Seasonal human coronavirus humoral responses in AZD1222 (ChaAdOx1 nCoV-19) COVID-19 vaccinated adults reveal limited cross-immunity.

Background: Immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is now widespread; however, the degree of cross-immunity between SARS-CoV-2 and endemic, seasonal human coronaviruses (HCoVs) remains unclear. Methods: SARS-CoV-2 and HCoV cross-immunity was evaluated in adult participants enrolled in a US sub-study in the phase III, randomized controlled trial (NCT04516746) of AZD1222 (ChAdOx1 nCoV-19) primary-series vaccination for one-year. Anti-HCoV spike-binding antibodies against HCoV-229E, HCoV-HKU1, HCoV-OC43, and HCoV-NL63 were evaluated in participants following study dosing and, in the AZD1222 group, after a non-study third-dose booster. Timing of SARS-CoV-2 seroconversion (assessed via anti-nucleocapsid antibody levels) and incidence of COVID-19 were evaluated in those who received AZD1222 primary-series by baseline anti-HCoV titers. Results: We evaluated 2,020/21,634 participants in the AZD1222 group and 1,007/10,816 in the placebo group. At the one-year data cutoff (March 11, 2022) mean duration of follow up was 230.9 (SD: 106.36, range: 1-325) and 94.3 (74.12, 1-321) days for participants in the AZD1222 (n = 1,940) and placebo (n = 962) groups, respectively. We observed little elevation in anti-HCoV humoral titers post study-dosing or post-boosting, nor evidence of waning over time. The occurrence and timing of SARS-CoV-2 seroconversion and incidence of COVID-19 were not largely impacted by baseline anti-HCoV titers. Conclusion: We found limited evidence for cross-immunity between SARS-CoV-2 and HCoVs following AZD1222 primary series and booster vaccination. Susceptibility to future emergence of novel coronaviruses will likely persist despite a high prevalence of SARS-CoV-2 immunity in global populations.

Initial micafungin treatment does not improve outcomes compared to fluconazole treatment in immunocompromised and critically ill patients with candidaemia.

BACKGROUND: Candidaemia is associated with poor outcomes including high mortality rates. Controversy remains regarding whether fluconazole or an echinocandin is the optimal choice for initial candidaemia treatment, particularly among high-risk patients such as the immunocompromised or critically ill. OBJECTIVES: To understand optimal initial treatment of candidaemia. METHODS: We conducted a retrospective study of immunocompromised or ICU adult patients with candidaemia from 2010 to 2014. Patients who received ≥3 consecutive days of initial treatment with fluconazole or micafungin were included. The primary outcome was complete response at day 14, defined as clinical improvement and blood culture sterilization. Secondary outcomes included microbiological and clinical success, survival and recurrent candidaemia. RESULTS: A total of 197 patients were included; 76 received fluconazole and 121 received micafungin. There was no difference in complete response between the fluconazole and micafungin groups (ICU: 38% versus 40%, P = 0.87; immunocompromised: 57% versus 59%, P = 0.80). Secondary outcomes including survival were also similar. In multivariable analysis, among ICU patients, Pitt bacteraemia score < 4 (P = 0.002) and time to antifungal (P = 0.037) were associated with meeting the primary outcome; white blood cell count > 11 cells × 103/µL on day 0 (P < 0.001) and Candida isolated from a non-blood site (P = 0.025) were associated with not meeting the primary outcome. Among immunocompromised patients, white blood cells > 11 × 103/µL (P = 0.003) and Candida isolated from a non-blood site (P = 0.026) were associated with not meeting the primary outcome. CONCLUSIONS: These data suggest that among ICU or immunocompromised patients, severity of illness rather than initial antifungal choice drove clinical outcomes.

Lessons learnt from daily oral PrEP delivery to inform national planning for PrEP ring introduction for women in low-income and middle-income countries: a qualitative inquiry of international stakeholders.

