Britta Wahren Group
photo: Lennart Nilsson, SMI photo archive
An Effective HIV Vaccine
Genetic vaccines have generated wide-spread interest for many applications, since DNA encoding a microbial gene results in in vivo expression of the desired gene, protein production and presentation as an endogenous foreign antigen. Due to these properties the polymorphic H LA system of humans can be targeted even with highly variable virus proteins, such as Human immunodeficiency virus (HIV), hepatitis C virus (HCV) or influenza.
HIV genes were constructed covering the highly variable sites of HIV envelopes and structural genes of Gag, subtypes A-E, the less variable parts of HIV regulatory genes and enzymes (1). Immunodominant non-neutralizing sequences were mutated, certain genes were changed to reduce toxicity and partial codon optimization was made to increase expression. Small size plasmids as well as divided doses of dominant versus subdominant genes together with a potent adjuvant for DNA show potent and broad immunological cross-reactivity. A boost with recombinant vaccinia-based vector including subtypes A and E genes effectively activated innate, humoral, helper cell, and cytotoxic responses, with memory retained up to over 3 years. This vaccine prime boost schedule has resulted in a very high immunogenicity in a clinical phase 1 prophylactic studies (2). We performed phase 2 clinical studies in Tanzania, Mocambique, Sweden and a pediatric immunoprophylactic study in children in Italy.
The DNA technology was also used to produce a targeting antibody directed against sensitive sites of the HIV-infected cell and virions. In a collaboration with US-based Immunomedics, the construction of this new class of anti-HIV agents was enabled using proprietary Dock-and-Lock (DNL) technology. The new molecules have three distinguished features. First, each comprises four copies of T20 (enfuvirtide, Hoffmann-LaRoche), an approved peptide that prevents the virus from infecting immune cells. Second, the multiple peptides are linked to a humanized antibody without compromising their activity. Third, the incorporation of the peptides to the antibody confers additional benefits, such as enhanced anti-viral potency and improved pharmacokinetics. As a result, both infected cells and activated enhanced virus replication have been destroyed in cell culture and in vivo in infected animals. The concurrent plan is to prove viral decrease in monkeys, and to take the antiviral antibody to a small human trial. This constitutes a new class of drugs that significantly destroys the virus HIV as well as the infected cells. It has the (Human Immunodeficiency Virus), and may potentially eradicate the virus completely.