Peak Viral Load Research Articles

Impairing RAGE signaling promotes survival and limits disease pathogenesis following SARS-CoV-2 infection in mice.

Cellular and molecular mechanisms driving morbidity following SARS-CoV-2 infection have not been well defined. The receptor for advanced glycation end products (RAGE) is a central mediator of tissue injury and contributes to SARS-CoV-2 disease pathogenesis. In this study, we temporally delineated key cell and molecular events leading to lung injury in mice following SARS-CoV-2 infection and assessed efficacy of therapeutically targeting RAGE to improve survival. Early following infection, SARS-CoV-2 replicated to high titers within the lungs and evaded triggering inflammation and cell death. However, a significant necrotic cell death event in CD45– populations, corresponding with peak viral loads, was observed on day 2 after infection. Metabolic reprogramming and inflammation were initiated following this cell death event and corresponded with increased lung interstitial pneumonia, perivascular inflammation, and endothelial hyperplasia together with decreased oxygen saturation. Therapeutic treatment with the RAGE antagonist FPS-ZM1 improved survival in infected mice and limited inflammation and associated perivascular pathology. Together, these results provide critical characterization of disease pathogenesis in the mouse model and implicate a role for RAGE signaling as a therapeutic target to improve outcomes following SARS-CoV-2 infection.

Impact of human immunodeficiency virus status on laryngeal cancer survival and locoregional control.

ObjectivesTo compare long‐term outcomes of laryngeal cancer (LC) in people living with HIV (PLWH) versus uninfected individuals and determine how clinical and viral factors—such as demographics, cancer stage, HIV viral load, and CD4 nadir—contribute to these outcomes.MethodsThis was a retrospective case–control study of 749 patients seen for LC at a single tertiary care center between 2003 and 2017. Of these, 22 had HIV at the time of LC diagnosis, and they were matched in a 1:4 ratio to uninfected controls based on sex, presence of smoking history, and age at cancer diagnosis. Kaplan–Meier survival curves and Cox proportional hazards models were constructed to identify overall and disease‐free survival differences based on HIV status, as well as other clinical and viral factors.ResultsCompared to all uninfected individuals, PLWH were diagnosed with LC approximately 6 years younger (p = .013). 1‐, 2‐, and 5‐year overall survival for PLWH were 86.4% (63.4%–95.4%), 77.3% (53.7%–89.9%), and 65.8% (40.8%–82.2%), respectively following LC diagnosis, and HIV was not significantly associated with overall (HR = 3.34 [0.59–18.79]) or disease‐free survival (HR = 2.12 [0.71–6.36]). The incidence rate of locoregional recurrence among PLWH was 541 compared to 371 per 10,000 person‐years in controls, which were not significantly different (p = .420). Furthermore, among PLWH, peak viral load and CD4 nadir were not associated with overall or disease‐free survival.ConclusionWhile previous work has shown that HIV is associated with elevated risk of LC, survival did not differ significantly between PLWH and uninfected individuals in this study.Level of evidence3.

Modelling upper respiratory viral load dynamics of SARS-CoV-2

Relationships between viral load, severity of illness, and transmissibility of virus are fundamental to understanding pathogenesis and devising better therapeutic and prevention strategies for COVID-19. Here we present within-host modelling of viral load dynamics observed in the upper respiratory tract (URT), drawing upon 2172 serial measurements from 605 subjects, collected from 17 different studies. We developed a mechanistic model to describe viral load dynamics and host response and contrast this with simpler mixed-effects regression analysis of peak viral load and its subsequent decline. We observed wide variation in URT viral load between individuals, over 5 orders of magnitude, at any given point in time since symptom onset. This variation was not explained by age, sex, or severity of illness, and these variables were not associated with the modelled early or late phases of immune-mediated control of viral load. We explored the application of the mechanistic model to identify measured immune responses associated with the control of the viral load. Neutralising antibodies correlated strongly with modelled immune-mediated control of viral load amongst subjects who produced neutralising antibodies. Our models can be used to identify host and viral factors which control URT viral load dynamics, informing future treatment and transmission blocking interventions.

