National Institute Of Allergy And Infectious Diseases Research Articles

TNF receptors orchestrate differential neutrophil responses critical to immunity against Staphylococcus aureusskin infection

Abstract As the leading cause of skin and soft tissue infections, Staphylococcus aureus is a major health burden and a continued threat to human health due to the emergence of antibiotic-resistance. Through this current study, we aimed to better characterize the protective immune mechanisms against S. aureus skin infection to identify novel targets for the development of host-directed immunotherapeutics as alternatives to antibiotics. Tumor necrosis factor (TNF) is a master regulatory cytokine whose inhibition is associated with the increased risk of S. aureus skin colonization and infection in humans. Despite the clinical implications, the contribution of TNF and its cognate receptors, TNFR1 and TNFR2, to immunity against S. aureus skin infection is unclear. Utilizing an in vivo mouse model of S. aureus intradermal infection, we determined that immune cell-derived TNF engages with both TNFR1 and TNFR2 to promote protection against S. aureus in the skin. Neutrophil-intrinsic TNFR1 and TNFR2 signaling directed differential antimicrobial mechanisms against S. aureus skin infections. Mechanistically, TNFR1 mediated neutrophil recruitment to the skin, whereas TNFR2 directed neutrophil activation (e.g.-NOX2 activation, ROS production, and PAD4-dependent neutrophil extracellular trap (NET) formation) and prevented systemic dissemination of skin infection. Collectively, our findings revealed non-redundant functions and cellular mechanisms mediated by TNFR1 and TNFR2 in neutrophils for immunity against S. aureus. This study was funded in part by grants R01AR073665 (NKA), R01AR069502 (NKA), R01AI111205 (NKA), and R01AI146177 (NKA) and from the United States National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and National Institute of Allergy and Infectious Diseases (NIAID).

Cell-specific P2RX7 promotes the longevity of lung tissue-resident helper CD4 T cells in response to influenza infection

Abstract Development of universal influenza (flu) vaccines requires better knowledge of lung-resident immune responses. That includes flu-specific CD4 T cells, which establish long-term lung residency and induce a diversified local protective response to subsequent infection. Tissue-resident helper (Trh) cells are a subset of lung-resident CD4 T cells that share phenotypic and functional features with follicular helper cells (Tfh). Trh cells serve to amplify lung-resident immune responses, and express high levels of the extracellular ATP (eATP) sensor P2RX7. Considering that eATP levels in the lung increase in response to flu infection, we used T cell-specific P2RX7-knockout (KO) mice to test the role of P2RX7 for CD4 T cell responses to flu. During acute phase of infection, we found that P2RX7 promotes the accumulation of flu-specific CD4 T cells inside the lung tissue. Moreover, P2RX7 promoted this establishment via induction of CXCR3 upregulation. Despite no specific defects in the Trh pool at the acute phase, T cell-specific P2RX7-KO led to a progressive decay of Trh cells. Consequently, lungs of T cell-P2RX7-KO mice had reduced lung B cell responses. Our single-cell RNAseq of lung flu-specific CD4 T cells showed reduced expression of cell survival and mitochondrial genes in P2RX7-KO Trh cells. Our findings suggest that lung eATP sensing by CD4 T cells induces lung-resident CD4 T cell accumulation in response to flu, impacting the survival of specific lung CD4 T cell subsets. National Institute of Allergy and Infectious Diseases (NIAID) (H.BdS.: R00 AI139381, R01 AI170649).

New syndromic combined immunodeficiency with severe neurodevelopmental defects caused by biallelic null variants in the PPM1D gene