INTRODUCTION: Some African countries plan to introduce and scale-up new long-acting pre-exposure prophylaxis methods (LA-PrEP), like the monthly dapivirine vaginal ring (PrEP ring) and injectable cabotegravir. National costed implementation plans, roadmaps for successful product implementation, are often overlooked. International stakeholders engaged in oral PrEP planning, introduction and scale-up are an information resource of lessons learned to advise LA-PrEP planning. We consulted such international stakeholders and synthesised oral PrEP lessons to inform the development of a costed rollout plan template for LA-PrEP. METHODS: From selected global health organisations (five international nongovernmental, four donor, four university/research and two multilateral), we interviewed 27 representatives based in America, Europe, Asia and Africa about strategic content and approaches for LA-PrEP policy, programming and implementation. We conducted a thematic analysis of the interview data for implementation considerations. RESULTS: From the consultations, we identified six implementation themes for LA-PrEP introduction and scale-up: (1) ethically increasing choice and avoiding coercion; (2) de-stigmatising PrEP by focusing on preference rather than risk-based eligibility; (3) integrating LA-PrEP into services that are more woman-oriented, couple-oriented and family-oriented, and providing private spaces for LA-PrEP delivery; (4) de-medicalising delivery of relatively safe products (eg, PrEP ring); (5) constructing multilevel, nuanced communication strategies to address measured and perceived product efficacy and effectiveness; and (6) devising product-agnostic, modular approaches to service delivery. Despite the widespread emphasis on integration, few stakeholders offered empirical examples of successful integration approaches and frameworks. CONCLUSIONS: Lessons learnt from stakeholder participants suggest standardised and modular processes can improve efficiencies in LA-PrEP planning and implementation. Tiered communication strategies addressing product efficacy and effectiveness will improve clients' and providers' efficacy in making informed decisions. Integration is important for LA-PrEP delivery, but data on empirical integration approaches and frameworks is minimal: further research in this discipline is needed.

Evaluating Dual Process Decision-Making Along the PrEP Consumer Journey: New Insights for Supporting PrEP Use.

With the rise of new and emerging Pre-Exposure Prophylaxis (PrEP) modalities, greater attention is needed to better understand how people who could benefit from PrEP make decisions to initiate, stop, pause, or switch PrEP regimens. In this study we borrow from the field of consumer research to create a consumer-derived PrEP Consumer Journey Model that describes key decision-making touchpoints a PrEP consumer moves through within and outside of a clinical context. Using in-depth interviews (n = 29) with gay and bisexual men who have sex with men, we evaluate which system 1 (emotional) and system 2 (cognitive) attributes are used for decision-making at different touchpoints along the PrEP Consumer Journey. Our results suggest system 1 attributes, such as feeling protected, reducing anxiety, enhancing pleasure, social norms, and taking ownership over health were more salient when consumers moved from pre-contemplation to information gathering, as well as evaluating post-uptake experience. System 2 attributes, including cost, side effects, dosing schedule, and sexual frequency, were present throughout the PrEP Consumer Journey, but particularly influential in the information gathering stage and when pausing, switching, or opting out of PrEP. We contend the PrEP Consumer Journey, and our findings related to decision-making, can help orient medical providers to anticipated patient concerns around PrEP use and ultimately provide more supportive and engaging PrEP counseling and services.

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.

Impact of LS Mutation on Pharmacokinetics of Preventive HIV Broadly Neutralizing Monoclonal Antibodies: A Cross-Protocol Analysis of 16 Clinical Trials in People without HIV.

