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Antibody levels predict vaccine efficacy Symptomatic COVID-19 infection can be prevented by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines. A “correlate of protection” is a molecular biomarker to measure how much immunity is needed to fight infection and is key for successful global immunization programs. Gilbert et al . determined that antibodies are the correlate of protection in vaccinated individuals enrolled in the Moderna COVE phase 3 clinical trial (see the Perspective by Openshaw). By measuring binding and neutralizing antibodies against the viral spike protein, the authors found that the levels of both antibodies correlated with the degree of vaccine efficacy. The higher the antibody level, the greater the protection afforded by the messenger RNA (mRNA) vaccine. Antibody levels that predict mRNA vaccine efficacy can therefore be used to guide vaccine regimen modifications and support regulatory approvals for a broader spectrum of the population. —PNK

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. CLINICALTRIAL ClinicalTrials.gov NCT04232540; https://clinicaltrials.gov/ct2/show/NCT04232540 INTERNATIONAL REGISTERED REPORT RR1-10.2196/41188

In the randomized, placebo-controlled PREVENT-19 phase 3 trial conducted in the U.S. and Mexico of the NVX-CoV2373 adjuvanted, recombinant spike protein nanoparticle vaccine, anti-spike binding IgG concentration (spike IgG) and pseudovirus 50% neutralizing antibody titer (nAb ID50) measured two weeks after two doses were assessed as correlates of risk and as correlates of protection against PCR-confirmed symptomatic SARS-CoV-2 infection (COVID- 19). These immune correlates analyses were conducted in the U.S. cohort of baseline SARS- CoV-2 negative per-protocol participants using a case-cohort design that measured the antibody markers from all 12 vaccine recipient breakthrough COVID-19 cases starting 7 days post antibody measurement and from 639 vaccine recipient non-cases (Mexico was excluded due to zero breakthrough cases with the efficacy data cut-off date April 19, 2021). In vaccine recipients, the baseline risk factor-adjusted hazard ratio of COVID-19 was 0.36 (95% CI: 0.20, 0.63), prdpercentile, 6934 is the 97.5thpercentile), vaccine efficacy to reduce the probability of acquiring COVID-19 at 59 days post marker measurement was 65.5% (95% CI: 23.0%, 90.8%), 87.7% (77.7%, 94.4%), and 94.8% (88.0%, 97.9%), respectively. At nAb ID50 titers of 50, 100, 1000, and 7230 IU50/ml (50 is the 5thpercentile, 7230 the 97.5thpercentile), these estimates were 75.7% (49.8%, 93.2%), 81.7% (66.3%, 93.2%), 92.8% (85.1%, 97.4%) and 96.8% (88.3%, 99.3%). The same two antibody markers were assessed as immune correlates via the same study design and statistical analysis in the mRNA-1273 phase 3 COVE trial (except in COVE the markers were measured four weeks post dose two). Spike IgG levels were slightly lower and nAb ID50 titers slightly higher after NVX-CoV2373 than after mRNA-1273 vaccination. The strength of the nAb ID50 correlate was similar between the trials, whereas the spike IgG antibodies appeared to correlate more strongly with NVX-CoV2373 in PREVENT-19, as quantified by the hazard ratio and the degree of change in vaccine efficacy across antibody levels. However, the relatively few breakthrough cases in PREVENT-19 limited the ability to infer a stronger correlate. The conclusion is that both markers were consistent correlates of protection for the two vaccines, supporting potential cross-vaccine platform applications of these markers for guiding decisions about vaccine approval and use.

