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Background: rVSVΔG-ZEBOV-GP is the first approved vaccine with clinical efficacy against Ebola virus disease. Although a seroprotective threshold has not been defined for those at occupational risk of exposure, the current vaccine strategy is to attain a sustained high level of antibody titres. The aim of this trial was to explore the effects of delayed boosting upon both the height and duration of antibody titres following primary immunisation., Methods: In this open-label phase 2 randomised controlled trial, we compared antibody titres at month 36 in participants who had received a homologous booster dose at month 18 following primary immunisation with those who had received no booster. From Oct 25, 2016, to Jan 29, 2020, healthy adults aged 18 years or older deemed at occupational risk of exposure to Ebola virus due to laboratory work, clinical duties, or travel to an active endemic region were recruited from four hospital clinics in the USA and one hospital clinic in Canada and received primary vaccination with 2×10 7 plaque-forming unit per mL of VSVΔG-ZEBOV-GP. 18 months later, individuals who consented and were still eligible were randomly assigned 1:1 to receive either a homologous booster dose or no booster. Study visits for safety and serial blood collections for antibody titres were done on enrolled participants at months 0, 1, 3, 6, 12, 18, 19, 24, 30, and 36. Through July, 2021, a web-based application was used for randomisation, including assignments with schedules for each of the five sites using mixed permuted blocks. The trial was not masked to participants or site staff. The primary endpoint was a comparison of geometric mean titres (GMTs) of anti-Ebola virus glycoprotein IgG antibody at month 36 (ie, 18 months after randomisation) for all randomly assigned participants who completed the 36 months of follow-up (primary analysis cohort). Investigators were aware of antibody titres from baseline (enrolment) through month 18 but were masked to summary data by randomisation group after month 18. This study is registered with ClinicalTrials.gov (NCT02788227)., Findings: Of the 248 participants who enrolled and received their primary immunisation, 114 proceeded to the randomisation step at month 18. The two randomisation groups were balanced: 57 participants (24 [42%] of whom were female; median age was 42 years [IQR 35-50]) were randomly assigned to the booster group and 57 (24 [42%] of whom were female; median age was 42 years [IQR 36-51]) to the no-booster group. Of those randomly assigned, 92 participants (45 in the booster group and 47 in the no-booster group) completed 36 months of follow-up. At 18 months after primary immunisation, GMTs in the no-booster group increased from a baseline of 10 ELISA units (EU)/mL (95% CI 7-14) to 1451 EU/mL (1118-1882); GMTs in the booster group increased from 9 EU/mL (6-16) to 1769 EU/mL (1348-2321). At month 19, GMTs were 31 408 EU/mL (23 181-42 554) for the booster group and 1406 EU/mL (1078-1833) for the no-booster group; at month 36, GMTs were 10 146 EU/mL (7960-12 933) for the booster group and 1240 EU/mL (984-1563) for the no-booster group. Accordingly, the geometric mean ratio (GMR) of antibody titres had increased almost 21-fold more in the booster versus no-booster group at 1 month after booster administration (GMR 20·6; 95% CI 18·2-23·0; p<0·0001) and was still over 7-fold higher at month 36 (GMR 7·8; 95% CI 5·5-10·2; p<0·0001). Consistent with previous reports of this vaccine's side-effects, transient mono-articular or oligo-articular arthritis was diagnosed in 18 (9%) of 207 primary vaccination recipients; after randomisation, arthritis was diagnosed in one (2%) of 57 participants in the no-booster group. No new cases of arthritis developed after booster administration. Four serious adverse events occurred following randomisation: one (epistaxis) in the booster group and three (gastrointestinal haemorrhage, prostate cancer, and tachyarrhythmia) in the no-booster group. None of the serious adverse events was judged attributable to the booster vaccination assignment., Interpretation: In addition to no new safety concerns and in marked contrast to earlier trials evaluating short-term boosting, delaying a rVSVΔG-ZEBOV-GP booster until month 18 resulted in an increase in GMT that remained several-fold above the no-booster group GMT for at least 18 months. These findings could have implications for defining the optimal timing of booster doses as pre-exposure prophylaxis in populations at ongoing risk for Ebola virus exposure., Funding: The Division of Intramural Research and the Division of Clinical Research of the National Institute of Allergy and Infectious Diseases at the US National Institutes of Health, Canadian Immunization Research Network through the Public Health Agency of Canada, Canadian Institutes of Health Research, and the US Defense Threat Reduction Agency., Competing Interests: Declaration of interests We declare no competing interests., (Published by Elsevier Ltd.)

