ß-catenin regulates HIV latency and modulates HIV reactivation.

Latency is the main obstacle towards an HIV cure, with cure strategies aiming to either elicit or prevent viral reactivation. While these strategies have shown promise, they have only succeeded in modulating latency in a fraction of the latent HIV reservoir, suggesting that the mechanisms controlling HIV latency are not completely understood, and that comprehensive latency modulation will require targeting of multiple latency maintenance pathways. We show here that the transcriptional co-activator and the central mediator of canonical Wnt signaling, ß-catenin, inhibits HIV transcription in CD4+ T cells via TCF-4 LTR binding sites. Further, we show that inhibiting the ß-catenin pathway reactivates HIV in a primary TCM cell model of HIV latency, primary cells from cART-controlled HIV donors, and in CD4+ latent cell lines. ß-catenin inhibition or activation also enhanced or inhibited the activity of several classes of HIV latency reversing agents, respectively, in these models, with significant synergy of ß-catenin and each LRA class tested. In sum, we identify ß-catenin as a novel regulator of HIV latency in vitro and ex vivo, adding new therapeutic targets that may be combined for comprehensive HIV latency modulation in HIV cure efforts.

Cytomegalovirus Immunoglobulin G (IgG) Titer and Coronary Artery Disease in People With Human Immunodeficiency Virus (HIV).

BACKGROUND: Cytomegalovirus (CMV) infection is thought to result in increased immune activation in people with human immunodeficiency virus (HIV, PWH). Although some data have linked asymptomatic CMV infection to cardiovascular disease among PWH, it remains unknown whether CMV is associated with increased or high-risk coronary plaque. METHODS: The Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) enrolled PWH aged 40-75 years on stable antiretroviral therapy (ART) with low-to-moderate atherosclerotic cardiovascular disease (ASCVD) risk. Among a subset of US REPRIEVE participants, coronary plaque was assessed by coronary computed tomography angiography. Here, we assessed the relationship between CMV immunoglobulin G (IgG) titer and (1) levels of immune activation, (2) inflammatory biomarkers, and (3) coronary plaque phenotypes at study entry. RESULTS: Of 672 participants, mean age was 51 years, 83% were men, median ASCVD risk score was 4.5%, and 66% had current CD4+ T-cell count ≥500 cells/mm3. Higher CMV IgG quartile group was associated with older age and lower current and nadir CD4+ T-cell counts. CMV IgG titer was associated with specific inflammatory biomarkers (sCD163, MCP-1, interleukin [IL]-6, hsCRP) in univariate analysis, but not after controlling for HIV-specific factors. In contrast, CMV IgG titer was not associated with coronary artery disease indexes, including presence of plaque, coronary artery calcium (CAC) score >0, vulnerable plaque presence, or Leaman score >5. CONCLUSIONS: No meaningful association was seen between CMV IgG titer and coronary artery disease indexes among ART-treated PWH at study enrollment. Longitudinal assessments in REPRIEVE will determine the relationship of CMV IgG titer to plaque progression and cardiovascular events. CLINICAL TRIALS REGISTRATION: NCT02344290.

Development of a predictive model for identifying women vulnerable to HIV in Chicago.

INTRODUCTION: Researchers in the United States have created several models to predict persons most at risk for HIV. Many of these predictive models use data from all persons newly diagnosed with HIV, the majority of whom are men, and specifically men who have sex with men (MSM). Consequently, risk factors identified by these models are biased toward features that apply only to men or capture sexual behaviours of MSM. We sought to create a predictive model for women using cohort data from two major hospitals in Chicago with large opt-out HIV screening programs. METHODS: We matched 48 newly diagnosed women to 192 HIV-negative women based on number of previous encounters at University of Chicago or Rush University hospitals. We examined data for each woman for the two years prior to either their HIV diagnosis or their last encounter. We assessed risk factors including demographic characteristics and clinical diagnoses taken from patient electronic medical records (EMR) using odds ratios and 95% confidence intervals. We created a multivariable logistic regression model and measured predictive power with the area under the curve (AUC). In the multivariable model, age group, race, and ethnicity were included a priori due to increased risk for HIV among specific demographic groups. RESULTS: The following clinical diagnoses were significant at the bivariate level and were included in the model: pregnancy (OR 1.96 (1.00, 3.84)), hepatitis C (OR 5.73 (1.24, 26.51)), substance use (OR 3.12 (1.12, 8.65)) and sexually transmitted infections (STIs) chlamydia, gonorrhoea, or syphilis. We also a priori included demographic factors that are associated with HIV. Our final model had an AUC of 0.74 and included healthcare site, age group, race, ethnicity, pregnancy, hepatitis C, substance use, and STI diagnosis. CONCLUSIONS: Our predictive model showed acceptable discrimination between those who were and were not newly diagnosed with HIV. We identified risk factors such as recent pregnancy, recent hepatitis C diagnosis, and substance use in addition to the traditionally used recent STI diagnosis that can be incorporated by health systems to detect women who are vulnerable to HIV and would benefit from preexposure prophylaxis (PrEP).