Monoclonal antibodies are commonly engineered with an introduction of Met428Leu and Asn434Ser, known as the LS mutation, in the fragment crystallizable region to improve pharmacokinetic profiles. The LS mutation delays antibody clearance by enhancing binding affinity to the neonatal fragment crystallizable receptor found on endothelial cells. To characterize the LS mutation for monoclonal antibodies targeting HIV, we compared pharmacokinetic parameters between parental versus LS variants for five pairs of anti-HIV immunoglobin G1 monoclonal antibodies (VRC01/LS/VRC07-523LS, 3BNC117/LS, PGDM1400/LS PGT121/LS, 10-1074/LS), analyzing data from 16 clinical trials of 583 participants without HIV. We described serum concentrations of these monoclonal antibodies following intravenous or subcutaneous administration by an open two-compartment disposition, with first-order elimination from the central compartment using non-linear mixed effects pharmacokinetic models. We compared estimated pharmacokinetic parameters using the targeted maximum likelihood estimation method, accounting for participant differences. We observed lower clearance rate, central volume, and peripheral volume of distribution for all LS variants compared to parental monoclonal antibodies. LS monoclonal antibodies showed several improvements in pharmacokinetic parameters, including increases in the elimination half-life by 2.7- to 4.1-fold, the dose-normalized area-under-the-curve by 4.1- to 9.5-fold, and the predicted concentration at 4 weeks post-administration by 3.4- to 7.6-fold. Results suggest a favorable pharmacokinetic profile of LS variants regardless of HIV epitope specificity. Insights support lower dosages and/or less frequent dosing of LS variants to achieve similar levels of antibody exposure in future clinical applications.

Estimating vaccine efficacy during open-label follow-up of COVID-19 vaccine trials based on population-level surveillance data.

While rapid development and roll out of COVID-19 vaccines is necessary in a pandemic, the process limits the ability of clinical trials to assess longer-term vaccine efficacy. We leveraged COVID-19 surveillance data in the U.S. to evaluate vaccine efficacy in U.S. Government-funded COVID-19 vaccine efficacy trials with a three-step estimation process. First, we used a compartmental epidemiological model informed by county-level surveillance data, a "population model", to estimate SARS-CoV-2 incidence among the unvaccinated. Second, a "cohort model" was used to adjust the population SARS-CoV-2 incidence to the vaccine trial cohort, taking into account individual participant characteristics and the difference between SARS-CoV-2 infection and COVID-19 disease. Third, we fit a regression model estimating the offset between the cohort-model-based COVID-19 incidence in the unvaccinated with the placebo-group COVID-19 incidence in the trial during blinded follow-up. Counterfactual placebo COVID-19 incidence was estimated during open-label follow-up by adjusting the cohort-model-based incidence rate by the estimated offset. Vaccine efficacy during open-label follow-up was estimated by contrasting the vaccine group COVID-19 incidence with the counterfactual placebo COVID-19 incidence. We documented good performance of the methodology in a simulation study. We also applied the methodology to estimate vaccine efficacy for the two-dose AZD1222 COVID-19 vaccine using data from the phase 3 U.S. trial (ClinicalTrials.gov # NCT04516746). We estimated AZD1222 vaccine efficacy of 59.1% (95% uncertainty interval (UI): 40.4%-74.3%) in April, 2021 (mean 106 days post-second dose), which reduced to 35.7% (95% UI: 15.0%-51.7%) in July, 2021 (mean 198 days post-second-dose). We developed and evaluated a methodology for estimating longer-term vaccine efficacy. This methodology could be applied to estimating counterfactual placebo incidence for future placebo-controlled vaccine efficacy trials of emerging pathogens with early termination of blinded follow-up, to active-controlled or uncontrolled COVID-19 vaccine efficacy trials, and to other clinical endpoints influenced by vaccination.

COVID-19 vaccine efficacy in participants with weakened immune systems from four randomized-controlled trials.

