A Randomized, Controlled Trial of Ebola Virus Disease Therapeutics.

BACKGROUND: Although several experimental therapeutics for Ebola virus disease (EVD) have been developed, the safety and efficacy of the most promising therapies need to be assessed in the context of a randomized, controlled trial. METHODS: We conducted a trial of four investigational therapies for EVD in the Democratic Republic of Congo, where an outbreak began in August 2018. Patients of any age who had a positive result for Ebola virus RNA on reverse-transcriptase-polymerase-chain-reaction assay were enrolled. All patients received standard care and were randomly assigned in a 1:1:1:1 ratio to intravenous administration of the triple monoclonal antibody ZMapp (the control group), the antiviral agent remdesivir, the single monoclonal antibody MAb114, or the triple monoclonal antibody REGN-EB3. The REGN-EB3 group was added in a later version of the protocol, so data from these patients were compared with those of patients in the ZMapp group who were enrolled at or after the time the REGN-EB3 group was added (the ZMapp subgroup). The primary end point was death at 28 days. RESULTS: A total of 681 patients were enrolled from November 20, 2018, to August 9, 2019, at which time the data and safety monitoring board recommended that patients be assigned only to the MAb114 and REGN-EB3 groups for the remainder of the trial; the recommendation was based on the results of an interim analysis that showed superiority of these groups to ZMapp and remdesivir with respect to mortality. At 28 days, death had occurred in 61 of 174 patients (35.1%) in the MAb114 group, as compared with 84 of 169 (49.7%) in the ZMapp group (P = 0.007), and in 52 of 155 (33.5%) in the REGN-EB3 group, as compared with 79 of 154 (51.3%) in the ZMapp subgroup (P = 0.002). A shorter duration of symptoms before admission and lower baseline values for viral load and for serum creatinine and aminotransferase levels each correlated with improved survival. Four serious adverse events were judged to be potentially related to the trial drugs. CONCLUSIONS: Both MAb114 and REGN-EB3 were superior to ZMapp in reducing mortality from EVD. Scientifically and ethically sound clinical research can be conducted during disease outbreaks and can help inform the outbreak response. (Funded by the National Institute of Allergy and Infectious Diseases and others; PALM ClinicalTrials.gov number, NCT03719586.).

Structural and molecular basis for Ebola virus neutralization by protective human antibodies.

Ebola virus causes hemorrhagic fever with a high case fatality rate for which there is no approved therapy. Two human monoclonal antibodies, mAb100 and mAb114, in combination, protect nonhuman primates against all signs of Ebola virus disease, including viremia. Here, we demonstrate that mAb100 recognizes the base of the Ebola virus glycoprotein (GP) trimer, occludes access to the cathepsin-cleavage loop, and prevents the proteolytic cleavage of GP that is required for virus entry. We show that mAb114 interacts with the glycan cap and inner chalice of GP, remains associated after proteolytic removal of the glycan cap, and inhibits binding of cleaved GP to its receptor. These results define the basis of neutralization for two protective antibodies and may facilitate development of therapies and vaccines.

Recombinant adenovirus serotype 26 (Ad26) and Ad35 vaccine vectors bypass immunity to Ad5 and protect nonhuman primates against ebolavirus challenge.

The use of adenoviruses (Ad) as vaccine vectors against a variety of pathogens has demonstrated their capacity to elicit strong antibody and cell-mediated immune responses. Adenovirus serotype C vectors, such as Ad serotype 5 (Ad5), expressing Ebolavirus (EBOV) glycoprotein (GP), protect completely after a single inoculation at a dose of 10(10) viral particles. However, the clinical application of a vaccine based on Ad5 vectors may be hampered, since impairment of Ad5 vaccine efficacy has been demonstrated for humans and nonhuman primates with high levels of preexisting immunity to the vector. Ad26 and Ad35 segregate genetically from Ad5 and exhibit lower seroprevalence in humans, making them attractive vaccine vector alternatives. In the series of studies presented, we show that Ad26 and Ad35 vectors generate robust antigen-specific cell-mediated and humoral immune responses against EBOV GP and that Ad5 immune status does not affect the generation of GP-specific immune responses by these vaccines. We demonstrate partial protection against EBOV by a single-shot Ad26 vaccine and complete protection when this vaccine is boosted by Ad35 1 month later. Increases in efficacy are paralleled by substantial increases in T- and B-cell responses to EBOV GP. These results suggest that Ad26 and Ad35 vectors warrant further development as candidate vaccines for EBOV.

Baseline assessment of collaborative tuberculosis/HIV activities in Kinshasa, the Democratic Republic of Congo.

Ninety-two clinics were surveyed in 2005 as part of a baseline assessment of HIV activities in Tuberculosis (TB) clinics in Kinshasa, Democratic Republic of Congo. Some HIV activities were implemented in 58% of TB clinics. The majority of health had > or = 1 health care worker (HCW) trained in either HIV counseling or testing (71%). Fifty-three clinics offered counseling and testing to TB patients; twenty-two (42%) routinely offered HIV CT to all patients, while others used selective criteria. While most offered on-site counseling (92%) and testing (77%), not all 53 clinics had a HCW trained in counseling and only 31 had access to a counseling room. Cotrimoxazole prophylaxis was offered in 51% of clinics; antiretroviral treatment in 17%. Shortcomings in human resources, infrastructure and quality of services were revealed. Strengthening those clinics already implementing HIV activities could be prioritized to achieve the goals set forward by the Global Plan to Stop TB.

Use of protective gear and the occurrence of occupational Marburg hemorrhagic fever in health workers from Watsa health zone, Democratic Republic of the Congo.

BACKGROUND: Occupational transmission to health workers (HWs) has been a typical feature of Marburg hemorrhagic fever (MHF) outbreaks. The goal of this study was to identify cases of occupational MHF in HWs from Durba and Watsa, Democratic Republic of the Congo; to assess levels of exposure and protection; and to explore reasons for inconsistent use of protective gear. METHODS: A serosurvey of 48 HWs who cared for patients with MHF was performed. In addition, HWs were given a questionnaire on types of exposure, use of protective gear, and symptoms after contact. Informal and in-depth interviews with HWs were also performed. RESULTS: We found 1 HW who was seropositive for MHF, in addition to 5 cases of occupational MHF known beforehand; 4 infections had occurred after the introduction of infection control. HWs protected themselves better during invasive procedures (injections, venipuncture, and surgery) than during noninvasive procedures, but the overall level of protection in the hospital remained insufficient, particularly outside of isolation wards. The reasons for inconsistent use of protective gear included insufficient availability of the gear, adherence to traditional explanatory models of the origin of disease, and peer bonding with sick colleagues. CONCLUSIONS: Infection control must not focus too exclusively on the establishment of isolation wards but should aim at improving overall hospital hygiene. Training of HWs should allow them to voice and discuss their doubts and prepare them for the peculiarities of caring for ill colleagues.