The Antibody Mediated Prevention trials showed that the broadly neutralizing antibody (bnAb) VRC01 prevented acquisition of human immunodeficiency virus-1 (HIV-1) sensitive to VRC01. Using AMP trial data, here we show that the predicted serum neutralization 80% inhibitory dilution titer (PT80) biomarker—which quantifies the neutralization potency of antibodies in an individual’s serum against an HIV-1 isolate—can be used to predict HIV-1 prevention efficacy. Similar to the results of nonhuman primate studies, an average PT80 of 200 (meaning a bnAb concentration 200-fold higher than that required to reduce infection by 80% in vitro) against a population of probable exposing viruses was estimated to be required for 90% prevention efficacy against acquisition of these viruses. Based on this result, we suggest that the goal of sustained PT80 >200 against 90% of circulating viruses can be achieved by promising bnAb regimens engineered for long half-lives. We propose the PT80 biomarker as a surrogate endpoint for evaluation of bnAb regimens, and as a tool for benchmarking candidate bnAb-inducing vaccines.

HIV infection depletes CD4 T cells and dysregulates formation of long-lived memory CD4 T cells. Studies show that antiretroviral therapy (ART) in people with HIV (PWH) more effectively restores CD4 T cell memory phenotypes when initiated early (< Fiebig V). We used a 31 marker mass cytometry panel to assess CD4 T cell phenotype in PWH treated in acute infection (AHI) (median 2.3 years post ART initiation) and chronic infection (CHI) (median 5.8 years post ART initiation) compared to healthy donors (HD) (n=10 per group). Markers of activation (HLA-DR, CD25), exhaustion (PD-1), survival (Bcl-2) and memory (CD127) were examined. CD4 T cell memory phenotypes of AHI clustered closely with HD whereas CHI had fewer central memory CD4 T cells. We also examined IL-7 signaling in CD4 T cells, measuring STAT5 phosphorylation (pSTAT5) in response to IL-7. CHI exhibited significantly lower pSTAT5 than HD in contrast to AHI who exhibited restored IL-7 signaling. This suggests ongoing and underappreciated functional defects in CD4 T cells in CHI. To examine this further, we are completing detailed analysis of CHI before and after ART initiation (pre-ART, day 2, 7, 10, 14, 28, month 5, 9 and 18). Data will be compared to our recent work showing that CD4 T cell memory subsets, activation and exhaustion markers are highly stable in durably suppressed CHI on ART over 19–27 months. New work is examining CD4 T cell function in immunological non-responders (INR) who fail to restore CD4 counts following ART. Altogether these studies will inform how HIV impacts formation of both CD4 memory and the HIV reservoir (which is largely harbored in long lived memory CD4 T cells) following ART initiation, potentially identifying novel therapeutic targets to accelerate HIV cure in CHI. This work was made possible by the National Institute of Allergy and Infectious Diseases U01 AI131310, Collaboratory of AIDS Researchers for Eradication (UM1 AI164567) and UNC WIHS (U01 AI103390).

Background We estimated the effect of initiating virologically suppressive antiretroviral therapy (ART) during acute HIV infection versus chronic HIV infection (AHI vs. CHI) on CD4/CD8 ratio normalization. Setting A prospective clinical cohort study. Methods We included patients initiating ART with AHI and CHI between 2000 and 2015 and compared time from ART initiation to the first normal CD4/CD8 ratio (defined as CD4/CD8 ≥1) using Kaplan-Meier curves and multivariable Cox proportional hazards models. Patient time was censored at virologic failure, lost to follow-up, or death. We also characterized CD4, CD8, and CD4/CD8 trajectories over the first 3 years of ART. Results The 1198 patients were 27% female and 60% African American, with a median age of 37 years (interquartile range 28-47) at ART initiation. The 83 AHI patients were more likely male, younger, and of white race, than CHI patients. After 2 years of suppressive ART, 70% of AHI patients achieved a normal CD4/CD8 ratio, compared to 6%-38% of CHI patients, with greater likelihood of normalization at higher baseline CD4 counts. Time to normalization was shortest among AHI patients, followed by CHI patients with higher baseline CD4. The adjusted hazard ratio for time to normalization for AHI patients compared to CHI patients with baseline CD4 >350 was 4.33 (95% CI: 3.16 to 5.93). Higher baseline CD4/CD8 ratio was also associated with time to normalization (adjusted hazard ratio 1.54; 1.46, 1.63, per 0.1 increase in ratio). Conclusions Initiating ART during AHI at higher baseline CD4 cell counts and CD4/CD8 ratios was associated with shorter time to CD4/CD8 ratio normalization.

