Status: a vaccine containing this adjuvant is nearing approval in U.S., one already marketed in Europe

Organizations involved:

Corixa Corp. – Manuf.; R&D; Tech.

Ribi ImmunoChem Res., Inc. – R&D; Tech.; Former

GlaxoSmithKline Biologicals S.A. – R&D; Tech.

GlaxoSmithKline Inc. – USA mark.

GlaxoSmithKline plc – Intl. mark.; Parent

SmithKline Beecham Biologicals S.A. – Former

Cross ref.: See the entries for vaccines containing this adjuvant — Fendrix, a recombinant hepatitis B virus (HBV) vaccine, and Cervarix, a human papillomavirus (HPV) vaccine, both from GlaxoSmithKline (GSK). See also the Aluminum-based Adjuvants entry.

Description: 3-Deacylated monophosphoryl lipid A is a monophosphorylated and 3-acylated derivative of lipid A, a bacterial endotoxin and one of the most potent immunostimulants known, found in the cell wall of Gram-negative bacteria. 3-Deacylated monophosphoryl lipid A (3-deacylated MPL), commonly referred to simply as monophosphoryl lipid A (MPL), is chemically similar to lipid A but lacks an acid-labile phosphoryl group and a base-labile acyl group at position 3. 3-Deacylated monophosphoryl lipid A is prepared from lipid A isolated from cultures of the heptoseless mutant strain R595 of Salmonella minnesota.

AS(04), formerly SBAS4, which is being used by GlaxoSmithKline (GSK) as an adjuvant in several vaccines in late-stage development, is described as a proprietary formulation of 3-deacylated MPL. AS(04) apparently involves combination (either in terms of both separately added to vaccine formulations, or as a mixture added to vaccine formulations) of MPL with an unspecified aluminum-based adjuvant, presumably either aluminum hydroxide (alum) or aluminum phosphate, currently the only FDA-approved vaccine adjuvants.

Nomenclature: Monophosphoryl Lipid A [BIO]; MPL [TR assigned to Corixa]; 3-deacylated monophosphoryl lipid A [SY]; AS(04) [SY]; AS04 [SY]; SBAS4 [SY]; 3-deacylated MPL [SY]; 3-deacylated monophosphoryl lipid A plus aluminum adjuvant [SY for AS(04)]

Biological.: Chemical modification of lipid A, e.g., MPL and AS(04), results in retention of the beneficial immune response-boosting activities of lipid A, while providing a safety profile potentially suitable for use in pediatric vaccines. MPL has been shown to be a potent immu-nostimulant. Monophosphorylation minimizes the undesired endotoxin effects of lipid A, while retaining its adjuvant properties. Deacylation at the 3-position further reduces toxicity while retaining adjuvant activity. AS(04) was designed to increase antibody responses, compared to aluminum adjuvant alone, and, more importantly induce TH1-type cytokine responses associated with improved cellular immunity, e.g., CD8+ cytotoxic T-cell (CTLs), a type of immunity not augmented by aluminum adjuvants, while retaining safety comparable to the established aluminum adjuvants.

MPL has shown potent immune modulating activity and adjuvant effects with a wide variety of vaccines, including potently increasing antibody responses and cellular immunity. MPL has demonstrated utility with peptide, bacterial subunit, synthetic polysaccharide, and other diverse antigens, and various vaccines for infectious diseases and allergy desensitization containing MPL have demonstrated safety and efficacy in human clinical trials involving thousands of doses. Humoral, cell-mediated, and mucosal immunity can be stimulated by altering MPL-containing vaccine formulations and delivery routes.

MPL’s mechanism of action involves activation of monocyte/macrophage lineage cells and stimulation of the release of several cytokines, including interleukin-1 (IL-1), interleukin-12 (IL-12), tumor necrosis factor-alpha (TNF-alfa) and granulocyte macrophage-colony stimulating factor (GM-CSF). Presumably through the action of these cytokines, lymphoid and antigen-presenting cells, including dendritic cells, are recruited to the local lymphoid organs where efficient immune-enhancing cellular interactions take place. These initial events mediated by MPL induce a strong TH1-type of cellular response characterized by increased production of interferon-gamma (IFN-g) and interleukin-2 (IL-2). In turn, IFN-g promotes production of complement-fixing antibodies (IgG2a in the mouse), a hallmark of the immune responses mediated by MPL.

Companies.: Ribi ImmunoChem Research Inc. was the original developer of MPL. Corixa Corp. acquired Ribi in mid-1999. GlaxoSmithKline plc (GSK) acquired Corixa in April 2005 for ~$300 million.

In Dec. 1992, Ribi co-exclusively licensed MPL adjuvants to SmithKline Beecham (SKB; now GlaxoSmithKline/GSK) for adjuvant use in pediatric and other vaccines, including diphtheria; pertussis; tetanus; Hemophilus influenzae B (meningitis); Lyme disease; herpes simplex virus; malaria; hepatitis A, B, and E viruses; polio; and human papillomavirus (HPV) vaccines. Lederle Praxis Biologicals, now merged into Wyeth, was the other co-exclusive licensee of MPL and shared rights to MPL for many of the same vaccines as SKB/GSK. Wyeth has been deemphasizing vaccine development in recent years, and does not have any vaccines in development using MPL.

In July 2004, Corixa entered into a new manufacturing and supply agreement with GSK. The agreement, which runs through 2012, guarantees payment to Corixa for supplying GSK with increasing annual quantities of MPL peaking in 2008, at the current maximum output of Corixa’s current Hamilton, Montana, MPL manufacturing facility (approximately 2 kilograms/year). Corixa agreed to expand cGMP compliant MPL production capacity in association with anticipated approvals of GSK vaccines that contain MPL adjuvant. Corixa received a multimillion dollar up front licensing fee, and granted GSK a co-exclusive license to manufacture MPL at amounts above the maximum annual output it manufactures. The agreement can be renewed at GSK’s option for multiple, three-year periods beyond 2012. Other aspects of the agreement include increased base pricing and annual price increases for MPL; payment of royalties to Corixa by GSK on all GSK vaccines containing MPL adjuvant until 10 years after market introduction of Cervarix, GSK’s human papilloma virus (HPV) vaccine (see related entry); and a provision for Corixa to repay a prior $5 million loan from GSK in stock instead of cash. Also, GSK and Corixa will co-fund a multi-year program to develop a large-scale production process, with any improvements co-owned by Corixa and GSK. If the process is implemented and results in increased Corixa plant production capacity, and if GSK revises orders of MPL to levels above those currently contemplated, GSK will receive a pre-negotiated discount on the amount it orders over and above Corixa’s current plant capacity.

In April 2005, GSK acquired Corixa, and will no longer need to pay royalties.

Status: Fendrix, a recombinant hepatitis B virus surface antigen (HBsAg) vaccine formulated with AS(04), from GSK received European Union approval in Feb. 2005. GSK has filed for FDA approval of Cervarix, a recombinant human papilloma virus vaccine (HPV) formulated with AS(04). See the entries for Fendrix and Cervarix in the Recombinant DNA Products section.

Trials: Vaccines containing MPL been shown to be well-tolerated and active in human clinical trials involving more than 10,000 subjects. A variety of antigens have been used successfully with MPL, including recombinant proteins, peptides, bacterial subunits, polysaccharides, polysaccharide conjugates and tumor cell lysates. Diseases targeted have included hepatitis B, allergies; human papillomavirus (cervical cancer and genital warts); herpes simplex virus type 2 (genital herpes); malaria; respiratory syncytial virus (RSV); and certain pediatric vaccines.