Trajectory of Viral RNA Load Among Persons With Incident SARS-CoV-2 G614 Infection (Wuhan Strain) in Association With COVID-19 Symptom Onset and Severity

The SARS-CoV-2 viral trajectory has not been well characterized in incident infections. These data are needed to inform natural history, prevention practices, and therapeutic development. To characterize early SARS-CoV-2 viral RNA load (hereafter referred to as viral load) in individuals with incident infections in association with COVID-19 symptom onset and severity. This prospective cohort study was a secondary data analysis of a remotely conducted study that enrolled 829 asymptomatic community-based participants recently exposed (<96 hours) to persons with SARS-CoV-2 from 41 US states from March 31 to August 21, 2020. Two cohorts were studied: (1) participants who were SARS-CoV-2 negative at baseline and tested positive during study follow-up, and (2) participants who had 2 or more positive swabs during follow-up, regardless of the initial (baseline) swab result. Participants collected daily midturbinate swab samples for SARS-CoV-2 RNA detection and maintained symptom diaries for 14 days. Laboratory-confirmed SARS-CoV-2 infection. The observed SARS-CoV-2 viral load among incident infections was summarized, and piecewise linear mixed-effects models were used to estimate the characteristics of viral trajectories in association with COVID-19 symptom onset and severity. A total of 97 participants (55 women [57%]; median age, 37 years [IQR, 27-52 years]) developed incident infections during follow-up. Forty-two participants (43%) had viral shedding for 1 day (median peak viral load cycle threshold [Ct] value, 38.5 [95% CI, 38.3-39.0]), 18 (19%) for 2 to 6 days (median Ct value, 36.7 [95% CI, 30.2-38.1]), and 31 (32%) for 7 days or more (median Ct value, 18.3 [95% CI, 17.4-22.0]). The cycle threshold value has an inverse association with viral load. Six participants (6%) had 1 to 6 days of viral shedding with censored duration. The peak mean (SD) viral load was observed on day 3 of shedding (Ct value, 33.8 [95% CI, 31.9-35.6]). Based on the statistical models fitted to 129 participants (60 men [47%]; median age, 38 years [IQR, 25-54 years]) with 2 or more SARS-CoV-2-positive swab samples, persons reporting moderate or severe symptoms tended to have a higher peak mean viral load than those who were asymptomatic (Ct value, 23.3 [95% CI, 22.6-24.0] vs 30.7 [95% CI, 29.8-31.4]). Mild symptoms generally started within 1 day of peak viral load, and moderate or severe symptoms 2 days after peak viral load. All 535 sequenced samples detected the G614 variant (Wuhan strain). This cohort study suggests that having incident SARS-CoV-2 G614 infection was associated with a rapid viral load peak followed by slower decay. COVID-19 symptom onset generally coincided with peak viral load, which correlated positively with symptom severity. This longitudinal evaluation of the SARS-CoV-2 G614 with frequent molecular testing serves as a reference for comparing emergent viral lineages to inform clinical trial designs and public health strategies to contain the spread of the virus.

Ferrets are valuable models for SARS-CoV-2 research.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulted in an ongoing pandemic with millions of deaths worldwide. Infection of humans can be asymptomatic or result in fever, fatigue, dry cough, dyspnea, and acute respiratory distress syndrome with multiorgan failure in severe cases. The pathogenesis of COVID-19 is not fully understood, and various models employing different species are currently applied. Ferrets can be infected with SARS-CoV-2 and efficiently transmit the virus to contact animals. In contrast to hamsters, ferrets usually show mild disease and viral replication restricted to the upper airways. Most reports have used the intranasal inoculation route, while the intratracheal infection model is not well characterized. Herein, we present clinical, virological, and pathological data from young ferrets intratracheally inoculated with SARS-CoV-2. Infected animals showed no significant clinical signs, and had transient infection with peak viral RNA loads at 4 days postinfection, mild to moderate rhinitis, and pulmonary endothelialitis/vasculitis. Viral antigen was exclusively found in the respiratory epithelium of the nasal cavity, indicating a particular tropism for cells in this location. Viral antigen was associated with epithelial damage and influx of inflammatory cells, including activated neutrophils releasing neutrophil extracellular traps. Scanning electron microscopy of the nasal respiratory mucosa revealed loss of cilia, shedding, and rupture of epithelial cells. The currently established ferret SARS-CoV-2 infection models are comparatively discussed with SARS-CoV-2 pathogenesis in mink, and the advantages and disadvantages of both species as research models for zoonotic betacoronaviruses are highlighted.

Infection Dynamics of SARS-CoV-2 in Mucus Layer of the Human Nasal Cavity - Nasopharynx

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the worldwide spread of coronavirus disease-2019 (COVID-19) since its emergence in 2019. Virus replication and infection dynamics after its deposition on the respiratory tissues require detailed studies for infection control. This study focused primarily on SARS-CoV-2 dynamics in the mucus layer of the nasal cavity and nasopharynx, based on coupled computational fluid-particle dynamics (CFPD) and host-cell dynamics (HCD) analyses. Considering the mucus milieu, we coupled the target-cell limited model with the convection-diffusion term to develop an improved HCD model. The infection dynamics in the mucus layer were predicted by a combination of the mucus flow field, droplet deposition distribution, and HCD. The effect of infection rate, β, was investigated as the main parameter of HCD. The results showed that the time series of SARS-CoV-2 concentration distribution in the mucus layer strongly depended on diffusion, convection, and virus production. β affected the viral load peak, its arrival time, and duration. Although the SARS-CoV-2 dynamics in the mucus layer obtained in this study have not been verified by appropriate clinical data, it can serve as a preliminary study on the virus transmission mode in the upper respiratory tract.

