Michel H. Klein

Recombinant viruses as a tool for therapeutic vaccination against human cancers

Viral vectors can be used to express a variety of genes in vivo, that encode tumor associated antigens, cytokines, or accessory molecules. For vaccination purposes, the ideal viral vector should be safe and enable efficient presentation of expressed antigens to the immune system. It should also exhibit low intrinsic immunogenicity to allow for its re-administration in order to boost relevant specific immune responses. Furthermore, the vector system must meet criteria that enable its industrialization. The characteristics of the most promising viral vectors, including retroviruses, poxviruses, adenoviruses, adeno-associated viruses, herpes simplex viruses, and alphaviruses, will be reviewed in this communication. Such recombinant viruses have been successfully used in animal models as therapeutic cancer vaccines. Based on these encouraging results, a series of clinical studies, reviewed herein, have been undertaken. Human clinical trials, have as of today, allowed investigators to establish that recombinant viruses can be safely used in cancer patients, and that such recombinants can break immune tolerance against tumor-associated antigens. These promising results are now leading to improved immunization protocols associating recombinant viruses with alternate antigen-presentation platforms (prime-boost regimens), in order to elicit broad tumor-specific immune responses (humoral and cellular) against multiple target antigens.

Therapeutic vaccines against melanoma and colorectal cancer.

Our overall strategy is to develop multivalent recombinant vaccines capable of eliciting broad immune responses in patients with malignant melanoma or colorectal cancer. We report herein results from initial studies conducted in cancer patients to evaluate the effect of intratumoral administration of recombinant canarypox viruses carrying cytokine genes. Our current focus is on the induction of tumor-specific T-cell responses using a prime/boost immunization schedule with a unique vector system derived from the canary pox virus called ALVAC, in which we incorporate genes encoding Tumor Associated Antigens (TAAs) of interest. Clinical studies in colorectal cancer evaluating an ALVAC CEA candidate vaccine have shown that this approach is safe and can induce tumor-specific T cell responses. Additional clinical studies evaluating candidate vaccines against melanoma and colorectal cancer, targeting either the gp100, Mage 1, Mage 3 or p53 molecules are ongoing.

Current progress in the development of human immunodeficiency virus vaccines: research and clinical trials.

In spite of extensive prevention programs, the HIV pandemic is still spreading worldwide, particularly in developing countries. AIDS is the leading cause of death in Africa and the fourth cause worldwide. WHO estimates that there are 16000 new cases of HIV infection daily and that 100 million individuals will be infected during the next decade. In spite of the spectacular results of triple therapy, the best strategy for controlling the HIV epidemics remains the development of an efficacious prophylactic vaccine. However, the development of such a vaccine remains a formidable challenge to both the industry and the scientific community (Esparza J. Bhamarapravati N. Accelerating the development and future availability of HIV-1 vaccines: why, when, where, and how? Lancet 2000; 355: 2061-6 [1]).

Comparative analysis of the immunostimulatory properties of different adjuvants on the immunogenicity of a prototype parainfluenza virus type 3 subunit vaccine

The immunogenicity of a parainfluenza virus type 3 (PIV-3) subunit vaccine consisting of affinity-purified haemagglutinin-neuraminidase (HN) and fusion (F) surface glycoproteins was tested in guinea-pigs and hamsters. The ability of several different immunopotentiating agents to enhance the antibody response of animals to the PIV-3 surface glycoproteins was evaluated. The immunity induced by HN and F alone was compared with the response elicited by purified proteins combined with Freunds complete adjuvant, aluminium phosphate, Syntexs threonyl-muramyl dipeptide (MDP) SAF-MF formulation, or Ribis adjuvant formulation containing BCG cell wall skeleton (CWS), trehalose dimycolate (TDM) and monophosphoryl lipid A (MPL) in a 2% squalene-in-water emulsion. Purified proteins were also incorporated into three different liposome formulations prepared by the detergent dialysis procedure. Immunization of guinea-pigs and hamsters with two 15 micrograms doses of the PIV-3 surface glycoproteins administered in the absence of adjuvant elicited high haemagglutination inhibition, neutralization and anti-fusion titres. The liposome preparations failed to enhance the antibody titres. Ribis adjuvant formulation was effective at inducing a good secondary response to the purified proteins while the immunostimulatory effects of aluminium phosphate, Syntex and Freunds adjuvants were clearly demonstrated in both primary and secondary responses. When administered without adjuvant, a 15 microgram dose of the HN and F mixture was capable of protecting hamsters against live virus challenge. The immunoprotective dose of the purified proteins could be reduced to at least 0.1 microgram by the addition of aluminium phosphate, Syntex or Freunds adjuvants.

Branhamella catarrhalis pathogenesis in SCID and SCID/beige mice

SCID and SCID/beige mice were used to study the pathogenesis of B. catarrhalis administered by intranasal, intraperitoneal or intravenous routes. Challenged adult animals did not appear overtly clinically ill. Similar symptoms were observed regardless of the challenge route, and pretreatment of mice with human transferrin did not enhance clinical virulence. Susceptibility to B. catarrhalis appeared to be age‐dependent as some mice under one week of age died following challenge. Postmortem findings included circumscribed pale foci on the liver, splenomegaly and mineralization of the myocardium. Presence of lesions did not correlate with the assessment of clinical well being, and severity of the lesions was found to be challenge strain‐dependent. Liver lesions and splenomegaly were not observed in animals challenged with heat‐killed bacteria or placebo. SCID/beige mice were more affected than SCID mice both clinically and pathologically, suggesting that natural killer cell and polymorphonuclear cell functions may be important in resolving B. catarrhalis challenge.

Prospects and challenges for prophylactic and therapeutic HIV vaccines

The best strategy for controlling the HIV pandemic remains the development of an efficacious prophylactic vaccine. Efficacy trials performed during this decade will yield information on the protective ability of first-generation vaccines. Several novel mixed-modality vaccines capable of inducing high-frequency CD8(+) T-cell responses in macaques are being evaluated in humans. New hope has been raised with the prospect of therapeutic HIV vaccines. However, the development of HIV vaccines remains a formidable challenge to both the industry and the scientific community.