BACKGROUND: Although the 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, 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 (NTIS) individuals starting at 14 days after completion of the primary series through the blinded phase for each of the four trials. An analysis of participants living with well-controlled HIV was conducted using the same methods. RESULTS: 3,852/30,351 (12.7%) Moderna participants, 3,088/29,868 (10.3%) Novavax participants, 3,549/32,380 (11.0%) AstraZeneca participants, and 5,047/43,788 (11.5%) Janssen participants were identified as having a TIS. Most TIS conditions (73.9%) were due to metabolism and nutritional disorders. Vaccination (versus 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 vs NTIS for either symptomatic or severe COVID-19 for each trial, nor was VE significantly different in the symptomatic endpoint for participants with HIV. CONCLUSIONS: For individuals with mildly immunocompromising conditions, there is no evidence of differences in VE against symptomatic or severe COVID-19 compared to those with non-tempered immune systems in the four COVID-19 vaccine randomized controlled efficacy trials.

A HIV-1 Gp41 Peptide-Liposome Vaccine Elicits Neutralizing Epitope-Targeted Antibody Responses in Healthy Individuals.

Background: HIV-1 vaccine development is a global health priority. Broadly neutralizing antibodies (bnAbs) which target the HIV-1 gp41 membrane-proximal external region (MPER) have some of the highest neutralization breadth. An MPER peptide-liposome vaccine has been found to expand bnAb precursors in monkeys. Methods: The HVTN133 phase 1 clinical trial (NCT03934541) studied the MPER-peptide liposome immunogen in 24 HIV-1 seronegative individuals. Participants were recruited between 15 July 2019 and 18 October 2019 and were randomized in a dose-escalation design to either 500 mcg or 2000 mcg of the MPER-peptide liposome or placebo. Four intramuscular injections were planned at months 0, 2, 6, and 12. Results: The trial was stopped prematurely due to an anaphylaxis reaction in one participant ultimately attributed to vaccine-associated polyethylene glycol. The immunogen induced robust immune responses, including MPER+ serum and blood CD4+ T-cell responses in 95% and 100% of vaccinees, respectively, and 35% (7/20) of vaccine recipients had blood IgG memory B cells with MPER-bnAb binding phenotype. Affinity purification of plasma MPER+ IgG demonstrated tier 2 HIV-1 neutralizing activity in two of five participants after 3 immunizations. Conclusions: MPER-peptide liposomes induced gp41 serum neutralizing epitope-targeted antibodies and memory B-cell responses in humans despite the early termination of the study. These results suggest that the MPER region is a promising target for a candidate HIV vaccine.

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.

Prevalence of SARS-CoV-2 Infection among Children and Adults in 15 US Communities, 2021

During January-August 2021, the Community Prevalence of SARS-CoV-2 Study used time/location sampling to recruit a cross-sectional, population-based cohort to estimate SARS-CoV-2 seroprevalence and nasal swab sample PCR positivity across 15 US communities. Survey-weighted estimates of SARS-CoV-2 infection and vaccine willingness among participants at each site were compared within demographic groups by using linear regression models with inverse variance weighting. Among 22,284 persons >2 months of age and older, median prevalence of infection (prior, active, or both) was 12.9% across sites and similar across age groups. Within each site, average prevalence of infection was 3 percentage points higher for Black than White persons and average vaccine willingness was 10 percentage points lower for Black than White persons and 7 percentage points lower for Black persons than for persons in other racial groups. The higher prevalence of SARS-CoV-2 infection among groups with lower vaccine willingness highlights the disparate effect of COVID-19 and its complications.

Examining Patient Preferences for Express, Telemedicine, and Standard Visits in a Sexual Health Clinic in New York City.

ABSTRACT: This study, completed at an sexually transmitted infection (STI) clinic in 2019 to 2020, evaluated patient preferences for telemedicine, express, and standard visits. Active PrEP users preferred telemedicine and express visits, patients with prior STIs preferred express visits, and cisgender women preferred standard visits. Configuring STI clinic visit types requires shared decision making and individualization.

High monoclonal neutralization titers reduced breakthrough HIV-1 viral loads in the Antibody Mediated Prevention trials.

