N Engl J Med
BACKGROUND: Efficacious vaccines are urgently needed to contain the ongoing coronavirus disease 2019 (Covid-19) pandemic of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A candidate vaccine, Ad26.COV2.S, is a recombinant, replication-incompetent adenovirus serotype 26 (Ad26) vector encoding a full-length and stabilized SARS-CoV-2 spike protein. METHODS: In this multicenter, placebo-controlled, phase 1-2a trial, we randomly assigned healthy adults between the ages of 18 and 55 years (cohort 1) and those 65 years of age or older (cohort 3) to receive the Ad26.COV2.S vaccine at a dose of 51010 viral particles (low dose) or 11011 viral particles (high dose) per milliliter or placebo in a single-dose or two-dose schedule. Longer-term data comparing a single-dose regimen with a two-dose regimen are being collected in cohort 2; those results are not reported here. The primary end points were the safety and reactogenicity of each dose schedule. RESULTS: After the administration of the first vaccine dose in 805 participants in cohorts 1 and 3 and after the second dose in cohort 1, the most frequent solicited adverse events were fatigue, headache, myalgia, and injection-site pain. The most frequent systemic adverse event was fever. Systemic adverse events were less common in cohort 3 than in cohort 1 and in those who received the low vaccine dose than in those who received the high dose. Reactogenicity was lower after the second dose. Neutralizing-antibody titers against wild-type virus were detected in 90% or more of all participants on day 29 after the first vaccine dose (geometric mean titer [GMT], 224 to 354) and reached 100% by day 57 with a further increase in titers (GMT, 288 to 488), regardless of vaccine dose or age group. Titers remained stable until at least day 71. A second dose provided an increase in the titer by a factor of 2.6 to 2.9 (GMT, 827 to 1266). Spike-binding antibody responses were similar to neutralizing-antibody responses. On day 14, CD4+ T-cell responses were detected in 76 to 83% of the participants in cohort 1 and in 60 to 67% of those in cohort 3, with a clear skewing toward type 1 helper T cells. CD8+ T-cell responses were robust overall but lower in cohort 3. CONCLUSIONS: The safety and immunogenicity profiles of Ad26.COV2.S support further development of this vaccine candidate. (Funded by Johnson & Johnson and the Biomedical Advanced Research and Development Authority of the Department of Health and Human Services; COV1001 ClinicalTrials.gov number, NCT04436276.).
Autologous, CCR5 gene-edited hematopoietic stem and progenitor cell (HSPC) transplantation is a promising strategy for achieving HIV remission. However, only a fraction of HSPCs can be edited ex vivo to provide protection against infection. To project the thresholds of CCR5-edition necessary for HIV remission, we developed a mathematical model that recapitulates blood T cell reconstitution and plasma simian-HIV (SHIV) dynamics from SHIV-1157ipd3N4-infected pig-tailed macaques that underwent autologous transplantation with CCR5 gene editing. The model predicts that viral control can be obtained following analytical treatment interruption (ATI) when: (1) transplanted HSPCs are at least fivefold higher than residual endogenous HSPCs after total body irradiation and (2) the fraction of protected HSPCs in the transplant achieves a threshold (76-94%) sufficient to overcome transplantation-dependent loss of SHIV immunity. Under these conditions, if ATI is withheld until transplanted gene-modified cells engraft and reconstitute to a steady state, spontaneous viral control is projected to occur.
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) with CCR5- donor cells is the only treatment known to cure HIV-1 in patients with underlying malignancy. This is likely due to a donor cell-mediated graft-versus-host effect targeting HIV reservoirs. Allo-HSCT would not be an acceptable therapy for most people living with HIV due to the transplant-related side effects. Chimeric antigen receptor (CAR) immunotherapies specifically traffic to malignant lymphoid tissues (lymphomas) and, in some settings, are able to replace allo-HSCT. Here, we quantified the engraftment of HSC-derived, virus-directed CAR T cells within HIV reservoirs in a macaque model of HIV infection, using potentially novel IHC assays. HSC-derived CAR cells trafficked to and displayed multilineage engraftment within tissue-associated viral reservoirs, persisting for nearly 2 years in lymphoid germinal centers, the brain, and the gastrointestinal tract. Our findings demonstrate that HSC-derived CAR+ cells reside long-term and proliferate in numerous tissues relevant for HIV infection and cancer.
