Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Conjugate or complex
Reexamination Certificate
1997-05-01
2001-06-26
Smith, Lynette R. F. (Department: 1645)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Conjugate or complex
C424S203100, C424S250100, C424S256100, C424S234100, C424S184100, C424S831000, C424S193100, C424S194100
Reexamination Certificate
active
06251401
ABSTRACT:
The present invention relates to a combined vaccine for the treatment of bacterial meningitis. In particular, the combined vaccine effectively protects against infection by
Haemophilus influenzae
type B (Hib) and
Neisseria meningitidis
(
meningococcus
) serotypes B and C (MenB, MenC).
Bacterial meningitis caused by infection with Hib, MenB and/or MenC represents a worldwide problem. Infection by these organisms can result in permanent disability and death among young children. Recently, however, a conjugate Hib vaccine has become generally available and has resulted in the effective control of Hib infections. Similar vaccines are shortly to become available for MenC infection and also for MenB infection (see Costantino et al., 1992 Vaccine, 10,691-698).
The Hib and meningococcal vaccines are based on conjugates between oligosaccharides derived from the bacterial surface, which define epitopes specific for the bacterium in question, conjugated to carrier proteins, such as non-toxic mutants of diphtheria toxin, for example CRM197.
Combination vaccines are now gaining widespread acceptance in developed countries. The rationale behind the use of combination vaccines, which comprise more than one antigen and are effective to immunise the recipient against a number of diseases, is that the administration cost of the vaccine may be drastically reduced when compared to a larger number of individual vaccines. As the administration cost may exceed the cost of a vaccine by some tenfold, the advantages of combination vaccines are evident where mass vaccination programmes are being considered. Combination vaccines are being actively promoted by the World Health Organisation (see, for example, CVI Forum, No. 5, November 1993, pp. 2-12; CVI Report of the First Meeting of the Consultative Group, Geneva, 16-17 December 1991, pp. 29-32).
These advantages have been recognised for some time, but only three such combination vaccines are currently widely available. The first to be introduced, in the 1950's, was DTP, a killed vaccine against diphtheria, tetanus and pertussis. The formulation of this triple vaccine presented no major problems as the components in the combination are mutually compatible and the preservative (merthiolate) and adjuvant (alum) used in each separate vaccine were identical. Furthermore, it was found that the whole-cell pertussis component enhanced the immune response to the diphtheria and tetanus toxoids.
In the 1960's , a live oral polio vaccine (OPV) was developed containing types 1, 2 and 3 polio viruses. A problem encountered with the formulation of OPV was the presence of interference between the vaccine components, a problem which had not arisen with DTP. The problem has been minimised by optimising the concentration of the various components.
More recently, a third combination vaccine, a live measles, mumps and rubella (MMR) vaccine has been introduced to most developed countries. Again, the concentration of each individual component needs to be adjusted to minimise the interference phenomenon between the components included in this vaccine.
Currently, there is a trend towards the development of supervaccines comprising a larger number of antigens, based on the DTP vaccine.
There are, however, disadvantages in the formulation of supervaccines based on DTP. Recent evidence has shown that administration of the Hib conjugate vaccine together with DTP reduces the effectiveness of the Hib conjugate in comparison with separate administration of DTP and Hib vaccine (see Abstract 300 from 33rd ICAAC2).
Conflicting data exist on the role of immunity of the carrier protein in influencing antibody response to the hapten or oligosaccharide component of a conjugate vaccine. Such influence is critical to the formulation of Hib-MenB/C vaccines, as the carrier proteins used are invariably similar or identical to the antigens included in the DTP vaccine, which is administered to infants at an early age. According to some studies, response to the conjugate is increased by prior exposure to the carrier, while according to others it is suppressed. (Barington, T. et al., Infection and Immunity 62:9-14 (1994); Schneerson, R. et al., J. Exp. Med 152:361-376(1980), Barington T. et al., Infect. Immun.61:432-438 (1993); Peeters, C.C.A.M. et al., Infect. Immun. 59:3504-3510.
It has now been determined that prior exposure to the carrier protein greatly increases response to the Hib conjugate vaccine.
Accordingly, the object of the present invention is to provide a combined Hib and meningococcus vaccine which may be used in the prophylaxis of bacterial meningitis which allows economical, safe and expedient vaccination against the prevalent causes of meningitis.
The invention therefore provides a meningitis vaccine comprising conjugated Hib and MenC oligosaccharides.
The combination vaccine of the invention has been found to 30 be effective in preventing infection by
Haemophilus influenzae
and
Neisseria meningitidis
serotype C, raising antibodies to the administered conjugated capsular oligosaccharides after the first dose. Moreover, the combination vaccine has been shown to be free from interference between the antigens used.
Avantageously, carrier priming may be exploited in order to maximise response to the vaccine. Carrier priming may be carried out by administration of a DTP vaccine.
The MenC component can be formulated in three different preferred configurations: buffered liquid form; lyophilized with a suitable excipient; and ready to use product with pertinent adjuvants. The Hib vaccine is stable after lyophilization with suitable excipient and in a buffered liquid form. In addition the two vaccines, MenC and Hib, can be lyophilized together with a suitable excipient and subsequently resuspended before use with suitable adjuvants. Any combinations of the stable formulations can be mixed prior to use.
The vaccine of the invention may further comprise a conjugate capsular oligosaccharide deriving from
Neisseria meningitidis
serotype B.
The carrier protein to which the oligosaccharide component of the vaccine of the invention is conjugated may be any protein known in the art for such a purpose. For example, it may be tetanus toxoid, diptheria toxoid, an outer membrane protein of
Neisseria meningitidis
, or a mutant or variant thereof.
The oligosaccharides are preferably size-selected and advantageously have a degreee of polymerisation of 4 or more.
The invention further provides a method for the prophylaxis or treatment of meningitis comprising administering to a subject a pharmaceutically effective amount of a combination vaccine according to the invention. The preferred administration regime is to administer at 2, 4 and 6 months of age, intramuscularly.
In a further aspect of the invention there is provided a combination vaccine according to the invention for use in medicine.
Moreover, the invention provides a Hib oligosaccharide conjugate and a
Neisseria meningitidis
serotype C oligosaccharide conjugate for simultaneous separate or sequential administration.
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Vella et al. Pediatrics 85 (4 pt 2) : 668-675, 1990.*
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Jacob et al. Eur. J. Immunol 16 : 1057-1062, 1986.*
Peeters et al. Injection and Immunity 60 (5) : 1826-1833, 1992.*
Peeters et al. Injection and Immunity 59 (10) : 3504-3510, 1991.*
Barington et al., “Non-Epitope-Specific Suppression of the Antibody Response toHaemophilus influenzaeType b Conjugate Vaccines by Preimmunization with Vaccine Components,”Infect. Immun., 1993, 61(2), 432-438.
Barington, T. et al., “Opposite Effects of Actively and Passively Acquired Immunity to the Carrier on Responses of Human Infants to aHaemophilus influenzaeType b Conjugate Vaccine,”Infect. Immun., 1994, 62(1), 9-14.
Costantino et al., “Development and phase 1 clinical testing of a conjugate vac
Ceccarini Costante
Costantino Paolo
D'Ascenzi Sandro
Giannozzi Aldo
Norelli Francesco
Blackburn Robert P.
Chiron S.p.A.
Devi S.
Harbin Alisa A.
Smith Lynette R. F.
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