PPM1D (protein phosphatase Mn2+/Mg2+-dependent 1D) is a phosphatase that targets proteins related to the DNA damage repair system. C-terminal variants in PPM1D have been associated with: i) malignancy as somatic variants; and ii) Jansen-de-Vries (JdV) syndrome as germline heterozygous variants. JdV syndrome curses with moderate neurodevelopmental alterations and behavioral problems, such as autistic spectrum disorders (ASD), without reports of immunodeficiency.We describe two siblings (9 and 11 years old) born to consanguineous parents with progressive B and NK cell lymphopenia, agammaglobulinemia, non-ulcerative colitis and severe neurodevelopmental defects including microcephaly, severe encephalopathy, profound cognitive deficiency, and refractory epilepsy. Exome analysis revealed a homozygous N-terminal truncating variant in PPM1D (p.Thr174fs*6) in the two siblings inherited from their healthy heterozygous parents. The siblings’ clinical phenotype was markedly more severe than in the reported JdV patients, suggesting a different mechanism of action. To test this, we included a pediatric patient with classical JdV syndrome carrying an heterozygous PPM1D variant (p. Ser403fs*30). Using primary cells and exogenous overexpression we showed that mutation p.T174fs*6 abrogated protein expression by increased proteasome degradation, leading to no protein expression in a homozygous patient and a reduction in a haplosufficient parent. In contrast, the JdV variant (p.Ser403fs*30) led to accumulation of the truncated protein with conserved phosphatase activity, resulting in a previously undescribed gain-of-function (GOF) mechanism.We also demonstrated that chemical inhibition of WT-PPM1D in-vitro dramatically decreased B cell viability. This data, similar to the reported B cell deficiency in PPM1D-KO mice, helps to address the humoral deficiency in the patients, while not observed in the heterozygous parents nor JdV patient. To further explore NK cell deficiency, we will evaluate PPM1D-KO mice. We have generated EBV-B cell-derived iPSCs from PPM1D-null, PPM1D-haplosufficient an GOF-JdV individuals, to generate artificial cerebral organoids that will allow us to explore PPM1D gene-dosage effect in neurodevelopment and its potential manipulation.Here we report a novel biallelic PPM1D-null deficiency impairing B cell development. Besides, PPM1D dysregulation either by no protein expression or GOF appears to cause neurodevelopment abnormalities. Future studies will help to understand pathophysiology of PPM1D and better targeted clinical management.PPM1D research interest group:JF Quesada1, Mercè Bolasell2, Julie E. Niemela3, Jennifer L. Stoddard3, Agustin Gil Silva3, Brigette Boast3, José R Regueiro4, Pierre Martine5, David Lopez Perez5, Ettore Appella5, Laia Alsina6,7,8, Harry L Malech9, Hye Sun Kuehn3, Sergio D. Rosenzweig31. Department of Genetics, Hospital Universitario 12 de Octubre, Madrid, Spain.2. Department of Genetic and Molecular Medicine IPER, Institut de Recerca, Hospital Sant Joan de Déu Barcelona, Barcelona, Spain.3. Immunology Service, Department of Laboratory Medicine, Clinical Center, NIH, Bethesda, Maryland, USA4. Department of Immunology, Complutense University School of Medicine and Hospital 12 de Octubre Health Research Insitute, Madrid, Spain5. Laboratory of Cell Biology, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892.6. Clinical Immunology and Primary Immunodeficiencies Unit. Allergy and Clinical Immunology Department. Hospital Sant Joan de Déu. Barcelona, Spain.7. Clinical Immunology Unit. Hospital Sant Joan de Déu-Hospital Clinic. Barcelona, Spain.8. Study Group for Immune Dysfunction Diseases in Children (GEMDIP). Institut de Recerca Sant Joan de Déu. Barcelona, Spain.9. Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD.

Fishing for novel dengue broadly neutralizing antibodies

Abstract Due to a patent filing, the content of this abstract is not available to be shared at this time. The abstract will be shared at the poster session. This work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health.

Spleen tyrosine kinase inhibition restores neutrophil homeostasis in COVID-19

Abstract Spleen tyrosine kinase (SYK) is a novel therapeutic target that inhibits neutrophil and macrophage activation in coronavirus disease 2019 (COVID-19). Fostamatinib, a SYK inhibitor, was studied in a phase 2 placebo-controlled randomized clinical trial and was associated with improvements in many secondary end points related to efficacy. Here, we used a multiomic approach to evaluate cellular and soluble immune mediator responses of patients enrolled in this trial. We demonstrated that SYK inhibition was associated with reduced neutrophil activation, increased circulation of mature neutrophils (CD10+CD33−), and decreased circulation of low-density granulocytes (LDG) and polymorphonuclear myeloid-derived suppressor cells (HLA-DR–CD33+CD11b−). Additionally, LDG transcriptional profiles were distinct in COVID-19 compared to during autoimmune conditions. Together, these data suggest that SYK inhibition may mitigate proinflammatory neutrophil cellular and soluble mediator responses thought to contribute to immunopathogenesis of severe COVID-19. This work has been funded in part by the Intramural Research Program of the NIH Clinical Center (NIHCC) including a Research Award for Staff Clinicians (FY2020/FY2021), NHLBI, National Institute of Allergy and Infectious Diseases (NIAID), and National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAIMS)

Indirect IgG ELISA and serotype-specific neutralizing antibody titers are associated with protection against dengue in children in Cebu, Philippines

