affect the bAb and nAb correlates. To address these questions, we assess post-boost BA.1 Spike-specific bAbs and nAbs as CoRs and as correlates of booster efficacy in COVE. For naive individuals, bAbs and nAbs inversely correlate with Omicron COVID-19: hazard ratios (HR) per 10-fold marker increase (95% confidence interval) are 0.16 (0.03, 0.79) and 0.31 (0.10, 0.96), respectively. In non-naive individuals the analogous results are similar: 0.15 (0.04, 0.63) and 0.28 (0.07, 1.08). For naive individuals, three vs two-dose booster efficacy correlates with predicted nAb titer at exposure, with estimates -8% (-126%, 48%), 50% (25%, 67%), and 74% (49%, 87%), at 56, 251, and 891 Arbitrary Units/ml. These results support the continued use of antibody as a surrogate endpoint.

Provider Perspectives on Rapid Treatment Initiation Among People Newly Diagnosed With HIV: A New Message of "Urgency"?

BACKGROUND: Early initiation of antiretroviral therapy improves human immunodeficiency virus (HIV) outcomes. However, achieving earlier treatment initiation is challenging for many reasons including provider awareness and clinic barriers; this study sought to understand perceptions of an early initiation program. METHODS: We interviewed 10 providers from 3 HIV clinics in North Carolina (October-November 2020). We asked providers about overall perceptions of early initiation and the pilot program. We developed narrative summaries to understand individual contexts and conducted thematic analysis using NVivo. RESULTS: Providers believed earlier initiation would signal an "extra sense of urgency" about the importance of antiretroviral therapy-a message not currently reflected in standard of care. Safety was a consistent concern. Cited implementation barriers included transportation assistance, medication sustainability, and guidance to address increased staff time and appointment availability. CONCLUSION: Our qualitative findings highlight the need for training on the safety of early initiation and addressing staffing needs to accommodate quicker appointments.

Doctor and clinic staff perspectives on a program to immediately start HIV treatment among patients newly diagnosed with HIVTreating human immunodeficiency virus (HIV) is easier than ever. Starting newly diagnosed persons on HIV medication as soon as possible is a now recommended goal. However, starting patients right away can be challenging. This study interviewed doctors and clinic staff to better understand their perspectives prior to implementing a program that would provide newly diagnosed patients with HIV treatment immediately. Results showed that some doctors are worried patients will not return after receiving their medications. Providers want support for linking patients to the clinic and ensuring they will be able to receive their next dose of medication when they come in. Other providers saw the benefits of reducing HIV stigma if the program can more quickly start patients on treatment. Some providers explained that when you go to the doctor and are sick you receive medications immediately, yet for newly diagnosed patients living with HIV, patients can be told to come back a month later to start treatment. Some providers believe shifting this messaging may also help patients take their medications better. Most providers saw the need for clinics to have more same-day appointment availability to meet the needs of the new program. Overall, providers were excited about the opportunity to improve the HIV care by offering HIV medications to newly diagnosed patients immediately.

Safety and pharmacokinetics of VRC07-523LS administered via different routes and doses (HVTN 127/HPTN 087): A Phase I randomized clinical trial.

