Research ArticleEbola

Therapeutic Intervention of Ebola Virus Infection in Rhesus Macaques with the MB-003 Monoclonal Antibody Cocktail

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Science Translational Medicine  21 Aug 2013:
Vol. 5, Issue 199, pp. 199ra113
DOI: 10.1126/scitranslmed.3006608

Figures

  • Fig. 1 Truncated telemetry analysis of NHPs.

    Baseline temperatures for each NHP were determined before challenge. Changes in this baseline reading at each time point for each NHP were calculated and are graphically represented. NHPs first presented with fever between 100 and 110 hours after exposure; survivors are represented in blue, nonsurvivors in black, and controls in red.

  • Fig. 2 Survival, mAb titers, and viral levels during the therapeutic protocol.

    (A) MB-003 provided 43% protection (three of seven) when used as a therapeutic against EBOV infection (P = 0.0291, log-rank Mantel-Cox; n = 1) compared with four of four historical controls infected by the same route, challenge dose, and stock and infusion regiment. (B) Total anti-EBOV glycoprotein antibody titers were determined by enzyme-linked immunosorbent assay (ELISA). (C and D) Viremia was assessed by agarose plaque assay (C) and quantitative RT-PCR (D). Survivors are represented in blue (open symbols), nonsurvivors in black, and controls in red. geq, genomic equivalence.

  • Fig. 3 Clinical analysis and observations for NHPs.

    Complete blood counts (CBCs) and chemical analyses were performed on samples collected over the course of the study (days 0, 3, 5, 7, 10, 14, 21, and 28). (A and B) Among nonsurvivors, thrombocytopenia (A) and anemia (B) were observed. (C and D) In most experimental nonsurvivors and both controls, elevated levels of aspartate aminotransferase (AST; C) and alanine aminotransferase (ALT; D) were observed. (E) Blood urea nitrogen assessment revealed elevated levels in most nonsurvivors. (F) All nonsurvivors had progressively more severe morbidity in daily observation scores. Survivors are represented in blue (open symbols), nonsurvivors in black, and controls in red.

Tables

  • Table 1 Symptom-initiated treatment of EBOV infection.

    NHPs were challenged intramuscularly with 1067 PFU of EBOV and monitored for clinical symptoms, fever, and the presence of viremia. Once NHPs presented with both fever and a positive RT-PCR result, administration of MB-003 was initiated. Three of seven experimental NHPs survived challenge, whereas both control NHPs succumbed to challenge.

    NHPPCR trigger
    (hours after exposure)
    Temperature trigger
    (hours after exposure)
    Limiting triggerInitial dosing
    (hours after exposure)
    TreatmentSurvival?
    A63105Temperature108MB-003No (D9)
    B75102Temperature104Control (PBS)No (D7)
    C87108Temperature109MB-003Yes
    D63103Temperature103MB-003No (D12)
    E111104PCR120MB-003Yes
    F99106Temperature108MB-003No (D8)
    G99109Temperature113Control (irrelevant mAb)No (D11)
    H87109Temperature113MB-003No (D10)
    I111109PCR119MB-003Yes
  • Table 2 Clinical findings, days 0 to 28.

    Thrombocytopenia was determined by Hemavet 950. Moderate petechial rash is defined as 10 to 40% of body surface area; severe petechial rash is defined as >40% of body surface area. AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; BUN, blood urea nitrogen; CRE, creatinine; GGT, γ-glutamyl transpeptidase; TBIL, total bilirubin; NS, nonsurvivor; S, survivor. ↑, two- to threefold increase; ↑↑, four- to fivefold increase; ↑↑↑, more than fivefold increase.

    NHPTreatmentSymptoms presented/clinical findings
    A (NS)MB-003Thrombocytopenia, AST ↑↑↑, BUN ↑, ALT ↑, CRE ↑, ALP, severe petechial rash, bleeding, dehydration, increasing
    unresponsiveness, euthanized D9
    B (NS)PBSThrombocytopenia, BUN ↑↑↑, CRE ↑↑↑, ALT ↑↑↑, AST ↑↑↑, ALP ↑↑, GGT ↑↑, severe petechial rash, dehydration,
    increasing unresponsiveness, euthanized D7
    C (S)MB-003Thrombocytopenia, ALT ↑↑, ALP ↑, GGT ↑
    D (NS)MB-003Thrombocytopenia, severe petechial rash, bleeding, some unresponsiveness, found dead D12
    E (S)MB-003Thrombocytopenia, ALP ↑, moderate petechial rash, unresponsiveness
    F (NS)MB-003Thrombocytopenia, BUN ↑, CRE ↑, ALT ↑↑↑, AST ↑↑↑, ALP ↑, GLU ↓ moderate petechial rash, dehydration, increasing
    unresponsiveness, euthanized D8
    G (NS)Irrelevant mAbThrombocytopenia, BUN ↑↑, CRE ↑, ALT ↑↑↑, AST ↑↑↑, ALP ↑↑, GGT ↑↑, GLU ↓ moderate petechial rash, bleeding,
    increasing unresponsiveness, loss of balance, euthanized D11
    H (NS)MB-003Thrombocytopenia, BUN ↑↑↑, CRE ↑↑↑, ALT ↑↑↑, AST ↑↑↑, TBIL ↑, severe petechial rash, bleeding, dehydration,
    increasing unresponsiveness, euthanized D10
    I (S)MB-003Thrombocytopenia, ALP ↑, mild dehydration