The Antibody Mediated Prevention (AMP) trials (NCT02716675 and NCT02568215) demonstrated that passive administration of the broadly neutralizing monoclonal antibody VRC01 could prevent some HIV-1 acquisition events. Here, we use mathematical modeling in a post hoc analysis to demonstrate that VRC01 influenced viral loads in AMP participants who acquired HIV. Instantaneous inhibitory potential (IIP), which integrates VRC01 serum concentration and VRC01 sensitivity of acquired viruses in terms of both IC50 and IC80, follows a dose-response relationship with first positive viral load (p = 0.03), which is particularly strong above a threshold of IIP = 1.6 (r = -0.6, p = 2e-4). Mathematical modeling reveals that VRC01 activity predicted from in vitro IC80s and serum VRC01 concentrations overestimates in vivo neutralization by 600-fold (95% CI: 300-1200). The trained model projects that even if future therapeutic HIV trials of combination monoclonal antibodies do not always prevent acquisition, reductions in viremia and reservoir size could be expected.

Safety, tolerability, pharmacokinetics, and immunological activity of dual-combinations and triple-combinations of anti-HIV monoclonal antibodies PGT121, PGDM1400, 10-1074, and VRC07-523LS administered intravenously to HIV-uninfected adults: a phase 1 randomised trial.

BACKGROUND: Preclinical and clinical studies suggest that combinations of broadly neutralising antibodies (bnAbs) targeting different HIV envelope epitopes might be required for sufficient prevention of infection. We aimed to evaluate the dual and triple anti-HIV bnAb combinations of PGDM1400 (V2 Apex), PGT121 (V3 glycan), 10-1074 (V3 glycan), and VRC07-523LS (CD4 binding site). METHODS: In this phase 1 trial (HVTN 130/HPTN 089), adults without HIV were randomly assigned (1:1:1) to three dual-bnAb treatment groups simultaneously, or the triple-bnAb group, receiving 20 mg/kg of each antibody administered intravenously at four centres in the USA. Participants received a single dose of PGT121 + VRC07-523LS (treatment one; n=6), PGDM1400 + VRC07-523LS (treatment two; n=6), or 10-1074 + VRC07-523LS (treatment three; n=6), and two doses of PGDM1400 + PGT121 + VRC07-523LS (treatment four; n=9). Primary outcomes were safety, pharmacokinetics, and neutralising activity. Safety was determined by monitoring for 60 min after infusions and throughout the study by collecting laboratory assessments (ie, blood count, chemistry, urinalysis, and HIV), and solicited and unsolicited adverse events (via case report forms and participant diaries). Serum concentrations of each bnAb were measured by binding antibody assays on days 0, 3, 6, 14, 28, 56, 112, 168, 224, 280, and 336, and by serum neutralisation titres against Env-pseudotyped viruses on days 0, 3, 28, 56, and 112. Pharmacokinetic parameters were estimated by use of two-compartment population pharmacokinetic models; combination bnAb neutralisation titres were directly measured and assessed with different interaction models. This trial is registered with ClinicalTrials.gov, NCT03928821, and has been completed. FINDINGS: 27 participants were enrolled from July 31, to Dec 20, 2019. The median age was 26 years (range 19-50), 16 (58%) of 27 participants were assigned female sex at birth, and 24 (89%) participants were non-Hispanic White. Infusions were safe and well tolerated. There were no statistically significant differences in pharmacokinetic patterns between the dual and triple combinations of PGT121, PGDM1400, and VRC07-523LS. The median estimated elimination half-lives of PGT121, PGDM1400, 10-1074, and VRC07-523LS were 32·2, 25·4, 27·5, and 52·9 days, respectively. Neutralisation coverage against a panel of 12 viruses was greater in the triple-bnAb versus dual-bnAb groups: area under the magnitude-breadth curve at day 28 was 3·1, 2·9, 3·0, and 3·4 for treatments one to four, respectively. The Bliss-Hill multiplicative interaction model, which assumes complementary neutralisation with no antagonism or synergism among the bnAbs, best described combination bnAb titres in the dual-bnAb and triple-bnAb groups. INTERPRETATION: No pharmacokinetic interactions among the bnAbs and no loss of complementary neutralisation were observed in the dual and triple combinations. This study lays the foundation for designing future combination bnAb HIV prevention efficacy trials. FUNDING: US National Institute of Allergy and Infectious Diseases, US National Institute on Drug Abuse, US National Institute of Mental Health, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development.

