Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Bacterium or component thereof or substance produced by said...
Reexamination Certificate
1998-09-02
2001-05-01
Stucker, Jeffrey (Department: 1648)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Bacterium or component thereof or substance produced by said...
C424S009200, C424S193100, C424S197110, C424S203100, C435S007320, C530S403000
Reexamination Certificate
active
06224880
ABSTRACT:
STATEMENT REGARDING FEDERALLY-SPONSORED R&D
Not applicable.
REFERENCE TO MICROFICHE APPENDIX
Not applicable.
FIELD OF THE INVENTION
This invention relates to methods of immufiing children against
Streptococcus pneumoniae
that comprise immunizations with a conjugated pneumoccocal polysaccharide vaccine at the ages of 2 and 4 months followed by immunization with an unconjugated pneumococcal polysaccharide vaccine at the age of 6 months. Optionally, these methods are followed by a further immunization with unconjugated pneumococcal polysaccharide vaccine at the age of 12 months.
BACKGROUND OF THE INVENTION
Streptococcus pneumoniae
is the cause of a variety of common respiratory and systemic infections of infancy and early childhood such as pneumonia, otitis media, and meningitis. Such pneumoccocal infections can range in severity from asymptomatic to life threatening. The emergence of strains of
S. pneumoniae
that are resistant to a variety of antibiotics has resulted in a great need for improved methods of vaccination against
S. pneumoniae.
This need is especially acute in the case of children between the ages of 6 months and 24 months, in whom disease caused by
S. pneumoniae
can be especially severe.
S. pneumoniae
is a gram-positive microorganism containing a cell wall surrounded by a polysaccharide capsule. The polysaccharide capsule is the primary virulence factor of
S. pneumoniae
and provides the basis for type-specific identification of approximately 90 different serotypes. Capsular polysaccharides stimulate the production of type-specific antibodies that can confer protection against
S. pneumoniae
(Fedson, 1988, in
Vaccines
(Plotkin and Mortimer, eds.), E.B. Saunders Co., Philadelphia, pp. 271-299 [Fedson]; Prober et al., 1983, J. Infect. Dis. 148:427-435; Koskela et al., 1982, Pediatr. Infect. Dis. 1:245-252). It is generally accepted in the art that the higher the level of a particular type-specific antibody, the greater the level of protection against that particular serotype of
S. pneumnoniae.
Thus, in the absence of human efficacy trials, the measurement of antibody levels following vaccination has come to be the art-recognized method of evaluating the effectiveness of new vaccines or new methods of vaccination. See, e.g., Fedson, at page 279: “Clinical and experimental observations have firmly established the association between the presence of type-specific serum antibody and the protection against infection by homologous pneumococcal organisms.” See, also, Schiffiman et al., 1980, J. Immunol. Meth. 33:133-144 (“Antibodies to pneumococcal capsular polysaccharides are determined for the following reasons: (1) to ascertain the immune response to a vaccine in order to assess protection against pneumococcal types in the vaccine . . . ”). Accordingly, there has been much effort expended in attempts to develop vaccines that will raise the level of type-specific antibodies to
S. pneumoniae
in vaccinees.
Currently licensed vaccines against
S. pneumoniae
are based on a combination of pneumococcal polysaccharides that are present in unconjugated form. For example, PNEUMOVAX®23, produced by Merck Sharp & Dohme, West Point, Pa., consists of a combination of 23 different purified pneumococcal polysaccharides. PNU-IMUNE®23 is an unconjugated vaccine produced by Lederle Laboratories, Pearl River, N.Y., containing the same 23 capsular polysaccharide antigens as is contained in PNEUMOVAX®23.