BACKGROUND: Broadly neutralizing antibodies (bnAbs) are a promising approach for HIV-1 prevention. In the Antibody Mediated Prevention (AMP) trials, a CD4-binding site targeting bnAb, VRC01, administered intravenously (IV), demonstrated 75% prevention efficacy against highly neutralization-sensitive viruses but was ineffective against less sensitive viruses. VRC07-523LS is a next-generation bnAb targeting the CD4-binding site and was engineered for increased neutralization breadth and half-life. We conducted a multicenter, randomized, partially blinded Phase I clinical trial to evaluate the safety and serum concentrations of VRC07-523LS, administered in multiple doses and routes to healthy adults without HIV. METHODS AND FINDINGS: Participants were recruited between 2 February 2018 and 9 October 2018. A total of 124 participants were randomized to receive 5 VRC07-523LS administrations via IV (T1: 2.5 mg/kg, T2: 5 mg/kg, T3: 20 mg/kg), subcutaneous (SC) (T4: 2.5 mg/kg, T5: 5 mg/kg), or intramuscular (IM) (T6: 2.5 mg/kg or P6: placebo) routes at 4-month intervals. Participants and site staff were blinded to VRC07-523LS versus placebo for the IM group, while all other doses and routes were open-label. Safety data were collected for 144 weeks following the first administration. VRC07-523LS serum concentrations were measured by ELISA through Day 112 in all participants and by binding antibody multiplex assay (BAMA) thereafter in 60 participants (10 per treatment group) through Day 784. Compartmental population pharmacokinetic (PK) analyses were conducted to evaluate the VRC07-523LS serum PK. Neutralization activity was measured in a TZM-bl assay and antidrug antibodies (ADAs) were assayed using a tiered bridging assay testing strategy. Injections and infusions were well tolerated, with mild pain or tenderness reported commonly in the SC and IM groups, and mild to moderate erythema or induration reported commonly in the SC groups. Infusion reactions were reported in 3 of 20 participants in the 20 mg/kg IV group. Peak geometric mean (GM) concentrations (95% confidence intervals [95% CIs]) following the first administration were 29.0 µg/mL (25.2, 33.4), 58.5 µg/mL (49.4, 69.3), and 257.2 µg/mL (127.5, 518.9) in T1-T3 with IV dosing; 10.8 µg/mL (8.8, 13.3) and 22.8 µg/mL (20.1, 25.9) in T4-T5 with SC dosing; and 16.4 µg/mL (14.7, 18.2) in T6 with IM dosing. Trough GM (95% CIs) concentrations immediately prior to the second administration were 3.4 µg/mL (2.5, 4.6), 6.5 µg/mL (5.6, 7.5), and 27.2 µg/mL (23.9, 31.0) with IV dosing; 0.97 µg/mL (0.65, 1.4) and 3.1 µg/mL (2.2, 4.3) with SC dosing, and 2.6 µg/mL (2.05, 3.31) with IM dosing. Peak VRC07-523LS serum concentrations increased linearly with the administered dose. At a given dose, peak and trough concentrations, as well as serum neutralization titers, were highest in the IV groups, reflecting the lower bioavailability following SC and IM administration. A single participant was found to have low titer ADA at a lone time point. VRC07-523LS has an estimated mean half-life of 42 days across all doses and routes (95% CI: 40.5, 43.5), over twice as long as VRC01 (15 days). CONCLUSIONS: VRC07-523LS was safe and well tolerated across a range of doses and routes and is a promising long-acting bnAb for inclusion in HIV-1 prevention regimens. TRIAL REGISTRATION: ClinicalTrials.gov/ NCT03387150 (posted on 21 December 2017).

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.

Sequence Analysis of Inducible, Replication-Competent Virus Reveals No Evidence of HIV-1 Evolution During Suppressive Antiviral Therapy, Indicating a Lack of Ongoing Viral Replication.

Background: Persistence of HIV-1 in reservoirs necessitates life-long antiretroviral therapy (ART). There are conflicting data using genetic analysis on whether persistence includes an actively replicating reservoir with strong evidence arguing against replication. Methods: We investigated the possibility of ongoing viral evolution during suppressive therapy by comparing near full-length viral genomic sequences using phylogenetic analysis of viral RNA in plasma before therapy initiation early after infection and from virus induced to grow from the latent reservoir after a period of suppressive ART. We also focused our analysis on evidence of selective pressure by drugs in the treatment regimen and at sites of selective pressure by the adaptive immune response. Results: Viral genomes induced to grow from the latent reservoir from 10 participants with up to 9 years on suppressive ART were highly similar to the nearly homogeneous sequences in plasma taken early after infection at ART initiation. This finding was consistent across the entire genome and when the analysis focused on sites targeted by the drug regimen and by host selective pressure of antibody and cytotoxic T cells. The lack of viral evolution away from pretherapy sequences in spite of demonstrated selective pressure is most consistent with a lack of viral replication during reservoir persistence. Conclusions: These results do not support ongoing viral replication as a mechanism of HIV-1 persistence during suppressive ART.

COVID-19 Vaccine Efficacy in Participants With Weakened Immune Systems From 4 Randomized Controlled Trials.

