Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Combination of viral and bacterial antigens
Reexamination Certificate
2002-05-23
2004-06-29
Wortman, Donna C. (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Combination of viral and bacterial antigens
C424S196110, C424S197110, C424S193100, C424S203100, C424S204100, C424S226100, C424S227100, C424S217100, C424S234100, C424S236100, C424S239100, C424S256100, C514S054000
Reexamination Certificate
active
06756040
ABSTRACT:
The present invention relates to new vaccine formulations, comprising a conjugated polysaccharide antigen linked to a carrier protein. In particular the invention relates to a vaccine formulation for the prevention of Haemophilus Influenzae Type B (Hib) infections and where the antigen is adsorbed on to aluminium phosphate. The invention also relates to a multivalent vaccine, that is a vaccine for the amelioration or treatment of more than one disease states. The present invention also relates to the production and use of such vaccines in medicine.
Vaccines that utilise polysaccharides are known in the art. For example a vaccine for the prevention of Haemophilus influenzae b (Hib) infections are based on the capsular polysaccharide (PRP) conjugated with a carrier protein. The polysaccharide is a polymer of ribose, ribitol and phosphate. These vaccines are typically presented as plain (ie without adjuvantation) formulations. Although in one case, (Pedvax Hib produce by Merck) a diluent containing aluminium hydroxide is utilised to reconstitute the lyophilised conjugate. Typically the carrier protein is a diphtheria or tetanus toxoid or an outer membrane protein of N. menigitidis. Examples of such conjugate vaccine antigens are disclosed in U.S. Pat. Nos. 4,365,170, 4,673,574, EP 208 375, EP 477508 and EP 161 188.
It is desirable to administer such conjugate vaccines with other antigens or vaccines at the same fine and this can involve multiple injections. Problems associated with multiple injections include a more complicated administration procedure and a large total injection volume. This is a particularly acute problem when the vaccine is intended for infants.
It has therefore been proposed to produce combination vaccines. One well known combination vaccine provides protection against Diphtheria, tetanus and B. pertussis infections. This vaccine comprises a whole cell or an accellular pertussis component which typically consists of two or three antigens—(detoxified PT, FHA and often, but not exclusively 69 kDa) although in certain circumstances other B. pertussis antigens may also be present and toxoided diphtheria and tetanus toxins. Such vaccines are often referred to as DTPw or DTPa. Other antigens would desirable be added to such a combination vaccine for the prevention of diseases like hepatitis B. or Polio.
It would be desirable to add polysaccharide conjugate vaccines to such a combination. However we have found that simple mixing of the components results in a reduction of antibody titres to the polysaccharide component.
The present inventors have discovered that this reduction can be inhibited if the conjugate antigen is adsorbed on to aluminium phosphate. In contrast, if the antigen is adsorbed on to aluminium hydroxide, there is a complete reduction of antibody titres to the polysaccharide component.
Accordingly the present invention provides a vaccine composition comprising a polysaccharide conjugate antigen adsorbed on to aluminium phosphate. Preferably the antigen is capsular polysaccharide (PRP) from Hib conjugated with a carrier protein.
Preferably the carrier protein is either diphtheria or tetanus toxoid, Diphtheria Crm
197
protein or an outer membrane protein from a bacteria such as N. meningitidis.
The polysaccharide conjugate may be prepared by any known coupling technique. For example the polysaccharide can be coupled via a thioether linkage. This conjugation method relies on activation of the polysaccharide with 1-cyano-4-dimethylamino pyridinium tetrafluoroborate (CDAP) to form a cyanate ester. The activated polysaccharide may thus be coupled directly or via a spacer group to an amino group on the carrier protein. Preferably, the cyanate ester is coupled with hexane diamine and the amino-derivatised polysaccharide is conjugated to the carrier protein using heteroligation chemistry involving the formation of the thioether linkage. Such conjugates are described in PCT published application WO93/15760 Uniformed Services University.
