Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Virus or component thereof
Reexamination Certificate
1998-08-26
2001-04-03
Wortman, Donna C. (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Virus or component thereof
C435S237000, C435S239000, C424S212100, C424S219100
Reexamination Certificate
active
06210683
ABSTRACT:
FIELD OF THE INVENTION
The present invention pertains to the use of recombinant human serum albumin in stabilizers for live virus vaccines including vaccines comprising varicella zoster, measles, mumps, and rubella viruses, individually or in combination.
BACKGROUND OF THE INVENTION
Varicella zoster virus (VZV) is a member of the herpesvirus family that causes chicken pox and zoster (shingles). Chickenpox is a highly contagious disease that occurs in persons with no antibodies or cell-mediated immunity to VZV. More than 90% of the population is exposed to VZV during the first two decades of life. In non-immunosuppressed children, chickenpox is characterized by mild to moderate fever and the development of maculopapular and vesicular lesions. These lesions appear primarily on the face and trunk and usually last from three to five days. Although generally not a serious problem in non-immunosuppressed children, VZV-caused disease is a severe threat to the immunosuppressed and to adults. In many cases, VZV becomes latent in dorsal root ganglion cells. Shingles, a painful chronic condition, occurs when VZV is reactivated from the latent state.
Measles is a negative-stranded RNA virus belonging to the genus Morbillivirus. The measles virus is highly contagious in its human host and is disseminated by coughing and sneezing from an infected host. The virus enters the bloodstream, spreads through the body and infects lymphoid tissues. A period of infectivity persists from approximately 6-7 days prior to appearance of a rash through about 2-3 days subsequent to appearance of the rash. Prodromal symptoms of fever and malaise occur about 10 days subsequent to exposure. This is followed by a hacking cough, coryza, conjunctivitis, and possibly photophobia. Koplik spots appear approximately 2 days prior to appearance of the rash. During the stage of maximal severity of the infection the patient may complain of headaches, abdominal pain, vomiting, diarrhea, and/or myalgia.
Mumps is a negative-stranded RNA virus belonging to the genus Paramyxovirus. The incubation period for the mumps virus is usually 17-21 days, but may range from 8 to 37 days. After infection and growth in the respiratory tract, the virus enters the bloodstream where it is systemically delivered to various body tissues. Mumps is characterized by swelling and tenderness of the parotid gland and occasionally other salivary glands. Prior to swelling the patient may experience pain behind the jaw and just below the ear, which is increased by pressure and movement of the jaws. More severe cases may include prodromal symptoms such as anorexia, headache, vomiting, myaglia, and high fever.
Rubella virus is a positive-stranded RNA virus which is the sole member of the family Togaviridae and which causes german measles. Rubella infection usually occurs by airborne spread of infected droplets. Many rubella infections are subclinical, with a ratio of approximately 2:1 of inapparent to overt disease. The incubation period for rubella virus is 14-21 days, with a characteristic pattern of adenopathy, rash and low grade fever. Rubella during early pregnancy frequently results in fetal infection, which may be chronic and may produce a spectrum of illness known as Congenital Rubella Syndrome (CRS).
Prevention of disease caused by varicella zoster, measles, mumps, and rubella viruses is a highly desirable goal and there are now commercially available live virus vaccines for these viruses. For example, there is now a vaccine for varicella zoster virus produced by Merck & Co., Inc. (VARIVAX®). Another vaccine produced by Merck & Co., Inc., M-M-R®II, is a live vaccine containing measles, mumps, and rubella viruses.
One difficulty in developing and using live virus vaccines such as VARIVAX® and M-M-R®II is that the viruses contained in such vaccines tend to be unstable. For example, cell-free live varicella zoster virus (VZV) is among the most labile of live viruses currently used in vaccines. The lability of VZV pertains not only to the virus as present in vaccine preparations, but also to the virus while it is being harvested from cell culture, and to the procedures used for lyophilizing the virus for long term storage (Bennett et al., 1991, Develop. Biol. Stand. 74:215-221). Because of this lability, VZV vaccines, like other live virus vaccines, must be combined with a stabilizing medium, even when lyophilized. See, e.g., U.S. Pat. Nos. 4,338,335; 4,147,772; and Howell & Miller, 1983, J. Clin. Microbiol. 18:658-662. Improvements in stabilizers for VZV are highly desirable since such improved stabilizers would permit more efficient harvesting of VZV from cell cultures as well as longer and more convenient storage of VZV vaccines. Should such improved stabilizers prove useful for other live viruses as well, they would be even more highly desirable.