Divergent Antibody Repertoires Found for Omicron versus Wuhan SARS-CoV-2 Strains Using Ig-MS.

SARS-CoV-2 Omicron (B.1.1.529) and its subvariants are currently the most common variants of concern worldwide, featuring numerous mutations in the spike protein and elsewhere that collectively make Omicron variants more transmissible and more resistant to antibody-mediated neutralization provided by vaccination, previous infections, and monoclonal antibody therapies than their predecessors. We recently reported the creation and characterization of Ig-MS, a new mass spectrometry-based serology platform that can define the repertoire of antibodies against an antigen of interest at single proteoform resolution. Here, we applied Ig-MS to investigate the evolution of plasma antibody repertoires against the receptor-binding domain (RBD) of SARS-CoV-2 in response to the booster shot and natural viral infection. We also assessed the capacity for antibody repertoires generated in response to vaccination and/or infection with the Omicron variant to bind to both Wuhan- and Omicron-RBDs. Our results show that (1) the booster increases antibody titers against both Wuhan- and Omicron- RBDs and elicits an Omicron-specific response and (2) vaccination and infection act synergistically in generating anti-RBD antibody repertoires able to bind both Wuhan- and Omicron-RBDs with variant-specific antibodies.

Next-Generation Serology by Mass Spectrometry: Readout of the SARS-CoV-2 Antibody Repertoire.

Methods of antibody detection are used to assess exposure or immunity to a pathogen. Here, we present Ig-MS, a novel serological readout that captures the immunoglobulin (Ig) repertoire at molecular resolution, including entire variable regions in Ig light and heavy chains. Ig-MS uses recent advances in protein mass spectrometry (MS) for multiparametric readout of antibodies, with new metrics like Ion Titer (IT) and Degree of Clonality (DoC) capturing the heterogeneity and relative abundance of individual clones without sequencing of B cells. We applied Ig-MS to plasma from subjects with severe and mild COVID-19 and immunized subjects after two vaccine doses, using the receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 as the bait for antibody capture. Importantly, we report a new data type for human serology, that could use other antigens of interest to gauge immune responses to vaccination, pathogens, or autoimmune disorders.

Utility of the Signal-to-Cutoff Ratio and Antigen Index from Fourth- and Fifth-Generation HIV-1/HIV-2 Antigen/Antibody Assays for the Diagnosis of Acute HIV Infection: Applicability for Real-Time Use for Immediate Initiation of Antiretroviral Therapy.