Abstract Standard measures of dengue virus (DENV) antibodies have not been established as protective against dengue. We assess whether an indirect dengue IgG ELISA (PanBio; Brisbane, QLD, Australia) and serotype-specific neutralizing antibody titers measured by a two-dilution focus reduction neutralization test (FRNT) are associated with protection against dengue. Healthy children (n = 1,214) aged 9–14 years in Cebu, Philippines were enrolled in a prospective population-based cohort study in May – June 2017 and were tested for dengue when they reported a febrile illness through March 2020. Serum samples were collected at enrollment, and all were tested by ELISA. FRNTs were performed using the WHO DENV1–4 reference strains on a random subset to quantify serotype-specific neutralizing antibodies (nAbs). Inverse probability weighting was used to adjust for subset size. The odds of dengue as predicted by antibody measures were assessed by logistic regressions and adjusted for age, gender, and residential site. Dengue naïve children were used as the reference group in all models. The probability of dengue was 9.2% (95% CI: 4.5 – 17.9) for the naïve group, 9.5% (4.8 – 17.8) for those with ELISA < 2, but 4.5% (2.8 – 7.2) for those with ELISA >= 2 (p=0.04). The probability was even lower at 1.4% (0.6 – 3.1) for those with the highest DENV1–4 geometric mean titers (GMT, p = 0.0001). Pre-vaccine nAbs to DENV2 and DENV3 were protective against a homotypic dengue case (DENV2: OR 0.28, 95% CI 0.12 to 0.65; DENV3: OR 0.27, 95% CI 0.13 to 0.57), but not heterotypic dengue. We show a commercial ELISA and serotype-specific nAbs are associated with the probability of dengue, providing useful assays for use in population and vaccine trials. This work was supported by the Philippine Department of Health, the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), and NIH Extramural Grant: P01AI106695.

Detection of envelope-dimer epitope-like broadly protective antibodies in dengue-immune children in the Philippines following vaccination and natural infection

Abstract The dengue vaccine, Dengvaxia, has been described as eliciting antibody-dependent enhancement (ADE) in dengue-naive individuals. There is an urgent need to develop an effective dengue virus (DENV) vaccine that elicits protective, cross-reactive (CR) neutralizing antibodies (NAbs), which are capable of neutralizing DENV1–4 without triggering ADE such as EDE Abs. Here, we investigated the CRNAbs profile following DENV natural infection versus vaccination in children with prior DENV infection (n=2,996) from a longitudinal vaccine (study) cohort in Cebu, Philippines. In total, 1,214 of these children remained unvaccinated while 1,782 children received a single dose of Dengvaxia in June of 2017 during a mass vaccination campaign. Serum samples were collected one month before and one year after the vaccine campaign. To measure baseline status and change in CRNAbs level following vaccination versus natural infection, we ran Focus Reduction Neutralizing Test (FRNT) using mature DENV1–4 virions and Blockade of binding (B0B) assay against EDE Abs on a random subset of these DENV-immune children’s samples (n=231). Furthermore, we also measured IgG binding against the DENV1–4 E protein monomer and DENV2 E protein dimer. Both vaccinated and naturally infected groups elicit CRNAbs that recognize the quaternary epitopes of EDE antibodies. We also see a significant increase in antibody response in both groups, but CRNAbs had a stronger correlation to mature FRNT in naturally infected compared to vaccinated populations, indicating differences in antibody quality. These results highlight the presence of EDE-like broadly NAbs that could possibly protect against the four DENV serotypes and provide an insight for future vaccine candidates. This work was supported by the Intramural Research Program (DIR) of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, the Philippine Department of Health and the University of North Carolina (PO1: P01AI106695).

Trends & Technology

Trends & Technology| April 2023 Trends & Technology ASA Monitor April 2023, Vol. 87, 11–15. https://doi.org/10.1097/01.ASM.0000924948.54149.57 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Search Site Citation Trends & Technology. ASA Monitor 2023; 87:11–15 doi: https://doi.org/10.1097/01.ASM.0000924948.54149.57 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll PublicationsASA Monitor Search Advanced Search Topics: trend, vaccines An experimental vaccine against Marburg virus (MARV) developed by researchers at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), was found to be safe and induced an immune response in a small, first-in-human clinical trial. This phase 1 study tested an experimental MARV vaccine candidate known as cAd3-Marburg. This vaccine uses a modified chimpanzee adenovirus called cAd3, which can no longer replicate or infect cells, and displays a glycoprotein found on the surface of MARV to induce immune responses against the virus. MARV causes a rapidly progressive febrile illness that leads to shock and death in a large proportion of infected individuals. The symptoms of MARV disease are akin to those seen with Ebola virus and can include fever, headache, chills, rash, abdominal pain, vomiting, and diarrhea. As the disease progresses, patients may suffer from multiple organ dysfunction, delirium, and significant... You do not currently have access to this content.