BACKGROUND: Although the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines are highly efficacious at preventing severe disease in the general population, current data are lacking regarding vaccine efficacy (VE) for individuals with mild immunocompromising conditions. METHODS: A post hoc, cross-protocol analysis of participant-level data from the blinded phase of four randomized, placebo-controlled, coronavirus disease 2019 (COVID-19) vaccine phase 3 trials (Moderna, AstraZeneca, Janssen, and Novavax) was performed. We defined a "tempered immune system" (TIS) variable via a consensus panel based on medical history and medications to determine VE against symptomatic and severe COVID-19 cases in TIS participants versus non-TIS individuals starting at 14 days after completion of the primary series through the blinded phase for each of the 4 trials. An analysis of participants living with well-controlled human immunodeficiency virus was conducted using the same methods. RESULTS: A total of 3852/30 351 (12.7%) Moderna participants, 3088/29 868 (10.3%) Novavax participants, 3549/32 380 (11.0%) AstraZeneca participants, and 5047/43 788 (11.5%) Janssen participants were identified as having a TIS. Most TIS conditions (73.9%) were due to metabolism and nutritional disorders. Vaccination (vs placebo) significantly reduced the likelihood of symptomatic and severe COVID-19 for all participants for each trial. VE was not significantly different for TIS participants versus non-TIS for either symptomatic or severe COVID-19 for each trial, nor was VE significantly different in the symptomatic endpoint for participants with human immunodeficiency virus. CONCLUSIONS: For individuals with mildly immunocompromising conditions, there is no evidence of differences in VE against symptomatic or severe COVID-19 compared with those with non-TIS in the 4 COVID-19 vaccine randomized controlled efficacy trials.

Safety and Immune Responses Following Anti-PD-1 Monoclonal Antibody Infusions in Healthy Persons With Human Immunodeficiency Virus on Antiretroviral Therapy.

Background: T cells in people with human immunodeficiency virus (HIV) demonstrate an exhausted phenotype, and HIV-specific CD4+ T cells expressing programmed cell death 1 (PD-1) are enriched for latent HIV, making antibody to PD-1 a potential strategy to target the latent reservoir. Methods: This was a phase 1/2, randomized (4:1), double-blind, placebo-controlled study in adults with suppressed HIV on antiretroviral therapy with CD4+ counts ≥350 cells/µL who received 2 infusions of cemiplimab versus placebo. The primary outcome was safety, defined as any grade 3 or higher adverse event (AE) or any immune-related AE (irAE). Changes in HIV-1-specific polyfunctional CD4+ and CD8+ T-cell responses were evaluated. Results: Five men were enrolled (median CD4+ count, 911 cells/µL; median age, 51 years); 2 received 1 dose of cemiplimab, 2 received 2 doses, and 1 received placebo. One participant had a probable irAE (thyroiditis, grade 2); another had a possible irAE (hepatitis, grade 3), both after a single low-dose (0.3 mg/kg) infusion. The Safety Monitoring Committee recommended no further enrollment or infusions. All 4 cemiplimab recipients were followed for 48 weeks. No other cemiplimab-related serious AEs, irAEs, or grade 3 or higher AEs occurred. One 2-dose recipient of cemiplimab had a 6.2-fold increase in polyfunctional, Gag-specific CD8+ T-cell frequency with supportive increases in plasma HIV RNA and decreases in total HIV DNA. Conclusions: One of 4 participants exhibited increased HIV-1-specific T-cell responses and transiently increased HIV-1 expression following 2 cemiplimab infusions. The occurrence of irAEs after a single, low dose may limit translating the promising therapeutic results of cemiplimab for cancer to immunotherapeutic and latency reversal strategies for HIV. Clinical Trials Registration. NCT03787095.

The Effects of Human Immunodeficiency Virus Type 1 (HIV-1) Antigen-Expanded Specific T-Cell Therapy and Vorinostat on Persistent HIV-1 Infection in People With HIV on Antiretroviral Therapy.