J Clin Invest
Characterization of the T cell response in individuals who recover from SARS-CoV-2 infection is critical to understand its contribution to protective immunity. A multiplexed peptide-MHC tetramer approach was used to screen 408 SARS-CoV-2 candidate epitopes for CD8+ T cell recognition in a cross-sectional sample of 30 COVID-19 convalescent individuals. T cells were evaluated using a 28-marker phenotypic panel, and findings were modelled against time from diagnosis, humoral and inflammatory responses. There were 132 SARS-CoV-2-specific CD8+ T cell responses detected across six different HLAs, corresponding to 52 unique epitope reactivities. CD8+ T cell responses were detected in almost all convalescent individuals and were directed against several structural and non-structural target epitopes from the entire SARS-CoV-2 proteome. A unique phenotype for SARS-CoV-2-specific T cells was observed that was distinct from other common virus-specific T cells detected in the same cross-sectional sample and characterized by early differentiation kinetics. Modelling demonstrated a coordinated and dynamic immune response characterized by a decrease in inflammation, increase in neutralizing antibody titer, and differentiation of a specific CD8+ T cell response. Overall, T cells exhibited distinct differentiation into stem-cell and transitional memory states, subsets, which may be key to developing durable protection.
Hum Gene Ther
Introduction On May 11, 2020, the National Institutes of Health (NIH) and the Bill & Melinda Gates Foundation (Gates Foundation) held an exploratory expert scientific roundtable to inform an NIH-Gates Foundation collaboration on the development of scalable, sustainable, and accessible HIV and sickle cell disease (SCD) therapies based on in vivo gene editing of hematopoietic stem cells (HSC). A particular emphasis was on how such therapies could be developed for low-resource settings in sub-Saharan Africa. Paula Cannon, Ph.D., of the University of Southern California and Hans-Peter Kiem, M.D., Ph.D., of the Fred Hutchinson Cancer Research Center served as roundtable co-chairs. Welcoming remarks were provided by the leadership of NIH, NHLBI, and BMGF, who cited the importance of assessing the state of the science and charting a path toward finding safe, effective, and durable gene-based therapies for HIV and sickle cell disease. These remarks were followed by three sessions in which participants heard presentations on and discussed the therapeutic potential of modified HSCs, leveraging HSC biology and differentiation, and in vivo HSC targeting approaches. This roundtable serves as the beginning of an ongoing discussion among NIH, the Gates Foundation, research and patient communities, and the public at large. As this collaboration progresses, these communities will be engaged as we collectively navigate the complex scientific and ethical issues surrounding in vivo HSC targeting and editing. Summarized excerpts from each of the presentations are below, reflecting the individual views and perspectives of each presenter.
Int J Infect Dis
OBJECTIVES: HPTN 075 enrolled men who have sex with men (MSM) and transgender women (TGW) in sub-Saharan Africa. Persons in HIV care or on antiretroviral treatment (ART) were not eligible to enroll. We evaluated antiretroviral (ARV) drug use, viral suppression, and drug resistance in this cohort over a 12-month follow-up period. METHODS: Assessments included 64 participants with HIV (39 MSM, 24 TGW, one gender not specified). ARV drugs were detected using a qualitative assay. Viral load (VL) and drug resistance testing were performed using commercial assays. RESULTS: Over 12 months, the proportion of participants using ARV drugs increased from 28.1% to 59.4% and the proportion with VLs <400 copies/mL increased from 21.9% to 57.8%. The rate of ART failure (detection of drugs without viral suppression) was similar at screening and 12 months (12.0% and 11.1%, respectively) and was similar among MSM and TGW. Two participants developed HIV drug resistance during follow-up. CONCLUSIONS: Over 12 months, ARV drug use in the cohort more than doubled and viral suppression increased nearly three-fold without a significant increase in ART failure or drug resistance. These results suggest that ART can be successfully scaled up for HIV prevention and treatment in this high-risk population.