Industry Update, October 2022.

Industry Update, October 2022.

An evaluation of programs to support new investigators at the National Institute of Allergy and Infectious Diseases: Striking a balance with funding for established investigators

As the largest funder of basic biomedical research in the US, the National Institutes of Health (NIH) has an interest in maintaining a sustainable, productive workforce of investigators. Over the years, NIH has implemented several programs to attract early-stage investigators and other applicants without prior NIH support. The latest of these is the Next Generation Researchers Initiative. These programs have been shown to be successful in meeting NIH-wide goals but their success for any particular NIH institute or center (IC), and in any particular year, is determined by a variety of factors, some extrinsic to an IC’s funding decision process. Each IC must balance support for new investigators with funding for productive ongoing programs of research. We examine historical trends in support of new investigators at the National Institute of Allergy and Infectious Diseases (NIAID) over a 22-year period, as well as trends in some major extrinsic influences on that support. The results indicate that NIH’s new investigator programs have succeeded in maintaining a balance between the support for new NIAID investigators while also continuing to support an expanded pool of established investigators. The programs have been particularly effective in providing support to early-stage investigators.

1953. Immune responses, viral shedding, and COVID-19 symptom burden from breakthrough SARS-CoV-2 infection in a 2:1 randomized, double-blind, placebo-controlled Phase 3 study of AZD1222 (ChAdOx1 nCoV-19) vaccination

Abstract Background Breakthrough infections post-COVID-19 vaccination increase with waning immunity and typically produce milder disease than infections in unvaccinated individuals. We investigated immuno-virologic responses and COVID-19 symptom burden upon breakthrough infection in participants from a Phase 3 study of 2-dose primary series AZD1222 vaccination (NCT04516746) to explore disease attenuation. Methods Study participants who experienced protocol-defined COVID-19 symptoms initiated a series of illness visits over 28 days with collection of sera, nasopharyngeal (NP) swabs and saliva samples (SS), and documentation of symptoms (data-cut off: July 30, 2021). For baseline-seronegative participants with PCR-confirmed SARS-CoV-2 infection ≥15 days after dose 2 of AZD1222 or placebo we assessed: anti-SARS-CoV-2 spike (S), nucleocapsid (N) and neutralizing antibody (Ab) titers by multiplex immunoassay and SARS-CoV-2 pseudovirus assay in sera; viral load by quantitative RT-PCR in NP swabs; and viral shedding by qualitative and quantitative RT-PCR in SS. Data were stratified by age and SARS-CoV-2 variant, and time since primary series dose 2. Results Illness Day 1 (ILL-D1) S Ab GMTs in AZD1222 vaccinees were similar to peak GMTs seen 14 days after dose 2 of AZD1222 and were higher vs placebo at all timepoints. The magnitude of S Ab response differed by age: median GMTs were lower at ILL-D1 and higher at ILL-D14 in vaccinees aged ≥65 vs 18–64 years (Fig.1). ILL-D1 overall, SARS-CoV-2 ancestral, alpha, and epsilon variant viral load titers in NP swabs were lower in vaccinees vs placebo (Fig 2). Mean viral load in NP swabs and viral shedding titers in SS were lower in vaccinees vs placebo at all timepoints. Vaccinees reported fewer COVID-19 symptoms than placebo participants, and experienced shorter symptom duration, particularly for fatigue and difficulty breathing. Figure 1. SARS-CoV-2 spike IgG antibody titers upon SARS-CoV-2 infection by participant age in AZD1222 vaccinees and placebo recipients during illness visits Figure 2. Quantification of viral load (nasopharyngeal swabs quantitative viral titer) by SARS-CoV-2 variant at Illness Visit Day 1 Conclusion Improved S Ab responses, lower viral loads, and reduced symptom burden upon breakthrough infection in vaccinees vs placebo recipients, suggest that robust recall responses to AZD1222 vaccination may attenuate COVID-19 disease severity and duration. These findings alongside data on cellular immune responses to breakthrough infection will inform understanding of protective immunity to SARS-CoV-2 infection. Disclosures Magdalena E. Sobieszczyk, MD, MPH, Bill and Melinda Gates Foundation: Grant/Research Support|Gilead Sciences: Grant/Research Support|Janssen Global Services, LLC: Grant/Research Support|Merck: Grant/Research Support|National Institute of Allergy and Infectious Diseases (NIAID): Grant/Research Support|National Institutes of Health (NIH): Grant/Research Support|Sanofi Pasteur Inc.: Grant/Research Support Ann R. Falsey, MD, BioFire Diagnostics: Grant/Research Support|Janssen: Grant/Research Support|Merck, Sharp and Dohme: Grant/Research Support|Novavax: Advisor/Consultant|Pfizer: Grant/Research Support Anne F. Luetkemeyer, MD, AstraZeneca: Grant/Research Support|Gilead Sciences: Grant/Research Support Grant C. Paulsen, MD, AstraZeneca: Grant/Research Support|Moderna: Grant/Research Support|Pfizer: Grant/Research Support Sharon A. Riddler, MD, National Institute of Allergy and Infectious Diseases (NIAID): Grant/Research Support|National Institutes of Health (NIH): Grant/Research Support|Novimmune: Advisor/Consultant Merlin L. Robb, MD, Walter Reed Army Institute of Research: Advisor/Consultant Charlotte-Paige M. Rolle, MD, MPH, Gilead Sciences: Board Member|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria|Janssen: Board Member|ViiV Healthcare: Board Member|ViiV Healthcare: Grant/Research Support|ViiV Healthcare: Honoraria|Vindico CME: Honoraria Beverly E. Sha, MD, Gilead Sciences: Grant/Research Support|MATEC: Honoraria|University of Chicago: Grant/Research Support|US Government: Grant/Research Support Bahar Ahani, BSC, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Anastasia A. Aksyuk, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Himanshu Bansal, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Justin A. Green, MD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Brett Jepson, MS, AstraZeneca: Contractor via Cytel Jill Maaske, MD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Kathryn Shoemaker, MS, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Stephanie Sproule, MMath, AstraZeneca: Contractor via Joule/System One Ann Marie Stanley, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Deidre Wilkins, BSC, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Tonya L. Villafana, PhD, MPH, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds Elizabeth J. Kelly, PhD, AstraZeneca: Employee|AstraZeneca: Stocks/Bonds.

