Merck + Co., Inc.

Stephen Marburg

Richard L Tolman

Janos Kollonitsch

Peter J Kniskern

William J Leanza

Lynn T Callahan

Arthur A Patchett

Malcolm MacCoss

David B Johnston

William J Miller

Arpi Hagopian

Emilio A Emini

Laura C Meurer

Dennis J Kubek

Pamela D Burke

John P Hennessey

Charlotte C Ip

George A Doldouras

Leroy M Perkins

Deborah A Jorn

John P Hennessey Jr

A novel conjugate vaccine comprising partially hydrolyzed, highly purified, capsular polysaccharide (Ps) from Streptococcus pneumoniae bacteria (pneumococci, Pn) linked to an immunogenic carrier protein, is produced by a new process. The conjugate is useful in the prevention of pneumococcal infections. Vaccines comprising a mixture of from one to ten different pneumococcal polysaccharide-immunogenic protein (Pn-Ps-PRO) conjugates induce broadly protective recipient immune responses against the cognate pathogens from which the polysaccharide components are derived. Young children and infants younger than 2 years old, normally unable to mount a protective immune response to the Pn-Ps alone, exhibit protective immune responses upon vaccination with these Pn-Ps-PRO conjugates.

Pneumococcal polysaccharide conjugate vaccine

A novel coconjugate comprising an immunogenic protein or protein complex having a first set of covalent linkages to low molecular weight moieties, --a.sup.--, which have an anionic or polyanionic character at physiological pH, and a second set of covalent linkages to peptides comprising Human Immunodeficiency Virus (HIV) Principal Neutralizing Determinants (PNDs), or peptides immunologically equivalent therewith, is useful for inducing anti-peptide immune responses in mammals, for inducing HIV-neutralizing antibodies in mammals, for formulating vaccines to prevent HIV infection or disease, including the Acquired Immune Deficiency Syndrome (AIDS), or for treating humans afflicted with HIV infection or disease.

Coconjugates of OMPC, HIV related peptides and anionic moieties

A conjugate immunogen, having polysaccharide moieties derived from bacterial sources, provides a multivalent vaccine with a low protein to polysaccharide ratio. The vaccine reduces complications associated with injection of protein immunogens due to pyrogenic responses, such as swelling and pain, and is particularly suitable for administration to infants.

Protein-dimeric polysaccharide conjugate vaccine

Homocysteine thiolactone derivatives in which the nitrogen is acylated with groups containing acidic functionalities have been synthesized. These include the succinyl, the carboxymethylglutaryl, the 3-phosphonopropionyl and the 3-sulfopropionyl derivatives. These thiolactones can be used to introduce a thiol functionality into proteins such as the outer membrane protein complex of Neisseria meninioitidis (OMPC) allowing conjugation with electrophilic ligands. This chemistry is similar to known N-acetyl-homocysteine thiolactone chemistry, but the pK.sub.a values are such that at pH 7, concomitant negative charge is introduced into the conjugate. Such negative charge neutralizes excess positive charge introduced when arginine- and lysine-rich peptides are bonded as ligands. In the case of OMPC, introduction of positive charge commonly effects irreversible precipitation of the conjugate. Conjugates prepared with the anionic thiolactones have improved solubility.

Acidic derivatives of homocysteine thiolactone

There are disclosed certain 6-piperazinopurines and heteroaromatic derivatives thereof which have oral hypoglycemic acitivity and with such ability to lower blood sugar are useful in the treatment of type II diabetes and/or obesity with associated insulin resistance. Processes for the preparation of such compounds and compositions containing such compounds as the active ingredient thereof are also disclosed.

Piperazinyl derivatives of purines and isosteres thereof as hypoglycemic

A solid support chemistry system which, with a dinitrofluorobenzene based assay, can be used to define titers of ligands and chemistry distal to the support. Cleavable diamine cystamines or 1,6-diamino-3,4-dihydroxyhexane are bonded to the solid support.

Method for determining the functionalization of a solid support

Covalently modified bacterial polysaccharides and proteins; covalent conjugates of such polysaccharides linked by a bigeneric spacer, which permits proof of covalency and facilitates purification of conjugated materials, with immunogenic bacterial membrane or other proteins, which conjugates are useful components of bacterial vaccines; and methods of preparing such polysaccharides, proteins and conjugates and of confirming the covalency of the linkage between polysaccharides and proteins.

Covalently-modified bacterial polysaccharides, stable covalent

Covalently-modified neutral bacterial polysaccharides; covalent conjugates of such polysaccharides linked by a bigeneric spacer, with immunogenic bacterial membrane or other proteins, which conjugates are useful components of bacterial vaccines; and methods of preparing such polysaccharides and conjugates.

Covalently-modified neutral bacterial polysaccharides, stable covalent

Covalently-modified polyanionic bacterial polysaccharides, stable

ADP-Ribosylating toxins are rendered enzymatically inactive by reactions with photolabile affinity reagents. The toxoids retain the antigenic and immunogenic properties of the original toxins. These bacterial toxoids can be used as immunogens to protect against the specific disease that the precursor toxins cause or, in the case of P. aeruginosa, the toxoid can be used in combination with E. coli J-5 vaccine to protect against gram-negative bacteremia in general.

Bacterial toxoids and gram-negative immune globulin therefrom

Novel .alpha.-difluoromethyl tyrosines and esters thereof are disclosed. The novel compounds have useful pharmacological activity.

.alpha.-Difluoromethyl amino acids and hypertension treating

ADP-ribosylating toxins are rendered exzymatically inactive by reactions with photolabile affinity reagents. The toxoids retain the antigenic and immunogenic properties of the original toxins. These bacterial toxoids can be used as immunogens to protect against the specific disease that the precursor toxins cause or, in the case of P. aeruginosa, the toxiod can be used in combination with E. coli J-5 vaccine to protect against gram-negative bacteremia in general.

A process for resolving a mixture of .alpha.-fluoromethylhistidine enantiomers is described. The process features use of an ester derivative of .alpha.-fluoromethylhistidine. Novel diastereoisomer salts of said derivative are also disclosed.

Acid addition salts of N-trityl-.alpha.-fluoromethylhistidine enantiomer

Alcohols are reacted with certain isocyanate compounds to produce the N-substituted carbamoyloxy derivatives which are cleaved to obtain the carbamate.

Cephalosporin compounds

A process for preparing .alpha.-fluoromethyl amino acids is disclosed. The process utilizes SF.sub.4 and BF.sub.3 or AlCl.sub.3 in HF to effect the fluorination.

Growing community of inventors

Metuchen, NJ, United States of America

Stephen Marburg