Identification of individuals with acute HIV infection (AHI) and rapid initiation of antiretroviral therapy (ART) are priorities for HIV elimination efforts. Fourth- and fifth-generation HIV-1/HIV-2 antigen (Ag)/antibody (Ab) combination assays can quickly identify patients with AHI, but false-positive results can occur. Confirmatory nucleic acid amplification testing (NAAT) may not be rapidly available. We reviewed the data for 127 patients with positive fourth-generation ARCHITECT and fifth-generation Bio-Plex immunoassay results who had negative or indeterminate confirmatory Ab testing results, which yielded 38 patients with confirmed AHI and 89 patients with false-positive results. The receiver operating characteristic (ROC) curves showed excellent discriminatory power, with an area under the curve (AUC) for the signal-to-cutoff (S/CO) ratio of 0.970 (95% confidence interval [CI], 0.935 to 1.00) and an AUC for the Ag index (AI) of 0.968 (95% CI, 0.904 to 1.00). A threshold of 3.78 for the S/CO ratio would maximize the sensitivity (96.3%) and specificity (93.4%). The threshold for AI was 2.83 (sensitivity of 100% and specificity of 96.4%). The S/CO ratio was significantly correlated with the viral load (Spearman correlation coefficient, 0.486 [P = 0.014]), but the AI was not. The viral loads were all high, with a median of >2.8 million copies/mL. Two false-positive results with AI and S/CO ratio values markedly higher than the medians were observed, indicating that biological false-positive results can occur. Review of the S/CO ratio or AI may be used to improve the accuracy of AHI diagnosis prior to confirmatory NAAT results being available.

Canonical Wnts Mediate CD8+ T Cell Noncytolytic Anti-HIV-1 Activity and Correlate with HIV-1 Clinical Status.

CD8+ T cells do not rely solely on cytotoxic functions for significant HIV control. Moreover, the noncytotoxic CD8+ T cell antiviral response is a primary mediator of natural HIV control such as that seen in HIV elite controllers and long-term nonprogressors that does not require combined antiretroviral therapy. In this study, we investigated the biological factors contributing to the noncytotoxic control of HIV replication mediated by primary human CD8+ T cells. We report that canonical Wnt signaling inhibits HIV transcription in an MHC-independent, noncytotoxic manner and that mediators of this pathway correlate with HIV controller clinical status. We show that CD8+ T cells express all 19 Wnts and CD8+ T cell-conditioned medium (CM) induced canonical Wnt signaling in infected recipient cells while simultaneously inhibiting HIV transcription. Antagonizing canonical Wnt activity in CD8+ T cell CM resulted in increased HIV transcription in infected cells. Further, Wnt2b expression was upregulated in HIV controllers versus viremic patients, and in vitro depletion of Wnt2b and/or Wnt9b from CD8+ CM reversed HIV inhibitory activity. Finally, plasma concentration of Dkk-1, an antagonist of canonical Wnt signaling, was higher in viremic patients with lower CD4 counts. This study demonstrates that canonical Wnt signaling inhibits HIV and significantly correlates with HIV controller status.

Dolutegravir plus lamivudine for initial treatment of HIV-1-infected participants with HIV-1 RNA <500 000 copies/mL: week 48 outcomes from ACTG 5353.

BACKGROUND: The AIDS Clinical Trials Group study A5353 demonstrated the efficacy and safety of dolutegravir and lamivudine for initial treatment of HIV-1 infection at week 24 in individuals with HIV-1 RNA 1000-500 000 copies/mL. Optimal ART for treatment-naive individuals must be durable. OBJECTIVES: The aim of this study was to estimate the efficacy and safety of dolutegravir plus lamivudine at week 48 and compare the efficacy in participants with baseline HIV-1 RNA ≤100 000 copies/mL versus >100 000 copies/mL. METHODS: Virological success was defined as HIV-1 RNA <50 copies/mL by FDA Snapshot criteria. Definition of virological failure included confirmed HIV-1 RNA >200 copies/mL at week 24 or later. The proportion of participants with virological success was estimated using two-sided exact Clopper-Pearson 95% CI. Comparison between screening HIV-1 RNA (≤100 000 versus >100 000 copies/mL) strata was carried out by Fisher's exact test. The study was registered with ClinicalTrials.gov, number NCT02582684. RESULTS: A total of 120 enrolled eligible participants were included in the analysis. At week 48, 102 of the 120 participants (85%; 95% CI 77%-91%) had virological success. Virological success was similar between screening HIV-1 RNA groups. Six (5%) participants had virological non-success and one additional participant experienced virological failure while on study but off study treatment. No new drug resistance mutations were observed. Six (5%) participants had study-related grade 3 or higher adverse events and none discontinued study treatment. CONCLUSIONS: These results add to the evidence that dolutegravir plus lamivudine is a safe and effective option for initial ART in individuals with HIV-1 RNA <500 000 copies/mL.

