Approach to Strain Selection and the Propagation of Viral Stocks for Venezuelan Equine Encephalitis Virus Vaccine Efficacy Testing under the Animal Rule
Abstract
:1. Introduction
2. Background
2.1. Alphaviral Committee and Workshop
2.2. Strain Selection
2.3. Approach to Selecting a Methodology for the Propagation of Challenge Material
2.4. Comparison of VEE in Humans and Animal Models
3. Summary of Workshop/Committee Proceedings
3.1. VEEV Strain Down-Selection for Animal Model
3.1.1. VEEV IAB Strains
3.1.2. VEEV IC Strains
3.2. Preparation of Challenge Material
3.3. VEE Disease and Pathophysiology in Humans
3.3.1. Background of VEE Disease
3.3.2. VEEV IAB (TrD) Infection
3.3.3. VEEV IC (INH-9813) Infection
3.4. Animal Models
3.4.1. VEEV Mouse Model
3.4.2. VEEV NHP Model
3.4.3. VEEV IAB TrD Animal Models
3.4.4. VEEV IC INH-9813 Animal Models
4. Discussion
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Source | Strain Selection Criteria |
---|---|
Department of Defense (DOD) | Strains that will support Food and Drug Administration (FDA) licensure for vaccine protection against at least two VEEV subtype I variants |
DOD | Strains relevant to a bioterrorism event |
FDA | Strains isolated from lethal human cases or associated with causing human disease |
FDA | Strains with known and low passage history |
Filovirus Animal Non-clinical Group (FANG) | Strains with no passage history in animals (if available) |
Strains with low passage history in cell culture | |
FDA | Strains that mirror the expected disease state in humans |
Logistics | Strains available and accessible to laboratories licensed to work with select agents |
Logistics | Ability to grow strain to yield sufficient challenge material for animal model |
Strain Type | Strain | VEEV Subtype i) | Source | Passage History | Place and Year of Isolation | Reference |
---|---|---|---|---|---|---|
Epizootic VEEV Strains | Trinidad Donkey (USAMRIID) | IAB | Donkey brain | GP1, CE14, SMB1, BHK-1 or 2 | Trinidad, 1943 | [17,18,19,20] |
Trinidad Donkey (USAMRIID) | IAB | Donkey brain | GP1, CE13, DE cells 1 | |||
Trinidad Donkey (CDC) | IAB | Donkey brain | GP1, V6, BHK1 | Trinidad, 1943 | [21,22] | |
69Z1 | IAB | Human | SM2, V1 | Guatemala, 1969 | [20] | |
69Z1 | IAB | Human | BHK1, unknown | Guatemala, 1969 | [20] | |
INH-9813 | IC | Human serum | V1 | Venezuela, 1995 | [23] | |
INH-6803 | IC | Human serum | V1 | Venezuela, 1995 | [23] | |
SH3 | IC | Human | V1 | Venezuela, 1993 | [10,24] | |
3908 | IC | Human serum | C6/36-1 | Venezuela, 1995 | [10,15,23,25] | |
6119 | IC | Human serum | BHK1 | Venezuela, 1995 | [20,23,26] | |
V198 | IC | Human serum | SM1, V1, DE1 | Colombia, 1962 | [26] | |
V178 | IC | Horse brain | SMB2, V3 | Colombia, 1961 | [23] | |
P676 | IC | Aedes triannulatus | SM1, V3, BHK1 | Venezuela, 1963 | [26] | |
Enzootic VEEV Strains | 3880 | ID | Human | SM3, V4, BHK1 | Panama, 1961 | [20,27,28] |
FSL0201 | ID | Human serum | V1 | Peru, 2000 | [29] | |
83U434 | ID | Hamster | CE cells 1, V1, BHK1 | Colombia, 1983 | [13,23] | |
An9004 | ID | Hamster | SM3, V1, BHK1 | Colombia, 1969 | [20,27] | |
66637 | ID | Hamster | SM1, V1 | Venezuela, 1981 | [13,20] | |
306425 | ID | Hamster | Unknown, BHK1 | Colombia, 1972 | [20] | |
ZPC738 | ID | Hamster | Unknown, BHK1 | Venezuela, 1997 | [13] | |
V209A | ID | Mouse | SM2, V2 | Colombia, 1960 | [20,27] | |
68U201 | IE | Hamster | SM1, BHK2, CE cells 3 | Guatemala, 1968 | [30] | |
93-42124 | IE | Horse (brain) | SM1, CE cells 1 | Chiapas, Mexico, 1993 | [30] | |
CPA-201 | IE | Horse | SMB1, RK1, BHK2 | Chiapas, Mexico, 1993 | [30] | |
96-32863 | IE | Horse (brain) | SM1, CE1 | Oaxaca, Mexico, 1996 | [30] |
Population Type | Pros | Cons |
---|---|---|
Uncloned (wild-type) | - Maintenance of wild-type diversity | - Cell culture adaptation often results in artificial amino acid substitutions and in vivo attenuation - Risk that multiple major variants present in the population can confound identification of genetic determinants of important phenotypes - Limited supply without additional passages |
Plaque-cloned | - Clear consensus sequence (verified by sequencing original population) and lack of multiple variants | - Possible reduced single nucleotide polymorphism diversity - Risk of selection of a suboptimal fitness mutant (change in the consensus and master sequence) - Limited supply without additional passages |
cDNA-cloned | - Clear consensus sequence (verified by sequencing the first-generation population) and lack of multiple major variants - Unlimited supply of the same master virus without passages | - Possible reduction in single nucleotide polymorphism diversity |
BALB/c Mouse | Cynomolgus Macaque | Humans | |
---|---|---|---|
Route of Exposure | SC (scruff of neck, footpad) Aerosol (whole body) | Aerosol | Aerosol (laboratory exposure) Parenteral (vector-borne, laboratory exposure, vaccine-related) |
