Aventis Pasteur and Merck

Aventis Pasteur, formerly known as Pasteur-Merieux Connaught, has a long-standing and diverse HIV research programme which has been largely funded by the French government. Their ALVAC canarypox recombinant HIV vaccines, incorporating a range of HIV proteins, have been through Phase I and II trials in the USA, Thailand and most recently Uganda, and are still being developed with a view to eventual Phase III trials. Other approaches in development include lipo-peptides directed at inducing very specific cellular immune responses and DNA vaccines (licensed from Vical) which could be used with their canarypox-based vaccines. Aventis Pasteur is working with EuroVacc on a DNA-MVA prime-boost system that is due to enter Phase I clinical trials in 2003-2004.

Recently, Aventis Pasteur has announced a collaboration with the US company Merck to explore the potential for combining their canarypox vaccines with Merck's recombinant adenovirus vaccines (used as a primer).

Merck is the world's largest commercial vaccine manufacturer and is the company which produced the first vaccine against hepatitis B. It now has an active HIV vaccine programme headed by Emilio Emini, who managed the development of Merck's protease inhibitor indinavir (Crixivan). Merck has reported obtaining a high level of protection against disease in monkeys exposed to a highly pathogenic challenge virus, with a prime-boost vaccine system.

Their initial strategy was to prime with a DNA vaccine and boost with a recombinant adenovirus (Ad5). Prototypes of both components, incorporating gag gene sequences, have entered phase I clinical trials in the USA and preliminary results were reported in 2002 at the 9^th Conference on Retroviruses and Opportunistic Infections in Seattle. Trials using the two components in prime-boost mode were to follow, but Merck appears to have concluded that the DNA primer was unsatisfactory.

Unexpectedly vigorous responses were obtained in animal studies using Ad5 as a primer followed by an ALVAC canarypox booster, where both contained versions of the HIV gag gene sequence. This has given rise to a collaboration between Merck and Aventis Pasteur to take that combination into clinical trials and develop candidate vaccines in which a wider range of HIV gene sequences are included in both Ad5 and canarypox.

GlaxoSmithKline

GSK Biologicals, based in Belgium, and formerly part of SmithKline Beecham, is one of the world's leading vaccine manufacturers. Work on HIV vaccines began in 1985, and concentrated initially on different adjuvants for use with a gp120 recombinant. It is developing a vaccine against genital herpes which might have a role in preventing HIV transmission where HSV-2 is a major co-factor. A vaccine against human papilloma viruses, sexually transmitted infections linked to cervical cancer, may also provide valuable pointers to the feasibility of testing future HIV vaccines in young adolescents.

GSK recently resumed and extended its HIV vaccine development work, reporting preclinical work in 2001 with macaque monkeys that appeared, in one series of experiments, to be protected against a severely pathogenic SHIV virus. (A second series of experiments didn't quite confirm this, however.)

Their latest vaccine candidate is based on recombinant proteins formulated in a novel adjuvant, formerly called SBAS-2 and now AS02A. (This is a combination of an adjuvant called QS21 and an oil/water emulsion, 3D-MPL.) The two HIV proteins were from subtype B viruses: gp120 and a 'fusion protein' of Nef and Tat. Antibody responses could not account for the protection observed; studies of cellular immune responses are still awaited.

This vaccine has now entered Phase I clinical trials in the USA through the NIH HIV Vaccine Trials Network, and was due to enter Phase I trials in Belgium during 2003.

AlphaVax Corporation

This company was set up by researchers at the University of North Carolina to create vaccines using alphaviruses, in particular Venezuelan Equine Encephalitis, as the basis for replicons (see HIV & AIDS Treatments Directory for a description). Following studies suggesting protection of monkeys against SIV using a VEE-based vaccine, AlphaVax has been working in partnership with IAVI and researchers at the University of Cape Town to develop a subtype C HIV vaccine candidate for testing in South Africa, with Phase I trials now expected to start in 2002/2003 (Olmsted 2000). AlphaVax is collaborating with Wyeth-Lederle on some of its non-HIV projects.

