APPENDIX A2

LISTING OF CANDIDATE HIV ADJUVANTS USED IN AVEG STUDIES

 

ADJUVANT
DESCRIPTION
MANUFACTURER
AVEG PROTOCOLS
Alum
[various preparations]
Aluminum phosphate
MicroGeneSys
002, 002A, 002B

003, 003A, 003B

102

Aluminum hydroxide and thimerosal
Genentech

 

 

 

 

 

 

VaxGen

006, 009, 010

013B Extension

014C

016, 016A, 016B

027

028

104

201

036

Aluminum hydroxide gel and thimerosal
UBI
011

017

018

023

Aluminum hydroxide (Alhydrogel)
Superflos
015

Alum + deoxycholate (DOC); Aluminum hydroxide, deoxycholate and thimerosal
IMMUNO-AG
004, 004A, 004B

010

013A, 013B

Alum-adsorbed liposomes containing monophosphoryl lipid A

This adjuvant preparation consists of liposomes made of phospholipids and cholesterol and contains monophosphoryl lipid A (MPL). A histologic assessment of the reactivity of alum-adsorbed liposomes containing lipid A administered either IM or IV was performed in mice. At 72 hours, an inflammatory response was noted with a predominance of macrophages containing phagocytized lipid material. Liposomes have been administered to over 200 individuals primarily for diagnostic, biodistribution, and therapeutic studies since the mid-1970s with no major difficulties.

Walter Reed Army Institute of Research
015
Bupivacaine

Bupivacaine-HCI is an amide-type local anesthetic agent, formulated with the DNA-plasmid vaccine as a facilitating agent, in a citrate buffer solution containing 0.25% bupivacaine-HCI.

Apollon
031

033

Granulocyte macrophage-colony stimulating factor (GM-CSF)

Recombinant human (rhu) granulocyte-macrophage colony-stimulating factor (GM-CSF) (Leukine)® is produced by recombinant DNA technology in yeast from a DNA sequence obtained from human T cells using a murine GM-CSF cDNA probe. The amino acid sequence differs from the natural substance by a leucine substitution at position 23.

Immunex
033
Incomplete Freund's Adjuvant (IFA)
Mineral oil + mannose monooleate
Wyeth-Lederle Vaccines and Pediatrics
020
MF59 ± MTP-PE

The adjuvant emulsion, MTP-PE/MF59, contains a muramyl tripeptide (MTP) linked covalently with dipalmitoyl phosphatidylethanolamine (PE) and MF59, a microfluidized oil-in-water emulsion. This emulsion, the adjuvant for the HIV-1 SF-2 rgp120, consists of 0.5% polysorbate 80 (Tween 80, polyoxyethylene sorbitan mono-oleate) and 0.5% sorbitan trioleate (Span 85, Arlacel 85) in a citrate buffer. Squalene (5%), a metabolizable lipid, constitutes the oil phase. For most studies, the preparation contains MF59 without MTP-PE.

Ciba/Geigy
005A, 005B, 005C

007A, 007B, 007C

008

010

012A, 012B

015

022, 022A

024

026

029

032

103, 103A, 103B

201

202

Monophosphoryl Lipid A (MPL)

Bacterial lipopolysaccharide endotoxin (LPS), and specifically its active moiety, lipid A, has been shown to be a potent immunologic adjuvant. Native dephosphorylated lipid A (DPL) is reactogenic and pyrogenic; however, simple chemical modifications to DPL result in nontoxic preparations which retain the adjuvant activity of DPL. The adjuvant to be employed in these studies is lipid A purified from Salmonella minnesota R595. Purified native lipid A is detoxified by removal of the phosphate group from the reducing end of the disaccharide back-bone of DPL by acid hydrolysis, producing MPL. Monophosphoryl lipid A is further detoxified by 3-O-deacylation with mild alkaline hydrolysis. Monophosphoryl lipid A at 50 µg per dose will be formulated with antigen in a 0.25% squalene emulsion.

RIBI
015
Polyphosphazene (PCPP)

Polyphosphazene (PCPP) is a synthetic microsphere hydrogel adjuvant developed for mucosal immunization. It is a white, odorless powder with a molecular weight of 3-10,000 kD. Vaccination of mice with PCPP resulted in sustained, high tier antibody, largely IgG1. After mucosal immunization, both IgG and IgA responses were induced and sustained.

Pasteur Merieux Connaught
034
QS21 ± alum

The QS21 adjuvant is a nontoxic saponin derived from the soapbark tree Quillaja saponaria6. The product is within the retentate of 10,000 MW filtration and aqueous extraction, and is further purified by organic solvents, silica chromatography, and reverse phase chromatography. Purity has been verified by reverse phase HPLC, measurement of endotoxin bioburden (<10 EU/mg), and removal of water (<5%) and solvents. With a molecular weight of 1990 kD, the molecule contains 8 monosaccharides, 2 fatty acids, and a triterpene aldehyde at C4. The fatty acids and aldehyde structures appear to contribute to the adjuvant properties, and the amphipathic molecule forms micelles at a concentration of 35 µM at pH 7.0.

Genentech

VaxGen

016, 016A, 016B

036

SAF-m Adjuvant ± MDP

The Syntex adjuvant formulation (SAF-m) is an emulsion consisting of squalane, Pluronic L121 block polymer and Tween 80 in phosphate-buffered saline. Various preparations of the SAF-m adjuvant with and without threonyl muramyl dipeptide (Termutide; N-acetylmuramyl-L-threonyl-D-Isoglutamine; MDP) have been tested in humans, guinea pigs, mice, rabbits, goats, baboons, and monkeys. In these studies, the SAF-m adjuvant, in combination with influenza, HSV gD2, and HIV-1 immunogens, has shown superior immunogenicity to that of alum and in some cases to that of MF59.

BIOCINE
015