Vaccine stabilizers are well known in the art as chemical compounds added to a vaccine formulation to enhance vaccine stability during low temperature storage or storage post-lyophilization.
One such chemical stabilizer is referred to as SPGA and is described in Bovarnick et al., 1950, J. Bact. 59:509-522. One liter of SPGA contains 0.218M sucrose (74.62 g), 0.00376 M KH
2
PO
4
(0.52 g), 0.0071 M K
2
HPO
4
(1.25 g), 0.0049 M potassium glutamate (0.912 g) and 1% serum albumin (10 g).
U.S. Pat. No. 3,783,098 discloses a modification of SPGA wherein monosodium glutamate is substituted for monopotassium glutamate. Also, use of a starch hydrosylate such as glucose or dextran maybe substituted wholly or partly for sucrose. Casein or PVP may be substituted wholly or partly for albumin as described in U.S. Pat. No. 3,915,794.
U.S. Pat. No. 4,000,256 describes an SPGA stabilizer containing, per liter of sterile distilled water: 74.62 g sucrose, 0.45 g KH
2
PO
4
, 1.35 g K
2
HPO
4
, 0.956 g monosodium L-glutamate, and 40 ml of a 25% solution of human serum albumin.
In general, an SPGA stabilizer contains from about 2 to about 10% of a particular sugar, (e.g., sucrose), from about 0.05 to about 0.3% of a mono- or dibasic alkali metal phosphate salt or mixture thereof, e.g., KH
2
PO
4
, K
2
HPO
4
, NaH
2
PO
4
, or Na
2
HPO
4
, from about 0.05 to about 0.2% of a glutamic acid alkali metal salt, e.g., sodium or potassium glutamate; and from about 0.5% to about 2% serum albumin, e.g., bovine serum albumin or human serum albumin.
Another chemical stabilizer known in the art comprises hydrolyzed gelatin, Medium O, and sorbitol. This chemical stabilizer, disclosed in U.S. Pat. No. 4,147,772, comprises approximately 3.5% hydrolyzed gelatin, 3.5% sorbitol, and 1.0% Medium O, along with minimal amounts of sodium bicarbonate and phenol red.
A vaccine stabilizer modified from U.S. Pat. No. 4,147,772 is disclosed in U.S. Pat. No. 4,273,762. This stabilizer comprises the components disclosed in U.S. Pat. No. 4,147,772 as well as minute amounts of DPG solution, which contains, among other compounds, cysteine, glutathionine, ascorbic acid, and vitamin A.
Stabilizers for live virus vaccines generally require high concentrations of sugars such as sucrose, mannitol, or sorbitol to improve virus stability during lyophilization and storage. In addition, the virus bulks contain relatively high concentrations of salts in the tissue culture media. Such high concentrations of sugars and salts make freeze drying of the vaccine preparations difficult. One problem is that physical collapse of the vaccine preparation may occur upon freeze drying. Polymer additives such as dextran, non-recombinant human serum albumin (HSA), as well as nonhydrolyzed and hydrolyzed gelatin have been added to vaccines to raise the collapse temperature. In the case of HSA and gelatin, the inclusion of these materials may raise potential safety concerns if these materials are derived from at-risk human or animal sources. These additives do not necessarily solely stabilize the virus against inactivation; they also help to prevent the physical collapse of the freeze-dried material during lyophilization and subsequent storage in the solid state. Thus, it would be
Burke Carl
Volkin David
Coppola Joseph A.
Merck & Co. , Inc.
Tribble Jack L.
Wortman Donna C.
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