Evolution of an Electronic Health Record Based-Human Immunodeficiency Virus (HIV) Screening Program in an Urban Emergency Department for Diagnosing Acute and Chronic HIV Infection.

BACKGROUND: Since 2006, Centers for Disease Control and Prevention guidelines recommend routine opt-out human immunodeficiency virus (HIV) testing among sexually active 13- to 64-year-olds. Earlier diagnosis and treatment of HIV infection reduces morbidity and mortality and can limit transmission to others. OBJECTIVE: Our aim was to increase HIV testing, diagnosis, and linkage to care in the emergency department (ED). METHODS: Beginning May 4, 2015, we utilized our electronic health record (EHR) to enhance HIV testing in patients seen in the Rush University Medical Center emergency department in Chicago, IL, who were 13-64 years of age, did not have HIV listed on their problem list, and did not have an HIV antigen/antibody (Ag/Ab) test in the EHR within the past rolling 12-month period. Strategies included use of a "Best Practice Advisory" and later auto-order screening linked to a complete blood count order. RESULTS: Our baseline HIV test rate was 2.5% of the target population by age (average of 93 tests per month). From May 4, 2015 to January 31, 2019, 137,749 patients of 240,091 ED visits met our test criteria and 23,588 (17.1% of the target population) HIV Ag/Ab tests were performed, resulting in 164 positive tests. We identified 18 acute seroconverters, 51 new chronically infected persons, and 95 known infected, many of who had not disclosed their status. Our positive test rate was 0.70%, which dropped to 0.29% if only newly diagnosed individuals were counted. CONCLUSIONS: EHR enhancements in a large urban ED identifies both newly diagnosed acute and chronically HIV-infected persons. Identification of previously diagnosed patients offers an opportunity to relink them to care.

ACTG A5353: A Pilot Study of Dolutegravir Plus Lamivudine for Initial Treatment of Human Immunodeficiency Virus-1 (HIV-1)-infected Participants With HIV-1 RNA <500000 Copies/mL.

Background: Limited data exist on initial human immunodeficiency virus type 1 (HIV-1) treatment with dolutegravir plus lamivudine. Methods: A5353 is a phase 2, single-arm, pilot study of once-daily dolutegravir (50 mg) plus lamivudine (300 mg) in treatment-naive participants with HIV-1 RNA ≥1000 and <500000 copies/mL. Exclusion criteria included active hepatitis B or major protease, reverse transcriptase, or integrase resistance. The primary efficacy measure was the proportion with HIV-1 RNA <50 copies/mL (FDA [US Food and Drug Administration] Snapshot) at week 24. Virologic failure (VF) was confirmed HIV-1 RNA >400 copies/mL at week 16/20 or >200 copies/mL at or after week 24. Dolutegravir levels and drug resistance testing were performed at VF. Results: One hundred and twenty participants (87% male, median age 30 years, 37 (31%) HIV-1 RNA >100000 copies/mL) initiated study treatment. Median entry HIV-1 RNA and CD4 count were 4.61 log10 copies/mL and 387 cells/mm3. Virologic efficacy at week 24 was 108/120 (90%, confidence interval [83%, 95%]), with comparable results in the >100000 copies/mL and ≤100000 copies/mL strata, that is, 89% (75%, 97%) and 90% (82%, 96%), respectively. Three participants with VF, had undetected plasma dolutegravir at ≥1 time points; the M184V and R263R/K mutations developed in 1 participant. Two participants experienced grade 3 possible/probable treatment-related adverse events; none discontinued treatment due to adverse events. Conclusions: Dolutegravir plus lamivudine demonstrated efficacy in individuals with pretreatment HIV-1 RNA up to 500000 copies/mL in this pilot trial, but a participant developed resistance mutations. Clinical Trials Registration: NCT02582684.

Acute HIV Discovered During Routine HIV Screening With HIV Antigen-Antibody Combination Tests in 9 US Emergency Departments.