While such unconjugated pneumococcal polysaccharide vaccines are highly effective in many patient populations, they are often not very effective in children younger than two years of age (Douglas et al., 1983, J. Infect. Dis. 148:131-137; Ahonkai et al., 1979, New Eng. J. Med. 301:26-27; Sell et al., 1981, Rev. Infect. Dis. 3:S97-S107). This is probably due to the immaturity of T cell independent humoral immune responses at that age. The lack of efficacy of unconjugated pneumococcal polysaccharide vaccines in children younger than two years old has led some researchers to conclude with respect to unconjugated vaccines that “The immunogenicity of polysaccharide pneumococcal vaccine . . . is absent or minimal for most of the capsular polysaccharides in children younger than 2 years of age. Hence, vaccination is not indicated until 2 years of age.” (Peter & Klein, 1996, Pediatrics in Review 17:335-341).
As a result of the lack of immunogenicity of unconjugated pneumococcal polysaccharide vaccines in children less than two years old, alternative vaccines have been sought. Some pneumococcal vaccines that are currently under development or in clinical testing utilize pneumococcal polysaccharides that have been conjugated to protein carriers. For example, PCV is a heptavalent conjugated pneumococcal polysaccharide vaccine produced by Merck Sharp & Dohme, West Point, Pa. PCV consists of seven serotypes of pneumococcal polysaccharides (4, 6B, 9V, 14, 18C, 19F, and 23F according to the Danish nomenclature) that have been conjugated to the outer membrane protein complex of
Neisseria meningitidis.
One hope for such conjugated pneumococcal polysaccharide vaccines is that they will be able to induce a better immune response in young children because, since these conjugated vaccines contain carrier proteins, they will be able to stimulate T cell dependent pathways of humoral immunity while unconjugated polysaccharide vaccines may be restricted to stimulating antibody production by T cell independent pathways. T cell dependent pathways of humoral immunity are not age-dependent and exist at birth.
Evidence that conjugated pneumococcal polysaccharide vaccines may be useful in very young children has been presented. Some investigators have used four doses of conjugated vaccine at 2, 4, 6, and 12 months. Other approaches utilized unconjugated instead of conjugated vaccine at age 12 months. For example, Anderson et al., 1996, J. Pediatrics 128:649-653 (Anderson) vaccinated children at 2, 4, and 6 months of age with a conjugated pneumococcal polysaccharide vaccine (PCV) and followed with a single dose of unconjugated polysaccharide vaccine (PNEUMOVAX®23) at age 12 or 15 months. This vaccination schedule resulted in a significant increase in antibody titers to all seven serotypes in the conjugated vaccine. However, an effective vaccination regimen that makes use of unconjugated vaccine at the age of six months or younger has not been reported. Accordingly, despite such studies as that of Anderson, there remains a great need for developing even more highly effective methods of immunizing young children against
S. pneumoniae
utilizing conjugated and unconjugated pneumococcal polysaccharide vaccines.
SUMMARY OF THE INVENTION
The present invention provides methods of immunizing children against pneumococcal disease that comprise two immunizations with a conjugated pneumoccocal polysaccharide vaccine prior to the age of 6 months followed by one immunization with an unconjugated pneumococcal polysaccharide vaccine at the age of 6 months. The present invention provides for the production of antibody titers in the immunized children to the
Streptococcus pneumoniae
serotypes found in the conjugated vaccine that exceed the titers produced by prior art methods.
BRIEF DESCRIPTION OF THE DRAWINGS
Not applicable.
DETAILED DESCRIPTION OF THE INVENTION
For the purposes of this invention, “pneumococcuse” or “pneumococcal” refers to
Streptococcus pneumoniae.
“Pneumococcal disease” refers to disease caused by
Streptococcus pneumoniae.
“Pneumococcal vaccine” and “pneumococcal polysaccharide vaccine” are used interchangeably.
This invention provides a novel method of combining immunizations using conjugated and unconjugated pneumococcal polysaccharide vaccines. Due to the low level of immunogenicity provided by unconjugated pneumococcal vaccines in children, especially those under 6 months of age, prior art methods of immunizing against pneumococcal disease had employed vaccinations using conjugated vaccine at ages 6 months and younger. These priming immunizations were followed with booster immun
Chan Christina Y.
Sadoff Jerald C.
Coppola Joseph A.
Merck & Co. , Inc.
Stucker Jeffrey
Tribble Jack L.
Winkler Ulrike
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