The conjugates can also be prepared by direct reductive amination methods as described in U.S. Pat. No. 4,365,170 (Jennings) and U.S. Pat. No. 4,673,574 (Anderson). Other methods are described in EP-0-161-188, EP-208375 and EP-0-477508.
A further method involves the coupling of a cyanogen bromide activated polysaccharide derivatised with adipic acid hydrazide (ADH) to the protein carrier by carbodiimide condensation. Such conjugation is described in Chu C. et al Infec Immunity, 1983 245 256.
In a preferred embodiment of the invention the ratio of PRP polysaccharide to carrier protein is reduced from a typical 1:3 to 1:0.3 to 1:2. Such low ratio conjugates are advantageous, since even in an unadjuvanted state, they do not suffer from interference problems.
In a preferred embodiment of the invention the formulation preferably contains at least one other component selected from antigens which afford protection against one or more of the following: Hepatitis A virus (HAV), diphtheria, tetanus, pertussis, Hepatitis B and polio.
Particular combination vaccines within the scope of the invention include a DTPa (diphtheria-tetanus-accellular pertussis)-Hib combination vaccine formulation, an Hib-Hepatitis B vaccine formulation, a DTPa-Hib-Hepatitis B vaccine formulation and an IPV (inactivated polio vaccine)-DTPa-Hib-Hepatitis B vaccine formulation.
The above combinations may optionally include a component which is protective against Hepatitis A.
Suitable components for use in such vaccines are already commercially available and details may be obtained from the World Health Organization. For example the IPV component may be the Salk inactivated polio vaccine. The Diphtheria, Tetanus and Pertussis vaccine may comprise an acellular product such as Infanrix DTPa (SmithKline Beecham Biologicals). The component affording protection against Hepatitis A is preferably the product known as ‘Havrix’ (SmithKline Beecham Biologicals) which is a killed attenuated vaccine derived from the HM-175 strain of HAV [see ‘Inactivated Candidate Vaccines for Hepatitis A’ by F. E. Andre, A Hepburn and E. D'Hondt,
Prog Med. Virol.
Vol. 37, pages 72-95 (1990) and the product monograph ‘Havrix’ published by SmithKline Beecham Biologicals (1991)]. The Hepatitis B component may comprise the ‘S’ antigen as in ‘Engerix-B’.
Advantageously the Haemophilus Influenzae B or combination vaccine according to the invention is a paediatric vaccine.
Vaccine preparation is generally described in Vaccine Design—The Subunit and adjuvant approach Ed Powell and Newman; Pellum Press. Encapsulation within liposomes is described, for example, by Fullerton, U.S. Pat. No. 4,235,877. Conjugation of proteins to macromolecules is disclosed, for example, by Likhite, U.S. Pat. No. 4,372,945 and by Armor et al., U.S. Pat. No. 4,474,757.
The amount of conjugate antigen in each vaccine dose is selected as an amount which induces an immunoprotective response without significant, adverse side effects in typical vaccinees. Such amount will vary depending on which specific immunogens are employed. Generally it is expected that each dose will comprise 1-1000 ug of total immunogen, preferably 2-100 ug, most preferably 4-40 ug. An optimal amount for a particular vaccine can be ascertained by standard studies involving observation of antibody titres and other responses in subjects. Following an initial vaccination, subjects may receive one or two booster injections at about 4 weeks intervals.
In a further aspect according to the invention, there is provided a method of producing the vaccine comprising adsorbing the conjugate antigen on to aluminium phosphate. The adsorbing is preferably done at a pH of between 5 and 6, preferably at about 5.4. In an embodiment the vaccine is freeze dried after standing for more than 24 hours. Alternatively, the vaccine of the invention may be combined with other antigens in a liquid form.
The invention further provides the first medical use of such a vaccine.
In a further embodiment the invention provides a method of preventing or ameliorating Heamo
Hauser Pierre
Peetermans Julien
Kinzig Charles M.
SmithKline Beecham Biologicals (s.a.)
Sutton Jeffrey A.
Venetianer Stephen
Wortman Donna C.
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