Table 5.
Summary of the selected VEEV IC INH-9813 strain in mice, nonhuman primates (NHPs), and humans.
| BALB/c Mouse | Cynomolgus Macaque | Humans (VEEV IC Strains) | |
|---|---|---|---|
| Route of Exposure | SC (scruff of neck); Aerosol (whole body) |
Aerosol (head only) | Parenteral (mosquito-borne). No aerosol-acquired VEEV IC cases reported |
| Disease and mortality | Lethal infection after SC and aerosol exposure due to encephalitis even at low challenge doses (100% mortality after 100 pfu challenge dose), with death or euthanasia 6–8 days after challenge [71] | Non-lethal infection (100%) in 11 NHPs after aerosol challenge (dose range 5 × 104 to 5.94 × 108 pfu; 30 pfu in a single NHP) [71] | 1995 Colombia/Venezuela outbreak with VEE IC INH-9813 strain (mosquito-borne disease) [6,23]. Generally non-lethal infection after SC exposure. No reported cases of aerosol-acquired VEEV IC. Infection common after exposure to low doses. Encephalitis uncommon; mainly in children/elderly |
| Exposure Dose | LD50 SC =5 pfu; LD50 aerosol = 53 pfu a |
ID50 aerosol ≤ 30 pfu (n = 1) | Low infective dose (human infective dose unknown) |
| Disease Onset | 48 h to 6 days | 24 to 48 h | 27.5 h to 4 days in 11 mosquito-borne VEE IC cases (strain unknown) [5] |
| Clinical Manifestation | VEEV INH-9813 resulted in infection after SC and aerosol exposure (100% infection). Mice with infection demonstrated initial signs of decreased grooming and ruffled fur 6 days after SC challenge or 48 h after aerosol challenge, followed by lethargy, hunched posture, and hind-limb paralysis (likely due to encephalitis), with death or euthanasia 6–8 days after SC or aerosol challenge |
VEEV INH-9813 resulted in 100% infection after aerosol challenge. NHPs demonstrated initial signs of fever and lethargy 24–48 h after challenge, with fever resolving by D7. Biphasic fever noted only at highest dose tested. Tremors of variable duration (4–8 days; maximum 26 days) in 50% of NHPs. All NHPs survived |
Mosquito-borne VEEV IC infection (strain unknown) similar to VEE IA/B infection in well-characterized outbreak in Texas (n-88) [5]. Self-limiting febrile illness of 1-week duration (asthenia may persist for 1–2 weeks). Symptoms included high fever, chills, severe headache, myalgias, malaise, and anorexia. Also, nausea, vomiting, sore throat, photophobia, ocular pain, arthralgia, somnolence and drowsiness reported. Encephalitis in 2% adults (mild) and 7.6% children. Encephalitis manifested by decreased sensorium, disorientation, delirium, nuchal rigidity, ataxia, seizures; coma and paralysis in severe cases |
| Clinical Laboratory | Unknown | Viremia detected starting on D1–D2 post-challenge and resolved by D3–D4. Lymphopenia typically noted early in infection. Elevated WBC count detected later in some NHPs (n = 6) |
VEE IC outbreak (strain unknown) [5]: Viremia documented in 40 cases from D0–D8 of illness (most common on D3 of illness). Lymphopenia (<1490 cells/mm3) in 80% cases on D1–D4 of illness; increase generally on D4 with recovery by D9. Leukopenia (<4500 cells/mm3) in 75% cases at D1–D2, (recovery of total WBC by D3/neutropenia by D6–D8) |
| Pathology | Pathology studies not performed | Mild to moderate lymphocytic perivascular cuffing with gliosis in CNS at day 28 post-challenge. No viral antigen detected in CNS | Autopsy of 21 mosquito-borne VEEV IC cases (strain unknown): Cerebrovascular congestion (n = 14), edema with inflammatory infiltrates in brain/spinal cord (n = 17), intracerebral hemorrhage (n = 7), vasculitis (n = 4), meningitis (n = 13), encephalitis (n = 7), cerebritis (n = 5). Vasculitis, fibrin thrombi, perivascular hemorrhage and edema, occasional necrosis of blood vessel walls. Inflammatory infiltrates with lymphocytic and mononuclear cells, neutrophils, histiocytes. Lymph nodes and spleen with marked lymphoid depletion/follicular necrosis; hepatocellular degeneration and congestion (11/18 cases); interstitial pneumonia (19/21 cases) and pulmonary edema (11/21 cases) [70] |
D = day; SC = subcutaneous. a Starting concentration and all-glass impinger samples for aerosol exposure quantitated by plaque assay to determine titer (pfu/mL); Guyton and Bide formulas used to calculate the inhaled exposure dose per animal.