STUDY OBJECTIVE: Newer combination HIV antigen-antibody tests allow detection of HIV sooner after infection than previous antibody-only immunoassays because, in addition to HIV-1 and -2 antibodies, they detect the HIV-1 p24 antigen, which appears before antibodies develop. We determine the yield of screening with HIV antigen-antibody tests and clinical presentations for new diagnoses of acute and established HIV infection across US emergency departments (EDs). METHODS: This was a retrospective study of 9 EDs in 6 cities with HIV screening programs that integrated laboratory-based antigen-antibody tests between November 1, 2012, and December 31, 2015. Unique patients with newly diagnosed HIV infection were identified and classified as having either acute HIV infection or established HIV infection. Acute HIV infection was defined as a repeatedly reactive antigen-antibody test result, a negative HIV-1/HIV-2 antibody differentiation assay, or Western blot result, but detectable HIV ribonucleic acid (RNA); established HIV infection was defined as a repeatedly reactive antigen-antibody test result and a positive HIV-1/HIV-2 antibody differentiation assay or Western blot result. The primary outcomes were the number of new HIV diagnoses and proportion of patients with laboratory-defined acute HIV infection. Secondary outcomes compared reason for visit and the clinical presentation of acute HIV infection. RESULTS: In total, 214,524 patients were screened for HIV and 839 (0.4%) received a new diagnosis, of which 122 (14.5%) were acute HIV infection and 717 (85.5%) were established HIV infection. Compared with patients with established HIV infection, those with acute HIV infection were younger, had higher RNA and CD4 counts, and were more likely to have viral syndrome (41.8% versus 6.5%) or fever (14.3% versus 3.4%) as their reason for visit. Most patients with acute HIV infection displayed symptoms attributable to acute infection (median symptom count 5 [interquartile range 3 to 6]), with fever often accompanied by greater than or equal to 3 other symptoms (60.7%). CONCLUSION: ED screening using antigen-antibody tests identifies previously undiagnosed HIV infection at proportions that exceed the Centers for Disease Control and Prevention's screening threshold, with the added yield of identifying acute HIV infection in approximately 15% of patients with a new diagnosis. Patients with acute HIV infection often seek ED care for symptoms related to seroconversion.

Neighborhood community characteristics associated with HIV disease outcomes in a cohort of urban women living with HIV.

Recent studies have found geographic variations in immune and viral human immunodeficiency virus (HIV) disease outcomes associated with census measures of neighborhood poverty and segregation. Although readily available, such aggregate census measures are not based on health behavior models and provide limited information regarding neighborhood effect pathways. In contrast, survey-based measures can capture specific aspects of neighborhood disadvantage that may better inform community-based interventions. Therefore, the aim of this study is to assess the measurement validity of multi-dimensional survey measures of neighborhood disorder compared with census measures as predictors of HIV outcomes in a cohort of 197 low-income women in a major metropolitan area. The multi-dimensional survey measures were related to each other and to census measures of concentrated poverty and racial segregation, but not so highly correlated as to be uniform. We found notable variation between community areas in women's CD4 levels but there was no corresponding geographic variance in viral load, and relationships between community area measures and viral load disappeared after adjustment for individual characteristics, including HIV treatment adherence. In multilevel models adjusting for individual characteristics including substance use, depression, and HIV treatment adherence, one survey measure of neighborhood disadvantage (poor-quality built environment) and one census measure (racial segregation) were significantly associated with greater likelihood of CD4 < 500 (p < .05).

Use of posaconazole delayed-release tablets for treatment of invasive aspergillosis.

A 65-year-old man developed Aspergillus brain abscesses following surgical resection of a sinus aspergilloma. He was treated with voriconazole for 1 year but infection recurred. We elected to treat with posaconazole delayed-release tablets, currently only indicated as antifungal prophylaxis in high-risk patients. A maintenance dose of 300 mg Q24 h resulted in a therapeutic serum concentration and appears safe and clinically effective thus far. This is the first report of successful use of posaconazole tablets for treatment of invasive aspergillosis.

Diffuse Desquamating Rash Following Exposure to Vancomycin-Impregnated Bone Cement.