The Index of Engagement in PrEP Care: Evaluation of Psychometric Properties and Predictive Potential.

BACKGROUND: The Index of Engagement in HIV Care is a psychometrically valid 10-item self-report measure with predictive power to classify individuals to higher and lower odds of disengaging from HIV care. Given high rates of disengagement from preexposure prophylaxis (PrEP) care, we adapted the HIV Index to PrEP. METHODS: We evaluated the psychometric properties of the PrEP-Index in a cross-sectional validation among PrEP-eligible persons seen in an HIV Prevention Program and conducted exploratory analysis to assess its potential utility as a prognostic tool. The PrEP Index contains 10 items with answers ranging from (1) not at all to (5) extremely. Possible PrEP-Index scores ranged from 10 to 50, with higher sum scores representing higher levels of engagement. RESULTS: Study participants were cisgender men who have sex with men, and racially and ethnically diverse (non-Hispanic White = 39.2%). Factor analyses supported the 1-factor structure. Among 347 respondents, 118 individuals (34.0%) were available for predictive validity analysis. The PrEP Index score was positively associated with visit constancy at 6 months ( = 0.2261; 95% confidence interval: 0.0363 to 0.4051). Finally, a patient scoring 45 on the PrEP-Index will be classified as not returning within 6 months (sensitivity = 0.73, specificity = 0.65). CONCLUSIONS: The PrEP-Index is a psychometrically valid and reliable scale that demonstrates potential utility in identifying individuals at elevated risk of falling out of PrEP care by 6 months, the time point by which the majority of PrEP discontinuations occur. The PrEP-Index could be a useful clinical prognostic tool to allow for efficient resource targeting by clinics to improve engagement in PrEP care.

Predictors of missed HIV screening opportunities among newly diagnosed individuals at an urban medical center in New York City, 2018-2022.

OBJECTIVE: To identify demographic and clinical factors predictive of having a missed opportunity (MO) for HIV screening. DESIGN: Retrospective cohort study. METHODS: Electronic medical records were queried for individuals newly diagnosed with HIV in different sites within a large urban academic medical center in New York City between 2018 and 2022. The primary outcome was having one or more MO for HIV screening within the institution, defined as any encounter at which screening was not performed in the 365 days preceding the HIV diagnosis. RESULTS: Over one third of new diagnoses had at least one MO in the preceding year. Older individuals, cisgender women and those assigned female sex at birth, and heterosexual individuals were more likely to have at least one MO. An initial CD4 < 200 cells/ul was more likely among men who have sex with women specifically. Most MOs occurred in the emergency department and outpatient settings, with minimal HIV prevention discussions documented during each MO. CONCLUSIONS: These findings suggest that populations perceived to be at lower risk for HIV are more likely to have MOs and possibly late diagnoses, and that universal HIV screening must be implemented into the workflows of emergency department and outpatient settings to facilitate early diagnosis and reduce the incidence of HIV.

Safety and immunogenicity of a recombinant oligomeric gp145 subtype C Env protein (gp145 C.6980) HIV vaccine candidate in healthy, HIV-1-uninfected adult participants in the US.