Spatio-Temporal Modeling of Immune Response to SARS-CoV-2 Infection

COVID-19 is a disease occurring as a result of infection by a novel coronavirus called SARS-CoV-2. Since the WHO announced COVID-19 as a global pandemic, mathematical works have taken place to simulate infection scenarios at different scales even though the majority of these models only consider the temporal dynamics of SARS-COV-2. In this paper, we present a new spatio-temporal within-host mathematical model of COVID-19, accounting for the coupled dynamics of healthy cells, infected cells, SARS-CoV-2 molecules, chemokine concentration, effector T cells, regulatory T cells, B-lymphocytes cells and antibodies. We develop a computational framework involving discretisation schemes for diffusion and chemotaxis terms using central differences and midpoint approximations within two dimensional space combined with a predict–evaluate–correct mode for time marching. Then, we numerically investigate the model performance using a list of values simulating the baseline scenario for viral infection at a cellular scale. Moreover, we explore the model sensitivity via applying certain conditions to observe the model validity in a comparison with clinical outcomes collected from recent studies. In this computational investigation, we have a numerical range of 104 to 108 for the viral load peak, which is equivalent to what has been obtained from throat swab samples for many patients.

Quantitative SARS-CoV-2 Viral-Load Curves in Paired Saliva Samples and Nasal Swabs Inform Appropriate Respiratory Sampling Site and Analytical Test Sensitivity Required for Earliest Viral Detection.

ABSTRACTEarly detection of SARS-CoV-2 infection is critical to reduce asymptomatic and presymptomatic transmission, curb the spread of variants, and maximize treatment efficacy. Low-analytical-sensitivity nasal-swab testing is commonly used for surveillance and symptomatic testing, but the ability of these tests to detect the earliest stages of infection has not been established. In this study, conducted between September 2020 and June 2021 in the greater Los Angeles County, California, area, initially SARS-CoV-2-negative household contacts of individuals diagnosed with COVID-19 prospectively self-collected paired anterior-nares nasal-swab and saliva samples twice daily for viral-load quantification by high-sensitivity reverse-transcription quantitative PCR (RT-qPCR) and digital-RT-PCR assays. We captured viral-load profiles from the incidence of infection for seven individuals and compared diagnostic sensitivities between respiratory sites. Among unvaccinated persons, testing saliva with a high-analytical-sensitivity assay detected infection up to 4.5 days before viral loads in nasal swabs reached concentrations detectable by low-analytical-sensitivity nasal-swab tests. For most participants, nasal swabs reached higher peak viral loads than saliva but were undetectable or at lower loads during the first few days of infection. High-analytical-sensitivity saliva testing was most reliable for earliest detection. Our study illustrates the value of acquiring early (within hours after a negative high-sensitivity test) viral-load profiles to guide the appropriate analytical sensitivity and respiratory site for detecting earliest infections. Such data are challenging to acquire but critical to designing optimal testing strategies with emerging variants in the current pandemic and to respond to future viral pandemics.

Letermovir conversion after valganciclovir treatment in cytomegalovirus high‐risk abdominal solid organ transplant recipients may promote development of cytomegalovirus‐specific cell mediated immunity