OBJECTIVE: To describe a case of systemic desquamating dermatitis following implantation of vancomycin antibiotic-laden cement (ABLC) in a patient with prior history of Stevens-Johnson (SJS) reaction to vancomycin. CASE SUMMARY: A 59-year-old man with a history of SJS reaction to systemic vancomycin and recurrent methicillin-susceptible Staphylococcus aureus prosthetic knee infection developed a painful, blistering rash after implantation of bone cement that had been mixed with 2 g of vancomycin. He was started empirically on steroids by his primary care provider and had desquamation about 1 week later. DISCUSSION: Systemic absorption of antibiotics from ABLC has been well documented in the literature. Reports of systemic toxicity are rare, and none have described systemic allergic reactions to vancomycin. This patient's prior episode of SJS was diagnosed at another academic medical center 6 years ago, and records are unavailable. Following low-level reexposure to vancomycin, he developed a diffuse painful desquamating rash. Application of the Naranjo nomogram yielded a score of 8 (probable adverse reaction). Although he did not experience fever, sore throat, or mucous membrane involvement to fulfill classic features of SJS, we believe that his severe rash represented a less-severe form of a systemic hypersensitivity reaction to vancomycin. CONCLUSION: Antibiotics contained in ABLC are systemically absorbed, though at low levels, and have been associated with systemic toxicities. Antibiotics to which a patient has had a potentially life-threatening reaction should not be used in ABLC. Particular attention should be paid to an individual's antibiotic allergy history prior to implantation of any ABLC.

Assessing Patient Acceptance of an Automated Algorithm to Identify Ciswomen for HIV Pre-Exposure Prophylaxis.

The use of HIV pre-exposure prophylaxis (PrEP) in cisgender women (ciswomen) lags far behind their need. Data elements from the electronic medical record (EMR), including diagnosis of a sexually transmitted infection (STI), can be incorporated into automated algorithms for identifying clients who are most vulnerable to HIV and would benefit from PrEP. However, it is unknown how women feel about the use of such technology. In this study, we assessed women's attitudes and opinions about an automated EMR-based HIV risk algorithm and determined if their perspectives varied by level of HIV risk. Respondents were identified using best practice alerts or referral to a clinic for STI symptoms from January to December 2021 in Chicago, IL. Participants were asked about HIV risk factors, their self-perceived HIV risk, and their thoughts regarding an algorithm to identify ciswomen who could benefit from PrEP. Most of the 112 women who completed the survey (85%) thought they were at low risk for HIV, despite high rates of STI diagnoses. The majority were comfortable with the use of this algorithm, but their comfort level dropped when asked about the algorithm identifying them specifically. Ciswomen had mixed feelings about the use of an automated HIV risk algorithm, citing it as a potentially helpful and empowering tool for women, yet raising concerns about invasion of privacy and potential racial bias. Clinics must balance the benefits of using an EMR-based algorithm for ciswomen with their concerns about privacy and bias to improve PrEP uptake among particularly vulnerable women.

Concurrent Testing for COVID-19 and HIV Infection at 6 High-Volume Emergency Departments in a Priority Jurisdiction for Ending the HIV Epidemic in the United States.

BACKGROUND: The COVID-19 pandemic caused disruptions in access to routine HIV screening. SETTING: We assess HIV and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing across 6 emergency departments (EDs) in Cook County, Illinois. METHODS: We retrospectively analyzed the number of SARS-CoV-2 tests, HIV screens, and the proportion of concurrent tests (encounters with both SARS-CoV-2 and HIV testing), correlating with diagnoses of new and acute HIV infection. RESULTS: Five sites reported data from March 1, 2020, to February 28, 2021, and 1 site from September 1, 2020, to February 28, 2021. A total of 1,13,645 SARS-CoV-2 and 36,094 HIV tests were performed; 17,469 of these were concurrent tests. There were 102 new HIV diagnoses, including 25 acute infections. Concurrent testing proportions ranged from 6.7% to 37% across sites (P < 0.001). HIV testing volume correlated with the number of new diagnoses (r = 0.66, P < 0.01). HIV testing with symptomatic SARS-CoV-2 testing was strongly correlated with diagnosis of acute infections (r = 0.87, P < 0.001); this was not statistically significant when controlling for HIV testing volumes (r = 0.59, P = 0.056). Acute patients were more likely to undergo concurrent testing (21/25) versus other new diagnoses (29/77; odds ratio = 8.69, 95% CI: 2.7 to 27.8, P < 0.001). CONCLUSIONS: Incorporating HIV screening into SARS-CoV-2 testing in the ED can help maintain HIV screening volumes. Although all patients presenting to the ED should be offered opt-out HIV screening, testing individuals with symptoms of COVID-19 or other viral illness affords the opportunity to diagnose symptomatic acute and early HIV infection, rapidly link to care, and initiate treatment.

