Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Recombinant virus encoding one or more heterologous proteins...
Reexamination Certificate
1998-05-20
2001-07-17
Mosher, Mary E. (Department: 1641)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Recombinant virus encoding one or more heterologous proteins...
C424S218100, C514S04400A
Reexamination Certificate
active
06261567
ABSTRACT:
INTRODUCTION
Venezuelan (VEE), Eastern (EEE), and Western (WEE) equine encephalitis alphaviruses are endemic to North and South America. They present potential medical threats to equines and people. Clinical symptoms of illness include fever, headache, photophobia, seizures, and encephalitis.
Currently, live or formalin-inactivated vaccines are used under Investigational New Drug (IND) status to immunize at-risk personnel. For VEE virus, a live-attenuated TC-83 vaccine [Alevizatos, A. C. et al. (1967)
Am. J. Trop. Med. Hyg
. 16: 762-768; Berge, T. O. et al. (1961)
Am. J. Hyg
. 73: 209-218] and a formalin-inactivated C-84 vaccine [Cole, F. E. et al. (1974)
Appl. Micro
. 27: 150-153] are available. In addition, a new vaccine candidate V3526 [Davis, N. L. et al. (1995)
Virology
212: 102-110] is under investigation. For EEE [Bartelloni, P. J. et al. (1970)
Am. J. Trop. Med. Hyg
. 19: 123-126] and WEE [Bartelloni, P. J. et al. (1971)
Am J. Trop. Med . Hyg
. 20: 146-149] viruses, formalin-inactivated IND vaccines are available. Although TC-83 has been used to control equine epizootics, most commonly used veterinary vaccines are inactivated products (please see Table 1 for alphavirus vaccines available).
The current alphavirus vaccines have several limitations, including the observation in horses [Calisher, C. H. et al. (1973)
Appl. Microl
. 26: 485-488] that prior immunity to EEE or WEE viruses interferes with the induction of protective immune responses to subsequent vaccination with the live-attenuated VEE vaccine TC-83. Interference may be mediated by cross-reactive, non-neutralizing (in plaque assay) antibodies that presumably inhibit viral replication of live-attenuated vaccine strains. The inability to induce virus-neutralizing antibodies to VEE virus in alphavirus-immune animals or people significantly limits the usefulness of the current live-attenuated TC-83 vaccine. The formalin-inactivated C-84 vaccine does not replicate and appears to be less susceptible to interference. However, C-84 is currently used only as a booster vaccine because it does not induce adequate protection in hamsters [Jahrling, P. B. and Stephenson, E. H. (1984)
J. Clin. Microbiol
. 19: 429-431], it requires multiple inoculations and periodic boosters, and it does not induce longlasting mucosal immunity [Hart, M. K. et al. (1997)
Vaccine
15: 363-369]. Therefore, it is not a suitable alternative to TC-83 vaccination.
Since immunity to one alphavirus does not protect animals adequately from subsequent exposure to a virulent heterologous alphavirus [Casals, J. (1963)
Am. J. Trop. Med. Hyg
. 12: 587-596], there is a need for a method to overcome alphavirus interference, and a vaccine which is able to bypass interference.
TABLE 1
Investigational New Drug (IND) Alphavirus Vaccines Used in this Study
Vaccine
Virus
Antigen Form
Dose
1
(PFU)
2
Schedule
Booster
CHIK
Chickungunya (CHIK)
live-attenuated
0.5 ml (10
5
PFU)
day 0
Not
available
TC-83
Venezuelan equine
live-attenuated
0.5 ml (10
4
PFU)
day 0
0.5 ml of
encephalitis (VEE)
C-84
C-84
VEE
formalin-
5.58 &mgr;g/0.5 ml dose
day 0, 7,
inactivated
28
V3526
3
VEE (vaccine candidate)
live-attenuated
0.5 ml (10
4
PFU)
day 0
Not
available
EEE
Eastern equine
formalin-
1.84 &mgr;g/0.5 ml dose
day 0, 28
0.5 ml
encephalitis (EEE)
inactivated
WEE
Western equine
formalin-
0.83 &mgr;g/0.5 ml dose
day 0, 7,
0.5 ml
encephalitis (WEE)
inactivated
28
1
Protein concentrations for C-84, EEE, and WEE were determined by Mike Shoemaker (unpublished observations, 1996).
