Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Combination of antigens from multiple viral species
Reexamination Certificate
2001-07-06
2003-05-13
Scheiner, Laurie (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Combination of antigens from multiple viral species
C424S204100, C424S212100, C424S226100, C435S173300, C435S235100, C435S325000
Reexamination Certificate
active
06562350
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a combined vaccine, its production and use, in particularly to hepatitis A-measles combined vaccine formulations comprising prophylactically effective titers of hepatitis A virus (HAV) and measles virus (MV) as virus components, and stabilizer components which is effective for stabilizing the virus components. The combined vaccine does not induce any interference on the immune response and the immunogenicity of the two viruses and having excellent storage stability, so that the combined vaccine could be stored at ambient temperature for a long time and could be used for preventing recipients, especially intants and young children against the two infections diseases. The present invention further relates to methods of making the combined vaccines which are lyophilized or unlyophilized by mixing the two different viruses or by propagating the two different viruses on a same diploid cell substrate.
BACKGROUND OF THE INVENTION
As well known that, immunization to protect against communicable disease is one of the most successful and cost-effective practices of modern medicine. In order to total control over the entire vaccination chain leading to increased social acceptance and use of vaccine in all countries and regions, especially in developing countries and regions, the measures including providing newer, polyvalent, more stable and cost-effective vaccines must be taken. For this purpose, so much research efforts for developing newer vaccines and vaccines having improved stability has been extensively made in many laboratories of the world, since the “Children's Vaccine Initiative” (CVI) had founded by United Nations Children's Fund (UNCF) and World Health Organization (WHO) in 1991. Therein, much attention is focused on making vaccine more user-friendly through development of combined vaccine and the introduction of less invasive inoculation technigues.
Popularization of the combined vaccines reduced the nember and manufacturing cost of vaccines, and increased immunity levels against disease, so that it has greatly increased vaccine coverage in the world, especially in developing countries including China.
Many combined vaccine have been licensed and used in immunization practices, for example in the past several decades a routine vaccination schedule for infants and children has included immunization with a live attenuated trivalent vaccine (MMR) for measles, mupms and rubella, and live trivalent vaccine (DTP) for diphtheria, tetanus and pertussis and so on. Recently, a haemophilus b conjugate vaccine combined by reconstitution with diphtheria and tetanus toxoids and acellular pertussis vaccine (DTaP-Hib) for use as fourth dose in childhood vaccination series has licenced by Food and Drug Administration (FDA) in the United States. Also, TriHlBit (Trademark) will be the first vaccine to be licensed combined vaccine in U.S. that combines PTaP with a haemophilus b conjugate vaccine. However, there has been no reports on combined vaccine comprising hepatitis A and measles viruses and on processes of making combined vaccine by propagating two or more different viruses on a same cells substrates.
SUMMARY OF THE INVENTION
The present invention provides a combined hepatitis A-measles vaccine (HM) comprising prophylactically effective titers of attenuated hepatitis A live virus and prophylactically effective titers of attenuated measles live virus, and with or without stabilizer for the viruses, by means of which vaccine the infection associated with hepatitis A virus and measles virus can be prevented without causing any interference between antigenicity of the two viruses due to their mixing or co-culturing.
The combined hepatitis A-measles vaccine according to the present invention, wherein the viral titers of hepatitis A virus is not less than 10
6.0
CCID
50
/ml (50% cell culture infectious dose per milliliter of virus stock), and the viral titers of measles virus is not less than 10
3.5
CCLD
50
/ml.
Within the scope of the present invention, the combined hapatitis A-measles vaccine is provided in the form of lyophilized or unlyophilized.
The present invention further provides a stabilized combined hepatitis A-measles vaccine formulation comprising virus components and stabilizer components, wherein the virus components comprise prophylactically effective titers of hepatitis A live virus and measles live virus, and the stabilizer components consisting essentially of from 0 to 2% (w/v) of human serum albumin (HSA), from 0.5 to 1.1% (w/v) of gelatin, from 5 to 10%(w/v) of trehalose, from 0.75 to 1.5% (w/v) of sodium glutamate, from 0.05 to 0.5% (w/v) of ascorbic acid, from 0.5 to 2.8% (w/v) of urea, from 5 to 10% (w/v) of mannitol or sorbitol or a 1:1 mixture of them, and from 0.5 to 1% (w/v) of nositol in terms of the concentrations in the stabilized live vaccine formulation prior to lyophilization, and wherein the stabilized combined vaccine optionally lyophilized or unlyophilized.
According to the present invention, there is provided a method of preparing combined hepatitis A-measles vaccine comprising mixing a stock material of attenuated hepatitis A live virus having viral titers of not less than 10
7.0
CCID
50
/ml with a stock material of attenuated measles live vaccine having viral titers of not less than 10
4.5
CCID
50
/ml at a suitable ratio, to thereby obtain a combined vaccine stock suspension, in which the viral titers of said hepatitis A virus is not less than 10
6.5
CCID
50
/ml and the viral titers of said measles virus is not less than 10
4.0
CCID
50
/ml.
The combined vaccine thus prepared is a useful vaccine which can be used to prevent the infections with both hepatitis A and measles without any reduction in immunogenic potencies and any deterioration of its properties. Moreover, the combined vaccine never caused interference between viral antigenecities due to their mixing, which interference is frequently abserved, in particulr in case of combined vaccine for animals.
According to the present invention, the present inventors are able to provide another method of preparing the combined hepatitis A-measles vaccine, comprising following steps:
(a) providing seed viruses of hepatitis A virus and measles virus previously prepared, respectively;
(b) inoculating the seed virus of hepatitis A virus obtained from step (a) into a human fetal lung diploid fibroblast cell cultures and following by culturing the cells to propagate the virus;
(c) when the positive hepatitis A virus-infected cells are more than 75%, inoculating the seed virus of measles virus obtained from step (a) into the same cell monolayers on which the hepatitis A virus have propagated, and the cells are cultured continuously;
(d) At the time when the positive hepatitis A virus-infected cells are more than 90% as detected in terms of immunofluoresence (IF) and the positive measles virus-infected cells are more than 90% as detected in terms of cytopathogenic effect (CPE), the cells infected with the two viruses are harvested and the vaccine stock materials containing the two viruses are collected to thereby obtain the desired combined vaccife.
In a preferred embodiment of the present invention, wherein the positive infectious rates on the diploid cells and viral titers of hepatitis A virus are detected by HAV-specific detection systems comprising immunofluorescence and enzyme-linked immunosorbent assay.
In a more preferred embodiment of the present invention, the method defined as above furthermore comprising suitable mixing the stock material of combined hepatitis A-measles vaccine obtained above with a stabilizer for attenuated live vaccine at about 1:1 volume ratio and then lyophilizing the resultant formulation thereby to obtain a lyophilized preparation of the combined hepatitis A-measles vaccine.
According to a preferred embodiment of the present invention, said stabilizer consisting essentially of from 0 to 2% (w/v) of human serum albumin, from 0.5 to 1% (w/v) of gelatin, from 5 to 10% (w/v) of trehalose, from 0.75 to 1.5% (w/v) o
Li Guangpu
Li Shuyan
Lu Jingye
Song Zongming
Wang Pengfu
Changchun Institute of Biological Products, Ministry of Public H
Saliwanchik Lloyd & Saliwanchik
Scheiner Laurie
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