Much remains unknown about the roles of CD4+ T helper cells in shaping localized memory B cell and CD8+ T cell immunity in the mucosal tissues. Here, we report that lung T helper cells provide local assistance for the optimal development of tissue-resident memory B and CD8+ T cells after the resolution of primary influenza virus infection. We have identified a population of T cells in the lung that exhibit characteristics of both follicular T helper and TRM cells, and we have termed these cells as resident helper T (TRH) cells. Optimal TRH cell formation was dependent on transcription factors involved in T follicular helper and resident memory T cell development including BCL6 and Bhlhe40. We show that TRH cells deliver local help to CD8+ T cells through IL-21-dependent mechanisms. Our data have uncovered the presence of a tissue-resident helper T cell population in the lung that plays a critical role in promoting the development of protective B cell and CD8+ T cell responses.
Ann Intern Med
J Pediatric Infect Dis Soc
BACKGROUND: In November 2020, the US Food and Drug Administration (FDA) provided Emergency Use Authorizations (EUA) for two novel virus-neutralizing monoclonal antibody therapies, bamlanivimab, and REGN-COV2 (casirivimab plus imdevimab), for the treatment of mild to moderate COVID-19 in adolescents and adults in specified high-risk groups. This has challenged clinicians to determine the best approach to use of these products. METHODS: A panel of experts in pediatric infectious diseases, pediatric infectious diseases pharmacy, pediatric intensive care medicine, and pediatric hematology from 29 geographically diverse North American institutions was convened. Through a series of teleconferences and web-based surveys, a guidance statement was developed and refined based on review of the best available evidence and expert opinion. RESULTS: The course of COVID-19 in children and adolescents is typically mild and there is no high-quality evidence supporting any high risk groups. There is no evidence for safety and efficacy of monoclonal antibody therapy for treatment of COVID-19 in children or adolescents, limited evidence of modest benefit in adults, and evidence for potential harm associated with infusion reactions or anaphylaxis. CONCLUSIONS: Based on evidence available as of December 20, 2020, the panel suggests against routine administration of monoclonal antibody therapy (bamlanivimab, or casirivimab and imdevimab), for treatment of COVID-19 in children or adolescents, including those designated by the FDA as at high risk of progression to hospitalization or severe disease. Clinicians and health systems choosing to use these agents on an individualized basis should consider risk factors supported by pediatric-specific evidence, and ensure implementation of a system for safe and timely administration that does not exacerbate existing healthcare disparities.
Infect Dis Model
Background: In late March 2020, a "Stay Home, Stay Healthy" order was issued in Washington State in response to the COVID-19 pandemic. On May 1, a 4-phase reopening plan began. We investigated whether adjunctive prevention strategies would allow less restrictive physical distancing to avoid second epidemic waves and secure safe school reopening. Methods: We developed a mathematical model, stratifying the population by age, infection status and treatment status to project SARS-CoV-2 transmission during and after the reopening period. The model was parameterized with demographic and contact data from King County, WA and calibrated to confirmed cases, deaths and epidemic peak timing. Adjunctive prevention interventions were simulated assuming different levels of pre-COVID physical interactions (pC_PI) restored. Results: The best model fit estimated ~35% pC_PI under the lockdown which prevented ~17,000 deaths by May 15. Gradually restoring 75% pC_PI for all age groups between May 15-July 15 would have resulted in ~350 daily deaths by early September 2020. Maintaining <45% pC_PI was required with current testing practices to ensure low levels of daily infections and deaths. Increased testing, isolation of symptomatic infections, and contact tracing permitted 60% pC_PI without significant increases in daily deaths before November and allowed opening of schools with <15 daily deaths. Inpatient antiviral treatment was predicted to reduce deaths significantly without lowering cases or hospitalizations. Conclusions: We predict that widespread testing, contact tracing and case isolation would allow relaxation of physical distancing, as well as opening of schools, without a surge in local cases and deaths.