Cross-Clade Immunity and Canarypox Vaccine

by Dale Lawrence and Jorge Flores

At the recent Conference on Advances in AIDS Vaccine Development, in Bethesda, Maryland, in February 1996, preliminary results of studies of an HIV-vaccine caused considerable excitement. This vaccine uses a Canarypox virus to serve as an HIV-vaccine 'vector.' In general, vaccines can either induce antibodies which prevent infection (induce "sterilizing immunity"), or produce cellular immunity to contain infection through immune attack upon HIV-producing cells, or do both. Immune responses of both above types were seen when priming immunization with HIV recombinant Canarypox (Pasteur-Merieux-Connaught) was followed by boosting with gp120 subunit (Biocine). Since this IMC Newsletter reaches most of the international staff at HIVNET sites, we thought it might be useful to summarize here: 1) preliminary plans for testing this vaccine concept in Uganda, 2) information influencing forthcoming HIVNET international HIV genetic variation protocols, and 3) associated vaccine development implications.

Canarypox, like its distant relative vaccinia, is a live virus. However, its inability to establish infection in humans has prompted its recent development into a clinically useful vaccine "vector." Through genetic engineering techniques, Canarypox has had inserted into its own genetic sequence (non-infectious) gene sequences of HIV. Following inoculation into the recipient, the inserted HIV gene sequences direct the formation of the associated proteins. To date, inserted sequences have included core ("gag" gene), transcriptional (polymerase), regulatory ("nef" gene), and envelope genes. Once the gene-coded proteins are made in the inoculated recipient, they are recognized internally as foreign "antigens" by the vaccinated recipient's immune system. Consequently, many aspects of the immune responses to these antigens develop as if a natural exposure and early infection had occurred. Depending on the type of target function played by the real HIV antigen after natural exposure or infection -- either as a target for neutralizing antibody immunity or as a target for vaccine-induced Cytotoxic T Lymphocytes (CTLs) -- vaccine-induced priming and boosting of such immune responses should be helpful for true prevention (sterilizing immunity) or for early containment of infection through eradication of HIV-infected cells.

A well-known characteristic of HIV is to mutate rapidly in infected persons. The resulting "variants" can "escape" from targeting by the person's rising immune responses. Upon serial transmission of HIV infection from one person to others, the new infections will involve variants that are increasingly dissimilar from the earlier HIV strains. This process has already resulted in such worldwide variation that various distinct groups, called Clades A-H, based on genetic sequencing of the HIV envelope, can be identified. Such genetic variation poses a major challenge for developing effective vaccines. Vaccine-induced neutralizing antibody immunity seems most efficient when directed against the identical (homologous) virus used as the vaccine prototype -- yet during the years necessitated to make and test a vaccine progressive accumulation of increasingly dissimilar HIV strains in the population continues to occur.

Scattered observations, and some theoretical concepts, have hinted at possible ways around this dilemma. HIVNET is especially interested in finding out if "cross-clade" immunity exists. Such cross-clade immunity could be based on antigenic similarities (CTL-inducing epitopes) shared across HIV clades or on less well understood patterns of HIV-antigen recognition by neutralizing antibodies. Regarding the first, HIV core elements (gag gene products) and regulatory gene products seem to be less subject to variation than the envelope. If vaccines capable of inducing CTL responses -- against core components of HIV are targeting its less variant (i.e., more "conserved") portion, then a CTL-inducing vaccine based on a prototype virus from one clade might have surprisingly strong effect against cells infected with (heterologous) HIV grouped into another clade.

Proof of such cross-clade cellular activity would considerably accelerate development of vaccines for countries with non-clade B strains. Thus, testing the existence and range of this cross- clade activity is an important step for both the vaccine manufacturers and the countries for whom no other candidate vaccines are immediately available. The Ugandan government and Pasteur-Merieux-Connaught have agreed to test this concept in HIVNET. A canarypox vector vaccine which incorporates genes from a clade B virus will be tested in Ugandan volunteers for cellular activity against the prevalent Ugandan strains (mostly clades A and D). Boosting with the Biocine clade B-based gp120 will not be used in this study as there is little expectation that this would be effective against heterologous virus. If this concept proves effective, a much clearer understanding of how to proceed with vaccine development for countries with non-clade B viruses will be available.

At least some vaccine manufacturers have begun exploring whether HIV envelope components -- presented either as recombinant subunits, pseudovirions, peptides, or vectors -- could be combined to provide immunization conveying antigens representative of two or more clades. This might provide broad reactivity and benefit populations in widely scattered geographic areas. Clarification of the underlying basis for these observations is important; both positive and negative findings may be useful.

Prompted by the reports at the recent NCDVG conference, Family Health International will be highlighting the importance of collecting at least 100 isolates of HIV from recent incident infections, and will facilitate a joint endeavor with international sites and designated HIVNET laboratories to better define the existence and extent of cross-clade immunity -- both neutralizing antibody and CTL activity. HIVNET's organizationally linked international sites are ideally situated to address this pressing scientific issue impacting HIV vaccine development. With prompt attention to the systematic collection and testing of suitable specimens, in accordance with jointly designed studies, we may accelerate development of HIV vaccines.