BACKGROUND: The histone deacetylase inhibitor vorinostat (VOR) can reverse human immunodeficiency virus type 1 (HIV-1) latency in vivo and allow T cells to clear infected cells in vitro. HIV-specific T cells (HXTCs) can be expanded ex vivo and have been safely administered to people with HIV (PWH) on antiretroviral therapy. METHODS: Six PWH received infusions of 2 × 107 HXTCs/m² with VOR 400 mg, and 3 PWH received infusions of 10 × 107 HXTCs/m² with VOR. The frequency of persistent HIV by multiple assays including quantitative viral outgrowth assay (QVOA) of resting CD4+ T cells was measured before and after study therapy. RESULTS: VOR and HXTCs were safe, and biomarkers of serial VOR effect were detected, but enhanced antiviral activity in circulating cells was not evident. After 2 × 107 HXTCs/m² with VOR, 1 of 6 PWH exhibited a decrease in QVOA, and all 3 PWH exhibited such declines after 10 × 107 HXTCs/m² and VOR. However, most declines did not exceed the 6-fold threshold needed to definitively attribute decline to the study intervention. CONCLUSIONS: These modest effects provide support for the strategy of HIV latency reversal and reservoir clearance, but more effective interventions are needed to yield the profound depletion of persistent HIV likely to yield clinical benefit. Clinical Trials Registration. NCT03212989.

Durability of Protection Against COVID-19 Through the Delta Surge for the NVX-CoV2373 Vaccine.

BACKGROUND: Protein-based vaccines for coronavirus disease 2019 (COVID-19) provide a traditional vaccine platform with long-lasting protection for non-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogens and may complement messenger RNA vaccines as a booster dose. While NVX-CoV2373 showed substantial early efficacy, the durability of protection has not been delineated. METHODS: The PREVENT-19 vaccine trial used a blinded crossover design; the original placebo arm received NVX-CoV2373 after efficacy was established. Using novel statistical methods that integrate surveillance data of circulating strains with post-crossover cases, we estimated placebo-controlled vaccine efficacy and durability of NVX-CoV2373 against both pre-Delta and Delta strains of SARS-CoV-2. RESULTS: Vaccine efficacy against pre-Delta strains of COVID-19 was 89% (95% CI, 75-95%) and 87% (72-94%) at 0 and 90 days after 2 doses of NVX-CoV2373, respectively, with no evidence of waning (P = .93). Vaccine efficacy against the Delta strain was 88% (71-95%), 82% (56-92%), and 77% (44-90%) at 40, 120, and 180 days, respectively, with evidence of waning (P < .01). In sensitivity analyses, the estimated Delta vaccine efficacy at 120 days ranged from 66% (15-86%) to 89% (74-95%) per various assumptions of the surveillance data. CONCLUSIONS: NVX-CoV2373 has high initial efficacy against pre-Delta and Delta strains of COVID-19 with little evidence of waning for pre-Delta strains through 90 days and moderate waning against Delta strains over 180 days.

A Randomised Clinical Trial of the Safety and Pharmacokinetics of VRC07-523LS Administered via Different Routes and Doses (HVTN 127/HPTN 087).

