Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Virus or component thereof
Reexamination Certificate
1999-08-11
2002-11-26
Brusca, John S. (Department: 1631)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Virus or component thereof
C424S206100, C435S069100
Reexamination Certificate
active
06485729
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a Neuraminidase (NA) supplemented compositions, and methods employing the same, including routes of administration. More specifically, the present invention relates to an immunological, antigenic, immunogenic, or vaccine composition comprising an anti-influenza vaccine wherein the improvement comprises having as an additive neuraminidase (NA) from at least one influenza virus strain; and, to methods for making and using the same. Such compositions and methods have advantages such as improved efficacy.
Several documents are cited in the text, with full citation thereat, or in the portion headed “References”, and each document cited herein (“herein cited documents”) and each document referenced or cited in herein cited documents are hereby incorporated herein by reference.
BACKGROUND OF THE INVENTION
The influenza viruses are divided into types A, B and C based on antigenic differences. Influenza A viruses are described by a nomenclature which includes the sub-type or type, geographic origin, strain number, and year of isolation, for example, A/Beijing/353/89. There are at least 15 sub-types of HA (H1-H13) and nine subtypes of NA (N1-N9). All subtypes are found in birds, but only H1-H3 and N1-N2 are found in humans, swine and horses (Murphy and Webster, “Orthomyxoviruses”, in Virology, ed. Fields, B. N., Knipe, D. M., Chanock, R. M., 1091-1152 (Raven Press, New York, 1990)). Influenza A and B virus epidemics can cause a significant mortality rate in older people and in patients with chronic illnesses.
Epidemic influenza occurs annually and is a cause of significant morbidity and mortality worldwide. Children have the highest attack rate, and are largely responsible for transmission of influenza virus in the human community. The elderly and persons with underlying health problems, e.g., immuno-compromised individuals, are at increased risk for complications and hospitalization from influenza infection. In the United States alone, more than 10,000 deaths occurred during each of the seven influenza seasons between 1956 and 1988 due to pneumonia and influenza, and greater than 40,000 deaths were reported for each of the two seasons (Update: Influenza Activity—United States and Worldwide, and Composition of the 1992-1993 Influenza Vaccine,
Morbidity and Mortality Weekly Report
. U.S. Department of Health and Human Services, Public Health Service, 41No. 18:315-323, 1992).
The influenza vaccines currently used are inactivated vaccines: they may be constituted of entire virions, or of virions subjected to treatment with agents which dissolve lipids (“split” vaccines), or else of purified glycoproteins (“sub-unit vaccines”). These inactivated vaccines mainly protect by causing synthesis of the receiver's antibodies directed against the hemagglutinin. Antigenic evolution of the influenza virus by mutation results in modifications in HA and NA. Accordingly, inactivated vaccines used at present only protect against strains having surface glycoproteins which comprise identical or cross-reactive epitopes. To provide a sufficient antigenic spectrum, conventional vaccines comprise components from several viral strains; they generally contain two type A strains and one type B strain. The choice of strains for use in vaccines is reviewed annually for each particular year and is predicated on WHO FDA recommendations. These recommendations reflect international epidemiological observations. Viral strains may be obtained from:
NIBSC (National Institute for Biological Standards and Control, London, UK).
WIC (World Influenza Centre, London, UK).
CDC (Centers for Disease Control, Atlanta, USA).
CBER (Center for Biologics Evaluation and Research, Washington, USA).
Current influenza virus seeds for vaccine production must be shown to have the appropriate HA antigen because of the reassortant procedure used to generate high yielding virus strains used for manufacturing. However, there is currently no requirement for or limit to NA content in influenza vaccines. There is evidence that the NA level in vaccines is quite variable. Kendal et al. (Kendal et al., 1980) reported that the NA specific activity for different lots may range approximately 40-fold. Kendal et al. also noted a rapid decline of NA activity during six months of storage. As a result, the frequency of antibody response to NA was poor (mean seroconversion rate of 18%) compared to the HA response (seroconversion rate of 64%). The frequency of response to NA in a population known to be primed to that NA ranged from 0 to 32% compared to a response rate of 29 to 91% for the HA antigen (Palese, et al., 1982).