2
Plaque forming units (PFU).
3
V3526 vaccine candidate is under development and has not been approved for human use yet.
SUMMARY OF THE INVENTION
The present invention satisfies the need discussed above. The present invention relates to a method and composition for overcoming alphavirus interference.
Vaccine interference prevents the induction of protective immune responses to live attenuated alphavirus vaccines in animals or people with pre-existing immunity to other alphaviruses. Cross-reactive, non-neutralizing antibodies may mediate interference by inhibiting replication of the vaccine strain after infection of susceptible cells by binding to glycoproteins on infected cells and causing lysis. The new VEE vaccine candidate, V3526, was developed [Davis, N. L. et al. (1995), supra] using site-directed mutagenesis to incorporate desired mutations into a full-length infectious clone. V3526 contains a cleavage site deletion in the precursor E2 (PE2) glycoprotein sequence and a viability-restoring mutation at glycoprotein E1:253. These mutations result in a virion that has glycoprotein spikes containing three uncleaved PE2-E1 heterodimers instead of the three cleaved E2-E1 heterodimers normally present in VEE viruses, including the TC-83 strain (Please see
FIG. 1
for an illustration of the changes in V3526).
We hypothesized that these mutations may alter the sequence, conformation and/or accessibility of cross-reactive epitopes such that cross-reactive antibodies could no longer bind the glycoproteins during viral replication. In the absence of binding by cross-reactive interfering antibodies, V3526 should induce similar neutralizing antibody titers in naive or alphavirus-immune recipients. This would overcome the problem of vaccine interference in alphavirus-immune individuals.
We found that prior EEE vaccination with a formalin-inactivated product did not adversely affect production of protective immunity against VEE after immunization with V3526. Similar results were seen when the first alphavirus vaccine was a live-attenuated Chikungunya vaccine, as opposed to a reduction in titers of neutralizing antibodies induced to the live-attenuated VEE product, TC-83.
In addition, a monoclonal antibody, K42, reactive with Sindbis virus E1 glycoprotein and which cross-reacts with different alphaviruses [Wang, K.-S. et al. (1991)
Virology
181: 694-702] was shown to interfere with neutralizing antibody responses to TC-83, but not to V3526, when the monoclonal antibody was passively administered to mice. This antibody binds a site on the virus E1 glycoprotein that is exposed on infected cells during virus maturation but is not exposed on virions. K42 was also found to bind to and cause cell death of, some TC-83-infected Vero cells, but does not do so with V3526-infected cells. Together these data suggest that alphavirus interference by the K42 antibody occurs at the surface of infected cells. The ability of V3526 to avoid interference is likely due to the conformational changes in its glycoprotein spikes that may sterically prevent binding of interfering antibodies.
Further, prior immunization with inactivated EEE vaccine did not interfere with subsequent responses to an influenza vaccine which was vectored in a packaged VEE virus replicon. A packaged replicon resembles a virus particle and would be susceptible to antibody-mediated inteference (clearance mechanisms) that occurs prior to cell infection. After the packaged replicon infects a cell, the influenza protein is made, but VEE virus proteins are not made. As no VEE virus structural proteins are expressed at the cell surface, replicon-infected cells will not be susceptible to interference that is mediated by cross reactive antibodies that bind sites that are exposed only on infected cells.
Therefore, it is an object of the present invention to provide a method for inducing in an alphavirus-immune recipient neutralizing antibodies against a second alphavirus comprising administering an alphavirus composition comprising said second alphavirus wherein said second alphavirus has been altered such that it is not recognized by interfering antibodies present in said alphavirus-immune recipient.
It is another object of the present invention to provide a method for providing immunity against a first alphavirus without preventing immunity from a second alphavirus comprising administering a first alphavirus vaccine wherein said alphavirus has been alt
Azarion Maryam
Hart Mary Katherine
Arwine Elizabeth
Harris Charles H.
Mosher Mary E.
The United States of America as represented by the Secretary of
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