Objectives: Tenofovir alafenamide, a prodrug of tenofovir, produces higher PBMC concentrations of tenofovir diphosphate (tenofovir-dp) than tenofovir disoproxil fumarate. To understand tenofovir alafenamide’s mucosal tissue distribution and its implications for pre-exposure prophylaxis, we characterized tenofovir-dp in female genital tract (FGT) and lower gastrointestinal (GI) tissues. Methods: Healthy seronegative women were given 5, 10 or 25 mg of tenofovir alafenamide (n = 8/group). Each participant provided plasma, PBMC and cervical, vaginal and rectal tissue samples over 14 days. Plasma, cell lysate and tissue homogenate concentrations were analysed by LC-MS/MS. Dose proportionality was declared in plasma and PBMCs if the natural log AUC versus natural log dose regression line 90% CI was within 0.57–1.43. In vitro tenofovir-dp formation was assessed in PBMCs and ectocervical (Ect1/E6E7) and vaginal (VK2/E6E7) cells incubated in 0.5 and 10 μM tenofovir alafenamide or tenofovir. clinicaltrials.gov: {"type":"clinical-trial","attrs":{"text":"NCT02357602","term_id":"NCT02357602"}}NCT02357602. Results: Following single doses of 5, 10 and 25 mg, median (IQR) tenofovir plasma AUC0–14 days was 52.8 (49.5–59.6), 78.1 (68.2–86.9) and 169.7 (131.2–211.4) ng·h/mL and tenofovir-dp PBMC AUC0–14 days was 2268 (1519–4090), 4584 (3113–5734) and 9306 (6891–10785) fmol·h/106 cells, respectively. Tenofovir was quantifiable in 52% and 92% of FGT and GI tissues, whereas tenofovir-dp was quantifiable in only 5% and 19% of FGT and GI tissues, respectively. Plasma tenofovir and PBMC tenofovir-dp were dose proportional (90% CI = 0.87–1.15 and 0.62–1.02, respectively). In vitro tenofovir-dp was 1.7–17-fold higher in epithelial cells than PBMCs. Conclusions: After tenofovir alafenamide dosing in vivo, tenofovir-dp was unquantifiable in most tissues (91%) although cervical and vaginal epithelial cells efficiently formed tenofovir-dp from tenofovir alafenamide in vitro. These findings warrant further investigation of tenofovir alafenamide’s pharmacology.

Only 80% of people living with HIV (PLWH) in the United States are linked to care, 40% are engaged in care, and 30% have achieved viral load suppression. We addressed linkage to care with a pilot program of a statewide referral call center to connect PLWH and their non-HIV specialty providers to HIV care. Callers received tailored referrals from nurses trained to work in an existing call center, using an electronic assessment tool and a comprehensive HIV provider list. Of 122 calls, 85% were from PLWH and 15% from providers calling about a patient. Overall, 88 of 104 (84.6%) PLWH and 16 of 18 (88.9%) providers accepted care referral, including 13% of PLWH callers without prior HIV care. Results indicated that the call center was an acceptable strategy for HIV care referral; the use of an existing call center facilitated feasibility of the program and improved linkage to HIV care.