Commercially available conventional influenza vaccines include a trivalent subvirion vaccine which contains 15 &mgr;g/dose of each the Has from influenza A/Texas/36/91 (NINI), A/Beijing/32/92 (H3N2) and B/Panama, 45/90 viruses (FLUZONE™ attenuated flu vaccine, Connaught Laboratories, Swiftwater, Pa.). A purified virus surface antigen vaccine is sold as Fluvirin® (an attenuated influenza viral vaccine produced by culturing in eggs). Each conventional vaccine can contain 15 micrograms of viral HA per 0.5 ml from A/Texas/36/91 (HINI), A/Shangdong/9/93 (H3N2), and B/Panama/45/90 influenza strains. Conventional vaccines generally contain 10 to 15 &mgr;g of hemagglutinin from each of the strains entering into their composition.
Previous clinical trials demonstrated that antibody to NA may be effective in inducing partial protection and in reducing the severity of illness. Examples are: Human Clinical Trials of NA specific vaccines. Clinical trials of NA-based vaccines consisted of NA-specific whole-viral antigenic hybrids containing the NA of interest and an irrelevant HA. In the first study, Couch et al. (Couch, R. B., et al., 1974) demonstrated reduction of viral replication and protection by an H7N2 virus vaccine in volunteers challenged with H3N2 virus and also showed solid resistance to reinfection and illness in subjects challenged six months later with the original virus.
In a two year study of 875 Buffalo school children, Ogra et al. (Ogra, P. L., et al., 1977) compared the effects of two vaccines under conditions of natural exposure and successive challenge by the Port Chalmers and Victoria variants of H3N2 virus. The two vaccines, X-41 and X-42, were manufactured under identical conditions. The X-41 vaccine contained HA and NA antigens of the Port Chalmers strain (comparable to conventional vaccine) and X-42 was an H7N2 antigenic hybrid possessing the irrelevant HA of an equine virus. The outcome of natural infection, first with Port Chalmers virus then with Victoria/75 virus in two successive winters is shown in the table below.
The infection rate in the first winter was shown to be the same in control and NA-specific vaccine groups. As expected, X-41 (conventional vaccine) caused a greater initial reduction of illness, although a lesser but significant reduction was seen with the NA-specific vaccine. In the second winter, the efficacy of NA vaccination was evident in that infection as well as the disease rate in the X-42 vaccines was reduced.
Comparison of NA-Specific (X-42) and Conventional
(X-41) Vaccines in School Children
Serologic Infection
Vaccine
Rate
Ill
Protection Ratio
a
Natural Infection I
(A/Port Chalmers H3N2) in 1975
X-41 (H3N2)
70/300 (23%)
28 (9%)
69
X-42 (H7N2)
119/300 (40%)
56 (18%)
37
Placebo
123/300 (45%)
82 (29%)
—
Natural Infection II
(A/Victoria/75 H3N2) in 1976
X-41 (H3N2)
35/220 (16%)
9 (4%)
80
X-42 (H7N2)
45/201 (22%)
12 (6%)
73
Placebo
73/185 (40%)
38 (20%)
—
a
(
%
ill
in
placebo
group
-
%
ill
in
vaccine
group
)
%
ill
placebo
×
100
A trial in Czechoslovakia by Vonka et al. (Vonka, V., et al., 1977) used an inactivated whole-virus vaccine prepared from an H1N2 reassortant. A total of 1,200 subjects were vaccinated and a comparable group serv
Hackett Craig S.
Johansson Bert E.
Kilbourne Edwin D.
Matthews James T.
Smith Gail Eugene
Brusca John S.
Frommer & Lawrence & Haug LLP
Kowalski Thomas J.
Moran Marjorie A.
Protein Sciences Corporation
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