To evaluate the association of conversion from valganciclovir to letermovir on cytomegalovirus-specific cellular immunity. Adult patients were included if they received a kidney or liver transplant between 8/1/2018-12/31/20, developed symptomatic, high-level CMV viremia and were converted to letermovir 480mg daily as monotherapy after treatment with ganciclovir-derivatives for a minimum of 4weeks and had subsequent CMV cell-mediated immunity (CMI) testing via ICS assay by flow cytometry (Viracor Eurofins T Cell Immunity Panel). Seven patients met inclusion criteria; 87.5% were male and recipients of a kidney transplant. All patients were CMV high risk (D+/R-). Mean time from transplant to CMV disease was 200±91 days. Peak viral load (VL) during CMV treatment was 540,341±391,211 IU/mL. Patients received a mean of 30±24weeks (range: 4-78weeks) of therapy with ganciclovir-derivatives at induction doses prior to letermovir introduction. The median absolute lymphocyte count (ALC) at letermovir initiation was 400/μL (IQR 575) and the median VL was 51.6 (range: ND-490) IU/mL. Most patients (n=5/7, 71.4%) experienced an increase in VL 1 and/or 2weeks after conversion to letermovir. All patients had positive CMI per ICS assay after conversion. Patients received a mean of 10.3±6.9weeks of letermovir prior to having a positive result. Median ALC at positivity was 900/μL. Immunosuppression was not further reduced from initiation of letermovir to demonstration of CMV CMI. No patient had progressive replication or breakthrough disease while maintained on letermovir and three patients (42.9%) underwent antiviral withdrawal without recurrence at the last follow-up. In this case series of abdominal transplant recipients with severe or persistent CMV infection, patients developed CMV-specific CMI after conversion to letermovir monotherapy. These data suggest that using letermovir in place of valganciclovir for secondary prophylaxis may address the lack of efficacy previously seen with this approach, as well as the issues that plague antiviral withdrawal with systematic monitoring. Future prospective studies are needed to evaluate this effect in a more controlled research environment with serial CMI testing to elucidate the optimal duration of letermovir when used in this way.

934. Epidemiology and Outcomes of Epstein-Barr Virus DNAemia in Adult Solid Organ Transplant Recipients

BackgroundImmunosuppression in solid organ transplantation (SOT) increases the risk of Epstein-Barr virus (EBV) DNAemia, which may herald development of post-transplant lymphoproliferative disease (PTLD). The objective of this study was to characterize the epidemiology and risk factors for EBV DNAemia and to describe the impact of these factors on development of PTLD in a cohort of SOT recipients.MethodsWe retrospectively examined adult (≥18 years) SOT recipients between 1/1/2015 to 12/31/2019. Demographics, immunosuppression, and clinical outcomes were examined. Subjects were stratified as having a positive (EBV viral load > 200 copies/mL) or negative viral load. Sustained EBV DNAemia was defined as EBV DNA detection ( > 200 copies/mL) on at least 3 consecutive samples. Categorical variables were analyzed using chi-square or Fishers exact test. Mann-U Whitney test was used for continuous variables. Results442 SOT recipients (258 kidney, 141 liver, 22 kidney-pancreas (KP), 15 kidney-liver, 6 pancreas) were examined. Most subjects (430, 97%) were EBV intermediate risk (recipient (R)+). 8 subjects (2%) were EBV high risk (donor (D)+, R-) and 4 (1%) were EBV low risk (D-/R-). EBV viral loads were obtained in 177/442 (40.0%) recipients. DNAemia was detected in 18/442 subjects (4.1%). It was most common in pancreas recipients(1/6; 16.7%) compared with kidney (10/258; 3.9%), liver (5/141; 3.5%), and KP recipients (1/22; 4.5%). DNAemia was most frequently observed in the D+/R- (3/8; 37.5%) group compared to intermediate risk (R+) (15/430; 3.5%) and D-/R- (0%) groups. Median time to EBV viral load detection was 14 months (range 3-60). In univariate analysis, EBV high-risk serostatus was the factor most strongly associated with development of EBV DNAemia (p< 0.001). Sustained DNAemia (median viral load 1829 copies/mL; peak viral load 1.9 million copies/mL) was observed in 8 subjects (1.8%). PTLD developed in 6 subjects (1.4%); 50% had sustained DNAemia prior to diagnosis.ConclusionWhile uncommon, development of sustained EBV DNAemia was associated with subsequent development of PTLD in our cohort of adult SOT recipients. These data provide guidance for identifying subjects at risk for PTLD above and beyond baseline EBV high-risk serostatus. Disclosures All Authors: No reported disclosures