A single-shot ChAd3-MARV vaccine confers rapid and durable protection against Marburg virus in nonhuman primates.

Marburg virus (MARV) causes a severe hemorrhagic fever disease in primates with mortality rates in humans of up to 90%. MARV has been identified as a category A bioterrorism agent by the Centers for Disease Control and Prevention (CDC) and priority pathogen A by the National Institute of Allergy and Infectious Diseases (NIAID), needing urgent research and development of countermeasures because of the high public health risk it poses. The recent cases of MARV in West Africa underscore the substantial outbreak potential of this virus. The potential for cross-border spread, as had occurred during the 2014-2016 Ebola virus outbreak, illustrates the critical need for MARV vaccines. To support regulatory approval of the chimpanzee adenovirus 3 (ChAd3)-MARV vaccine that has completed phase 1 trials, we showed that the nonreplicating ChAd3 vector, which has a demonstrated safety profile in humans, protected against a uniformly lethal challenge with MARV/Ang. Protective immunity was achieved within 7 days of vaccination and was maintained through 1 year after vaccination. Antigen-specific antibodies were an immune correlate of protection in the acute challenge model, and their concentration was predictive of protection. These results demonstrate that a single-shot ChAd3-MARV vaccine generated a protective immune response that was both rapid and durable with an immune correlate of protection that will support advanced clinical development.

Introducing the Bacterial and Viral Bioinformatics Resource Center (BV-BRC): a resource combining PATRIC, IRDand ViPR.

The National Institute of Allergy and Infectious Diseases (NIAID) established the Bioinformatics Resource Center (BRC) program to assist researchers with analyzing the growing body of genome sequence and other omics-related data. In this report, we describe the merger of the PAThosystems Resource Integration Center (PATRIC), the Influenza Research Database (IRD) and the Virus Pathogen Database and Analysis Resource (ViPR) BRCs to form the Bacterial and Viral Bioinformatics Resource Center (BV-BRC) https://www.bv-brc.org/. The combined BV-BRC leverages the functionality of the bacterial and viral resources to provide a unified data model, enhanced web-based visualization and analysis tools, bioinformatics services, and a powerful suite of command line tools that benefit the bacterial and viral research communities.