Disease and Mortality | Lethal infection after SC and aerosol exposure due to encephalitis even at low challenge doses, with death 5–7 days post-challenge [48,64] | Generally non-lethal infection after SC and aerosol exposure at high challenge doses (100% infection after aerosol challenge 1 × 108 pfu); death uncommon. Increased severity of CNS disease after aerosol challenge [52,64]. | Generally non-lethal infection after SC or aerosol exposure [52] Infection common after exposure to low doses. Encephalitis uncommon (<0.5%); mainly in children/elderly |
Exposure Dose | LD50 SC ~10 pfu; LD50 aerosol <1 pfu a | ID50 unknown | Low infective dose (exposure dose unknown in humans) |
Disease Onset | 24–72 h | 24–48 h | 24–72 h (range 24 h–8 days) |
Signs and Symptoms; Progression of Disease | Nearly 100% mice infected develop disease. Mice infected by the SC route demonstrated initial signs of decreased grooming and ruffled fur 2–3 days after challenge; followed by lethargy, hunched posture, and hind-limb paralysis; death or euthanasia 5–7 days after challenge. Mice infected by aerosol route demonstrated onset of similar signs 2–3 days after challenge, and death or euthanasia 6–7 days after challenge. | Aerosol VEEV TrD challenge results in fever and lethargy within 24–48 h after challenge. Fever resolved by D9. May have mild tremors. Generally NHPs have full recovery. | Self-limiting febrile illness, usually <1 week duration (asthenia may persist 1–2 weeks). Symptoms of high fever, chills, severe headache, back pain, malaise, myalgia, anorexia, nausea, sore throat, fatigue, photophobia, and/or vomiting. Encephalitis uncommon (<1% cases); manifested by decreased sensorium, confusion, gait abnormalities; severe cases with seizures, paralysis, or coma. Most cases recover without neurological sequelae. |
Clinical Laboratory | Not done. | Viremia observed initially on D1–D2 that resolved by D3–D4 Lymphopenia observed early in illness. Increase in WBC observed later in some NHPs [37] | Viremia common D1–D4 (range D1–D7 illness) after aerosol and SC challenge. VEEV isolation from pharynx common D1–D4 (range D1–D7) in VEE IAB TrD and VEE IAB Co1938 strains [52]. Lymphopenia common D1–D3 of illness, with improvement after D3 and recovery by D6. Leukopenia may occur D3–D5; resolves by D5–D8 illness [52]. |
Pathology | Death due to encephalitis. CNS entry occurs via the olfactory system. Histological lesions present in both neural and extraneural tissues; CNS lesions characterized by necrotizing panencephalitis and myelitis; congestion and minor hemorrhage, damaged endothelial cells, perivascular edema, minimal necrosis and infiltration of a few neutrophils and mononuclear cells (no vasculitis) [48,64] | Limited pathology studies in cynomolgus macaques with TrD strain. Intraperitoneal challenge of Rhesus macaques showed histopathology findings initially in lymphoid tissues; lesions in olfactory cortex and thalamus by D6, and in hypothalamus and throughout brain by D8. Predominant lesions of gliosis and multifocal perivascular cuffing composed of lymphocytes. CNS lesions most severe between D14 and D21 post-challenge (observed in 18/20 NHPs). Aerosol challenge rhesus macaques (VEEV-subtype unknown) noted VEEV in nasal mucosa, lungs, cervical/hilar lymph nodes by 18 h, olfactory bulb by 48 h; more severe CNS infection than intraperitoneal challenge (higher CNS viral titers, increased neuronal damage, neuronophagia, and neutrophil infiltration); CNS infection preceded onset of viremia [52,64,65,66]. | CNS pathology available in humans with VEEV IC (see Table 5). |
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] |
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Rusnak, J.M.; Glass, P.J.; Weaver, S.C.; Sabourin, C.L.; Glenn, A.M.; Klimstra, W.; Badorrek, C.S.; Nasar, F.; Ward, L.A. Approach to Strain Selection and the Propagation of Viral Stocks for Venezuelan Equine Encephalitis Virus Vaccine Efficacy Testing under the Animal Rule. Viruses 2019, 11, 807. https://doi.org/10.3390/v11090807
Rusnak JM, Glass PJ, Weaver SC, Sabourin CL, Glenn AM, Klimstra W, Badorrek CS, Nasar F, Ward LA. Approach to Strain Selection and the Propagation of Viral Stocks for Venezuelan Equine Encephalitis Virus Vaccine Efficacy Testing under the Animal Rule. Viruses. 2019; 11(9):807. https://doi.org/10.3390/v11090807
Chicago/Turabian StyleRusnak, Janice M., Pamela J. Glass, Scott C. Weaver, Carol L. Sabourin, Andrew M. Glenn, William Klimstra, Christopher S. Badorrek, Farooq Nasar, and Lucy A. Ward. 2019. "Approach to Strain Selection and the Propagation of Viral Stocks for Venezuelan Equine Encephalitis Virus Vaccine Efficacy Testing under the Animal Rule" Viruses 11, no. 9: 807. https://doi.org/10.3390/v11090807