Pathogenesis, Treatment and Prevention of Emerging Infectious Diseases

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

Research in this project is currently focused on six areas. These are: characterization of the survivors of the anthrax attacks of 2001; characterization of emerging respiratory infections including SARS, COVID-19, and influenza; evaluation of licensed and experimental vaccines and treatments for Ebola virus; characterizing the long-term sequelae of Ebola virus infection; evaluating experimental therapeutics and biomarkers for COVID-19; characterizing the long- term sequelae of SARS-CoV-2 infection; identifying therapeutic interventions for mpox. The anthrax study has enrolled a cohort of volunteers who are currently undergoing an extensive diagnostic evaluation during long-term follow-up. Tecovirimat is available for the treatment of mpox (formerly known as monkeypox) in Europe and the United States, on the basis of findings from efficacy studies in animals and safety evaluations in healthy humans. We conducted a double-blind, randomized, placebo-controlled trial of tecovirimat in patients with mpox in the Democratic Republic of Congo (DRC). Patients with at least one mpox skin lesion and positive polymerase-chain-reaction results for clade I MPXV were assigned in a 1:1 ratio to receive tecovirimat or placebo. All patients received supportive care. The primary end point was days to resolution of all mpox lesions. A total of 597 patients underwent randomization. The competing-risks hazard ratio for lesion resolution was 1.13 (95% confidence interval [CI], 0.97 to 1.31; P = 0.14). Thus, this drug, being made widely available to treat mpox based on animal efficacy data and human safety data was fond not to be effective in the setting of endemic clade I mpox. In a five-year follow-up of the PREVAC randomized trial of the two most widely use Ebola virus vaccines (Merck's Ervebo [rVSV-ZEBOV] and Johnson & Johnson's two-dose combination [Ad26.ZEBOV/MVA-BN-Filo]), polyfunctional Ebola virus-specific CD4+ T-cell responses increased after Ad26 priming and were further boosted by MVA. In contrast, minimal such responses were observed in the rVSV groups. Utilizing in-vitro expansion for eight days demonstrated persistence of EBOV-specific T-cell responses for up to 60 months. Cytokine production analysis identified shared biomarkers between the Ad26-MVA and rVSV groups. A correlation was noted between EBOV-specific T-cell responses and anti-EBOV IgG responses. Antibody responses declined more slowly in the rVSV-ZEBOV group and titers were higher in children than adults. An open-label phase 2 randomized controlled trial of 248 adults compared antibody titers at month 36 in participants who had received a homologous booster dose at month 18 following primary immunization with those who had received no booster. Participants were drawn from healthy adults aged 18 years or older in the US and Canada deemed at occupational risk of exposure to Ebola virus due to laboratory work, clinical duties, or travel to an active endemic region. The geometric mean ratio of antibody increased approximately 20-fold more in the booster versus no-booster group at 1 month after booster administration and was still over 7-fold higher at month 36. In the first step to determine a correlate of protection from the rVSV-ZABOV vaccine and obtain a better estimate of the efficacy of the vaccine, an assay was developed to distinguish responses to the vaccine from responses to the virus. The assay was designed to measure the immune response to the core protein vesicular stomatitis virus (VSV), a component of the vaccine that was not present in Ebola virus. IgG antibodies to the VSV core were first detected 10-14 d post-vaccination, further increased at 28 d, and remained stable through 360 d. This assay is now being used to obtain an estimate of vaccine effectiveness. The VATICO study randomized 66 hospitalized recovered COVID-19 individuals to receive either immediate or deferred vaccination, with one or two doses of mRNA SARS-CoV-2 vaccines. We measured binding and neutralizing antibodies against SARS-CoV-2 at enrollment and longitudinally. Median (IQR) time from SARS-CoV-2 infection to first vaccination was 68 (53-75) days in the immediate group, and 151 (137-173) days in the deferred group. At week 48, timing or number of vaccine doses did not influence the change in antibody levels relative to baseline. These results suggest possible benefits of prompt vaccination after recovery from COVID-19. The longitudinal natural history study followed 495 recovered COVID-19 patients and uninfected controls to characterize long-term medical sequelae, identify risk factors, and monitor antibody and cell-mediated immune responses to SARS-CoV-2 over time.