Evaluating the predictive utility of patient‐oriented scoring of atopic dermatitis (PO‐SCORAD) versus Patient‐Oriented Eczema Measure (POEM) for peanut sensitivity in patients with atopic dermatitis

AbstractBackgroundCurrent Guidelines from the National Institute of Allergy and Infectious Disease (NIAID) are based on the Learning Early About Peanut Allergy Study (LEAP Study) results and recommend early introduction of peanuts to children with atopic dermatitis (AD) depending on their disease severity. There is yet to be a widely accepted method of evaluating AD severity among clinicians. Thus, the purpose of this study was to determine the association between AD severity as measured by patient‐oriented scoring of atopic dermatitis(PO‐SCORAD) and Patient Oriented Eczema Measure (POEM) surveys and peanut sensitivity as measured by Immunoglobulin E (IgE) or skin prick test levels.ObjectivesThe primary objective of this study was to determine the association between AD severity as measured by PO‐SCORAD and POEM surveys and peanut sensitivity as measured by IgE or skin prick test levels. The secondary objective of this study was to determine the rate of peanut sensitisation amongst patients with ‘mild AD’ as defined by PO‐SCORAD score of 1−27 and a POEM score of 0‐7.MethodsPatients between 3 months and 18 years old undergoing IgE or skin prick testing for peanut allergy were recruited from two allergy clinics in the Chicagoland area. Patients or their guardians completed a PO‐SCORAD survey and POEM survey.ResultsThere was no significant difference in AD severity (as measured by PO‐SCORAD or POEM score) between sexes or age groups (<12 months vs. ≥12 months). Moreover, there was no significant relationship found between PO‐SCORAD or POEM scores and rate of peanut sensitivity.ConclusionDespite no significant relationship found between PO‐SCORAD or POEM score and peanut sensitivity, the hypothesis that AD severity can predict risk of peanut sensitivity may still be valid based on a growing body of evidence. The negative results of this study are likely due to the small study population used due to limitations of the COVID‐19 pandemic. Moreover, evaluating AD severity through PO‐SCORAD and POEM surveys may not be ideal for paediatric patients.

Editorial introductions.

Editorial introductions.

Impact of extramural DAIT/NIAID pharmacy programs, research pharmacist scientist oversight on study performance, and lessons learned

PurposeOver the past two decades, the involvement of a Pharmacist Scientist in clinical settings has improved patient safety, decreased medication errors, and enabled successful conduct of clinical trials and faster product development [1–5]. The impact of an oversight by a Pharmacist Scientist on clinical trial performance and execution in terms of Pharmacy and Investigational Product (IP)-related deviations has not been evaluated by a sponsor. MethodsThis was a retrospective observational study conducted by the Division of Allergy, Immunology and Transplantation (DAIT), National Institute of Allergy and Infectious Diseases (NIAID). We assessed the association of the number of Pharmacy and Investigational Product (IP)-related deviations with Pharmacist oversight and use of DAIT Pharmacy/ Pharmaceutical services in two groups: Intervention Group (IG) and the Control Group (CG). ResultsWe evaluated monitoring data from 116 studies conducted between 2006 through 2020. Forty-one eligible clinical trials were included and analyzed: 13 trials were in the IG with Pharmacist oversight and use of Pharmacy Services; 28 trials were in the CG with no Pharmacist oversight and zero to partial use DAIT Pharmacy/ Pharmaceutical Services. The evaluation revealed the expected risk of having a pharmacy and IP-related deviations were 2.94 times higher (95% CI 1.28, 6.67, = 0.01) in trials not having Pharmacist oversight and zero to partial use of Pharmaceutical/ Pharmacy Program services. This significant finding was associated with having Pharmacist oversight when adjusting for study size (# of sites and patients needed), anticipated study duration, design complexity, and whether recruitment was completed or not. ConclusionWe found a statistically significant association between Pharmacist Scientist involvement and oversight from protocol development to study execution and a reduction in Pharmacy and IP-related deviations.

P361 Demystifying the NIH grant application process for international investigators

Poster session 3, September 23, 2022, 12:30 PM - 1:30 PM The National Institute of Allergy and Infectious Diseases (NIAID) funds one of the largest medical mycology research portfolios. The portfolio includes the major human fungal pathogens and covers basic fungal biology and the more translational areas of therapeutics, vaccines, and diagnostics. NIAID utilizes many granting mechanisms that are open to US and international researchers. These include investigator-initiated applications (R01, R21, and R03s) and targeted announcements for fungal research. Additionally, NIAID has a suite of preclinical services supporting therapeutic, diagnostic, and vaccine development. These services are free and available to investigators in academia, not-for-profit organizations, industry, or governments worldwide. The NIAID granting mechanism can be complicated. Tips and tricks for navigating the NIAID application process and preclinical services will be discussed.