1010. Cross-Species Translation of Correlates of Protection for COVID-19 Vaccine Candidates Using Quantitative Tools

BackgroundSeveral COVID-19 vaccines have been authorized, and the need for rapid, further modification is anticipated. This work uses a Model-Based Meta-Analysis (MBMA) to relate, across species, immunogenicity to peak viral load (VL) after challenge and to clinical efficacy. Together with non-clinical and/or early clinical immunogenicity data (ECID), this enables prediction of a candidate vaccine’s clinical efficacy. The goal of this work was to enable the accelerated development of vaccine candidates by supporting Go/No-Go and study design decisions, and the resulting MBMA can be instrumental in decisions not to progress candidates to late stage development.MethodsA literature review with pre-specified inclusion/exclusion criteria enabled creation of a database including nonclinical serum neutralizing titers (SN), peak VL after challenge with SARS-CoV-2 (VL), along with data from several clinical vaccine candidates. Rhesus Macaque (RM) and golden hamster (GH) were selected (due to availability and consistency of data) for MBMA modeling. For both RM and GH, peak post-challenge VL in lung and nasal tissues were used as surrogates for clinical disease and were related to pre-challenge SN via the MBMA. The VL predictions from the RM MBMA were scaled to incidence rates in humans, with a scaling factor between RM and human SN estimated using early Phase 3 efficacy data. This enabled clinical efficacy predictions based on ECID. To qualify the model’s predictive power, efficacies of COVID-19 vaccine candidates were compared to those predicted from the MBMA and their respective Ph1/2 SN data. More recently available clinical data enable building a clinical MBMA; comparing this to the RM MBMA further supports SN as predictive.ResultsThe MBMA analyses identified a sigmoidal decrease in VL (increasing protection) with increase in SN in all three species, with more SN needed (in both RM and GH) for protection in nasal swabs than in BAL (see figure). The comparison between predicted and reported clinical efficacies demonstrated the model’s predictive power across vaccine platforms.RM and GH MBMA Protection Models and Translational Prediction with Observed Efficacies Sizes of circles indicate relative weight of the data in the respective quantitative model. Model and data visualizations have been harmonized (across tissue-types) separately for each of RM and GH using VACHER (Lommerse, et al., CPT:PSP, in press).ConclusionBy quantifying adjustments needed between species and assays, translational MBMA can inform development decisions by using nonclinical SN and VL, and ECID to predict protection from COVID-19.Disclosures Anna Largajolli, PhD, Certara (Employee) Nele Plock, PhD, Certara (Employee, Shareholder)Merck & Co., Inc. (Independent Contractor) Bhargava Kandala, PhD, Merck & Co., Inc. (Employee, Shareholder) Akshita Chawla, PhD, Merck & Co., Inc. (Employee, Shareholder) Seth H. Robey, PhD, Merck & Co., Inc. (Employee, Shareholder) Kenny Watson, PhD, Certara (Employee, Shareholder) Raj Thatavarti, MS, Certara (Employee, Shareholder) Sheri Dubey, PhD, Merck & Co., Inc. (Employee, Shareholder) S. Y. Amy Cheung, PhD, Certara (Employee, Shareholder) Rik de Greef, MSc, Certara (Employee, Shareholder) Jeffrey R. Sachs, PhD, Merck & Co., Inc. (Employee, Shareholder)

933. Incidence and Risk Factors for Cytomegalovirus Infection in Intestinal Transplant Recipients

BackgroundCytomegalovirus (CMV) infection is the most common infection after solid organ transplantation. Data on CMV infection in intestinal transplant recipients is limited. MethodsThis is a single-center retrospective cohort study which includes all consecutive intestinal transplant recipients who were transplanted between 2009 and 2019. We excluded recipients that showed CMV seronegativity of both donor and recipient. We also excluded those patients who did not have more than 3 months of follow-up. Univariate and multivariate analyses were performed to identify the risk factors for CMV infection. Of note, at our center CMV prophylaxis in intestinal transplant recipients is one year of valganciclovir. ResultsA total of 173 recipients were transplanted; 46 recipients were because of CMV serostatus and 32 due to short follow-up. Ninety-five recipients were included finally. The characteristics of our cohort are summarized in Table 1. Of note, the median age was 32 years [range 0-67] and 44 (46.3%) were male. Eighteen (18.9%) recipients needed to stop valganciclovir prophylaxis due to the side effect, especially cytopenia. Twenty-one recipients developed CMV infection including asymptomatic viremia (12/21, 57.1%), CMV syndrome (5/21, 23.8%) and end-organ disease (2 (9.5%) pneumonitis and 2 (9.5%) colitis) at median time of 155 [Interquartile range, IQR 28-254] days from transplant. The median peak viral load and time to negativity were 16000 [IQR 1500-43892] IU/ml and 56 [IQR 49-109] days, respectively. Younger age (p=0.007, Odds ratio 1.03, 95% confidence interval 1.003-1.055) was the independent factor associated with CMV infection. ConclusionDespite prolonged prophylaxis, 21 (22.1%) of intestinal transplant recipients developed CMV infection around 5 months post-transplant. This may be because they cannot tolerate valganciclovir prophylaxis and early termination was required. Further strategy should be developed to prevent CMV infection in this vulnerable population.Disclosures All Authors: No reported disclosures