Chiron and PowderJect

Founded in 1981, Chiron is one of the largest biotechnology companies, with a vaccine division that has a strong HIV programme. Chiron's recombinant gp120 vaccine has been studied as a booster to follow a canarypox vaccine from Aventis Pasteur (see The HIV & AIDS Treatments Directory; also Duliege 1996, Suriyanon). Chiron is researching a number of other approaches, including a p24 vaccine and DNA-based vaccines. It recently became the recipient of substantial NIH funding as a partner in one of its new vaccine design and development teams.

An Anglo-US-Swedish biotechnology company and vaccine manufacturer, which has developed a technique for vaccine or drug delivery based on microscopic gold pellets shot into the skin or mucous membranes using a helium propulsion system. In mice, this enables immune responses to be obtained with smaller doses of a vaccine, and in humans it would be a welcome alternative to hypodermic needles. PowderJect's DNA vaccine programme began in 1991, including HIV, hepatitis B, and malaria among its targets. The US Army funded some of its early work on HIV. In 1998, PowderJect entered into a major commercial partnership with GlaxoSmithKline, which includes an option for GlaxoSmithKline to market an HIV therapeutic vaccine being developed by PowderJect. The lead product in this agreement is a preventive DNA vaccine against hepatitis B virus, which was shown in 1999 to induce high levels of antibodies, the first time that a ‘protective’ immune response has been obtained with a DNA vaccine in human beings. In 2000, PowderJect acquired Celltech’s Medeva vaccines business, which means that it is evolving into a vaccine manufacturer in its own right.

Immune Response Corporation

Formed by the late Dr Jonas Salk, the polio vaccine pioneer, to develop a whole killed virus-based vaccine now known as Remune. This has been entered into trials as a therapeutic vaccine, although there are no plans to put it into preventive trials. IRC entered into partnership with the pharmaceutical company Agouron (part of Pfizer) to commercialise this product, subject to clinical trial results; unfortuately, these results led Pfizer to end the collaboration (Remune is discussed below in the section on therapeutic vaccines).

Maxygen

This company has developed a 'gene shuffling' system which uses evolutionary principles to improve desired attributes of biological products such as enzymes. One of the challenges in HIV vaccine development is to generate broadly neutralising antibodies against HIV. Some neutralising antibodies have been described, but 'reverse engineering' a vaccine to produce them is not an easy task. A three-year programme between IAVI and Maxygen, funded by the Rockefeller Foundation through its social venture capital scheme, DBLV LLC, announced in 2001, aims to generate new vaccine candidates that produce higher levels of immune responses against a broader range of HIV strains than previously seen. Maxygen's HIV vaccine work is based on a collaboration with the Scripps Institute which described the structure of a broadly neutralising antibody in a paper in Science jointly published with the Oxford Institute of Glycobiology (Saphire).

Retroscreen Limited

is a small company set up by the Royal London Hospital which holds patents on a process developed by a team headed by Professor John Oxford to inactivate (‘kill’) HIV grown in cell cultures for use in a potential vaccine. For added safety, they propose to use attenuated strains of the virus, with key genes deleted. No clinical trials are planned so far.

Targeted Genetics Corporation

A Seattle-based company founded in 1992 as an offshoot of Immunex. It is commercialising a technology based on Adeno-Associated Virus developed at the Children’s Research Institute of Columbus, Ohio. IAVI has selected this technology as the basis for its third Vaccine Development Partnership with a view to producing a vaccine that could be tested in eastern or southern Africa.

Therion Biologics

A small biotechnology company based in Cambridge, Massachusetts. It has an HIV vaccine programme including a recombinant vaccinia virus bearing HIV env, gag and pol genes from subtype B and E viruses in Phase I trials in the USA. It is being sponsored by IAVI to develop another version for manufacture and testing in India. The company owns the commercial rights to live attenuated HIV viruses being developed by Dr Ronald Desrosiers and colleagues at the New England Regional Primate Center, although the company has no plans to put these into clinical trials in humans.

Wyeth-Lederle Vaccines and Pediatrics

This is the vaccines division of the American Home Products Corporation. Wyeth-Lederle bought out Apollon, a Philadelphia biotechnology company which was the first to run Phase I clinical trials of DNA vaccines against HIV in human volunteers. Wyeth Lederle is one of the larger producers of vaccines for children, with a research programme that includes new vaccines against herpesviruses as well as HIV. Their HIV vaccine programme has studied gp120 V3 peptides (with Duke University), recombinant adenovirus and mucosal immunisation approaches.