Background: Broadly neutralizing antibodies (bnAbs) are a promising approach for HIV-1 prevention. In the only bnAb HIV prevention efficacy studies to date, the Antibody Mediated Prevention (AMP) trials, a CD4-binding site targeting bnAb, VRC01, administered intravenously (IV), demonstrated 75% prevention efficacy against highly neutralization-sensitive viruses but was ineffective against less sensitive viruses. Greater efficacy is required before passively administered bnAbs become a viable option for HIV prevention; furthermore subcutaneous (SC) or intramuscular (IM) administration may be preferred. VRC07-523LS is a next-generation bnAb targeting the CD4-binding site and was engineered for increased neutralization breadth and half-life. Methods: Participants were recruited between 02 February 2018 and 09 October 2018. 124 healthy participants without HIV were randomized to receive five VRC07-523LS administrations via IV (T1: 2.5 mg/kg, T2: 5 mg/kg, T3: 20 mg/kg), SC (T4: 2.5 mg/kg, T5: 5 mg/kg) or IM (T6: 2.5 mg/kg or P6: placebo) routes at four-month intervals. Safety data were collected for 144 weeks following the first administration. VRC07-523LS serum concentrations were measured by ELISA after the first dose through Day 112 in all participants and by binding antibody multiplex assay (BAMA) thereafter in 60 participants (10 per treatment group) through Day 784. Compartmental population pharmacokinetic (PK) analyses were conducted to evaluate the VRC07-523LS serum pharmacokinetics. Neutralization activity was measured in a TZM-bl assay and anti-drug antibodies (ADA) were assayed using a tiered bridging assay testing strategy. Results: Injections were well-tolerated, with mild pain or tenderness reported commonly in the SC and IM groups, and mild to moderate erythema or induration reported commonly in the SC groups. Infusions were generally well-tolerated, with infusion reactions reported in 3 of 20 participants in the 20 mg/kg IV group. Peak geometric mean (GM) concentrations (95% confidence intervals) following the first administration were 29.0 µg/mL (25.2, 33.4), 58.5 µg/mL (49.4, 69.3), and 257.2 µg/mL (127.5, 518.9) in T1-T3 with IV dosing; 10.8 µg/mL (8.8, 13.3) and 22.8 µg/mL (20.1, 25.9) in T4-T5 with SC dosing; and 16.4 µg/mL (14.7, 18.2) in T6 with IM dosing. Trough GM concentrations immediately prior to the second administration were 3.4 µg/mL (2.5, 4.6), 6.5 µg/mL (5.6, 7.5), and 27.2 µg/mL (23.9, 31.0) with IV dosing; 0.97 µg/mL (0.65, 1.4) and 3.1 µg/mL (2.2, 4.3) with SC dosing, and 2.6 µg/mL (2.05, 3.31) with IM dosing. Peak VRC07-523LS serum concentrations increased linearly with the administered dose. At a given dose, peak and trough concentrations, as well as serum neutralization titres, were highest in the IV groups, reflecting the lower bioavailability following SC and IM administration. A single participant was found to have low titre ADA at a lone timepoint. VRC07-523LS has an estimated mean half-life of 42 days (95% CI: 40.5, 43.5), approximately twice as long as VRC01. Conclusions: VRC07-523LS was safe and well-tolerated across a range of doses and routes and is a promising long-acting bnAb for inclusion in HIV-1 prevention regimens.

CD3 downregulation identifies high-avidity human CD8 T cells.

CD8 T cells recognize infected and cancerous cells via their T-cell receptor (TCR), which binds peptide-MHC complexes on the target cell. The affinity of the interaction between the TCR and peptide-MHC contributes to the antigen sensitivity, or functional avidity, of the CD8 T cell. In response to peptide-MHC stimulation, the TCR-CD3 complex and CD8 co-receptor are downmodulated. We quantified CD3 and CD8 downmodulation following stimulation of human CD8 T cells with CMV, EBV, and HIV peptides spanning eight MHC restrictions, observing a strong correlation between the levels of CD3 and CD8 downmodulation and functional avidity, regardless of peptide viral origin. In TCR-transduced T cells targeting a tumor-associated antigen, changes in TCR-peptide affinity were sufficient to modify CD3 and CD8 downmodulation. Correlation analysis and generalized linear modeling indicated that CD3 downmodulation was the stronger correlate of avidity. CD3 downmodulation, simply measured using flow cytometry, can be used to identify high-avidity CD8 T cells in a clinical context.

Dominant CD4+ T cell receptors remain stable throughout antiretroviral therapy-mediated immune restoration in people with HIV.

In people with HIV (PWH), the post-antiretroviral therapy (ART) window is critical for immune restoration and HIV reservoir stabilization. We employ deep immune profiling and T cell receptor (TCR) sequencing and examine proliferation to assess how ART impacts T cell homeostasis. In PWH on long-term ART, lymphocyte frequencies and phenotypes are mostly stable. By contrast, broad phenotypic changes in natural killer (NK) cells, γδ T cells, B cells, and CD4+ and CD8+ T cells are observed in the post-ART window. Whereas CD8+ T cells mostly restore, memory CD4+ T subsets and cytolytic NK cells show incomplete restoration 1.4 years post ART. Surprisingly, the hierarchies and frequencies of dominant CD4 TCR clonotypes (0.1%-11% of all CD4+ T cells) remain stable post ART, suggesting that clonal homeostasis can be independent of homeostatic processes regulating CD4+ T cell absolute number, phenotypes, and function. The slow restoration of host immunity post ART also has implications for the design of ART interruption studies.

HIVepsilon-seq-scalable characterization of intact persistent proviral HIV reservoirs in women.