944. CMV Peak Viral Load, Recurrence, Duration, and Outcomes in Kidney Transplant Recipients

BackgroundCytomegalovirus (CMV) infection continues to cause morbidity in kidney transplant recipients, despite prophylaxis and pre-emptive therapy. Predictors of poor outcomes remain incompletely characterized. We questioned whether markers of CMV replication (CMV peak viral load, recurrent episodes, or duration of CMV DNAemia) are associated with adverse outcomes in the current era.MethodsWe studied 605 people who underwent kidney transplant at Johns Hopkins University (2010 – 2018). Mean follow-up was 45.5 months. The average age was 51.85 years and 39.7% were female. Donor-seropositive, recipient seronegative (D+/R-) patients received valganciclovir 900 mg/day for 6 months, while R+ patients received valganciclovir 450 mg/day for 3 months. CMV recurrence was defined as CMV DNAemia after two undetectable CMV PCR’s. Outcomes of acute rejection, graft failure, and death were evaluated in univariate analysis; p values were calculated by Fisher’s exact test. ResultsPeak CMV viral load was not associated with any outcomes (Table 1). There was a trend of increased graft failure in people who had long duration ( >6 month) DNAemia (Table 2). More than two episodes of CMV reactivation was associated with graft failure and rejection (Table 3). ConclusionCMV reactivation is associated with kidney rejection and failure in univariate models. Multivariate analyses and longitudinal modeling will provide increased data upon which to better instruct preventative strategies. AcknowledgmentsFunding for the research study was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA Disclosures Robin K. Avery, MD, Aicuris (Grant/Research Support)Astellas (Grant/Research Support)Chimerix (Research Grant or Support)Merck (Grant/Research Support)Oxford Immunotec (Grant/Research Support)Qiagen (Grant/Research Support)Takeda/Shire (Grant/Research Support) Yuexin Tang, PhD, JnJ (Other Financial or Material Support, Spouse’s employment)Merck & Co., Inc. (Employee, Shareholder) Kieren Marr, MD, Merck (Grant/Research Support, Advisor or Review Panel member)

Preferential and persistent impact of acute HIV-1 infection on CD4+ iNKT cells in colonic mucosa

SignificanceEvidence suggests that HIV-1 disease progression is determined in the early stages of infection. Here, preinfection invariant natural killer T (iNKT) cell levels were predictive of the peak viral load during acute HIV-1 infection (AHI). Furthermore, iNKT cells were preferentially lost in AHI. This was particularly striking in the colonic mucosa, where iNKT cells were depleted more profoundly than conventional CD4+T cells. The initiation of antiretroviral therapy during AHI-prevented iNKT cell dysregulation in peripheral blood but not in the colonic mucosa. Overall, our results support a model in which iNKT cells are early and preferential targets for HIV-1 infection during AHI.

Sex Differences in EBV Viremia after Haplo-HSCT Imply Sex Bias during Immune Reconstitution

Objective: Posttransplant infection is common and tough to deal, patients after HSCT rely on immune reconstitution for protection. We desperately need a deeper understanding of how the system works to help the patients overcome the infection.Method: This study analyzed the disease course of EBV viremia after haplo-HSCT, as well as the laboratory testing data. The sex bias during immune reconstitution was manifested by comparing the outcomes between male and female patients,Results: 236 patients received haplo-HSCT in 2013 in our center, at a median follow up of 5 years, among whom 78 patients underwent EBV infection. The incidence of EBV viremia after transplantation is 33.1% in total, with a significant difference between men and women (40.0% and 26.7% respectively, p=0.034). Men tended to have earlier onset time (14-434d after HSCT) and longer duration (7-70d) than women (17-592d after HSCT, 7-30d). Both the initial and peak viral load were higher in men than in women (initial viral load＞10 4/ml: men 6.52% vs. women 3.13%, peak viral load＞10 5/ml: men 8.70% vs. women 3.13%). To explain this phenomenon, we analyzed the laboratory testing data on 30d and 60d after HSCT. And we found that male patients had higher plasma levels of immunoglobulin M on 60d after HSCT if infected by EBV, referring to more robust induction of innate immune (p=0.033). By contrast, female patients had significantly increased CD4+ T cell during EBV infection, representing more robust activation of adaptive immune (p=0.019).Conclusion: These findings provide a possible explanation for the observed sex biases in EBV viremia after haplo-HSCT, and provide an important basis for the recognition of immune reconstitution, furthermore, raise concern of the development of a sex-based approach to the treatment and care of male and female patients with infection after HSCT. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Community transmission and viral load kinetics of the SARS-CoV-2 delta (B.1.617.2) variant in vaccinated and unvaccinated individuals in the UK: a prospective, longitudinal, cohort study