Description: In March 2020, the White House Coronavirus Task Force determined that clinicians in the United States needed expert treatment guidelines to optimally manage patients with COVID-19, a potentially life-threatening disease caused by a new pathogen for which no specific treatments were known to be effective., Methods: The U.S. Department of Health and Human Services requested that the National Institutes of Health (NIH) take the lead in expeditiously convening a panel of experts to create "living" guidelines that would be widely accessible and capable of frequent updating as important new information became available., Recommendations: The purpose of this article is to expand on the experiences of the NIH COVID-19 Treatment Guidelines Panel (the Panel) over the past 4 years, summarize the Panel's final recommendations for COVID-19, highlight some challenges and unanswered questions about COVID-19 management, and inform future responses to public health emergencies. The Panel was formed in March 2020, and the first iteration of the guidelines was released in April 2020. Now that the public health emergency has ended, the NIH COVID-19 Treatment Guidelines have sunsetted. This role will now fall to professional societies and organizations, such as the American College of Physicians, the Infectious Diseases Society of America, the Pediatric Infectious Diseases Society, and the World Health Organization, all of which have been active in this area., Competing Interests: Disclosures: Disclosure forms are available with the article online.

Regulatory compliance is challenging for multinational clinical trials. Conflicts between country requirements impedes research and slows the approval of medicines, leading the pharmaceutical industry to devote significant resources to this area. Many academic centers and nonprofits cannot support industry-level investment and are vulnerable to noncompliance. To address an insufficiency in public access to this information, the National Institute of Allergy and Infectious Diseases developed ClinRegs-a public access database of clinical research regulations. This report describes ClinRegs' features, maintenance, and usage. From September 2019 through August 2020, ClinRegs had 68 504 users, 60% from outside the United States, demonstrating the demand for accessible, reliable, country-specific regulatory information. Tools such as ClinRegs can help increase regulatory compliance and free up resources for research. We encourage our partner agencies and biomedical research industries to promote greater regulatory knowledge sharing and harmonization for the betterment of clinical research and improved public health., (Published by Oxford University Press for the Infectious Diseases Society of America 2021.)

The development of the National Institutes of Health (NIH) COVID-19 Treatment Guidelines began in March 2020 in response to a request from the White House Coronavirus Task Force. Within 4 days of the request, the NIH COVID-19 Treatment Guidelines Panel was established and the first meeting took place (virtually-as did subsequent meetings). The Panel comprises 57 individuals representing 6 governmental agencies, 11 professional societies, and 33 medical centers, plus 2 community members, who have worked together to create and frequently update the guidelines on the basis of evidence from the most recent clinical studies available. The initial version of the guidelines was completed within 2 weeks and posted online on 21 April 2020. Initially, sparse evidence was available to guide COVID-19 treatment recommendations. However, treatment data rapidly accrued based on results from clinical studies that used various study designs and evaluated different therapeutic agents and approaches. Data have continued to evolve at a rapid pace, leading to 24 revisions and updates of the guidelines in the first year. This process has provided important lessons for responding to an unprecedented public health emergency: Providers and stakeholders are eager to access credible, current treatment guidelines; governmental agencies, professional societies, and health care leaders can work together effectively and expeditiously; panelists from various disciplines, including biostatistics, are important for quickly developing well-informed recommendations; well-powered randomized clinical trials continue to provide the most compelling evidence to guide treatment recommendations; treatment recommendations need to be developed in a confidential setting free from external pressures; development of a user-friendly, web-based format for communicating with health care providers requires substantial administrative support; and frequent updates are necessary as clinical evidence rapidly emerges.

The ongoing outbreak of Ebola in West Africa has raised a general awareness that at present there are no Ebola-specific medical countermeasures (MCMs) with proven effectiveness. This paper recapitulates discussions held at the 6th International Filovirus Symposium in March 2014 as well as the subsequent design of a randomized clinical trial design for treating Ebola virus-infected patients evacuated from West Africa to the United States. A number of different drugs or biologics were critically reviewed and 3 different postexposure strategies were identified as being farthest along in development; passive immunotherapy with monoclonal antibodies, postexposure vaccination with constructs involving viral vectors (such as vesicular stomatitis virus), and antisense compounds directly targeting the viral genome such as modified phosphorodiamidate morpholino oligomer-based compounds and small interfering RNA products. At the time of the meetings, there were no investigational new drugs (INDs) in place for the candidate MCMs. Developers and sponsors of these candidate products were strongly encouraged to prepare pre-IND packets and submit pre-IND meeting requests to the Food and Drug Administration. Some of these investigational products have already been used under emergency authorizations to treat patients in Africa as well as patients evacuated to the United States or Western Europe., (Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Recent studies have demonstrated that cell populations intended for therapeutic purposes that are cultured in heterologous animal products can acquire xenoantigens, potentially limiting their utility. In investigations of the immune response to murine embryonic stem cells, we found that a strong antibody response was generated after the second infusion. Both polyclonal and monoclonal antibody responses, derived from immunized mice, were found to be specific for bovine apolipoprotein B-100, which binds to abundant low-density lipoprotein receptors on the cell surface and is internalized. Here we show that in the majority of patients administered 3 different types of cell-based therapies using cells grown in fetal calf serum-containing media, an antibody response to bovine apolipoprotein B-100 develops after the second infusion and is the dominant specificity. The known and potential clinical effects of such antibodies are discussed.

The Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT) is a large ongoing randomized trial of subcutaneous interleukin-2 (IL-2) plus antiretroviral therapy versus antiretroviral therapy alone in patients with HIV (human immunodeficiency virus) disease and CD4 cell counts of at least 300 cells/mm(3). The primary objective is to determine whether the addition of IL-2 to combination antiretroviral therapy improves morbidity and mortality. The aim is to recruit 4000 participants and follow them for an average of 5 years. Eligible subjects will be recruited at 275 investigational sites in 23 countries around the world. Coupled with broad eligibility criteria this will ensure widely applicable results. A range of secondary objectives will also be addressed in this setting that will include the conduct of observational studies and nested substudies with a public health focus. This article describes the rationale supporting the trial in addition to reviewing the study design, coordination, and governance.

Objectives: To summarize the results of a 6-year, ongoing, prospective study of the risk for human immunodeficiency virus type 1 (HIV-1) transmission among health care workers, and to estimate the magnitude of the risk for HIV-1 infection associated with different types of occupational exposures., Design: Prospective cohort study; the median follow-up for employees sustaining parenteral exposures was 30.2 months (range, 6 to 69 months)., Subjects: Health care workers at the Clinical Center, National Institutes of Health, including those reporting parenteral and nonparenteral occupational exposures to HIV-1., Measurements and Main Results: One thousand three hundred and forty-four clinical health care workers reported 179 percutaneous and 346 mucous membrane exposures to fluids from HIV-1-infected patients during a 6-year period. Responding to a supplementary questionnaire, 559 of these workers reported 2712 cutaneous exposures to blood from HIV-1-infected patients and more than 10,000 cutaneous exposures to blood from all patients during a 12-month period. Occupational transmission of HIV-1 occurred in a single worker after a parenteral exposure to blood from an HIV-1-infected patient. No infections occurred after either mucous membrane or cutaneous exposures to blood from HIV-1-infected patients. Use of newer diagnostic technologies (for example, antigen detection, gene amplification) has not resulted in the identification of occupationally transmitted seronegative infections., Conclusions: Combining our results with those of other prospective studies, the risk for HIV-1 transmission associated with a percutaneous exposure to blood from an HIV-1-infected patient is approximately 0.3% per exposure (95% CI, 0.13% to 0.70%); the risks associated with occupational mucous membrane and cutaneous exposures are likely to be substantially smaller. These data support the use of barrier precautions and suggest a need for strategies that change health care providers' attitudes and behaviors.

A model of activation, proliferation, and differentiation of human lymphocyte responses is described, and the complex immunoregulatory modulation of this system discussed with regard to normal immune function and the aberrancies expressed in diseases characterized by abnormalities of immune function. Recent advances in technology of cloning and hybridizing human T cells as well as hybridizing human B cells have had a critical impact on the field of human immunobiology and have made available potentially unlimited amounts of purified antibodies and immunoregulatory factors. Of particular note has been the optimization of conditions for the production of B-cell hybridomas from human peripheral blood B cells secreting monoclonal antibody directed against predetermined antigenic specificities to which a subject has been immunized. Furthermore, the development of antigen-specific human T-cell clones has allowed a precise delineation of the genetic restriction in monocyte-T-cell interactions as well as the functional capability of T-cell subsets. Precise definition of these systems has allowed a greater understanding of the mechanisms of diseases characterized by aberrancies of immune function.

To assess the risk of nosocomial transmission of human T-cell lymphotropic virus type III/lymphadenopathy-associated virus (HTLV-III/LAV), we prospectively evaluated a cohort of 531 health care workers. One hundred fifty of these employees reported percutaneous or mucous membrane exposures to blood or body fluids from a patient with the acquired immunodeficiency syndrome (AIDS) during the treatment of 238 such patients since 1981. None of these 150 employees had serologic evidence of HTLV-III/LAV infection on follow-up from 6 to 46 months after exposure. Of the 150, 46 were studied immunologically and 29 had lymphocytes cultured for HTLV-III/LAV. Results of all studies were normal. Of the 531 employees, 3 (0.56%) had serologic evidence of HTLV-III/LAV infection. All were seropositive at the time of study entry; none reported adverse nosocomial exposures. All acknowledged membership in one or more established risk groups for AIDS. This study provides strong evidence that the risk of nosocomial transmission of HTLV-III/LAV is extremely low.

The acquired immunodeficiency syndrome (AIDS) is a disease which is characterized by a profound defect in cell-mediated immunity leading to opportunistic infections and unusual neoplasms such as Kaposi's sarcoma. It is caused by a retrovirus of the human T cell leukemia/lymphoma virus family and has been termed HTLV-III/lymphadenopathy-associated virus. The virus selectively infects the T4 helper/inducer subset of T cells, accounting for the profound defects in immunity noted in AIDS patients. AIDS is transmitted sexually, and by blood and blood products, accounting for its relative confinement to specific risk groups. The disease is now seen worldwide, and as of September 1984, approximately 6,000 cases have been reported in the USA alone. There is no effective treatment for the disease at present, and the mortality of the full-blown syndrome approaches 100%. Hopefully, with the recent isolation of the causative agent of the syndrome, effective therapies and vaccinations will be forthcoming.