IMPORTANCE: The lack of a reliable method to accurately detect when replication-competent HIV has been cleared is a major challenge in developing a cure. This study introduces a new approach called the HIVepsilon-seq (HIVε-seq) assay, which uses long-read sequencing technology and bioinformatics to scrutinize the HIV genome at the nucleotide level, distinguishing between defective and intact HIV. This study included 30 participants on antiretroviral therapy, including 17 women, and was able to discriminate between defective and genetically intact viruses at the single DNA strand level. The HIVε-seq assay is an improvement over previous methods, as it requires minimal sample, less specialized lab equipment, and offers a shorter turnaround time. The HIVε-seq assay offers a promising new tool for researchers to measure the intact HIV reservoir, advancing efforts towards finding a cure for this devastating disease.

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.

Modifiers of COVID-19 vaccine efficacy: Results from four COVID-19 prevention network efficacy trials.

Questions remain regarding the effect of baseline host and exposure factors on vaccine efficacy (VE) across pathogens and vaccine platforms. We report placebo-controlled data from four Phase 3 COVID-19 trials during the early period of the pandemic. This was a cross-protocol analysis of four randomized, placebo-controlled efficacy trials (Moderna/mRNA1273, AstraZeneca/AZD1222, Janssen/Ad26.COV2.S, and Novavax/NVX-CoV2373) using a harmonized design. Trials were conducted in the United States and international sites in adults ≥ 18 years of age. VE was assessed for symptomatic and severe COVID-19. We analyzed 114,480 participants from both placebo and vaccine arms, enrolled July 2020 to February 2021, with follow up through July 2021. VE against symptomatic COVID-19 showed little heterogeneity across baseline socio-demographic, clinical or exposure characteristics, in either univariate or multivariate analysis, regardless of vaccine platform. Similarly, VE against severe COVID-19 in the single trial (Janssen) with sufficient endpoints for analysis showed little evidence of heterogeneity. COVID-19 VE is not influenced by baseline host or exposure characteristics across efficacy trials of different vaccine platforms and countries when well matched to circulating virus strains. This supports use of these vaccines, regardless of platform type, as effective tools in the near term for reducing symptomatic and severe COVID-19, particularly for older individuals and those with common co-morbidities during major variant shifts. Clinical trial registration numbers: NCT04470427, NCT04516746, NCT04505722, and NCT04611802.

Immunogenicity of NVX-CoV2373 in PREVENT-19: A Phase 3, Randomized, Placebo-Controlled Trial in Adults in the United States and Mexico.

Background: NVX-CoV2373, an adjuvanted, recombinant SARS-CoV-2 spike (rS) protein vaccine, consistently demonstrated protective efficacy against COVID-19 in clinical trials and has received regulatory authorizations or approvals worldwide. Methods: PREVENT-19 (NCT04611802) is a phase 3, randomized, observer-blinded, placebo-controlled trial evaluating safety, immunogenicity, and efficacy of NVX-CoV2373 in ≈30 000 participants ≥18 years in the United States and Mexico. Vaccine humoral immune response (ie, serum immunoglobulin [IgG] antibodies, hACE2 receptor binding inhibition antibodies, and neutralizing antibodies to SARS-CoV-2) (ancestral strain) was assessed in 1200 participants randomly selected and equally divided between participants 18-64 and ≥65 years. Results: In the per protocol analysis, NVX-CoV2373 induced vigorous serum antibody responses among the 1063 analyzed participants who were SARS-CoV-2 seronegative at baseline, received both doses of study treatment, and had serology results available 2 weeks after dose 2. Geometric mean (GM) responses in both younger and older adults were higher among recipients of vaccine versus placebo for IgG (64 259 vs 121 and 37 750 vs 133 ELISA units, respectively), hACE2 receptor binding inhibition GM titers (GMTs) (222 vs 5 and 136 vs 5, respectively), and neutralizing antibody GMTs (1303 vs 11 and 900 vs 11, respectively). Humoral responses were 30-40% lower in participants ≥65 years or HIV-positive; however, seroconversion rates were high and comparable between the age cohorts, regardless of HIV serostatus. Conclusions: NVX-CoV2373 elicited robust humoral immune responses against ancestral SARS-CoV-2 virus 2 weeks following the second vaccination in adult PREVENT-19 participants, consistent with previously reported high vaccine efficacy.