SummaryBackgroundThe SARS-CoV-2 delta (B.1.617.2) variant is highly transmissible and spreading globally, including in populations with high vaccination rates. We aimed to investigate transmission and viral load kinetics in vaccinated and unvaccinated individuals with mild delta variant infection in the community.MethodsBetween Sept 13, 2020, and Sept 15, 2021, 602 community contacts (identified via the UK contract-tracing system) of 471 UK COVID-19 index cases were recruited to the Assessment of Transmission and Contagiousness of COVID-19 in Contacts cohort study and contributed 8145 upper respiratory tract samples from daily sampling for up to 20 days. Household and non-household exposed contacts aged 5 years or older were eligible for recruitment if they could provide informed consent and agree to self-swabbing of the upper respiratory tract. We analysed transmission risk by vaccination status for 231 contacts exposed to 162 epidemiologically linked delta variant-infected index cases. We compared viral load trajectories from fully vaccinated individuals with delta infection (n=29) with unvaccinated individuals with delta (n=16), alpha (B.1.1.7; n=39), and pre-alpha (n=49) infections. Primary outcomes for the epidemiological analysis were to assess the secondary attack rate (SAR) in household contacts stratified by contact vaccination status and the index cases’ vaccination status. Primary outcomes for the viral load kinetics analysis were to detect differences in the peak viral load, viral growth rate, and viral decline rate between participants according to SARS-CoV-2 variant and vaccination status.FindingsThe SAR in household contacts exposed to the delta variant was 25% (95% CI 18–33) for fully vaccinated individuals compared with 38% (24–53) in unvaccinated individuals. The median time between second vaccine dose and study recruitment in fully vaccinated contacts was longer for infected individuals (median 101 days [IQR 74–120]) than for uninfected individuals (64 days [32–97], p=0·001). SAR among household contacts exposed to fully vaccinated index cases was similar to household contacts exposed to unvaccinated index cases (25% [95% CI 15–35] for vaccinated vs 23% [15–31] for unvaccinated). 12 (39%) of 31 infections in fully vaccinated household contacts arose from fully vaccinated epidemiologically linked index cases, further confirmed by genomic and virological analysis in three index case–contact pairs. Although peak viral load did not differ by vaccination status or variant type, it increased modestly with age (difference of 0·39 [95% credible interval –0·03 to 0·79] in peak log10 viral load per mL between those aged 10 years and 50 years). Fully vaccinated individuals with delta variant infection had a faster (posterior probability >0·84) mean rate of viral load decline (0·95 log10 copies per mL per day) than did unvaccinated individuals with pre-alpha (0·69), alpha (0·82), or delta (0·79) variant infections. Within individuals, faster viral load growth was correlated with higher peak viral load (correlation 0·42 [95% credible interval 0·13 to 0·65]) and slower decline (–0·44 [–0·67 to –0·18]).InterpretationVaccination reduces the risk of delta variant infection and accelerates viral clearance. Nonetheless, fully vaccinated individuals with breakthrough infections have peak viral load similar to unvaccinated cases and can efficiently transmit infection in household settings, including to fully vaccinated contacts. Host–virus interactions early in infection may shape the entire viral trajectory.FundingNational Institute for Health Research.

134 Virus kinetics and biochemical derangements in children with Ebolavirus disease

Abstract Primary Subject area Infectious Diseases Background In the second largest outbreak of Ebolavirus disease (EVD) on record (Democratic Republic of Congo, 2018-2020), 3470 cases were confirmed, 29% of them among children under 18 years of age. Objectives To describe virologic and biochemical characteristics of pediatric patients with EVD, and to compare these to a control group of adults with EVD. Design/Methods Retrospective medical record review of children &amp;lt; 16 years old from two treatment centres in North Kivu, DRC. A control group of patients 16-44 years old was included as a reference comparator group. Patient demographics, serial measurements of viral load, serial biochemistry panel, and frequent point-of-care glucose test results were abstracted from the chart record. Funding provided by the Association for Health Innovation in Africa (AFHIA). Results Seventy-three children and 234 adults were included, admitted from April 24 to October 14, 2019. Pediatric patients commonly had electrolyte imbalances (36% hypokalemia, 52% hyperkalemia, and 74% hyponatremia), AKI (51%), elevated liver enzymes (median peak ALT 380 IU/L and AST 570 IU/L), and rhabdomyolysis (48%). Viral load at admission (7.2 versus 6.5 log10copies/mL, p=0.0001), peak viral load (7.5 versus 6.7 log10copies/mL, p&amp;lt;0.0001), and time to clearance of viremia (16 versus 12 days p&amp;lt;0.0001) were significantly different in children. Duration of hospital stay (20 versus 16 days, p&amp;lt;0.0001) was prolonged in children, a direct consequence of slower clearance of viremia. There was no significant difference between groups in other laboratory values. Factors including ALT &amp;gt;525 U/L, viral load (VL) &amp;gt;7.6 log10copies/mL, BUN &amp;gt;7.5 mmol/L, and CRP &amp;gt;100 mg/L were associated with mortality in children, as in adults. In a multivariable logistic regression model, ALT and VL remained statistically significant independent predictors of mortality. Conclusion Pediatric patients with EVD, like adults, experience multi-organ involvement with life-threatening kidney and liver injury, rhabdomyolysis, and electrolyte imbalances. Pediatric patients have significantly higher viral loads throughout the course of EVD than adults.