Effectiveness of an electronic health record model for HIV pre-exposure prophylaxis.

Pre-exposure prophylaxis (PrEP) to prevent human immunodeficiency virus (HIV) is extremely effective when taken correctly, though grossly under-prescribed for at-risk patients. We initiated a best practice advisory (BPA) in the Epic electronic medical record (EMR) to identify patients who met criteria for PrEP use. We evaluated this model to determine its effectiveness in identifying patients and its use by providers for increasing prescription of PrEP. The BPA fired 145 times with five total new PrEP prescriptions. Over half of the patients identified were cisgender women, a group that is both under prescribed PrEP and missed by prior EMR PrEP algorithms. Half of the patients were African American, a group at high risk of HIV infection. Though the model was effective at identifying patients, provider initiation of PrEP or acknowledgment of the BPA was low. Further education of providers regarding PrEP usage and expansion of BPA messages are needed to increase rates of PrEP initiation.

Bulk IgG glycosylation predicts COVID-19 severity and vaccine antibody response.

Although vaccination efforts have expanded, there are still gaps in our understanding surrounding the immune response to SARS-CoV-2. Measuring IgG Fc glycosylation provides insight into an infected individual's inflammatory state, among other functions. We set out to interrogate bulk IgG glycosylation changes from SARS-CoV-2 infection and vaccination, using plasma from mild or hospitalized COVID-19 patients, and from vaccinated individuals. Inflammatory glycans are elevated in hospitalized COVID-19 patients and increase over time, while mild patients have anti-inflammatory glycans that increase over time, including increased sialic acid correlating with RBD antibody levels. Vaccinated individuals with low RBD antibody levels and low neutralization have the same IgG glycan traits as hospitalized COVID-19 patients. In addition, a small vaccinated cohort reveals a decrease in inflammatory glycans associated with peak IgG concentrations and neutralization. This report characterizes the bulk IgG glycome associated with COVID-19 severity and vaccine responsiveness and can help guide future studies into SARS-CoV-2 protective immunity.

Robust humoral and cellular recall responses to AZD1222 attenuate breakthrough SARS-CoV-2 infection compared to unvaccinated.

Background: Breakthrough severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in coronavirus disease 2019 (COVID-19) vaccinees typically produces milder disease than infection in unvaccinated individuals. Methods: To explore disease attenuation, we examined COVID-19 symptom burden and immuno-virologic responses to symptomatic SARS-CoV-2 infection in participants (AZD1222: n=177/17,617; placebo: n=203/8,528) from a 2:1 randomized, placebo-controlled, phase 3 study of two-dose primary series AZD1222 (ChAdOx1 nCoV-19) vaccination (NCT04516746). Results: We observed that AZD1222 vaccinees had an overall lower incidence and shorter duration of COVID-19 symptoms compared with placebo recipients, as well as lower SARS-CoV-2 viral loads and a shorter median duration of viral shedding in saliva. Vaccinees demonstrated a robust antibody recall response versus placebo recipients with low-to-moderate inverse correlations with virologic endpoints. Vaccinees also demonstrated an enriched polyfunctional spike-specific Th-1-biased CD4+ and CD8+ T-cell response that was associated with strong inverse correlations with virologic endpoints. Conclusion: Robust immune responses following AZD1222 vaccination attenuate COVID-19 disease severity and restrict SARS-CoV-2 transmission potential by reducing viral loads and the duration of viral shedding in saliva. Collectively, these analyses underscore the essential role of vaccination in mitigating the COVID-19 pandemic.