Safety, efficacy, and immunogenicity of the NVX-CoV2373 vaccine.

INTRODUCTION: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in significant morbidity and mortality worldwide. As SARS-CoV-2 moves into endemic status, vaccination remains a key element in protecting the health of individuals, societies, and economies worldwide. AREAS COVERED: NVX-CoV2373 (Novavax, Gaithersburg, MD) is a recombinant protein vaccine composed of SARS-CoV-2 spike trimer nanoparticles formulated with saponin-based Matrix-M™ adjuvant (Novavax, Gaithersburg, MD). NVX-CoV2373 is authorized for emergency use in adults and adolescents aged ≥12 years in the United States and numerous other countries. EXPERT OPINION: In clinical trials, NVX-CoV2373 showed tolerable reactogenicity and favorable safety profiles characterized by mostly mild-to-moderate adverse events of short duration and by low rates of severe and serious adverse events comparable to those seen with placebo. The two-dose primary vaccination series resulted in robust increases in anti-spike protein immunoglobulin G, neutralizing antibody titers, and cellular immune responses. NVX-CoV2373 vaccination was associated with complete protection against severe disease and a high (90%) rate of protection against symptomatic disease in adults, including symptomatic disease caused by SARS-CoV-2 variants. Additionally, the NVX-CoV2373 adjuvanted recombinant protein platform offers a means to address issues of COVID-19 vaccination hesitancy and global vaccine equity.

Establishing Novel Antiretroviral Imaging for Hair to Elucidate Nonadherence: Protocol for a Single-Arm Cross-sectional Study.

BACKGROUND: Adherence to antiretroviral (ARV) therapy is critical for achieving HIV RNA suppression in people living with HIV and for preventing HIV infection in uninfected individuals using preexposure prophylaxis. However, a high level of adherence can be challenging to achieve for people living with HIV on lifelong ARVs and for HIV-negative individuals using daily preexposure prophylaxis who are not at daily risk for HIV infection. Current biological measures of adherence are invasive and use bioanalytical methods that do not allow for real-time feedback during a clinic visit. This study was designed to test the feasibility and acceptability of using MedViewer, a novel, minimally invasive, hair-based assay that measures longitudinal ARV drug adherence in real time and provides an output for provider-patient discussion. OBJECTIVE: The primary objectives were to investigate the feasibility of delivering the MedViewer results as planned, the acceptability of participation in a discussion of the MedViewer results, and the appropriateness of using MedViewer for adherence counseling. The secondary objectives were to investigate additional dimensions of feasibility, acceptability, and appropriateness of using the MedViewer test during a routine clinic visit for people with HIV. METHODS: The proposed study was a single-arm cross-sectional study among patients receiving HIV care and providers of HIV care in a southeastern infectious disease clinic. The study originally planned to implement the MedViewer test with 50 eligible patients who were living with HIV across 2 viral load strata (undetectable or detectable plasma HIV RNA over the previous 2 years), administer brief visit-specific questionnaires to all patient and provider participants, and conduct qualitative in-depth interviews and quantitative end-line questionnaires with a subsample of patient participants (n=30) and all provider participants. RESULTS: The Establishing Novel Antiretroviral Imaging for Hair to Elucidate Nonadherence study was funded by the National Institute of Allergy and Infectious Diseases and approved by the local institutional review board on November 4, 2019. Provider participant enrollment began on January 17, 2020, and patient participant enrollment began on January 22, 2020. Participant enrollment was halted on March 16, 2020, because of the COVID-19 pandemic (16 providers and 10 patients on study). Study activities resumed on February 2, 2021, with COVID-19 modifications approved by the local institutional review board. Participant enrollment closed on October 8, 2021, and data collection closed on November 15, 2021. In total, 36 unique patient participants, representing 37 samples, and 20 provider participants were enrolled. Data analysis and manuscript writing will take place throughout 2023. CONCLUSIONS: We anticipate that the data collected through this study will provide important insights regarding the feasibility, acceptability, and appropriateness of incorporating new real-time longitudinal, minimally invasive adherence tests into routine clinical care and identify potential barriers to medication adherence among patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT04232540; https://clinicaltrials.gov/ct2/show/NCT04232540. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/41188.