The Internet and mobile devices are increasingly used by men who have sex with men to find potential partners. Lack of partner information, besides e-mail addresses or user profiles, limits the ability to adequately perform partner notification by traditional means and test those at high risk. To streamline North Carolina Internet Partner Notification (IPN) services, University of North Carolina at Chapel Hill collaborated with the North Carolina Division of Public Health beginning in July 2011 to formalize state IPN and text messaging for partner notification (txtPN) policies and centralize notification practices by designating a single IPN/txtPN field coordinator within the University of North Carolina at Chapel Hill.We compared the number of IPN and txtPN contacts initiated and their outcomes in July 1, 2011, to June 30, 2012, and compared with outcomes in January 1, 2010, to December 31, 2010, the year before the collaboration.Overall, 362 IPN contacts were initiated compared with 133 initiated in 2010. More than half (59.1%) were black; mean age was 28.8 years. Almost all were men who have sex with men (83.7%). Approximately two-thirds (n = 230; 63.5%) of contacts were successfully notified using centralized IPN. Seven new cases of HIV infection, 11 new cases of syphilis, and 19 known previous HIV-positive persons were identified. Text messaging for partner notification was used for 29 contacts who did not initially respond to traditional notification or IPN; 14 (48%) responded to txtPN in a median time of 57.5 minutes (interquartile range, 9-2708).Centralization of IPN services augmented partner detection of new HIV and syphilis diagnoses. Text messaging for partner notification represents a potentially effective method for augmenting traditional partner services. In addition, IPN and txtPN allow identification of HIV-infected persons in need of linkage to care.

Inability to recognize incident infection has traditionally limited both scientific and public health approaches to HIV disease. Recently, some laboratories have begun adding HIV nucleic acid amplification testing to HIV diagnostic testing algorithms so that acute (antibody-negative) HIV infections can be routinely detected within the first 1–3 weeks of exposure. In this review article, we will highlight critical opportunities for HIV treatment and prevention that are presented by these diagnostic strategies.

Antiretroviral therapy (ART) has prolonged and improved the lives of persons infected with HIV. Theoretically, it can also be used to prevent the transmission of HIV. The pharmacology of ART in the male and female genital tract can be expected to affect the success of the intervention, and ART agents differ considerably in their ability to concentrate in genital tract secretions. Emergency ART is considered to be the standard of care after occupational exposures to fluids or tissues infected with HIV. More recently, ART for prophylaxis after nonoccupational HIV exposures has been widely used and most countries have developed specific guidelines for its implementation. However, developing clinical trials to prove the efficacy of ART postexposure prophylaxis has not been possible. Experiments with rhesus macaques suggest that therapy must be offered as soon as possible after exposure (within 72 hours) and must be continued for 28 days. Additional nonhuman primate experiments have demonstrated protection from HIV infection with ART preexposure prophylaxis, and several clinical trials are under way to evaluate the safety and efficacy of this approach. The degree to which ART offered to infected persons reduces infectiousness is of considerable public health importance, but the question has not been sufficiently answered. This article provides a review of the data on the use of ART to prevent the sexual transmission of HIV and identify challenges to improving and clarifying this approach.

The highly infectious phase of acute human immunodeficiency virus (HIV) infection, defined as the interval between the appearance of HIV RNA in plasma and the detection of HIV-1-specific antibodies, contributes disproportionately to HIV transmission. The current HIV diagnostic algorithm consists of a repeatedly reactive immunoassay (IA), followed by a supplemental test, such as the Western blot (WB) or indirect immunofluorescence assay (IFA). Because current laboratory IAs detect HIV infection earlier than supplemental tests, reactive IA results and negative supplemental test results very early in the course of HIV infection have been erroneously interpreted as negative. To address this problem, CDC has been evaluating a new HIV diagnostic algorithm. This report describes two evaluations of this algorithm. An HIV screening program at a Phoenix, Arizona emergency department (ED) identified 37 undiagnosed HIV infections during July 2011-February 2013. Of these, 12 (32.4%) were acute HIV infections. An ongoing HIV testing study in three sites identified 99 cases with reactive IA and negative supplemental test results; 55 (55.6%) had acute HIV infection. CDC and many health departments recognize that confirmatory supplemental tests can give false-negative results early in the course of HIV infection. This problem can be resolved by testing for HIV RNA after a reactive IA result and negative supplemental test result.