BACKGROUND: An approach to a preventive HIV vaccine is induction of effective broadly neutralizing antibodies (bnAbs) and effector binding antibodies (bAbs). Preclinical studies suggest that trimeric envelope (Env) proteins may elicit nAbs, which led to the development of the recombinant gp145 subtype C Env protein (gp145 C.6980) immunogen. HVTN 122 was a Phase 1 trial that evaluated the safety, tolerability, and immunogenicity of gp145 C.6980 in adults. METHODS: Healthy, HIV-1 seronegative adults received three intramuscular injections of gp145 C.6980 with aluminum hydroxide (alum) at months 0, 2, and 6 at either 300 mcg (high dose, n = 25) or 100 mcg (low dose, n = 15), or placebo/saline (placebo, n = 5). Participants were followed for 12 months. RESULTS: Forty-five participants were enrolled. High and low doses of the study protein were well-tolerated, with mild or moderate reactogenicity commonly reported. Only one adverse event (mild injection site pruritis) in one participant (low dose) was considered product-related; there were no dose-limiting toxicities. High and low dose recipients demonstrated robust bAb responses to vaccine-matched consensus gp140 Env and subtype-matched gp120 Env proteins two weeks post-last vaccination (response rates >90 %), while no responses were detected to a heterologous subtype-matched V1V2 antigen. No significant differences were seen between high and low dose groups. Participants in both experimental arms demonstrated nAb response rates of 76.5 % to a tier 1 virus (MW9635.26), but no responses to tier 2 isolates. Env-specific CD4 + T-cell responses were elicited in 36.4 % of vaccine recipients, without significant differences between groups; no participants demonstrated CD8 + T-cell responses. CONCLUSIONS: Three doses of novel subtype C gp145 Env protein with alum were safe and well-tolerated. Participants demonstrated bAb, Env-specific CD4 + T-cell, and tier 1 nAb responses, but the regimen failed to induce tier 2 or heterologous nAb responses. CLINICAL TRIALS REGISTRATION: NCT03382418.

Implementation and resource needs for long-acting PrEP in low- and middle-income countries: a scoping review.

INTRODUCTION: Several low- and middle-income countries (LMICs) are preparing to introduce long-acting pre-exposure prophylaxis (LAP). Amid multiple pre-exposure prophylaxis (PrEP) options and constrained funding, decision-makers could benefit from systematic implementation planning and aligned costs. We reviewed national costed implementation plans (CIPs) to describe relevant implementation inputs and activities (domains) for informing the costed rollout of LAP. We assessed how primary costing evidence aligned with those domains. METHODS: We conducted a rapid review of CIPs for oral PrEP and family planning (FP) to develop a consensus of implementation domains, and a scoping review across nine electronic databases for publications on PrEP costing in LMICs between January 2010 and June 2022. We extracted cost data and assessed alignment with the implementation domains and the Global Health Costing Consortium principles. RESULTS: We identified 15 implementation domains from four national PrEP plans and FP-CIP template; only six were in all sources. We included 66 full-text manuscripts, 10 reported LAP, 13 (20%) were primary cost studies-representing seven countries, and none of the 13 included LAP. The 13 primary cost studies included PrEP commodities (n = 12), human resources (n = 11), indirect costs (n = 11), other commodities (n = 10), demand creation (n = 9) and counselling (n = 9). Few studies costed integration into non-HIV services (n = 5), above site costs (n = 3), supply chains and logistics (n = 3) or policy and planning (n = 2), and none included the costs of target setting, health information system adaptations or implementation research. Cost units and outcomes were variable (e.g. average per person-year). DISCUSSION: LAP planning will require updating HIV prevention policies, technical assistance for logistical and clinical support, expanding beyond HIV platforms, setting PrEP achievement targets overall and disaggregated by method, extensive supply chain and logistics planning and support, as well as updating health information systems to monitor multiple PrEP methods with different visit schedules. The 15 implementation domains were variable in reviewed studies. PrEP primary cost and budget data are necessary for new product introduction and should match implementation plans with financing. CONCLUSIONS: As PrEP services expand to include LAP, decision-makers need a framework, tools and a process to support countries in planning the systematic rollout and costing for LAP.

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.