423.3: Long-term Outcomes Following HLA-Incompatible Living Donor Kidney Transplantation

Introduction: Incompatible living donor kidney transplantation (ILDKT) offers a survival benefit compared to dialysis for patients with donor specific antibody (DSA) who do not have a compatible living donor. Longer-term outcomes have not been characterized in this population, but must be quantified to inform treatment selection for patients with an incompatible willing donor, and counseling for ILDKT recipients. Method: We compared 1,406 ILDKT to 17,542 compatible LDKT (CLDKT) recipients using a 25-center cohort from the United States 1997-2016, linked to national registry data (SRTR). Participating centers classified ILDKT recipients as positive Luminex, negative flow crossmatch (PLNF, n=376); positive flow, negative cytotoxic crossmatch (PFNC, n=687); or positive cytotoxic crossmatch (PCC, n=343). We used multivariable Cox regression to quantify the risk of mortality and death-censored graft failure (DCGF), and multilevel mixed-effects linear regression to evaluate eGFR decline (CKD-EPI creatinine equation 2021) in ILDKT and CLDKT recipients. Results: The cumulative mortality risk for CLDKT, PLNF, PFNC, and PCC was: 1.6%, 1.9%, 3.2%, and 8.2% at one year; 22.5%, 18.4%, 29.4%, and 36.1% at ten years; and 39.1%, 36.1%, 45.4% and 51.6% at fifteen-years (p<0.001) (Figure 1A). Although this translated to an equivalent mortality risk for PLNF recipients (aHR=0.830.961.12, p=0.6) after adjustment, PFNC and PCC recipients had a 1.48-fold (aHR=1.301.481.68, p<0.001) and 1.66-fold (aHR=1.331.662.08, p<0.001) higher risk compared their CLDKT counterparts, respectively. The cumulative risk of DCGF for CLDKT, PLNF, PFNC, and PCC was: 1.9%, 2.1%, 3.4%, and 11.1% at one year; 16.8%, 20.5%, 33.1%, and 41.0% at ten years; and 25.5%, 33.1%, 45.2% and 52.5% at fifteen-years (p<0.001) (Figure 1B). After adjustment, this translated to higher DCGF across all levels of DSA strength (aHR PLNF=1.141.411.73, PFNC=1.491.711.95, PCC=1.612.082.67; p for all≤0.001). Conversely, ILDKT and CLDKT recipients had comparable average eGFR immediately post-transplant (difference=-4.22-1.511.20 mL/min/1.73m2, p=0.3). However, ILDKT recipients had faster decline in eGFR per year compared to CLDKT recipients (difference in slope=-1.06-0.76-0.47 mL/min/1.73m2 per year, p<0.001; decline over 5 years for ILDKT=-9.01-7.55-6.10 mL/min/1.73m2 vs. CLDKT=-4.19-3.74-3.29 mL/min/1.73m2). Conclusion: Patient and graft survival following ILDKT is good through fifteen years post-transplant, supporting this modality, but survival is worse compared to CLDKT recipients. ILDKT recipients bear close monitoring to maximize graft life.This work was supported by grant numbers K01DK101677 (Massie) and R01DK98431 (Segev) from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Dr. Segev is supported by the K24AI144954 (Segev) from the National Institute of Allergy and Infectious Diseases (NIAID).

423.2: Patient and Graft Survival After A1/A2-Incompatible Living Donor Kidney Transplantation

