Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Virus or component thereof
Reexamination Certificate
2001-06-12
2002-04-16
Scheiner, Laurie (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Virus or component thereof
C424S193100, C424S196110, C424S210100, C424S690000, C424S682000, C435S235100, C435S236000
Reexamination Certificate
active
06372223
ABSTRACT:
The present invention concerns an influenza virus vaccine composition with a reduced influenza virus antigen content and with aluminum as an adjuvant. In addition, the present invention concerns the use of the vaccine composition in the production of a drug and for the induction of an effective immune response in higher vertebrates, in particular in humans.
Influenza virus infections pose an increasing risk to the health, particularly to the health of the elderly and of persons suffering from chronic diseases, since the infection in these groups of persons frequently leads to an increase in the mortality rate. Since the introduction of an inactive influenza vaccine containing inactive virus material from infected embryonated chicken eggs in the 1940s, the risk and the course of the infection have improved and the mortality rate in the elderly has decreased.
For a vaccine which leads to a positive ratio between the vaccine dose and the IgG antibody response to be effective, health authorities recommend a vaccine dose between 10 &mgr;g and 15 &mgr;g of HA (hemagglutination) antigen per dose.
The short-term production of large quantities of antigen for the manufacture of vaccine during a pandemic, in particular by means of the method using embryonated chicken eggs which has been used so far, is not only labor-intensive and requires a supply of large quantities of eggs but, due to the short intervals of time between identifying the virus type and making the vaccine available, also requires a considerable logistic effort. In addition, due to the increasing awareness that especially the group of people at risk should be vaccinated early on, the future demand for an effective vaccine will increase more and more.
Based on present estimates, the effectiveness of a human influenza virus vaccine is in a range from 30% to 80%. To increase the effectiveness, it has been proposed that the vaccine dose be increased. Studies carried out by Palache et al. (1993, Vaccine 11, pp. 3-9) and Palache et al. (1993, Vaccine 11, pp. 892-908), however, show that an increase in the vaccine dose is not always sufficient to increase the antibody response and to protect those vaccinated since the degree of the antibody response is highly dependent on the antigen. Although it was found that there is a tendency toward an increased immune response if a higher antigen dose is used, this tendency is less pronounced above a range from 10 &mgr;g to 15 &mgr;g and often does not justify the side effects caused by the high vaccine dose.
Other approaches to increasing the immune response, in particular in the elderly, targeted using additional adjuvants. Thus, antigen preparations containing mineral oil emulsions did indeed elicit an immune response that was superior to that of vaccines without this adjuvant; however, they were also responsible for more severe side effects (Fukumi et al., 1967, In: Symposium Series. Immunobiology Standard, Vol. 5, p. 237 ff., Karger, Basel, New York).
In clinical studies involving humans, aluminum, the only adjuvant allowed for use in humans, did not provoke a greater immunogenicity of influenza virus antigen although the immune response in mice had been increased by the adjuvant (Davenport et al., 1968, J. Immunol. 100, pp. 1139-1140, Nicholson et al., 1979, J. Biol. Stand. 7, pp. 123-136, Bachmayr et al., 1976, Split and subunit vaccines. In: Influenza: Virus, Vaccines, Strategy (Ed. P. Selby), Academic Press, New York, pp. 149-152, Jennings et al., 1981, J. Hyg. 81, pp.1-16). Studies carried out by Skea et al. (1993, Vaccine 11, pp. 1018-1026) to examine the increase in the immune response to an influenza virus vaccine also showed that aluminum compounds by themselves are not very effective adjuvants for influenza virus antigen. But Skea et al. (cit. loc.), by increasing the adhesion of HA antigen to aluminium by specific anti-influenza virus HA antibodies, were able to elicit a 1500 times higher immogenicity in mice and a 5 times higher immunogenicity in rabbits compared to aluminum by itself. Based on this, they reasoned that the adjuvant activity of aluminum can be considerably improved by increasing the physical adhesion between the antigen and the adjuvant. So far, data from experiments in higher mammals or humans, however, have not yet been made available.
A number of experiments in which adjuvants with an acceptable reactivity were tested has been carried out. Thus, immunostimulating complexes (ISCOMS™), oil-in-water adjuvants (Coulter et al., 1998, Vaccine 16, pp. 1243-1253), Vaxcel™, TiterMax™, Syntex, AlPO
4
, Freund's complete and incomplete adjuvant (Robuccio et al., 1995, Lab. Animal Sci. 45, pp. 420-426), poly(amidoamine) dendrimer (WO 97/28809), and MF59 (Keitel et al., 1993, Vaccine 11, pp. 909-913, Martin, 1997, Biologicals 25, pp. 209-213) were tested for their adjuvant activity on influenza virus HA antigen. It was found that the adjuvants used increase the immune response to different degrees. On the other hand, depending on the adjuvant concentration used, they also cause more or less severe side effects.
An additional problem that arises especially when groups of high-risk individuals, such as persons suffering from allergies and patients with asthma, are vaccinated with the conventional influenza virus vaccine from chicken eggs relates to the fact that these individuals are particularly prone to developing side effects, such as allergic reactions to chicken proteins. In many cases, even a small quantity of chicken protein was enough to provoke life-threatening, hypersensitive, allergic reactions. As a result, it became the general practice to dilute the influenza virus vaccine at a ratio of 1:10 to reduce the quantity of chicken protein that was administered along with the vaccine. Studies carried out by Guarnaccia et al. (1990, Ann. Allergy 65, pp. 218-221), however, showed that the reduction of the normally administered quantity of influenza virus antigen also leads to a considerable reduction of the immune response and therefore recommended that quantity of antigen not be reduced since such a reduction fails to ensure an adequate protection of the patients against a viral infection.
Thus, the problem to be solved by the present invention is to make available a vaccine composition which does not have the disadvantages described above, such as high antigen dose, adjuvants which provoke side effects, or allergic reactions to chicken proteins.
This problem is solved according to the present invention by making available an influenza virus vaccine containing influenza virus antigen obtained from a cell culture, with a maximum of 1 &mgr;g to 5 &mgr;g of influenza virus antigen per dose and with aluminum as an adjuvant.
In corroboration of the results obtained by Guarnaccia et al. (1990, Ann. Allergy 65, pp. 218-221) it was found that a reduction of the influenza antigen quantity in a vaccine dose also leads to a decreased immune response in mice. Also, in agreement with the results obtained by Davenport et al. (1968, J. Immunol. 100, pp. 1139-1140, Hjorth et a., 1997, Vaccine 15, pp. 541-546), it was possible to show that with a vaccine composition which contains influenza virus antigen that has been isolated by conventional means from infected embryonated chicken eggs and, at the same time, aluminum as an adjuvant, the HA titer is increased. But with a vaccine dose with a content of antigen that has been reduced to as much as {fraction (1/10)} of the normally adequate antigen dose (1.5 &mgr;g), the addition of aluminum led to an HA titer that is approximately as high as the vaccine containing 10 times the quantity of antigen (Table 1).
Surprisingly, however, it was found that the same quantity of an antigen of the same influenza virus strain that was isolated from a cell culture infected with influenza virus induced 2 times as high an antibody titer as the antigen that is isolated from chicken eggs. In addition, it was possible to show that the addition of aluminum to a preparation containing antigen that has been isolated from a cell culture increases th
Barrett Noel
Dorner Friedrich
Kistner Otfried
Mundt Wolfgang
Baxter Aktiengesellschaft
Scheiner Laurie
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