Within Host Dynamics of SARS-CoV-2 in Humans: Modeling Immune Responses and Antiviral Treatments.

In December 2019, a newly discovered SARS-CoV-2 virus was emerged from China and propagated worldwide as a pandemic, resulting in about 3–5% mortality. Mathematical models can provide useful scientific insights about transmission patterns and targets for drug development. In this study, we propose a within-host mathematical model of SARS-CoV-2 infection considering innate and adaptive immune responses. We analyze the equilibrium points of the proposed model and obtain an expression of the basic reproduction number. We then numerically show the existence of a transcritical bifurcation. The proposed model is calibrated to real viral load data of two COVID-19 patients. Using the estimated parameters, we perform global sensitivity analysis with respect to the peak of viral load. Finally, we study the efficacy of antiviral drugs and vaccination on the dynamics of SARS-CoV-2 infection. Results suggest that blocking the virus production from infected cells can be an effective target for antiviral drug development. Finally, it is found that vaccination is more effective intervention as compared to the antiviral treatments.

Management of ganciclovir resistance cytomegalovirus infection with CMV hyperimmune globulin and leflunomide in seven cardiothoracic transplant recipients and literature review.

Cytomegalovirus (CMV) disease caused by genetically resistant CMV poses a major challenge in solid organ transplant recipients, and the development of resistance is associated with increased morbidity and mortality. Antiviral resistance affects 5%-12% of patients following ganciclovir (GCV) therapy, but is more common in individuals with specific underlying risk factors. These include the CMV D+R- serostatus, type of transplanted organ, dose and duration of (Val)GCV ([V]GCV) prophylaxis, peak viral loads, and the intensity of immunosuppressive therapy. Guideline recommendations for the management of GCV resistance (GanR) in solid organ transplant recipients are based on expert opinion as there is a lack of data from controlled trials. Second-line options to treat GanR include foscarnet (FOS) and cidofovir (CDV), but these drugs are often poorly tolerated due to high rates of toxicity, such as renal dysfunction and neutropenia. Here, we report seven cardiothoracic transplant recipients with GCV resistance CMV infection from our centre treated with CMV immunoglobulin (CMVIG) +/- leflunomide (LEF) and reviewed the literature on the use of these agents in this therapeutic setting.

An observational study of breakthrough SARS-CoV-2 Delta variant infections among vaccinated healthcare workers in Vietnam.

BackgroundData on breakthrough SARS-CoV-2 Delta variant infections in vaccinated individuals are limited.MethodsWe studied breakthrough infections among Oxford-AstraZeneca vaccinated healthcare workers in an infectious diseases hospital in Vietnam. We collected demographic and clinical data alongside serial PCR testing, measurement of SARS-CoV-2 antibodies, and viral whole-genome sequencing.FindingsBetween 11th–25th June 2021 (7-8 weeks after the second dose), 69 staff tested positive for SARS-CoV-2. 62 participated in the study. Most were asymptomatic or mildly symptomatic and all recovered. Twenty-two complete-genome sequences were obtained; all were Delta variant and were phylogenetically distinct from contemporary viruses obtained from the community or from hospital patients admitted prior to the outbreak. Viral loads inferred from Ct values were 251 times higher than in cases infected with the original strain in March/April 2020. Median time from diagnosis to negative PCR was 21 days (range 8–33). Neutralizing antibodies (expressed as percentage of inhibition) measured after the second vaccine dose, or at diagnosis, were lower in cases than in uninfected, fully vaccinated controls (median (IQR): 69.4 (50.7-89.1) vs. 91.3 (79.6-94.9), p=0.005 and 59.4 (32.5-73.1) vs. 91.1 (77.3-94.2), p=0.002). There was no correlation between vaccine-induced neutralizing antibody levels and peak viral loads or the development of symptoms.InterpretationBreakthrough Delta variant infections following Oxford-AstraZeneca vaccination may cause asymptomatic or mild disease, but are associated with high viral loads, prolonged PCR positivity and low levels of vaccine-induced neutralizing antibodies. Epidemiological and sequence data suggested ongoing transmission had occurred between fully vaccinated individuals.FundingWellcome and NIH/NIAID