Background: ABO type B and O kidney transplant candidates often have increased difficulty identifying a compatible donor for living donor kidney transplantation (LDKT) and are harder to match in kidney paired donation (KPD) registries. A2-incompatible (A2i) LDKT increases access to LDKT for these patients. Kidney transplantation across the A2 barrier (A2 -> O, A2 -> B, A2B -> B) is believed to be safer than that across the A1 barrier (A1 -> O, A1 -> B, A1B -> B) because A2 kidneys express fewer A antigens on their renal endothelial surfaces. However, the differential risk of A2i LDKT and its relative benefit when compared to A1-incompatible (A1i) LDKT, if any, remains unknown. To better inform living donor selection, we evaluated the association between A2i LDKT and patient and graft survival. Methods: We used inverse probability weighted Cox regression to compare mortality, death-censored graft failure, and all-cause graft loss in A2i vs. ABO-compatible (ABOc) recipients. These methods were repeated to compare mortality, death-censored graft failure, and all-cause graft loss between A1i vs. comparable ABOc LDKT recipients. Results: Using data from the Scientific Registry of Transplant Recipients (SRTR) 2000-2019, we identified 345 A2i LDKT recipients. Mortality was comparable among A2i and ABOc recipients; weighted 1/5/10-year mortality was 1.0%/7.7%/24.3%, respectively, among A2i LDKT recipients vs. 1.8%/8.7%/23.1%, respectively, among comparable recipients in the ABOc LDKT weighted cohort (wHR 0.751.021.40, p=0.9). However, A2i recipients faced higher risk of death-censored graft failure; weighted 1/5/10-year graft failure was 7.9%/16.4%/28.3% for A2i vs. 2.2%/9.7%/20.4% for ABOc recipients (wHR in year 1 = 2.053.766.88; through year 5 = 1.231.983.19; through year 10 = 1.131.672.46). By comparison, 1/5/10-year weighted hazard ratios for death-censored graft failure among A1-incompatible recipients were 0.164.7019.07/0.471.595.35/0.421.213.53. Conclusions: This registry analysis considered the differential risk of A2i LDKT in the United States and demonstrated comparable mortality to ABOc LDKT recipients, but an increased risk of death-censored graft failure for A2i LDKT recipients, particularly in the first year post-transplant. Nonetheless, A2i LDKT remains an excellent treatment option, providing access to LDKT for patients who must otherwise remain on the waitlist in hopes of receiving DDKT. Our findings further the field’s understanding of the risks and benefits of A2i LDKT, and should inform patient counseling, KPD matching algorithms, and post-operative monitoring procedures in the future.K24AI144954 from the National Institute of Allergy and Infectious Diseases (NIAID). K01DK101677 from the National Institute of Diabetes andDigestive and Kidney Diseases (NIDDK).

314.1: Response to a Pandemic: The Fall and Rise of Kidney Transplantation in the United States

Background: Following the outbreak of COVID-19 in the United States, the number of kidney waitlist additions and living-donor and deceased-donor kidney transplants (LDKT/DDKT) decreased substantially but began recovering within a few months. Since then, there have been several additional waves of infection, most notably, the Delta and current Omicron surge beginning in August and December 2021, respectively. By 1/12/2022, the Omicron surge peaked at 802,699 confirmed new cases, compared to a pre-Omicron peak of 251,772 confirmed new cases on 1/8/2021, demonstrating an immense disease burden on the American population that could have been enough to disrupt transplant practices. Methods: Using data from the Scientific Registry of Transplant Recipients (SRTR), we compared observed waitlist registrations, waitlist mortality, waitlist removal, LDKT, and DDKT in the United States over four distinct pandemic waves to expected events based on calculations from pre-epidemic and non-wave pandemic data, while accounting for seasonality and secular trends. Four distinct time periods/waves of high COVID-19 incidence in the United States were identified for analysis. Wave 1 was defined March 15, 2020 – May 31, 2020; Wave 2 was defined December 1, 2020 – January 31, 2021; Wave 3 was defined August 1, 2021 – September 30, 2021; and Wave 4 was defined December 1, 2021 – January 31, 2022. Waves 1, 2, 3, and 4 were referred to as the Initial, Winter 2021, Delta, and Omicron waves during our analysis. Results: Although the number of daily waitlist additions has been increasing since May 2020, the size of the active waitlist has consistently declined, reaching a minimum of 53,180 on 1/31/2022. The recent Omicron surge knocked LDKT from 12% below expected (IRR = 0.820.880.95) during the Delta wave to 34% below expected (IRR = 0.610.660.71). DDKT, in contrast, was relatively unaffected by the Omicron wave (IRR = 0.830.870.91 and 0.820.850.89 during the Delta and Omicron waves, respectively). Waitlist death declined from 20% above expected (IRR = 1.111.201.30) during Delta to 19% below expected (IRR = 0.740.810.89) during Omicron, whereas waitlist removal remained at expected levels throughout both (IRR = 0.951.041.13 and 0.991.081.18 during Delta and Omicron, respectively). Note, this was the first time that an outcome returned to expected levels since the start of the pandemic. Conclusions: The Omicron wave brought substantial declines in DDKT and LDKT that have not been seen since the Initial wave. Due to vaccine mandates in place at many transplant centers across the nation, the American SRTR population now has high levels of vaccination including high levels of second and third booster shots. Hence, despite the Omicron wave’s exceptionally high COVID-19 infection incidence in the American national cohort, there was no increase in waitlist mortality, likely due to vaccination.Ben-Dov family. K24AI144954 from National Institute of Allergy and Infectious Diseases (NIAID). K01DK101677 from National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).